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Breast

1. Demographics and Risk Factors

Updated: July 2005

Breast cancer is the most common life-threatening cancer among women in British Columbia and the second most common cause of cancer mortality. Age-standardized incidence rates increased somewhat over the 15 year period from 1977-91, but have been declining slightly in the last 10 years. Mortality from breast cancer appears to have decreased by 30% over the last decade in Canada, the US and UK. The reasons for this decline appear multifactorial and are likely a combination of screening, earlier diagnosis and multi-disciplinary care including more adjuvant therapy. In BC the estimated number of cases for the year 2004 was 2,700. Although breast cancer is more frequently seen in older women, due to the large number of middle age women at risk, the actual number of women diagnosed with breast cancer is highest in the 50-60 age range rather than younger. See Table 1 below.

Numerous risk factors for breast cancer have been well established, including age, mammographic density, nulliparity or late age at first birth, early menarche, late menopause, and use of hormonal replacement therapy. All these factors increase risk, while early age at first birth, physical activity and lactation, appear to reduce risk. There is growing evidence that premenopausal and post-menopausal breast cancer may be different entities. International differences in breast cancer incidence curves have led to the hypothesis that environmental factors may influence the development of postmenopausal breast cancer whereas genetic and other endogenous factors may influence premenopausal breast cancer.

A summary of known risk factors for breast cancer is shown in Table 1 below, which also indicates the strength of the risk factor in the development of breast cancer.

Table 1. 

Risk Factors Associated with Breast Cancer by Level of Risk
Weak risk factors for breast cancer (RR <2)
  • Family history of postmenopausal breast cancer, except if associated with male breast cancer + bilateral disease
  • High Socioeconomic status
  • Nulliparity
  • Later age at first birth (> 30 yr vs >20 yr)
  • Later age at menopause (>55 yr vs >45 yr)
  • Early age at menarche (<11 yr vs >15 yr)
  • Postmenopausal obesity
  • Alcohol consumption
  • Diet
  • Hormone replacement therapy (long term usage)
Moderate risk factors for breast cancer (RR 2-4)
 
  • Older age
  • North American and Northern European residence
  • Family history of premenopausal breast cancer
  • Personal history of breast cancer
  • Breast hyperplasia without atypia
  • Mammographic density occupying >50% of the breast volume
Strong risk factors for breast cancer (RR>4)
 
  • Family history of premenopausal bilateral breast cancer or premenopausal breast cancer in mother, grandmother, sister, daughter and aunt or DEL of ovarian cancer in mother, grandmother, sister, aunt or of male breast cancer or of breast cancer at any age in multiple (3) female relatives
  • Evidence of susceptibility gene including, but not restricted to, BRCA1/ BRCA2, PTEN, TP53, CDH1, STK11, PALB2
  • Personal history of lobular carcinoma in situ
  • Breast atypical hyperplasia
  • Mammographic density occupying > 75% of the breast volume

Reference: (BC Med J 1997;39:496-500)​​

2. Prevention

Updated 28 September 2011

Several strategies are available for primary prevention among women with an increased risk of developing breast cancer. For women with confirmed BRCA1 or BRCA2 mutations, or other gene mutations predisposing to breast cancer, referral to the high risk screening program at the BC Cancer Agency and counselling about cancer prevention and screening options for breast and other associated hereditary cancers is available. 

Three drugs have been shown to effectively reduce the risk of developing estrogen receptor positive pre invasive (ductal carcinoma in situ, DCIS) and invasive breast cancer among women with elevated risk, as determined by the sum of their risk factors using a validated risk prediction tool (including, but not restricted to, the Gail model or Tyrer-Cuzick (IBIS) model).​​

Tamoxifen reduces the risk of developing primary breast cancer by 50%. In the largest study, among 13,388 women randomized to tamoxifen or placebo, DCIS and invasive breast cancer occurred in the 244 placebo group and 124 in the tamoxifen group over a 5.5 year period.(1) Taking tamoxifen for five years in this population resulted in a doubling in the incidence of endometrial cancer, from 0.09% increased to 0.23%, a small increase in the incidence of stroke, from 0.36% to 0.58%, and of deep venous thrombosis (.08 vs 0.13% per year). Other primary prevention studies have shown similar effects. (2,3) The protective effect of 5 years of tamoxifen persists after its discontinuation, to at least ten years from treatment start. There was no increase in cardiac events and there was a modest reduction in hip, wrist, and vertebral fractures in the tamoxifen group.

Raloxifene (Evista®) has also demonstrated reduction in both DCIS and invasive breast cancer by the same degree as tamoxifen in a large clinical trial comparing the two drugs.(4) The advantage of raloxifene over tamoxifen is a greatly reduced incidence of postmenopausal vaginal bleeding, the need for endometrial investigations, and of endometrial cancer (incidence 0.2% for tamoxifen versus 0.12% for raloxifene). Long term follow up again shows an effect that lasts beyond five years of exposure (5).

Exemestane, an irreversible steroidal aromatase inhibitor, has recently been shown to reduce the risk of ER+ breast cancer in postmenopausal women by 65% compared to placebo in a large prevention trial (6). The placebo group had a 0.55% annual incidence rate of breast cancer compared with 0.19% in the exemestane group. There was no increased incidence of cardiovascular events, second cancers, fractures, or self reported development of osteoporosis. More women on exemestane reported joint and musculoskeletal pain while on medication (30% versus 17%). Long term follow up is clearly warranted for more safety data and to determine the duration of the protective effect that five years of therapy provides. Ongoing trials are exploring the effectiveness of other aromatase inhibitors in this setting.

The effectiveness of secondary prevention on breast cancer mortality through screening mammography has been clearly demonstrated in randomized controlled trials, even though 10% of breast cancers will not show up on a mammogram. Asymptomatic women between the ages of 40-79 should be encouraged to have regular screening mammography at the Screening Mammography Program of BC (SMPBC) centres or mobile vans, at intervals as set out in the SMPBC. See Chapter 3: Screening/Early Detection. Appointments can be booked through 660-3639 for the Lower Mainland and at 1-800-663-9203 for the rest of the province.

Women younger than age 40 at very high risk (2 or more first degree relatives with the disease) are eligible to attend the SMPBC on a physician referral basis. Such women may also be interested in and eligible for a referral for genetic counselling and testing. Women over the age of 79, who are in good general health (life expectancy of 10 or more years) may benefit from screening and can be referred to the SMPBC.

Annual physical examination of healthy women should include a clinical breast examination. The physical examination serves as a screening procedure, and provides an opportunity for the health professional to teach breast self-examination. It should be noted however that the value of breast self-examination alone in reducing mortality from breast cancer has not been convincingly demonstrated.


References:

  1. Tamoxifen for Prevention of Breast Cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. Fisher B, Costantino JP, Wickerham DL, et al. Journal of the National Cancer Institute, 90 (18), 1998.
  2. Long-Term Results of Tamoxifen Prophylaxis for Breast Cancer—96-Month Follow-up of the Randomized IBIS-I Trial. Cuzick J, Forbes JF, Sestak I, et al. J Natl Cancer Inst 99: 272 – 82, 2007.
  3. Twenty-Year Follow-up of the Royal Marsden Randomized, Double-Blinded Tamoxifen Breast Cancer Prevention Trial. Powles TJ , Ashley S, Tidy A Smith IE , Dowsett M. J Natl Cancer Inst 99: 283 – 90, 2007.
  4. Effects of Tamoxifen vs Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes. The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial.. Vogel VG, Costantino JP, Wickerham DL, et al. JAMA, June295: 2727, 2006.
  5. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial:Preventing Breast Cancer. Vogel VG, Costantino JP, Wickerham DL, et al. Cancer Prev Res; 3(6); 696–706, 2010.
  6. Exemestane for Breast-Cancer Prevention in Postmenopausal Women Paul E. Goss, M.D., Ph.D., James N. Ingle, M.D.,  José E Alés-Martínez, This article (10.1056/NEJMoa1103507) was published on June 4, 2011, at NEJM.org. N Engl J Med 2011.
  7. Benefit of screening mammography in women aged 40-49: a new meta-analysis of randomized controlled trials. Hendrick RE, Smith RA, Rutledge JH 3rd, Smart CR. J Natl Cancer Inst Monograph.22:87-92,1997.
  8. Efficacy of screening mammography among women aged 40 to 49 years and 50 to 69 years: comparison of relative and absolute benefit. Kerlikowske K. J Natl Cancer Inst Monogr. 22:79-86, 1997.

3. Screening/Early Detection

Updated Aug 2009

About one in nine women living to age ninety will eventually be diagnosed as having breast cancer. Risk increases with advancing age and the following screening procedures are recommended for women over forty years of age. The criteria to estimate the level of risk for women under age forty are described in below. These women require individualized assessment of risk and benefit from the Hereditary Cancer Program.  

High Risk Groups in Women Under Age Forty

A woman with two or more first-degree relatives with premenopausal or bilateral breast cancer is at particularly high risk and should be referred for genetic counselling and assessment for hereditary cancer. The Hereditary Cancer Program is a joint activity of the B.C. Cancer Agency and the Provincial Medical Genetics Program. Some families, accounting for perhaps up to 10% of breast cancers, may be carriers of specific genetic mutations. Testing is available for families at risk of mutations in breast cancer predisposition genes including, but not restricted to, BRCA1 or BRCA2. Women with gene mutations are candidates for programs of special surveillance. Women who are potentially at high risk of breast cancerbased on their personal and/or family history of cancer should be referred to the Hereditary Cancer Program.

A woman with a sister or mother with bilateral breast cancer would be at four-fold risk of breast cancer del comma if the case were postmenopausal or nine-fold if the case were premenopausal. This person could also be at risk if she met any of the following criteria, especially if they occur in combination with a family history of female breast cancer:

  • family history of ovarian cancer 
  • family history of male breast cancer
  • Ashkenazi Jewish heritage

3.1 Breast Self-examination
Women may be encouraged to do regular breast self-examination (BSE). For premenopausal women this is best done in the week following the menstrual period. For postmenopausal women a specific day of the month should be chosen. The examination should include inspection of the breast and palpation of the breast and axilla. To perform adequate BSE the patient needs instruction in the technique and the manner in which she is carrying this out. This should be checked at subsequent examinations by her family physician.There is no evidence that BSE improves survival, but regular self-examination does allow a woman to know her own body and therefore she may recognize changes early.

3.2 Family Physician
The combination of physical examination by a physician and mammographic screening has been shown to reduce mortality from breast cancer. The relative importance of the physical examination vis-a-vis the mammogram remains unclear. It is recommended that all women over the age of 20 years receive an annual physical examination of the breasts by their family physician both as a screening procedure and as an opportunity to teach breast self-examination. Ten percent of breast cancers will not show up on a mammogram in older women, but as many as 25-30% of breast cancers are not seen on screening mammograms in women age 40 to 49.

3.3 Screening Mammography

British Columbia’s Breast Screening Policy reflects the latest evidence and our commitment to reducing breast cancer deaths by finding cancer at an early stage. Key policy recommendations include:

BREAST SCREENING

Average Risk, Ages 40-49

Health care providers are encouraged to discuss the benefits and limitations of screening mammography with asymptomatic women in this age group.

If screening mammography is chosen, it is available every two years. Patients will be recalled every two years. A health care provider’s referral is not required but is recommended.

Average Risk, Ages 50-74

Routine screening mammograms are recommended every two years for asymptomatic women at average risk of developing breast cancer. Patients will be recalled every two years. A health care provider’s referral is not required.

Average Risk, Ages 75+

Health care providers are encouraged to discuss the benefits and limitations of screening mammography with asymptomatic women in this age group.

Health care providers should discuss stopping screening when there are comorbidities associated with a limited life expectancy or physical limitations for mammography that prevent proper positioning.

If screening mammography is chosen, it is available every two to three years. Patients will not be recalled by the Screening Mammography Program of BC. A health care provider’s referral is not required but is recommended.

Higher than average risk, Ages 40-74 with a first degree relative with breast cancer

Routine screening mammograms are recommended every year. Patients will be recalled every year. A health care provider’s referral is not required.

High risk, With a known BRCA1 or BRCA2 mutation or prior chest wall radiation or strong family history of breast cancer

Age 40-74: please refer to recommendation for "Higher than average risk" women.

Under age 40: The Screening Mammography Program accepts women at high risk of developing breast cancer with a health care provider’s referral, provided they do not have breast implants or an indication for a diagnostic mammogram. Please discuss patient with a screening program radiologist before referral.

OTHER PROCEDURES

Breast Self Exam (BSE)

Routine breast self examinations (when used as the only method to screen for breast cancer) are not recommended for asymptomatic women at average risk of developing breast cancer.

Women should be familiar with their breast texture and appearance and bring any concerns to their health care provider. 

Clinical Breast Exam(CBE) 

There is insufficient evidence to either support or refute routine clinical breast exams (in the absence of symptoms) alone or in conjunction with mammography. The patient and her health care provider should discuss the benefits and limitations of this procedure to determine what is best for the patient.

This excludes women with prior breast cancer history. 

Magnetic Resonance Imaging (MRI)

Routine screening with breast MRI of women at average risk of developing breast cancer is not recommended.

Exceptions are higher than average risk groups include: BRCA1 and/or BRCA2 carriers, first degree family relatives of BRCA1 and/or BRCA2 not tested, and prior Hodgkin’s disease (or other lymphoproliferative diseases) at a young age (between the ages of 10-30 years old) treated with chest radiation. 

Please see BC Guidelines & Protocols for details on screening in other age groups at: www.bcguidelines.ca/gpac/

3.4 Other Methods

There has been considerable interest in methods of detection of non-palpable abnormalities in the breast that do not use ionizing radiation. Such methods include thermography, U/S (ultrasound) and diaphanography, but in the screening of asymptomatic women none of these techniques approach the sensitivity or the specificity of mammography and cannot be recommended at the present time as the sole screening method. Ultrasound may be very useful, in conjunction with mammogram, for diagnosis of (to assess) breast lesions, and in that situation is part of the workup of a mass. However, in the absence of any abnormality on physical examination or mammogram, U/S is not required, is not a validated screening method, and is not funded by MSP.

MRI (magnetic resonance imaging) has been studied in high-risk women with and without identified genetic mutations. These studies have shown downstaging of MRI-detected invasive breast cancers (smaller cancers and more node-negative cancers) compared to cancers detected in women not having breast MRI screening. At this time there are no studies demonstrating a survival benefit using MRI screening, but modelling studies have predicted a survival benefit based on the downstaging of MRI-detected cancers. It is not yet clear which women at high risk but with no identified gene mutation are most likely to benefit from the additional of breast MRI screening to their usual mammographic screening program.​

4. Diagnosis


Updated: 4 July 2005

The diagnosis of a breast cancer depends on the presentation of the lesion by mammographic screening, other radiological imaging (such as ultrasound) or by physical presentation. In all cases it is important to combine the radiologic assessment of the entire affected breast and the contralateral breast with the general health of the woman, examination of the breast and nodal areas, and a pathological diagnosis. The treatment of the breast cancer will depend on combining the results of these investigations. Although most breast lumps are not cancerous, the practitioner must be aware that breast cancer can appear at any age, and if there is any suspicion, a definitive diagnosis should be obtained promptly.

Diagnostic mammograms should be done on any suspicious finding on a screening mammogram and for women with a palpable finding. In a woman with a palpable mass, however, the finding of a normal mammogram should not delay the histological diagnosis of the mass.

4.1.1 Abnormality Detected by Mammogram Alone


These abnormalities may take the form of either a mass, change in architecture or abnormal calcifications within the breast. If there is an abnormality that is not clearly malignant but new, further imaging with additional views and magnification views should be undertaken. A suspicious new finding should be further assessed with additional imaging (see below) and a pathological diagnosis. A stereotactic core biopsy under mammographic guidance may be undertaken and will allow a diagnosis of the mammographic finding.

4.1.2 Discrete Mass Lesions


If in the opinion of the diagnostic radiologist a mass is thought to be benign (e.g., there is a strong possibility of a non-palpable cyst or a small fibroadenoma), then an ultrasound examination may be helpful in distinguishing between a cystic and a solid lesion. If the lesion is thought to be cystic, then aspiration of the lesion under ultrasound control by the diagnostic radiologist may both diagnose and treat the abnormality and may be all that is needed.

If such a mass is found to be solid on ultrasound, or if the mammographic appearances are not clearly those of a benign abnormality, then one or more of the following are mandatory: fine needle aspiration under ultrasound guidance, or stereotactic core needle biopsy, or open surgical biopsy guided by fine wire localization, depending upon the level of suspicion, size and discreteness of the lesion.  In most cases a core biopsy is recommended to get adequate tissue for pathological diagnosis and to plan surgical intervention if necessary.

4.1.3 Cluster of Fine Calcifications


Where this abnormality is identified and if in the opinion of the diagnostic radiologist the appearance is sufficiently suspicious, a stereotactic core needle biopsy or an open biopsy is required. If the abnormality is less suspicious, then a follow up mammogram in four to six months may be recommended by the radiologist.

4.1.4 Widespread Calcification within the Breast


This finding is the most difficult to evaluate. It may be associated with an entirely benign condition such as sclerosing adenosis but it may also either mask or be caused by widespread in situ carcinoma (e.g. comedo carcinoma). In these instances there is often no one specific area that can be biopsied. The chance of malignancy is increased if, in addition to coarse calcifications, there are clusters of fine calcifications.

Repeat mammograms are not always helpful in this situation since it may be hard to distinguish new lesions against a background of calcification within the breast. Stereotactic core needle biopsies of the most suspicious areas may be helpful and are used increasingly. These are available at a number of locations throughout the province. Random biopsy may provide false reassurance but the alternative of mastectomy is clearly a very serious recommendation to make without prior proof of in situ disease. Members of the Breast Tumour Group would be happy to see these patients in consultation.

Further information about stereotactic core needle biopsy may be obtained through the Department of Diagnostic Imaging, BC Cancer Agency, Vancouver Cancer Centre, (604) 877-6098 ext. 2280.

4.1.5 Palpable Mass

Diagnosis with Mammograms

While mammograms may be helpful in the assessment of a palpable mass, their real importance in this situation is to assess the rest of the breast and the contralateral breast. A negative mammogram is not uncommon in the presence of a palpable mass in the following circumstances:

  1. lobular carcinoma
  2. women with very dense breasts
  3. a very large palpable malignancy which may appear radiologically as though there is increased density in the whole of the breast
  4. a lesion at the extreme periphery of the breast
  5. young patient
  6. lactating breast
In these situations further imaging of the breast with ultrasound or MRI may provide additional information.

A normal mammogram should not be a cause for delay in biopsy. All solitary breast masses require diagnosis by biopsy, unless their appearance is cystic.

In general, mammographic examination is recommended before biopsy of a palpable mass, in order to detect any other significant abnormalities, although it is not recommended in a pregnant woman. An ultrasound may be useful prior to biopsy in this situation.

Diagnosis with Ultrasound

If there are multiple lesions within the breast thought to be cystic and it is considered impractical to aspirate all of them, then ultrasound may be used to make sure that the lesions are indeed all cystic and that one of them is not solid. Ultrasound can be useful in the management of a solitary palpable mass to determine if biopsy is indicated.

4.1.6 Cystic Lesions

If it is thought that a lesion may be cystic, then aspiration of the cyst should be undertaken. If the cyst disappears following aspiration and the fluid is free of blood, then biopsy is not necessary. If the cyst recurs, repeat aspiration may be done. If a cyst is "simple" on ultrasound, biopsy and aspiration are not required but all "complicated" or partly solid cysts should be biopsied.

4.1.7 Solid Lesions

Fine needle aspiration, stereotactic core needle biopsy or open surgical biopsy should be done to establish a definitive diagnosis.

If, on clinical grounds, the lesion is thought likely to be a benign fibroadenoma, then excisional biopsy should be carried out directly, including a small cuff of surrounding breast tissue. In selected circumstances, such as mammographic findings compatible with a benign fibroadenoma, in a young woman who has a negative needle aspirate and no palpable mass, radiological and clinical follow up may be appropriate. If it is thought that the lesion may be malignant, fine needle aspiration cytology can be very useful. If the cytology report indicates the presence of malignant cells, investigations for the potential presence of metastatic disease should be undertaken (see Staging).

If a needle aspiration cytology is negative, malignancy cannot be ruled out and a core or open biopsy of a solid lesion is necessary.

Positive cytology is regarded as sufficient to discuss the management of the breast mass with the patient. However, malignancy must be confirmed by frozen section at the time of either mastectomy or segmental resection if one-stage management is desired by the patient. A core biopsy may also confirm a malignancy prior to a surgical procedure.

4.1.8 Nipple Discharge

Bilateral nipple discharge is not associated with carcinoma, other than on a chance basis.

Clinical assessment of a patient with nipple discharge should determine the signficance of the symptom and determine the next step in management.  A history including the duration of symptoms, colour and spontaneity of the discharge, history of trauma, laterality (unilateral vs bilateral) of the discharge, and the history of medications, hormone use or hormonal imbalance. Clinical examination should include a general examination of the bresat with expression of the discharge. A trigger point may be identified.

Rarely is unilateral nipple discharge a sign of underlying breast cancer, but it is considered to be more likely indicative of malignancy under the following circumstances:

  1. If it is associated with an underlying mass
  2. If it is spontaneous (although spontaneous nipple discharge has been reported to occur in as many as 10% of women)
  3. If on examination it comes from a single duct
  4. If it is serous, serous sanguinous or bloody it may be papilloma, DCIS, hyperplasia or trauma
Both careful clinical examination of the breast and mammography are required for assessment. Galactogram should be considered as well. If there is a palpable mass or an abnormality on the mammogram, clearly a biopsy is indicated. Should the nipple discharge fulfill one or more of the criteria listed above, local excision of the involved duct system is indicated.

The commonest cause of a blood stained discharge is a solitary papilloma of the duct; this does not of itself confer a high risk of breast cancer. Sometimes multiple papillomatosis is identified histologically and does confer an increased possibility of subsequent malignancy. Mammography may be negative with a papilloma and ultrasound may be necessary as well as cytology of the discharge, galactography or ductography, MRI, ductoscopy, or duct excision. Cytology has variable results and the presence of negative cytology does not rule out an intraductal lesion. No one diagnostic test has been shown to be optimal.

Opalescent nipple discharge is least likely to be associated with malignancy.

As with all breast abnormalities, nipple discharge is much more likely to be associated with malignancy in the postmenopausal woman. Radiological investigation of the duct system is not often very informative but may provide a diagnosis of DCIS and/or a papilloma.

4.1.9 Eczema of the Nipple

Any eczematous lesion of the nipple and the areolar area must be viewed with high suspicion because of the possibility of Paget's disease. Repeated clinical examination of the breast is mandatory. If, after local treatment, it does not heal within seven days, mammography and a biopsy of the eczematous area is indicated. An MRI may be useful if the mammogram is normal in the prescence of diagnosed Pagets disease.

4.1.10 Male Breast

Breast cancer can occur in the male (ten to twenty cases per annum in B.C.). Persistent or suspicious lesions should be biopsied and malignancy investigated and staged as for women, including a contralateral mammogram. Gynecomastia may be unilateral and is relatively common in the normal population. A number of medications, particularly digoxin, cimetidine and estrogen, can cause gynecomastia. Male breast cancer is more common in older men, men with a family history of female breast cancer, obesity, alcohol abuse or if there has been excessive radiation exposure to the area.

Diagnostic Pathology



Updated: 4 July 2005

4.2.1 Biopsy of the Non-palpable Lesion


Usually a fine wire localization is required for the investigation of a non palpable lesion within the breast, although stereotactic core biopsies are being used with increasing frequency. In order to determine the most appropriate procedure for investigation of such lesions, it is important for the Surgeon and Radiologist to review the mammograms together to evaluate the type, site, extent and multi-focality of the abnormality. This is critical in order to determine the placement of the wire, position of the incision and the volume of the tissue to be removed in order to remove or adequately sample the mammographic abnormality.

The Surgeon should clearly mark and orient the specimens for the Pathologist. The specimen should then be radiographed to ensure that the area of concern was removed. The specimen, together with the specimen radiograph, should then be sent directly to the Pathologist who should carefully mark the resection margins, prior to cutting the specimen, so that the relationship of the lesion to the surgical margins can be ascertained. Frozen section in this context is not desirable unless the Surgeon is proceeding directly to further definitive surgery as it results in distortion of the tissue and may complicate definitive diagnosis.

If the biopsy is reported to be benign and there is doubt that the abnormal area has been completely removed, then either an immediate re-excision should be performed or the patient should return for a repeat examination and mammography 2-4 months after the operative procedure, when the breast tenderness has subsided.

4.2.2 Biopsy of the Palpable Mass


Biopsies of a palpable mass need careful review of the patient's mammograms to evaluate the extent of the lesion and possible multi-focality of calcifications elsewhere within the breast which may influence the surgical approach. Either fine needle aspiration cytology or a core biopsy is suitable as an initial diagnostic procedure if the lesion is thought to be malignant or highly suspicious for malignancy. An unequivocal positive diagnosis on a fine needle aspirate given by an experienced Cytologist has an accuracy greater than 95%. A negative fine needle aspirate or a negative core biopsy does not exclude malignancy and open biopsy is usually advisable. On occasion, lesions mammographically thought to be benign can be followed and the biopsy deferred, as, for example, in a young woman with a small lesion which is thought both mammographically and cytologically to represent a typical fibroadenoma.

Open biopsy investigation as an initial step is recommended where facilities for fine needle aspiration cytology or core biopsy are not available. Incisional biopsy may be carried out if the lesion is considered inoperable in order to provide tissue for diagnosis and hormone receptor studies. If clinically the lesion is thought to represent inflammatory carcinoma a skin biopsy should be taken in order to assess the presence of carcinoma within dermal lymphatics.

4.2.3 Preoperative Investigations


Reasonable investigations are recommended to determine the presence or absence of blood borne metastatic disease prior to definitive management. These include:

  • Bilateral mammography 
  • CBC 
  • Liver enzymes and alkaline phosphatase 
  • Chest X-ray
Bone scan is not ordinarily recommended for clinical stage T1, T2, N0 cancer since asymptomatic patients are unlikely (<2%) to have a positive bone scan due to metastatic disease. For tumours greater than 5 cm, or where there are palpable axillary lymph nodes or an elevated alkaline phosphatase a bone scan should be carried out.

If the liver enzymes are elevated an ultrasound of the liver should be done.

4.2.4 Procedures for Handling Surgical Specimens


In order to provide sufficient detail for treatment planning the pathology report should include, as a minimum the following information:

  • orientation, type and size of the specimen 
  • size of the invasive carcinoma -- measured in millimeters 
  • type of invasive carcinoma 
  • grade of invasive carcinoma 
  • presence or absence of lymphatic or vascular invasion 
  • type, grade, and extent of in situ carcinoma -- indicating the distance the in situ carcinoma extends beyond any invasive carcinoma which may be present 
  • multifocality of either the invasive or in situ component 
  • relationship of carcinoma to marked margins -- measured in millimeters when close 
  • number of nodes sampled and number of nodes involved 
  • presence or absence and extent of extranodal spread of carcinoma in axillary fat 
  • estrogen and progesterone receptor status 
  • HER2/neu testing by IHC and/or FISH

A detailed, written handout with recommendations for processing specimens for pathologic assessment is available from the Vancouver Cancer Centre, Department of Pathology (1-800-663-3333) on request.


4.2.5 Partial and Modified Radical Mastectomy


The specimen removed at partial mastectomy must be oriented. At least two boundaries should be marked with sutures of different color or length so that the specimen can be oriented in three dimensions (e.g., long suture = lateral, short suture = superior).The pathologist should mark the margins of the specimen with silver nitrate or India ink and, if this has not already been done, send a portion of tumour for receptor studies. With a correctly marked specimen the pathologist will then be able to make an accurate estimate of the size of the tumour-free margin and to identify the location of any margin thought to be inadequately excised. If the margin is inadequate in a location where it is possible to improve the situation surgically then a re-excision should be carried out.

For a modified radical mastectomy, the deep aspect and axillary end should be marked for orientation so that the location as well as the number of nodes removed and involved by malignancy can be ascertained.

4.2.6 Hormone Receptor Levels and HER2 Testing


The estrogen receptor status of breast carcinoma can be determined by immunocytochemical staining of tissue specimens or of aspirates. When possible it is preferable to submit the specimens unfixed immediately to the pathologist who can select the most appropriate technique for handling each individual specimen. Progesterone receptors are also indicated as they may provide evidence of a potentially hormone sensitive tumour.

Immunocytochemical staining is the standard technique to test for estrogen receptors. It can be performed on fresh tissue, frozen tissue, core biopsies scrapings obtained from the surface of small lesions or frozen sections, and on aspirates with reliable results. Staining may also be performed on fixed tissue blocks, but the results may not be as accurate depending upon the fixative used and on delay in fixation of the specimen. In addition, estrogen receptor staining may be a useful technique in evaluating metastases in patients with unknown primaries in whom the possibility of metastatic breast carcinoma is in the differential diagnosis. For further information consult your hospital pathologist or regional pathologist as several hospitals, including the BC Cancer Agency, provide estrogen receptor staining.

HER2/neu (cerbB2) (human epidermal growth factor receptor 2) is an oncogene which is over-expressed in approximately 20% of breast cancers. Testing is done on the primary tumour and/or the recurrent tumour. HER2 overexpression is associated with a poor prognosis, possibly differences in response to different cytotoxics and is a predictor for responsiveness to Herceptin® (trastuzumab).

Accurate and reliable identification of HER2 overexpression is necessary. At this time the predominant need for HER2 testing is to determine patients who are candidates for Herceptin® which is only approved in the metastatic setting and in clinical trials in the adjuvant setting. Initial testing should be done by immunohistochemistry by experts in accredited laboratories. A quality assurance program for labs in BC has been established. The DAKO 04B5 is the choice initial IHC screen. For 2+ tests, FISH testing is of value to identify true HER2 positive over-expression which may benefit from Herceptin® therapy and may be of greater predictive value than the IHC testing. HER2 testing may also be of value in determining the type of adjuvant therapy that is used as there is some evidence that anthracyclines based regimens are superior in this setting compared to non-anthracyclines but this is still controversial. As well there are some papers to suggest that HER2 overexpression may result in some tamoxifen resistance but this is being further studied and at this time hormonal recommendations are not based on HER2 status.

MRI (Magnetic Resonance Imaging)

Updated: July 16, 2009

Clinical Indications for Breast MRI

Introduction:

Although MRI has advanced some areas of oncologic imaging, as well as neurological and musculoskeletal imaging, the transformation is less complete in breast imaging where other well established and less expensive techniques can often provide necessary information.

The purpose of these recommendations is three-fold, in the absence of substantial randomized controlled trial data on the usefulness and value of breast MRI:

  • To provide education and awareness to ordering physicians on the potential uses and pitfalls of breast MRI.
  • To help radiologists and ordering physicians utilize the resource effectively in the appropriate clinical settings.
  • To encourage collaboration in useful clinical research projects for the above.

Mammography is the standard breast imaging modality against which other modalities can be judged since there is an extensive body of trial data and a long period of surveillance follow-up. MRI has not yet met the challenge of proving that it can help to decrease mortality, recurrence or impact of treatment. Nor do we know its true positive predictive value. Specificity is variable, particularly in premenopausal women where incidental enhancing lesions are often identified.  There is currently no literature of level 1 evidence to support the use of MRI for any specific indication. It is not certain which women or imaging questions will be best served by this modality and at what costs.

Breast MRI should be used in a problem solving mode only after high quality mammography and ultrasound have been carried out.  As well, it should be done by a radiologist with expertise in breast MRI, as these images require specialized knowledge for interpretation.

MRI sensitivity rates for the detection of invasive breast cancer are estimated to be as high as 95-100%, which compares well to mammography at 85%. However, a significant limitation is specificity, which is highly variable ranging from 37-97%.  Like all breast imaging studies, breast MRI must be correlated with other imaging findings in light of clinical findings.

The Breast Tumour Group (of the BC Cancer Agency) has discussed these indications which have been developed by Drs. Patricia Hassell and Moira Stilwell.  The consensus was that as there is not level one evidence we cannot claim that these are standard Guidelines but are suggested clinical indications and are divided into those that are more established in terms of benefit, those that are not established but may be indicated for specific patients and those that should not be routinely recommended.  MRIs within the context of clinical trials should be considered outside of these indications.

Other than cancer indications there is the following indication in patients without cancer.

Evaluation of silicone implants

MRI has been shown to be more reliable than CT, ultrasound or mammography for assessment of rupture/integrity/complications of silicone breast implants. The mean sensitivity was 38% for mammography, 59% for ultrasound and 78% for MRI.     

A. Recommended Uses of Breast MRI for Cancer (highest level of evidence)

1.  Screening of high risk patients – patients with hereditary cancer risk

In patients who have tested positive for mutations of the BRCA 1 and 2 genes or who are at high risk of breast cancer due to a family history of the disease, MRI has been shown to detect cancers before mammography, ultrasound or clinical examination could detect the malignancy. The greater incidence of high grade invasive malignancies in this high risk group does provide the rationale for using MRI as a screening modality in known mutation carriers (including, but not restricted to, BRCA1 and BRCA2) DEL. DEL as we are in process of changing to annual imaging using both MMG and MRI concurrently. In British Columbia, the role of breast MRI screening in high risk women with a strong family history of breast cancer but no known gene mutation is under review. Studies have suggested that ultrasound may also have a role in following these women but recent literature does not support continued ultrasound screening in asymptomatic high risk women. There is no scientific evidence concerning the role of MRI in patients with biopsy proven ADH or LCIS. There are ongoing studies as although there are more cancers detected this has not yet translated into decreasing mortality.​

2.  Evaluation of occult breast cancer

In patients with an occult primary presenting with axillary lymphadenopathy or Paget's disease, MRI has been shown to identify the primary in many patients, thus allowing for conservative surgery rather than mastectomy.  This is not indicated if mammography clearly shows a suspicious lesion. Trials are ongoing studying the impact of MRI on this group of patients.

B. Possible Uses of Breast MRI

These include a number of clinical scenarios where other imaging modalities have not provided adequate assessment and where a further evaluation with an MRI showing more disease may impact and/or change management.

1. Evaluation of local extent of breast cancer

MRI can be useful in pre-operative assessment of local disease extent when this is unclear either by physical examination, mammography or ultrasound.  Mammography is more accurate in determining the size and additional sites of malignancy.  However, not all women benefit from having an MRI as 8% underwent additional biopsy or surgery for findings detected on the MRI which subsequently proved to be benign.  This may be particularly indicated in lobular carcinoma where mammography may be less sensitive and where there may be multicentric disease.

2. Positive margins – post segmental resection

MRI can be useful in determining the extent of residual disease when margins are positive and the mammogram is not helpful. In the majority of cases however, as further surgery is indicated, it will not necessarily impact on treatment. 

3. Post surgical scar vs. recurrent tumor

In cases where mammography and ultrasound are inconclusive in patient suspected of recurrent disease, MRI can be helpful.  Breast tissue can show enhancement for up to 18 months following radiation therapy, however.  In many of these situations a biopsy will be necessary to rule out disease and may be a preferable diagnostic test.

4. Problem mammogram

MRI can be useful in a small number of patients when there is an equivocal mammographic finding, i.e. a possible architectural distortion, or mass seen only in one view, in whom there is no ultrasound or clinical correlate.  Many of these patients have heterogeneously dense breasts. 

5. Response to chemotherapy

MRI has been used to monitor treatment response to neoadjuvant chemotherapy in patients with locally advanced cancer.  There is controversy over the ability of MRI to determine complete or partial response to treatment. Change in tumor vascularity/enhancement appear to explain changes in functional dynamic contrast assessment and can be seen after only one cycle of chemotherapy.  MRI tends to underestimate residual disease.   At this time this should only be used in association with a clinical trial.  

C. Inappropriate Use of Breast MRI

1. Screening of general population

At present there is no data to support the use of MRI as a screening tool.  To date, there are no studies demonstrating decreased mortality by the use of MRI.  Not all cancers seen on mammography can be identified in MRI.  This is especially true for DCIS. 

2. Differentiation of benign vs malignant lesions

Because of an overlap between the enhancement and morphological characteristics of benign and malignant lesions, MRI cannot be used as a substitute for biopsy.

Review of Pathology

Updated: 6 May 2004

BCCA breast pathologists review slides in the following situations:

  1. It is the policy of the Breast Tumour Group that all node negative invasive breast cancer have a formal pathology review as this is a situation which can significantly change the prognosis of an early breast cancer and may initiate a change in adjuvant management. This review will be done promptly on all referred cases and is available for non referred cases.  For referred cases this is prompted by the referral clerk.  For nonreferred cases, forms​ are available.  

  2. Cases where there is a need to further clarify specific aspects of the tumour where it may impact treatment, such as margins, can be reviewed prior to a final decision regarding treatment.  These reviews are prompted by a treating oncologist - radiation, medical, surgical and are requested on an additional information form.  

Pathology Reporting for Breast Cancer

​Updated  Tuesday, April 28, 2009

In order to assist with optimal management of patients with breast cancer, the oncologists in British Columbia have requested the following information to be included in pathology reports. For the convenience of the reporting pathologist, the required information is presented in the form of a checklist. This information may be incorporated in the standard report format or may be listed in the form of a synoptic report.​

Breast Cancer Pathology Reporting Checklist

In order to assist with optimal management of patients with breast cancer, the oncologists in British Columbia have requested the following information to be included in pathology reports. For the convenience of the reporting pathologist, the required information is presented in the form of a checklist. This information may be incorporated in the standard report format or may be listed in the form of a synoptic report.

BREAST CANCER - CHECKLIST

GROSS ASSESSMENT

Side: Right/Left (note - if bilateral please describe each side individually).
Specimen Type:
FNA, Needle Core Biopsy
Surgical Biopsy (incisional/excisional), Wide Excision/ Partial Mastectomy
Total Mastectomy +/- sentinel node biopsy/axillary dissection
Measurement of Specimen: Largest piece
Presence or Absence of Tumour
Number of Tumours: solitary/ multiple
Size of Tumour: 3 dimensions if possible
Gross Relationship of Tumour to Margins: measurement to closest margin
Gross Involvement of Skin or Skeletal Muscle.

HISTOLOGICAL ASSESSMENT

Histological Diagnosis: State any specific type of carcinoma.
Size: check if greater than gross estimate; use a micrometer if possible. Greatest dimension.
Grade: note - see below
Lymphatic Invasion Outside the Tumour: Yes/ No
Venous Invasion: Yes/ No
Margins (Invasive ca.):
Distance to Closest Margin
State Which Margin If Possible
Look for deep fascia
Skeletal Muscle: State If Invaded.
Skin:
Ulceration
Dermal Invasion
Dermal Lymphatic Invasion
Nipple:
Paget's Disease
Stromal Invasion
Estrogen Receptor Status: see below
PR Status
Her-2 neu Status
Intraductal Component:
Present/ Absent
Pattern of DCIS (Type)
Grade of DCIS
EIC Pattern:- Yes /No (note - see below)
For DCIS Alone, Measurement of Size is Important.
Margin Status - measure distance of DCIS to closest margin.
ER status now required
Calcification in the Tumour (or DCIS): Yes/ No
Lymph Nodes: Total Number
Number Positive for Metastases
Size of Biggest Metastasis
Extranodal Extension - measure distance from capsule

See Sentinel node biopsy.

Pathological TNM Stage: see below.

Handling of Specimens

All specimens should be measured and margins inked. Ideally, all wire-guided biopsies and wide excisions short of complete mastectomy should be processed in entirety.

Where the specimen is very large, acceptable alternative methods of sampling and blocking can be found in the following guidelines: http://www.rcpath.org/index.asp?PageID=695 

Label all blocks separately and designate each block as to site in the gross description.(e.g. Block A = Nipple; B-E = Tumour; F = deep margin etc.). Blocks from wire-guided biopsies and wide excisions should be taken sequentially so the size of the tumour can be assessed by calculating the number of blocks involved multiplied by the block thickness.

Margin status: State how the block is taken in relation to the margin. Usually blocks are taken perpendicular to the margin but if taken "en face" this must be recorded in the dictation or on a specimen diagram.

Submit all lymph nodes and state the number included in each cassette. In general the entire node should be processed.

Sentinel nodes should be handled as in the separate SLN biopsy protocol

Frozen sections should be avoided if possible - especially on lesions, which measure <1cm. in diameter.

Grading System for Invasive Carcinoma of Breast

General Guidelines:

  1. The system is applicable to all invasive carcinomas.
  2. Special subtypes of breast carcinoma (lobular, tubulolobular, tubular, papillary, mucinous, cribriform, medullary, adenoid cystic, sarcomatoid (metaplastic), squamous, adenosquamous) should be noted separately but should also be assigned an overall grade. Strict criteria should be used to recognise these special types of breast cancer which have prognostic significance (Ellis 1992; Tavassoli 1992; Rosen 1993).
  3. Since the term "differentiation" used in the context of breast carcinoma is an ambiguous term, it is recommended that grades 1,2 or 3 be used instead of, or at least in addition to, the terms "well, moderately, or poorly differentiated".
  4. Grading cannot be performed adequately on material that has been frozen for the purposes of "frozen section" or "quick section". Well-fixed, well-cut, and optimally stained H&E sections are essential.
  5. The Nottingham modification of the Bloom and Richardson method of grading is used most widely and is recommended for the BCCA. The system described below incorporates modifications suggested by Elston, Contesso, and Helpap. The three separate parameters are scored independently as follows :-

(I) Nuclear Grade

Nuclear score 1: Nuclei are small to medium-sized, relatively uniform in size and shape, and lacking clumped chromatin or prominent nucleoli. Nuclei may have small, inconspicuous nucleoli. Uniformity of size and shape are the most important features.
Nuclear score 2: Nuclei are medium to large in size but exhibit only moderate variability in size, shape and intensity and pattern of staining. Nucleoli may be quite prominent as long as the nuclei are relatively monotonous in appearance. Nucleoli with irregular outlines, giant or "macronucleoli" are absent. Bizarre giant cells are absent.
Nuclear score 3: Nuclei are large and vesicular and/or contain coarse clumps of chromatin. There is considerable variation in the size and shape of nuclei. Typically, nucleoli are very large, often multiple and may have irregular outlines. Giant nuclei, polylobated nuclei and multinucleate tumour giant cells may be present. Karyorrhexis, karyolysis and pyknosis of nuclei are often encountered.

Note: The above descriptions are given as guidelines, which may be supplemented by study of illustrations of the different nuclear grades in the references, cited below. Furthermore, since there is a morphological continuum in the nuclear appearance in breast carcinomas, the extremes of the spectrum are easily recognised but, in some cases, the scoring of nuclei is to some extent subjective and differences of interpretation between pathologists are to be expected. It must be stressed that it is impossible to assign a nuclear score based on the frozen section or post-frozen paraffin embedded material.

(II) Tubule Formation

The assessment of tubular differentiation or tubule formation applies to the neoplasm overall and requires examination of several sections at scanning magnification. A reliable tubular score cannot be assigned when only needle biopsies or small pieces of the tumour are examined.

Tubule score 1: >75% of the neoplasm is composed of tubular structures with visible lumina. Solid trabecula, vacuolated single cells, alveolar nests and solid sheets of cells comprise less than 25% of the tumour.
Tubule score 2: 10-75% of the tumour has a tubular pattern.
Tubule score 3: <10% tubule formation.

(III) Mitosis Score

The mitosis score is assessed in the peripheral areas of the neoplasm and not the sclerotic central zone. The neoplasm is scanned at intermediate magnification to determine the area in which mitoses are most abundant (usually areas of poor tubule formation where cells are arranged in sheets or large nests). Only definite mitotic figures are counted with care to avoid including pyknotic nuclei in the count. Although the Nottingham grading system uses a scoring system based on the number of mitoses per 10HPF's, the Oncologic Standards Committee considers that a mitotic count per square millimetre is most accurate. Mitoses are only counted in the invasive component of the lesion.

Score 1: <4 mitoses per square mm.
Score 2: 4-7 mitoses per square mm.
Score 3: >7 mitoses per square mm.

Alternatively the number of mitoses in 10 high power fields (HPFs) is counted. Using a Nikon Labophot microscope with a 40X objective lens (i.e. X400) and a field surface area of 0.152mm2, the scores are as follows :-

Score 1: 0-5 mitoses
Score 2: 6-10 mitoses
Score 3: >10 mitoses

In practice, Contesso's method of scoring of mitoses is quicker and easier to perform especially on small biopsies (e.g. Core biopsies). At least 20HPF's of the same area as stated above are assessed and scored as follows :-

Score 1: No field contains more than 1 mitosis.
Score 2: Two mitoses present in any one HPF.
Score 3: Three or more mitoses present in any one HPF.

Composite Score

The scores for the three separate parameters (tubules, nuclei and mitoses) are summated and the overall grade of the neoplasm is determined as follows :-

Grade 1: 3-5 points.
Grade 2: 6-7 points.
Grade 3: 8 or 9 points.

Grading of Ductal Carcinoma In Situ (DCIS)

The following patterns of DCIS are recognised:

  1. Cribriform
  2. Micropapillary - papillary structures lack fibrovascular cores.
  3. Papillary - fibrovascular cores present within papillary structures.
  4. Solid
  5. Comedocarcinoma - defined as DCIS with extensive central necrosis (>2/3 the diameter of the duct). The latest consensus committee abandoned the requirement for high nuclear grade in combination with necrosis.
  6. Others:
    1. Clinging
    2. Apocrine DCIS.
    3. Signet ring cell DCIS
    4. Low-grade endocrine DCIS

Grading of DCIS

Low Grade (Grade 1): Grade 1 or 2 nuclei and no zonal necrosis.

Intermediate grade (Grade 2): Grade 1 or 2 nuclei with zonal necrosis

High grade (Grade 3): Nuclear grade 3 with or without necrosis

Quantitation: A rough estimate of the volume of DCIS relative to the overall tumour should be given as a percentage. "Extensive intraduct component (EIC)" is used to qualify invasive carcinomas with DCIS, which may take two forms as follows :-

  1. Prominent DCIS with in the invasive tumour mass (comprising 25% or more of the volume) AND DCIS in adjacent breast ducts and/or lobules extending clearly beyond the boundaries of the invasive carcinoma.
  2. Widespread DCIS with microscopic stromal invasion is also placed in the EIC category.

This assessment is important because EIC carcinomas treated with breast conservation have a higher risk of local recurrence within the breast unless the margins are well clear (Schnitt 1984).

Lobular Carcinoma

In general, it is possible to grade lobular carcinoma. Usually, classical lobular carcinoma will attain a total score of 5 (tubules 3; nuclei 1; mitoses 1) giving the tumour an overall grade 1. Although some of the data are somewhat inconclusive, histological variants of lobular carcinoma are thought to differ in their degree of aggressiveness as follows:

  1. Good Prognosis (Grade 1): Tubulolobular carcinoma. This variant features tubular structures that are lined by very uniform small cells resembling those of classical lobular carcinoma. Single-file strands of identical cells are also present. Some authorities would regard this variant as a ductal carcinoma (tubular type).
  2. Fairly good Prognosis (Grade 1): (marginally better than that of ductal carcinoma NOS.) Classical lobular carcinoma.
    Criteria include:
    a) Small uniform cells; grade 1 nuclei
    b) Single-file rows in a fibrous stroma.
    c) Targetoid (concentric, "bull's-eye") pattern around pre-existing ducts.
  3. Intermediate prognosis (Grade 2):
    Classical pattern with Grade 2 nuclei.
    Alveolar variant - round and oval nests of uniform small cells.
    Large cell variant
    Mixed patterns of lobular carcinoma.
  4. Poor prognosis patterns (Grade 3):
    Solid variant - large sheets of uniform small cells with round nuclei.
    Pleomorphic lobular carcinoma - pattern resembles classical lobular carcinoma but the nuclei are grade 2-3, mitoses are easily identified, apocrine change is common, and ER is often negative.
    Signet-ring cell variant (>20% of cells should be signet-ring type)

Lymphatic Invasion:

Only invasion of lymphatics beyond the advancing edge of the tumour is important.
If in doubt call it negative.
Please state if there is extensive lymphatic/vascular invasion (>10 lymphatics involved).

Venous Invasion:

Large calibre, thick-walled blood vessels containing tumour emboli either within the tumour in the surrounding tissue are included.

Neural Invasion:

Neural invasion has been shown not to be of prognostic significance in most studies. This is confirmed in a recent analysis of the BCCA data.

Extranodal Extension:

Tumour cells must be outside the nodal capsule.
Please state if "minimal" extra nodal spread (<1mm from capsule) or extensive infiltration of perinodal tissues with "matting" of nodes.

Breast Markers:

Breast markers on invasive carcinoma should be done on the core biopsy sample where relevant. Only if the results appear incongruous with the histology, should the markers be repeated on the excision specimen.
DCIS should be stained for ER in the excision specimen. PR and Her2-neu status of DCIS is not relevant for management of the patient.

1) Estrogen Receptors

Please select a block containing invasive carcinoma and normal breast tissue if possible.
Immunostains are graded subjectively on a scale 0-3+.

0 :- Negative nuclear staining; positive internal control staining. Allred scores 0(1,2)
1+ :- Allred scores 3-4
2+ :- Allred scores 5 and 6
3+ :- Allred scores 7 and 8

DCIS is also submitted for immunostaining

Allred Score: Percentage of nuclei staining + Intensity + Total score

% Nuclei stainingScore
00
<1%1
1-10%2    
11-33%3
34-66%4
>67%5


Intensity score:

No staining0
Weak 1
Moderate 2
Strong 3


2) Progesterone Receptors: Recommended on all invasive breast cancers.
PR is graded as for ER using the Allred (UKNEQUAS) scoring method.

3) Her-2neu: Required on all invasive breast cancers.

Pathological TNM Stage

The e-book AJCC Cancer Staging Handbook is available online for BCCA Staff (see the StatRef! website). The book is also avaiable from the BCCA Library, or your local health sciences library

Tumour

pTX :- unable to assess size.
pT1-mic :- <0.1 mm microinvasive
pT1a :- Tumour diameter 0.1-5mm
pT1b :- 6-10mm
pT1c :- 11-20mm
pT2 :- 21-50mm
pT3 :- >50mm
pT4 :- Extension of tumour (any size) to skin and/or chest wall (excluding pec. major muscle).

Nodes – please see official TNM publication for details of complicated classes.

pNX :- Nodal Status Unknown
pN0 :- Negative Nodes
pN0i+ :- <0.2mm metastases (single cells or isolated tumour cell clusters)
pN1mi:- micrometastases 0.2-<2mm diameter
pN1a metastases >2mm diameter
1-3 positive nodes
N1b Internal mammary SNL positive not clinically apparent
pN1c Internal mammary SNL +ve (clinically occult) plus 1-3 axillary nodes +ve.
pN2a 4-9 axillary nodes +ve.
pN2b Internal mammary nodes +ve on micro and clinically.
pN3a >10 axillary nodes +ve or infraclavicular nodes +ve
pN3b complicated
pN3c Supraclavicular node +ve

Distant Metastases

pMX :- Unknown Status
pM0 :- No Distant Metastases
pM1:- Distant Metastases Present

References

Processing, Reporting and Special Histological Types including Prognostic Factors

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Lobular carcinoma

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  3. Fechner RE. Histological variants of infiltrating lobular carcinoma of the breast. Hum Pathol 1975;6:373-378.
  4. Fisher ER, et al. Tubulolobular invasive breast cancer: a variant of lobular invasive cancer. Hum Pathol 1977;8:679-683.
  5. Weidner N, Semple JP. Pleomorphic variant of invasive lobular carcinoma of the breast. Hum Pathol 1992;23:1167-1171.
  6. Eusebi V, et al. Pleomorphic lobular carcinoma of the breast: An aggressive tumour showing apocrine differentiation. Hum Pathol 1992;23:655-662.
  7. Frost AR. The significance of signet-ring cells in infiltrating lobular carcinoma of the breast. Arch Pathol Lab Med 1995;119:64-68.

DCIS Grading

  1. Schnitt SJ, et al. Developing a Prognostic index for ductal carcinoma in situ of the breast. Are we there yet? Cancer 1996;77:2189-2192.
  2. Silverstein MJ, et al. A prognostic index for ductal carcinoma in situ of the breast. Cancer 1996;77:2267-2274.
  3. Silverstein MJ, et al. Prognostic classification of breast ductal carcinoma in situ. Lancet 1995;345:1154-1157.
  4. Fisher ER, et al. Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) protocol B-17. Intraductal carcinoma (ductal carcinoma in situ). Cancer 1995;75:1310-1319.
  5. Holland R, et al. Microcalcification associated with ductal carcinoma in situ: mammographic-pathologic correlation. Semin Diagn Pathol 1994;11:181-192
  6. Holland R, et al. Ductal carcinoma in situ: a proposal for a new classification. Semin Diagn Pathol 1994;11:167-180.
  7. Leal CB, et al. Ductal carcinoma in situ of the breast; histological categorization and its relationship to ploidy, and immunohistochemical expression of hormone receptors, p54, and c-erbB-2 protein. Cancer 1995;75:2123-2131.
  8. Sneige N, et al. Ductal carcinoma in situ treated with lumpectomy and irradiation: histopathological analysis of 49 specimens with emphasis on risk factors and long term results. Hum Pathol 1995;26:642-649.
  9. Douglas-Jones AG, et al. A critical appraisal of six modern classifications od ductal carcinoma in situ of the breast (DCIS): correlation with grade of associated invasive carcinoma. Histopathology 1996;29:397-409.
  10. Consensus conference on the classification of ductal carcinoma in situ. Human Pathology 1997;28:1221-1225.

Estrogen Receptors

  1. Allred DC, Harvey JM, Berardo M, Clark GM. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Modern Pathology 1998;11(2):155-168
  2. Leake R, et al. Immunohistochemical detection of steroid receptors inbreast cancer: a working protocol. J Clin Pasthol 2000;53:634-635
  3. Pertschuk LP, et al. Immunocytochemical estrogen and progestin receptor assays in breast cancer with monoclonal antibodies. Histopathologic, demographic and biochemical correlations and relationship to endocrine response and survival. Cancer 1990;66:1633-1670.
  4. Pertschuk LP, et al. Estrogen receptor immunocytochemistry in paraffin embedded tissues with ER1D5 predicts breast cancer endocrine response more accurately than H222Spgamma in frozen sections or cytosol-based ligand assays. Cancer 1996;77:2514-2519.
  5. Andersen J, et al. Immunohistochemical estrogen receptor determination in paraffin-embedded tissue. Prediction of response to hormone treatment in advanced breast cancer. Cancer 1989;64:1901-1908.
  6. Goulding H, et al. A new immunohistochemical antibody for the assessmnet of estrogen receptor status on routine formalin-fixed tissue samples. Human Pathol 1995;26:291-294.

5. Staging

​Updated: Thursday, July 13, 2006

Breast Staging Diagram

Investigations for Staging

The major information for staging of the breast cancer is the pathology report. However, a full history should be undertaken to assess any physical symptoms which may suggest metastatic disease. A full physical examination should be done to carefully assess other nodes, especially supraclavicular nodes, lungs, liver and bones. If the physical examination and history are normal and do not suggest metastatic disease, other staging investigations may not be necessary. If there are any findings these should have imaging and further laboratory investigations.


Prior to chemotherapy, a hematology and chemistry panel should be done to rule out bone or liver metastases and to ensure adequate marrow, hepatic and renal function. In node positive or locally advanced disease, a bone scan may be done if it is thought that there may be a risk of bone metastases at presentation or if a baseline test would be helpful. Baseline tumour markers CEA, CA15-3 and CA125 may be considered as part of the initial staging. If normal, they need not be repeated, unless there is a documented recurrence. If they are abnormal, they may suggest metastatic disease, possibly occult.

6. Management


Updated: March 2014

Referral information for the new patient visit

Recent years have seen an increased emphasis on early diagnosis of breast cancer through public education with instruction in breast self-examination, regular physical examinations by the family doctor and the use of mammography. It is hoped that this trend will lead to earlier diagnosis for a sizable proportion of women with breast cancer and thus to a better prognosis.

One result of earlier diagnosis has been the increasing number of women seen with in situ disease. This has led to re-evaluation of both the risk to these individual women and subsequent recommendations for management of in situ disease while still conserving the breast.

Long term follow-up has confirmed that wide excision followed by radiation therapy produces survival and local control which is equivalent to mastectomy, so that breast conservation is now considered standard therapy for most women with operable breast cancer. Attention to the details of surgical technique is important to achieve a high level of local control while maintaining an optimal cosmetic result.

Adjuvant systemic therapy has been demonstrated to reduce the risk of cancer recurrence and improve survival. Adjuvant systemic therapy with either chemotherapy or hormonal therapy should be offered to women according to the treatment policies as defined in Adjuvant Systemic Therapy. These policies are reviewed continuously by the provincial breast systemic policy group and updated accordingly. The role of combining both tamoxifen and chemotherapy continues to evolve.

For patients with locally advanced disease, early utilization of systemic and locoregional therapies shows promising results. In the management of metastatic disease the prime interest continues to be reduction and possible prevention of morbidity with emphasis on the quality of life.

Weekly conferences are held (Tuesday p.m..at the Vancouver Island Cancer Centre; Friday p.m. at the Vancouver Cancer Centre; Friday p.m. at the Cancer Centre for the Southern Interior and every 2-4 weeks on Tuesday afternoons at the Fraser Valley Cancer Centre) to consider the multi-disciplinary management of patients. This may be related to the initial treatment of patients or to the management of metastatic disease. The conferences are attended by diagnostic radiologists, medical oncologists, pathologists, radiation oncologists and surgeons. The clinical history, examination, the pathology slides and diagnostic imaging studies are reviewed. The family physician and surgeon are welcome to attend any conference when a patient of theirs is being presented.

Women with breast cancer are requesting information about their diagnosis and treatment options and should be encouraged to decide which treatment pathway is best for them. A delay of a few weeks between the diagnosis and definitive treatment has not been shown to be harmful and can allow a woman time to gather information and consider her options. There is a virtual Information Kit​ available that we encourage patients to access.  The BCCA Library has videos, pamphlets and books for loan to patients - call 604.675.8001 or 1.888.675.8001, local 8001. See also BCCA Centres and Clinics and information for patients and the public

The information in this section of the Cancer Management Guidelines is our current approach to patients with breast cancer. It is not intended to be a comprehensive manual on breast cancer and its treatments nor is it intended to imply that the approach given here is the only acceptable approach. The text, Diseases of the Breast, edited by Harris, Lippincott-Raven, Philadelphia, 4th ed. (2009), is a good source for a more comprehensive discussion of breast cancer.

 

1.0 In Situ Disease

Updated: November 2004

1) Paget's Disease of the Nipple

The standard management of Paget's disease remains surgical excision. Since Paget's disease of the nipple is often associated with an underlying breast mass, the breast should be imaged with a mammogram and ultrasound, and if these investigations are non-diagnostic, an MRI of the breast should be considered. A partial mastectomy may be offered to selected patients if breast conservation will lead to an adequate cosmetic result. Such patients should be referred to a radiation oncologist for consideration of post operative radiotherapy. A sample of underlying breast tissue should be taken with the nipple to evaluate if an associated in-situ or invasive cancer is present. We encourage referral of patients to the BC Cancer Agency if partial mastectomy is to be considered.

2) Ductal Carcinoma in Situ (DCIS)

Appropriate management of DCIS requires detailed mammographic evaluation of the breast to obtain an assessment of the preoperative extent of the lesion. Close cooperation and communication between the radiologist, surgeon and pathologist is crucial to ensure adequate local therapy in women treated with breast conservation.

We are not presently recommending low axillary dissection for DCIS. However, the larger the focus of ductal carcinoma in situ, the higher the chance a focus of micro-invasive disease is present. Therefore, an axillary lymph node dissection, or sentinel node biopsy, may be appropriate in a patient with DCIS >5cm in diameter.

Although total mastectomy remains an option for women with DCIS, recent evidence has demonstrated that radiotherapy reduces the incidence of subsequent in situ and invasive breast recurrences. Currently, adjuvant radiotherapy is recommended for women with DCIS tumour >1 cm in diameter or comedo carcinoma who are interested in breast conservation, and in all patients with close margins (<5mm) of excision.

Women with well differentiated DCIS (cribriform, solid, papillary), <1cm in diameter with complete radiographic and pathologic excision (at least 5 mm of normal breast tissue between foci of DCIS and the inked margins) may be managed by wide excision alone.

Women with very diffuse areas of DCIS (e.g., >5 cm or greater than or equal to ¼ of the breast on mammogram) have a substantial risk of recurrence even after excision and radiotherapy and mastectomy is recommended. The Van Nuys prognostic index (which incorporates age, margin status, grade and size of the DCIS lesion can be useful at estimate the risk of relapse with breast conservation (Silverstein MJ Am J Surgery 186(2003); 337-343).

Tamoxifen has been shown in one randomized study (NSABP B24) to decrease the occurrence of both invasive and in situ disease in women with in situ disease when used in combination with radiation. The cumulative evidence of events at 5 years:

 placebotamoxifen 
all breast cancer events13.4%8.2%p= <0.1
contralateral breast cancer3.4%2.0%p= 0.01

 

The rate of endometrial cancer per 1000 women per year was 0.45 for placebo and 1.53 for tamoxifen.

However, a second smaller randomized trial did not demonstrate a statistically significant advantage to the addition of tamoxifen. This later trial did not include patients with margins and very few women over the age of 50, unlike the former trial. This emphasizes the importance of consideration of prognostic factors and the balance of risk and benefits in the consideration of tamoxifen in this setting. In addition, updated analysis of the NSABP B24 trial suggests that the benefit of tamoxifen in DCIS may be confined to those patients with ER positive tumours. Therefore, patients with DCIS who are considered appropriate candidates for tamoxifen should have ER receptors assessed.

The following guidelines should be used when considering tamoxifen in women with a diagnosis of in situ disease only:
– adjuvant tamoxifen should be offered to women with DCIS, after consideration of known risk factors in particular age and margin status, and after confirmation of ER positivity. It should not be considered for women with bilateral mastectomies, with an increased risk of endometrial cancer or thromboembolic events, or for women with a life expectancy of <10 years or who have recently been on tamoxifen for prevention. The tamoxifen dose should be 20 mg/day for 5 years.

3) Lobular Carcinoma In Situ

Use of this term is controversial. Most modern authors regard this as indicating a high risk for the development of infiltrating carcinoma in either or both breasts. Certainly the risk for subsequent carcinoma is not confined to the segment of the breast involved by the in situ change. The risk to each breast is approximately equal and approaches fifteen percent within ten to fifteen years. Patients can be given the option of either careful follow up or occasionally, bilateral mastectomy with or without immediate or delayed reconstruction. Recently tamoxifen was shown to decrease the risk of invasive cancer in women with lobular cancer in situ in the NSABP prevention trial using tamoxifen 20 mg daily for 5 years. Therefore these women are candidates for 5 years of tamoxifen prescription.

2.0 Systemic Management - Introduction

​Revised 18 January 2013

SYSTEMIC MANAGEMENT, EARLY BREAST CANCER

The systemic management of invasive non-metastatic breast cancer is complex. The management of locally advanced and of metastatic breast cancer is discussed separately. The prognosis for a patient following treatment of early breast cancer varies according to their age, co-morbidities, and the stage and the biomarker profile of their cancer. The majority of patients with early breast cancer will be cured with appropriate multi-disciplinary therapy.

Invasive breast cancer can be divided into three broad groups that influence systemic treatment decisions: 1) hormone receptor positive/her2 negative cancers; 2) her2 positive cancers; 3) and triple marker negative (ER-PR-her2-, "triple-negative") cancers. Within each of these groups, treatment recommendations are also influenced by patient age, co-morbidity, and personal preferences, as well as the stage and other histopathologic features of the cancer.

Clinical Trials

The majority of advances in the management and improvements in the cure rates of early breast cancer have come from successful completion of scientifically rigorous clinical trials. Patients should be given the opportunity to participate in clinical trials if available for their stage and type of breast cancer.

2.1 Hormone Receptor Positive

​Revised 18 January 2013

The BC Cancer Agency maintains current Chemotherapy Protocols.

1. Definition

Hormone receptor positive breast cancers express estrogen receptors (ER) and or progesterone receptors (PR, PgR) on their nuclei, as evinced by immunohistochemical (IHC) assay. There are two main immunohistochemical scoring systems used by the province to describe the degree of ER and PR expression. The Allred score is made up of a measure of the intensity of the IHC stain and the percentage of cells which take up the stain for the receptor.1 The maximum score (strongest expression) is 8. A simpler scoring method is often used in which the hormone receptor staining strength is expressed from 0 (no staining) to 3 (strong, ubiquitous staining). Cancers with an IHC score of 0 or an Allred score of 2 or 0 do not benefit from hormone receptor targeted therapy. Cancers with an Allred score of 3 have weak staining in a small percentage of cells, and the benefit of therapy targeted at the receptor is debatable in this setting. An IHC score of 1+ is similar to an Allred score of 3 or 4. An IHC score of 2+ can be considered comparable to an Allred score of 5 or 6, and an IHC score of 3+ would be roughly equivalent to an Allred score of 7 or 8.

2. Hormone therapy 

Hormone therapy for five years should be considered for all women with hormone receptor positive breast cancer (estrogen receptor [ER] and/or progresterone receptor [PR] allred score 4-8/8; or 1+ , 2+ or 3+) based on robust large clinical trial data sets establishing a significant survival benefit.2 The absolute benefit depends on both the absolute recurrence risk and the relative strength of hormone receptor expression. The decision to treat cancers with an Allred score of 3 with hormone therapy should be individualized.

2A. Premenopausal women

For premenopausal women, the hormone therapy of choice is tamoxifen (BRAJTAM). An alternative for women with contraindications to tamoxifen is surgical oophorectomy (permanent) or medical menopause (LHRHa; reversible), with or without an aromatase inhibitor (BRAJLHRHT).3 For select low stage, non grade 3 disease, hormone therapy with both tamoxifen and an LHRHa may be an acceptable and/or superior alternative to chemotherapy.4

Duration of therapy:

The current standard of care for most premenopausal women is 5 years of hormone therapy. Women who remain premenopausal after 5 years of tamoxifen may derive a small additional survival benefit from continuing tamoxifen to a total of 10 years.5 Women becoming menopausal near the end of five years of tamoxifen should be considered for extended adjuvant therapy with an aromatase inhibitor for a further 3-5 years, based on evidence of disease free survival and, for node positive disease, modest overall survival benefits.6 When menopausal status is uncertain, extended adjuvant therapy should be with tamoxifen, given that aromatase inhibitors are not beneficial in premenopausal women.

2B.  Postmenopausal women

For postmenopausal women, there are several hormone therapy options. They include 5 years of an aromatase inhibitor; 5 years of tamoxifen; and the sequential use over a total of 5 years of tamoxifen and aromatase inhibitor for about 2 and half years each (BRAJTAM, BRAJANAS, BRAJEXE, BRAJLET). Compared with 5 years of tamoxifen, the use of an aromatase inhibitor (for either five years, or for 2.5 years preceded or followed by tamoxifen) is associated with 3% fewer disease free survival events (defined as any of contralateral breast cancer, relapse of prior breast cancer, and death from any cause).7 Despite this, overall survival gains from the introduction of aromatase inhibitors in adjuvant therapy remain elusive.

Duration of therapy:

Menopausal women completing five years of tamoxifen should consider an additional 3-5 years of an aromatase inhibitor or of tamoxifen (if unable to tolerate aromatase inhibitors), depending on the recurrence risk of the original cancer. This is associated with a modest disease free survival improvement over stopping therapy at five years, and for women with node positive breast cancer, a small survival gain.5,6

Ongoing studies are examining whether longer than 5 years is beneficial if the first five years of therapy included an aromatase inhibitor.

The choice of treatment strategy must take into consideration patient co-morbidities and drug side effects, as well as the absolute recurrence risk associated with their cancer. As a guideline, the BC Cancer Agency Breast Tumour group recommends the following:

Table 1. BCCA Breast Tumour Group guidelines for hormone therapy in menopausal non- metastatic hormone receptor positive breast cancer

Disease characteristics Hormone therapy
T1N0 grade 1 Tamoxifen for 5 years, unless not tolerated or contraindicated

Any of

Grade 3

4+ nodes involved

ER1+ (allred score 3, 4)

Aromatase inhibitor for 5 years, unless not tolerated or contraindicated.
All other stages, grades

Tamoxifen for 2-3 years then aromatase inhibitor to complete 5 years

OR

Aromatase inhibitor for 2-3 years, then tamoxifen to complete 5 years

 
Table 2. Contraindications to starting or continuing Tamoxifen

Issue Type of contraindication Notes
Personal DVT, PEAbsoluteUnless patient anticoagulated for duration of tamoxifen use
Close family history of DVT, PERelativeCoagulation studies may rule out a familial hypercoagulable state making tamoxifen safer
Newly diagnosed Endometrial cancerAbsolutePatients should discontinue tamoxifen permanently if they develop endometrial cancer while on tamoxifen.  Patients with remote history of low stage curatively treated endometrial cancer may safely take tamoxifen
Severe depressionRelativeTamoxifen may exacerbate depression
Patients taking buproprion (wellbutrin), fluoxetine (paxil), or paroxetine (prozac)RelativeThese drugs are metabolized by the same enzyme which metabolizes tamoxifen to its active metabolite endoxifen. Whether this is clinically important is controversial. Each case must be considered individually balancing the potential benefits and risks of switching to a different antidepressant. Patients who can safely and easily switch to a different anti-depressant are encouraged to do so.

DVT=deep venous thrombosis; PE=pulmonary embolis

Table 3. Contraindications to Aromatase Inhibitors

Issue Type of contraindication Notes
PremenopausalAbsoluteUnless a patient is continuously menopausal, aromatase inhibitors are ineffective. Patients under the age of 50 who have a chemotherapy induced menopause may recover ovarian function thus for women pre or perimenopausal at diagnosis, tamoxifen is recommended as initial therapy.
Severe osteopenia or osteoporosis Relative

Aromatase inhibitors increase the rate of normal bone mineral losses in menopausal women. Women with normal bone density carry a 20-50% risk of developing osteopenia and a 1% risk of osteoporosis with 2-5 years of AIs; women with osteopenia have a 10% risk of developing radiologic osteroporosis with 2-5 years of AIs. (Bone Health)

Moderate to Severe joint painRelativeAIs cause joint and muscle pain in about 1/3 of patients and may increase pre-existing pain. AIs do not cause erosive joint changes.
Moderate to severe dyslipidemiaRelativeAIs can cause elevation of triglycerides and cholesterol. These values should be monitored and a switch in hormone therapy or addition of lipid lowering agent should be considered for marked elevations

 
For a complete list of side effects refer to the product monographs and BCCA specific patient and professional education information (BCCA Chemotherapy Protocols).

2C. Secondary Prevention

An added benefit of adjuvant hormone therapy for women who have not undergone bilateral mastectomy

(ie women who have an intact contralateral breast) is the reduction in risk of contralateral breast cancer (40-50% relative risk reduction for tamoxifen; 65% relative risk reduction for aromatase inhibitor with / without prior tamoxifen).8,9

3. Chemotherapy

3A. Criteria for Consideration of Chemotherapy

Chemotherapy may be indicated for some hormone receptor positive breast cancers in addition to hormone therapy and local management. The decision to recommend chemotherapy is based on a number of patient and tumor factors weighed together. In general, if the cancer exhibits any or several of the characteristics listed below, the benefits of chemotherapy should be considered:

  • Tumor >2cm
  • Lymphatic and/or vascular invasion present
  • Grade 3
  • Weak ER and PR expression (Allred score 3-5; ER 1+ by IHC)
  • Node positive

None of these features alone or in combination mandates the use of chemotherapy. The decision making process is complex and involves balancing the potential benefits of adjuvant chemotherapy with the potential harms (side effects) and must be considered on a case by case basis. Other important factors in this decision making process include patient factors such as age, life-expectancy, and co-morbidities. Patient preference and willingness to accept chemotherapy side effects must also be considered. Cancers without any of the above features arising in very young women (35 and younger) may still warrant chemotherapy, as young age is an independent adverse prognostic factor.10 Clinicians must make individual recommendations based on clinical judgment and specialized knowledge of breast cancer management. Recurrence risk assessment tools such as Adjuvant Online can facilitate discussion with patients and illustrate the probable benefits of hormone therapy and chemotherapy in individual cases.

There are several tissue based prognostic tools which may be of value in guiding management recommendations for some women with node-negative, ER-positive and HER-2 negative breast cancer. One such test is the Oncotype Dx Recurrence Score Assay® which is performed on a tissue sample of the resected breast cancer by Genomic Health (GH), an American company which developed the assay. A Recurrence Score (RS) is generated based on the level of mRNA expression for several genes within the tumour sample. This score provides an estimated risk of breast cancer recurrence over 10 years in the context of appropriate locoregional management and 5 years of hormonal therapy. Furthermore, retrospective analyses suggest that only cancers with a high RS (31 or higher) derive additional protective benefit from chemotherapy.11,12 These preliminary findings are being prospectively tested in node negative breast cancer in the fully accrued TAILORx trial (see ClinicalTrials.gov).

The BC Cancer Agency Breast Tumour Group has outlined minimum eligibility criteria for provincially funded Oncotype Dx Assay®. These may not be the same as criteria established by other jurisdictions. At present a provincially funded Oncotype Dx Assay can only be obtained through consultation with a Medical Oncologist and with compassionate access program (CAP) approval. Patients may choose to pay for the test through their own means; their medical oncologist can facilitate the process

Table 4. Minimum eligibility criteria for BC funded Oncotype Dx Assay®

Eligible for funded Oncotype Dx AssayIneligible for funded Oncotype Dx Assay

§ 80 years of age or younger, and

Fit for chemotherapy, and

Node-negative or N0i+ breast cancer which is hormone receptor positive (ER+ and/or PR+) and HER-2 negative

PLUS

§ Any grade 3 cancers

OR

§ Grade 2 cancers (if centrally reviewed) and T1c or larger

OR

§ Grade 2 cancers that are T1a or T1b in women 40 years of age and younger at diagnosis

§ Grade 1 cancers (any size) in women 40 years of age and younger

§ Node positive breast cancer

§ HER-2 positive breast cancer

§ Grade 1 cancers in women older than 40 yeasr of age at diagnosis

§ Grade 2 cancers smaller than T1c in women older than 40 years of age

§ Patients unwilling to consider or unfit to receive chemotherapy

§ Patients who have only had core biopsy and not definitive surgery

 
The Breast Tumour Group feels that there is insufficient data at this time to warrant the routine use of the Oncotype Dx Assay® for clinical decision making in node positive breast cancer. An ongoing clinical trial (RESPONDRx) may establish its role in determining the benefit of chemotherapy in low volume (1-3) node positive breast cancer.

3B. Chemotherapy Regimens

There are numerous active adjuvant chemotherapy regimens. The choice of regimen (drugs, doses, and number of cycles) should be evidence based whenever possible. The standard regimens available to Oncologists practicing in British Columbia can be found on the chemotherapy protocol, breast webpage (BCCA Chemotherapy Protocols). Within British Columbia, deviations from these protocols require CAP approval.

Premenopausal women

In general terms, 4-6 months of chemotherapy containing both an anthracycline and taxane is preferred for premenopausal women with node positive breast cancer (hyperlink BRAJACTG, UBRAJACTW, BRAJFECD, UBRAJDAC, BRLAACD).13,14 Among women with node negative, but large and/or grade 3 cancers, acceptable chemotherapy options include shorter regimens such as DC (BRAJDC), and longer regimens with and without taxanes (BRAJFEC, BRAJFEC-D, BRAJACTG, UBRAJACTW, BRAJAC).

Postmenopausal women

Postmenopausal who are relatively young and fit may be considered for the same chemotherapy regimens as for premenopausal women with similar cancer stage and grade. For older (>60 years old) and less fit menopausal women, the choice of chemotherapy regimen must consider the fact that this population may derive considerably less benefit and more toxicity than younger, fitter women receiving the same regimen.13 Shorter, less toxic regimens, or no chemotherapy, may be the most suitable recommendation in these cases.

Patients with cardiac co-morbidity

There are a number of adjuvant chemotherapy regimens that do not incorporate anthracyclines. These are particularly good choices for patients at risk for cardiac injury. Patients with significant cardiac co-morbidities should undergo left ventricular ejection fraction assessment prior to initiating chemotherapy. Patients with an LVEF that is below the institutional lower limit of normal should not receive anthracycline based chemotherapy. Anthracyclines may also be best avoided in patients with multiple cardiac risk factors even if they have a normal LVEF. Cumulative lifetime anthracycline exposure for an otherwise healthy individual should not exceed 480mg/m2 (the equivalent cardiotoxic dose of epirubicin is 860mg/m2) . Patients who have received anthracyclines for a prior malignancy are more safely treated with non-anthracycline regimens (BRAJDC, BRAJCMF)

References

  1. Elledge RM, Green S, Pugh R, et al. Estrogen receptor (ER) and progesterone receptor (PgR), by ligand-binding assay compared with ER, PgR and pS2, by immunohistochemistry in predicting response to tamoxifen in metastatic breast cancer: A Southwest Oncology Group study. Int J Cancer 2000; 89:111-117
  2. Early Breast Cancer Trialists' Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 365:1687-1717

  3. Gnant, M, Blineritsch B, Schippinger W et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Eng J Med 2009; 360:679-691

  4. Thurlimann B, Price KN, Gelber RD, et al. Is chemotherapy necessary for premenopausal women with lower-risk node-positive, endocrine responsive breast cancer? 10-year update of International Breast Cancer Study Group Trial 11-93. Breast Cancer Res Treat 2009; 113:137-144

  5. Davies C, Pan H, Godwin J, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Online publication Dec 5, 2012, Lancet

  6. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Eng J Med 2003; 349:1793-1802

  7. Dowsett M, Cuzick J, Ingle J, et al. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol 2010; 28:509-518

  8. De Schryver A, Huys J, Vakaet L. Systemic treatment of early breast-cancer by hormonal, cytotoxic, or immune therapy: 133 randomized trials involving 31000 recurrences and 24000 deaths among 75000 women. Lancet 1992; 339:1-15.

  9. the ATAC Trialists' Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002; 359:2131-2139

  10. Aebi S, Gelber S, Castliglione-Gertsch M, et al. Is chemotherapy alone adequate for young women with oestrogen-receptor-positive breast cancer? Lancet 2000; 355:1869-74

  11. Paik S, Shak S, Tang G, et al. A multi-gene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Eng J Med 2004; 351:2817-2826

  12. Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 2006; 24: 3726-3734.

  13. De Laurentiis M, Cancello G, D'Agostino D, et al. Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials. J Clin Oncol 2008; 26:44-53

  14. Hayes DF, Thor AD, Dressler LG, et al. HER2 and response to paclitaxel in node-positive breast cancer. N Eng J Med 2007; 357:1496-1506

2.2 HER2 Positive

Revised 18 January 2013

The BC Cancer Agency maintains current Chemotherapy Protocols.

1 Definition of HER2 Positive

All breast cancer cells have some HER2 receptors. So called Her2 positive (her2+) cancers express a 20+ fold higher level of surface receptors than her2 negative cancers. This confers a more aggressive natural history to these cancers, which also more frequently have grade 3 than other grade histology.15 Her2 is most commonly tested using either IHC or fluorescence in situ hybridization (FISH). In BC, all breast cancers should be tested for Her2, usually on the core biopsy, although any specimen, including archival tissue, can be used. Cancers with an IHC score of 0 or 1+ are considered negative; those with a 2+ score are equivocal and a FISH test is done to determine if there is gene amplification. In randomized clinical trials exploring the benefit of adding trastuzumab (Herceptin) to chemotherapy for breast cancer, cancers that had a FISH ratio of 2.0 or higher, or an IHC of 3+ were considered to be Her2 positive and eligible to participate.16,17 A FISH ratio between 1.8 and 2.2 may technically be considered equivocal18 but for treatment related decisions a FISH ratio of 2.0 or higher is considered positive and eligible for trastuzumab (Herceptin). Her2 positive cancers can be hormone receptor (ER or PR) negative or positive.

2 Systemic Treatment of HER2+ Cancer

The standard of care adjuvant treatment of her2+ early breast cancer of stage T1cN0 or higher in British Columbia is combination chemotherapy with trastuzumab (BRAJACTT, BRAJFECDT, BRAJDCARBT, BRLAACDT). The preferred regimen contains both an anthracycline and taxane.14 The trastuzumab can be given concurrently with the non-anthracycline portion of the chemotherapy (preferred) or following completion of chemotherapy, and should be continued for one year (17 treatments, given 3 weeks apart).

Chemotherapy and trastuzumab may also be given to patients with a T1bN0 her2+ cancer, particularly if the cancer is hormone receptor negative, recognizing that the risk of recurrence exceeds 25% and is dramatically reduced with therapy.19 T1aN0 cancers derive less absolute benefit than higher stage cancers from chemotherapy and trastuzumab because they have a lower recurrence risk. Clinicians wishing to offer chemotherapy and trastuzumab to a patient for a T1aN0 cancer must receive CAP approval first.

The most commonly used regimen is AC followed by paclitaxel (BRAJACTT), however for node negative, T1b and T1c ER2 positive breast cancers, a shorter regimen may be sufficient, such as DC combined with trastuzumab (BRAJDCT) or AC followed by trastuzumab (BRAJAC and BRAJTR). To avoid anthracyclines, clinicians may prefer a regimen that includes docetaxel and carboplatin (BRAJDCARBT).  Other regimens include an anthracycline and docetaxel (BRAJFECDT; BRLAACDT). Despite a more aggressive natural history, her2+ breast cancers treated with appropriate local therapy and chemotherapy/trastuzumab have a very favourable prognosis with low rates of relapse.20

Trastuzumab does not to be interrupted for delivery of adjuvant radiation.21

3 Contraindications to Trastuzumab

The primary contraindication to trastuzumab is a left ventricular ejection fraction (LVEF) below the institutional lower limit of normal, indicating left ventricular dysfunction or borderline function. Because of synergistic toxicity with concomitant administration, trastuzumab should not be given concurrently with anthracyclines.22 About 40% of patients experience an infusion reaction with the first dose of trastuzumab, characterized by chills, shakes, -fever, and shortness of breath. This is usually transient, self-limited, and responsive to acetaminophen and supportive care measures. With rare exceptions, infusion reactions do not occur after the first infusion, so pre-medication is not required. Care should be taken to determine whether an observed reaction is due to trastuzumab or an accompanying drug, such as a taxane, as reactions to the latter drug can recur with subsequent infusions.

4 Cardiac Monitoring

LVEF assessment with ECHO or MUGA should be considered prior to chemotherapy start for women with cardiac risk factors, as there are several chemotherapy options that do omit anthracylines. LVEF assessment is required prior to starting trastuzumab, and every three months during trastuzumab therapy. Patients with subnormal LVEF should not be treated with trastuzumab. Each trastuzumab containing BCCA protocol (BCCA Chemotherapy Protocols) contains an algorithm to guide continuing or interrupting trastuzumab in the event of changes in LVEF. Cardiology referral is advised for patients developing signs and symptoms of cardiac dysfunction, and caution should exercised in resuming trastuzumab in these cases, even if LVEF recovers and symptoms resolve. If trastuzumab is restarted after an interruption due to cardiac toxicity, more frequent LVEF monitoring is recommended, as outlined in the BCCA trastuzumab containing protocols.

5 Hormone Therapy

HER2 positive cancers that are also hormone receptor positive should also receive hormone therapy as described above for hormone receptor positive cancers.

Refe​rences

  1. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of HER-2/neu oncogene. Science 1987; 235: 177-182

  2. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab After Adjuvant Chemotherapy in HER2-Positive Breast Cancer. N Eng J Med 2005; 353: 1659-1672

  3. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Eng J Med 2005; 353: 1673-1684

  4. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/college of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 2007; 25:118-145

  5. Chia S, Norris B, Speers C, et al. Human epidermal growth factor receptor 2 overexpresssion as a prognostic factor in a large tissue microarray series of node-negative breast cancers. J Clin Oncol 2008; 26:5697-5704

  6. Viani GA, Afonso SL, Stefano EJ, De Fendi LI, and Soares FV. Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials. BMC Cancer 2007; 7:153

  7. Halyard MY, Pisansky TM, Dueck AC, et al. Radiotherpay and adjuvant trastuzumab in operable breast cancer: tolerability and adverse event data from the NCCTG phase III trial N9831. J Clin Oncol 2009; 27:2638-2644

  8. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Eng J Med 2001; 344: 783-792

2.3 Triple Negative Breast Cancers

​Revised 18 January 2013

1 Definition

Triple negative breast cancer (TNBC) are cancers which are negative for ER, PR, and HER2 expression. Cancers that have Allred scores of 3/8 for ER and PR are generally considered to benefit minimally from hormone therapy and are often treated as triple negative cancers.

Triple negative cancers are associated with a higher recurrence risk than hormone receptor positive breast cancers of the same stage.23 In addition to a more adverse natural history, these cancers do not benefit from hormone therapy or any identified adjuvant targeted therapy.

Chemotherapy is strongly recommended for all fit patients with TNBC of T1cN0 or higher stage, regardless of age and menopausal status. Younger, fit patients may also benefit from chemotherapy for T1aN0 and T1bN0 cancers, although the absolute benefits are smaller. For every patient, particularly those who are frail, elderly, or have multiple debilitating co-morbidities, one must always weigh the benefits of chemotherapy against the potential risks of giving it.

The Breast Tumor group recommends anthracycline-taxane based chemotherapy of 4-6 months duration for fit patients with T1cN0 or higher stage triple negative breast cancers (BRAJACTG, UBRAJACTW, BRAJFECD, BRLAACD). The choice of regimen depends on patient factors, tumor stage, and clinician judgment. In select older patients, or patients with small T1c or with T1bN0 disease, shorter regimens (BRAJDC, BRAJAC) may be acceptable alternatives to longer therapy.

 References:

  1. Dent R, Trudeau M, Pritchard KI, et al. Triple-negative breast cancer : clinical features and patterns of recurrence. Clin Cancer Res 2007; 13:4429-4434

2.4 Neoadjuvant Therapy

Added 20 April 2013

The use of systemic therapy prior to surgery (neoadjuvant therapy or NAT) has been studied since the early 1970s1. There are several potential advantages to the use of NAT2:

  • Allows for immediate assessment of tumour response
  • Allows for evaluation of new and novel agents
  • Allows for evaluation of change in biomarkers with treatment
  • May allow for earlier control of micro-metastases

The key landmark study by Wolmark et al in 2001 (NSABP B-18) demonstrated that NAT was safe, with no difference in outcomes of disease free survival (DFS) or overall survival (OS) in patients who received either pre-operative chemotherapy or post-operative chemotherapy3. It was demonstrated, however, that patients who had a complete pathological response (pCR) to NAT had an improved OS compared to those who did not achieve a pCR with NAT.

NAT has been since studied in multiple settings, tumour subtypes, and with many different types of agents. The summary below will address the key questions with regards to the use of neoadjuvant therapy:

  • Who should be considered a candidate for NAT?
  • What are the key steps in the pathway of care for patients treated with NAT?
  • What are the options for type of NAT?

Who is a candidate for NAT?

1. Inflammatory Breast Cancer – NAT is strongly recommended

Patients with inflammatory breast cancer (IBC) should receive neoadjuvant chemotherapy with aim to render the disease operable.

Inflammatory breast cancer is a clinical diagnosis. A breast mass may or may not apparent, but the overlying skin involvement (classically termed peau d'orange) is visible on clinical exam. As expected, there is much controversy in the literature with regards to the "true" clinical parameters that define inflammatory breast cancer. According to international expert panel4, at a minimum, the following clinical criteria are required:

  1. Rapid onset of breast erythema, edema and/or peau d'orange, and/or warm breast, with or without an underlying palpable mass
  2. Duration of history no more than 6 months
  3. Erythema occupying at least one-third of the breast
  4. Pathologic confirmation of invasive carcinoma.

The distinctive pathological finding is the involvement of the dermal lymphatic vessels by tumour cells which results in the skin erythema and edema. A biopsy (either core or open) to confirm the diagnosis should include skin to allow for the examination of dermal lymphatics.

This subtype of breast cancer is rare. Estimates from US datasets (SEER) suggest an incidence in the US of 1-5%5. While the incidence has increased since the early 1980s, this stage of cancer remains uncommon.

Response rates and overall survival rates in this population are typically lower than for other stages of disease, with reported pathologic complete response ranging from 18-40% and 5 year OS rates ranging from 35-55%4. More intensive chemotherapy regimens are associated with higher rates of response. Treatment options are outlined in the section below (see Treatment Options below ). As this subtype of breast cancer is aggressive, rapidly progressive, and associated with a high risk of recurrence/mortality, it is recommended that NAT be started in patients with IBC as soon as possible. (see Pathway of Care Chart below).

2. Locally Advanced Breast Cancer – NAT is strongly recommended

The definition of locally advanced breast cancer (LABC) varies across different randomized controlled trials. The Canadian Consensus for the definition of LABC is (pan Canadian consensus, www.labcnetwork.org) :

  • T3 or T4 tumours with any clinical N status,
  • any size tumour (T) with N2 or N3 disease

This is consistent with the MD Anderson definition of Stage IIB or Stage III disease6. Patients with a diagnosis of LABC fall into one of two categories: those who have neglected seeking medical attention for a breast tumour for some time (these tumors often have a more indolent course of slowly growing disease over many months to years with no signs of metastases), and those with rapidly growing, aggressive disease, for whom timely management and coordination of care is key (see Pathway of Care Chart below). At initial diagnosis, however, it may be difficult to distinguish between these two types of presentation.

The incidence of LABC is estimated at 10% of all breast cancer diagnoses. These cancers have a higher risk of recurrence than earlier stage disease6.

There is a wide range of response rates, pathologic complete response, and overall survival associated with LABC, depending on the underlying intrinsic subtype of the cancer (triple negative and Her2+ having higher rates of pCR than luminal A and B subtypes)7. Intrinsic subtype is not routinely ascertained at diagnosis at present, but clinical and pathological factors that predict for likelihood a higher likelihood of a pathologic complete response are young age, high grade, basal-like or Her2+ breast cancer8.

3. Earlier stage breast cancer – NAT is an option

In British Columbia, most patients with early stage breast cancer decisions about chemotherapy are made after surgery. However, there are certain features of a cancer known from a core biopsy that favour the use of chemotherapy as part of the overall management of the cancer. Given that many randomized controlled trials of neoadjuvant chemotherapy included tumours that did not meet the LABC definition8, and given that there is no survival detriment in starting with chemotherapy, any patient who is a candidate for adjuvant systemic chemotherapy can be considered for neoadjuvant systemic therapy. This is of particular benefit for patients who may be able to convert from a planned mastectomy to breast conserving surgery in the presence of good clinical response. The main disadvantage of NAT in non LABC is in cases where the axilla is clinically negative prior to NAT, because it leaves uncertainty regarding the need for and benefit of regional radiation.

If the need for chemotherapy is uncertain based on core biopsy, the best option is to proceed to surgery first (ie small tumour, unclear if there is any nodal involvement, ER+, older and less healthy patient).

What are the key steps in the pathway of care for patients treated with NAT?

The neoadjuvant treatment of breast cancer requires a coordinated effort amongst surgical oncology, medical oncology, radiation oncology, nursing, pathology, radiology and clerical booking staff. One of the main barriers to use of NAT can be efficiencies in communication amongst all care providers. Strategies to overcome this are currently underway in many centres (see Locally Advanced Breast Cancer Network).

Referral:

If a patient is felt to be an appropriate candidate for NAT by a surgeon or family physician, an urgent referral should be sent to medical oncology. If a biopsy has not yet been done, a surgical consult may also be required. Radiation oncology should be consulted early in the patient's course, as the breast cancer can change in size and volume dramatically from initial presentation due to NAT.

Work up:

Work up prior to initial neoadjuvant treatment should preferably include the following: histological confirmation and receptor status (ER, PR, Her2 on the core biopsy specimen; breast imaging; imaging of the ipsilateral axilla with FNA of any suspicious appearing lymph nodes; or FNA of any clinically apparent lymph nodes; clinical staging (accurate tumour measurement on clinical exam); metastatic survey including imaging of the chest, abdomen (in the cases of clinically stage IIB-stage III disease).

Systemic Therapy:

Options for systemic therapy are outlined in the section below. After initiation of NAT, patients should be assessed clinically at each cycle (or monthly in the case of neoadjuvant endocrine therapy). Upon re-assessment, clinical measurement of the tumour and lymph nodes should be recorded and compared to the previous cycle. Cancers that are responding should continue the planned treatment protocol. Hormone therapy should be given after completion of NAT if cancer is ER positive (See Systemic Management - Early Breast Cancer in 2.0 Syste​mic Management - Introduction​). If the cancer is her2 positive, trastuzumab should be given for one year, starting during the non-anthracycline portion of the chemotherapy.

If the tumour enlarges while on NAT, treatment should be changed. Non-cross resistant chemotherapeutic agents salvage radiotherapy, or surgery are all appropriate options to consider in this setting. Discussion of these cases at a multi-disciplinary tumour board should be considered. Cancers showing equivocal response may benefit the most from tumor board multidisciplinary review, to explore ways to improve clinical response.

Local therapy:

Following NAT, patients should undergo definitive local therapy which usually involves surgery and radiation. Patients with inflammatory breast cancer, locally advanced breast cancer with at least T3 should have a mastectomy. Breast conserving surgery is acceptable for T2 disease if the cosmetic result is felt to be adequate and a clip has been placed prior to NAT to guide the surgeon to the original site of the cancer. If a mastectomy with autologous tissue reconstruction is planned, radiation is generally preferred prior to surgery, to minimize the negative cosmetic effect on the reconstructed breast of radiation. In other circumstances, radiation generally follows surgery. Surgery should be planned for 3-4 weeks following completion of NAT, to allow adequate immune and general recovery first. The typical timelines reported in randomized controlled trials of NAT in breast cancer patients is 3-4 weeks from the last dose of chemotherapy.9,10,11,12

Patients with locally advanced breast cancer should undergo axillary dissection, whether or not a sentinel node procedure is done simultaneously. A stand alone sentinel node biopsy may be appropriate for patients receiving NAT for non-locally advanced breast cancer, depending on their clinical stage.

Patients with technically inoperable tumours after NAT should have radiotherapy next with a view to further local down-staging. If they become operable, mastectomy and axillary dissection should follow.

Residual disease after NAT

Pathology findings following NAT are designated with a 'y' in front of the 'p" (example ypT2N1) to reflect that the cancer has been exposed to treatment. In general, the less disease present, the better the prognosis, with a large jump (improvement) in prognosis occurring with a pathological complete response (pCR).8 The improved disease free and overall survival associated with a pCR has been shown in cancers of all biomarker profiles (triple negative, ER positive, and her2 positive).13

The definition of pathological complete response varies in clinical trials. The strictest definition allows no residual invasive disease or in situ disease in the axilla or breast. The least strict definition considers only the absence of invasive disease in the breast, allowing for residual nodal metastases. The Canadian expert consensus for the definition of pathological complete response is no evidence of invasive disease in the breast or axilla (pan-Canadian consensus 2012). This definition allows for residual DCIS and is consistent with the definition most often reported in clinical trials of NAT.

There is not data to support that additional chemotherapy is of benefit in patients who have residual disease at surgery following NAT. Clinical trial options can be considered if available. Hormone therapy and trastuzumab should be given according to standard of care.

What are the options for type of NAT?

Chemotherapy

Preoperative chemotherapy (NAT) has several functions:

  • to control/ eradicate micrometastases,
  • to improve the loco-regional control
  • to render the patient operable, if they presented with inoperable disease.

In general, there is a preference for chemotherapy regimens that include an anthracycline and a taxane, either concurrently or sequentially Chemotherapy Breast Protocols, based on demonstration of improved outcome compared with anthracycline only regimens.14 Recommended regimens include BRLAACD and UBRAJACTW, but avoidance of anthracyclines or taxanes, or abbreviated courses, may be necessary for some patients with co-morbidities. Trastuzumab (BRLAACDT) should be added if the cancer is her2+. NAT is typically given for about six months (8 cycles) prior to definitive local therapy, provided there is no adverse progression of the disease on therapy.

Hormone Therapy

The likelihood of achieving a pCR with endocrine therapy is significantly lower than with chemotherapy.

Neoadjuvant endocrine therapy may be an appropriate option in patients found to have hormone receptor positive disease and who are unfit for chemotherapy. Canadian experts from the Canadian Consensus for the Treatment of Locally Advanced Breast Cancer recommend endocrine therapy for patients with ER+PR+Her2- disease and multiple co-morbidities, or who are older than 80 years. The duration of neoadjuvant hormone therapy is not well defined, but studies have been conducted using an interval of 4-8 months.15 The overall goals of care should be discussed with the patient and the duration of therapy should reflect this (ie if the goal is curative then a pre-defined duration of NAT with endocrine therapy followed by surgery; if the goal of care is control then there may be no pre-defined duration of NAT).

Aromatase inhibitors and Tamoxifen have been studied in the neoadjuvant setting.16 In serial biopsy studies, aromatase inhibitors have demonstrated a greater drop in proliferation markers (Ki67) than tamoxifen. Anastrozole, Exemestane, and Letrozole have all demonstrated similar effect on proliferation indices. One study showed better clinical response rates with letrozole than tamoxifen.17 For these reasons, aromatase inhibitors are preferred in menopausal women, although tamoxifen can be used in patients with contraindications or intolerance to AIs.

The above guideline can be summarized in the following pathway of care:

 

References:

1. Hortobagyi GN, Blumernschein GR, Spanos W et al. Multimodal treatment of locoregionally advanced breast cancer. Cancer 1983: (51): 763-768.

2. Chia S, Swain SM, Byrd DR, et al. Locally advanced and inflammatory breast cancer. J Clin Oncol 2008: 25(5):786-90.

3. Wolmark N, Wang J, Mamounas E, et al. Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr. 2001;(30):96-102.

4. Dawood S, Merajver D, Viens P, et al. International expert panel on inflammatory breast cancer: consensus statement for standardized diagnosis and treatment. Annals of Oncology 2011: (22): 515-523.

5. Levine PH, Steinhorn SC, Ries LG, et al. Inflammatory breast cacner: the experience of the Surveillance, Epidemiology and End Results (SEER) Program. J Natl Cancer Inst 1985; (74):291-297.

6. Brito RA, Valero V, Buzdar AU, et al. Long-term results of combined-modality therapy for locally advanced breast cancer with ipsilateral supraclavicular metastases: The University of Texas M.D. Anderson Cancer Center experience. J Clin Oncol. 2001 Feb 1;19(3):628-33.

7. Von Minckwitz G, Kaufmann M, Duemeel S, et al. for the GBG and AGO-B Study Groups. Correlation of various pathologic complete response (pCR) definitions with long-term outcome and prognostic value of pCR in various breast cancer subtypes: results from the German neoadjuvant meta-analysis. J Clin Oncol. 2011; 29(Suppl.): 1028.

8. Kaufmann M, von Minckwitz G, Mamounas EP,et al. Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. Ann Surg Oncol. 2012 May;19(5):1508-16.

9. Smith, I.C., et al., Neoadjuvant Chemotherapy in Breast Cancer: Significantly Enhanced Response With Docetaxel. J Clin Oncol, 2002. 20(6): 1456-1466.

10. Thomas E, Holmes F, Smith T, Buzdar A, et al. The use of alternate, non-cross resistant adjuvant chemotherapy on the basis of pathologic response to a neoadjuvant doxorubicin based regimen in women with operable breast cancer: long term results from a prospective randomized trial. J Clin Oncol 2004; vol 22 (12).

11. von Minckwitz G, Rezai M, Loibl S, et al. Capecitabine in Addition to Anthracycline- and Taxane-Based Neoadjuvant Treatment in Patients With Primary Breast Cancer: Phase III GeparQuattro Study. J Clin Oncol April 20, 2010 vol. 28

12. Untch M, Rezai M, Loibl S, et al. Neoadjuvant Treatment With Trastuzumab in HER2-Positive Breast Cancer: Results From the GeparQuattro Study. J Clin Oncol April 20, 2010 vol. 28 no. 12, 2024-2031

13. Cortazar P, Zhang L, Untch M, et al. Meta-Analysis results form the Collaborative Trials in Neoajduvant Breast cancer (CTNeoBC). Cancer Research 72 (24) supplement 2012: S1-11

14. Heysa SD, Hutcheona AW, Sarkara TK, et al, on behalf of the Aberdeen Breast Group. Neoadjuvant Docetaxel in Breast Cancer: 3-Year Survival Results from the Aberdeen Trial. Clinical Breast Cancer. Volume 3, Supplement 2, October 2002, Pages S69–S74

15. Shenkier, T., et al., Clinical practice guidelines for the care and treatment of breast cancer: 15. Treatment for women with stage III or locally advanced breast cancer. CMAJ, 2004. 170(6): 983-994.

16. Smith IE, Dowsett M, Ebbs SR, et al. Neoadjuvant Treatment of Postmenopausal Breast Cancer With Anastrozole, Tamoxifen, or Both in Combination: The Immediate Preoperative Anastrozole, Tamoxifen, or Combined With Tamoxifen (IMPACT) Multicenter Double-Blind Randomized Trial. J Clin Oncol August 1, 2005 vol. 23 no. 22: 5108-5116

17. Eiermann W, Paepke S, Appfelstaedt, J, et al. Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized double-blind multicenter study. Ann Oncol 2001;12(11):1527-32.

2.5 Miscellaneous Considerations

​ Revised 18 January 2013

1 Order of systemic and local therapy

Chemotherapy for non-locally advanced breast cancer is generally preferable after rather than before surgery, although survival and cure rates do not appear to be affected by this order.24 Surgical excision of the tumor and nodes provides optimal histopathologic information upon which to make the best systemic and radiation recommendations. If on the basis of a core biopsy and patient characteristics, there is sufficient information to recommend chemotherapy, it is acceptable to proceed with chemotherapy first, even when a cancer is not locally advanced. Reasons to choose chemotherapy first include time delay to scheduling immediate reconstruction in patients electing or requiring mastectomy; down sizing a tumor in patients who are borderline for breast conservation; and participation in pre-operative therapy clinical trials.

2 Bone Modifying Agents

There is insufficient evidence to routinely recommend bisphosphante therapy to adjuvant breast cancer patients. Several trials have suggested a modest benefit to adding zoledronic acid to the adjuvant therapy in women who are already menopausal or in whom menopause is induced.3,25 Studies with earlier generation bisphosphonates did not show a benefit, however.26 Data from longer follow up and corroborating evidence from ongoing trials are anticipated. While not funded by the BCCA, Oncologists may recommend intermittent zoledronic acid for three years in selected early breast cancer patients based on existing evidence.

3 Resected Local and Loco-Regional Recurrences

Data supports the use of aggressive locoregional and systemic management for the highest likelihood of cure in patients who develop an isolated in breast, chest wall, or axillary recurrence that is resectable. Chemotherapy in this setting has been shown to increase survival and cure rates.27 The choice of chemotherapy depends on patient factors, prior therapy given, and time elapsed since prior adjuvant therapy.

Follow up following treatment of early breast cancer is discussed elsewhere (Follow-up).

References:

  1. Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of Nationnal Surgical Adjvuant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol 26: 778-785

  2. Coleman RE, Marshal H, Cameron D, et al. Breast-cancer adjuvant therapy with zoledronic acid. N Eng J Med 2011; 365:1396-1405

  3. Hillner BE, Ingle JN, Berenson JR, et al. American Society of Clinical Oncology Guideline on the role of bisphosphonates in breast cancer. J Clin Oncol 2000; 18:1378-1391

  4. Aebi S, Gelber S, Lang I, et al. Chemotherapy prolongs survival for isolated local or regional recurrence of breast cancer: the CALOR trial (chemotherapy as adjuvant for locally recurrent breast cancer; IBCSG 27-02, NSABP B-37, BIG 1-02). Cancer Treatment 2012: 24 suppl 3: abstract S3-3

3.0 Hepatitis B Screening & Prophylaxis in Breast Cancer

Published 23 November 2005

Recommendations

  • Patients known to be HBsAg positive should receive lamivudine prophylaxis 100mg/day starting the week before chemotherapy and continuing until 8 weeks after the chemotherapy finishes.
  • A Special Access Form must be completed for lamivudine to contribute to a patient's deductible. This is available at: PharmaCare.

  • Decisions regarding baseline screening for HBsAg carrier status should take into account the patient's risk factors and the marked regional variation in HBsAg carrier rates.
  • Patients with identifiable risk factors should be screened for HBsAg.  Screening is optional for patients from regions with low HBsAg prevalence and without known risk factors.
  • Screening and the use of lamivudine for hepatitis C is not recommended

Risk Factors for HBV

  1. Patients from endemic regions ¨CSoutheast Asia, China, Africa, and the Inuit
  2. Sexual activity ¨C accounts for 50% cases in USA (esp. promiscuity/prostitution)
  3. Percutaneous (IVDU, sharing razors/tooth brushes, tattoo, piercing, acupuncture
  4. Blood transfusion5. Organ transplantation

Of note, there is no clear risk factor in 20-30% cases (possible under-reporting) (1)

Prevalence of HBsAg Positivity in Various Regions of BC

Based on a prenatal screen in 1215 BC women aged 15-44 years old the age-standard HBsAg positivity rate (active carriers) was 1.4% (2).  This was similar to the crude 1.0% rate for BC and the Yukon for 1996-2000 detected by Canadian Blood Services.  Results from Nova Scotia were 0.1% and Barrie Ontario 0.3%.  There is a marked regional variation amongst the 35,000 carriers in BC(3).  The extrapolated carrier rates are:  Interior BC 0.1%, Northern BC 0.15%, Vancouver Island 0.19%, Fraser Region 0.65%, Vancouver Coastal 1.94%.

HBV Review:   HBV is a partially double stranded, hepatotropic DNA virus that replicates through an RNA template using the enzyme DNA polymerase (1).  Approximately 350 million people worldwide are infected.  Eight percent of the population of Southeast Asia, China, and Africa, and 10% of the population of Hong Kong are chronic carriers of the virus.  These patients are serum-positive for Hepatitis B surface Antigen, HBsAg.

Life Cycle:  When an adult is infected with the virus there is a 2-4 week incubation period during which the patient has no symptoms and liver enzymes are normal as the virus itself is usually not cytopathic.  Hepatic inflammation and elevated liver enzymes are secondary to the patient developing an immune response to antigens presented on infected hepatocytes in an attempt to eradicate the virus.  Over 95% of infected adults will clear the virus and become HBsAg negative and develop antibodies to HBsAg. If this is unsuccessful the patient will remain HBsAg positive and will be a chronic carrier of the virus.  However, in endemic parts of the world the majority of infections occur in the perinatal period (vertical transmission to the neonate).  Unlike adults, most neonates do not clear the infection and 95% become chronic asymptomatic carriers of HBV.

Antibodies/Antigens

HBsAg - HBV surface antigen; patient is actively infected
Antibody to HBsAg - develops when patient clears the virus
Antibody to HBcAg - antibody to HBV core antigen; remains positive in all patients who were exposed to the virus (whether they clear it or not).  Patients who were vaccinated against HBV are negative for antibodies to HBcAg but are positive for antibodies to HBsAg.
HBeAg - marker of active viral replication

Chemotherapy and HBV

Patients who are HBsAg positive can have a flare of hepatitis while on chemotherapy. This is usually defined as a ≥ 3x increase in ALT (or an absolute ALT over 100 u/L) compared to baseline levels with a ≥10x increase in HBV DNA level (or an absolute DNA level > one million copies/ml). The severity of the hepatitis is graded as mild (ALT ≤2x ULN), moderate (ALT 2-5x ULN), or severe (>5xULN) (4) Hepatitis flares while on chemotherapy may result in delays of chemotherapy administration, permanent discontinuation, and even fatalities. (5) It is estimated that over 20-40% of patients who are HBsAg positive will have an HBV flare while on chemotherapy. (4, 6, 7)

Risk Factors for HBV Flare in HBsAg Positive Patients on Chemotherapy(8)

Detectable HBV DNA OR(odds ratio) = 8.4; use of steroids (for antiemetics or in CHOP) OR = 2.7; Lymphoma OR 5.0; Breast cancer OR = 4.2.  Other series have suggested that male sex, HBeAg positivity, and pre-chemotherapy liver enzyme levels are risk factors.

Prevention of Flares

Lamivudine is a nucleoside analogue that interferes with HBV replication.   In patients with detectable HBV DNA, almost 100% will have a temporary clearance of the virus after 4-12 weeks of lamivudine therapy (1).  However, this results in a sustained remission in less than 20%.  Initial studies showed lamivudine prophylaxis to be effective at preventing flares in HBsAg positive lymphoma patients (9).  Lamivudine has also been used to successfully treat established HBV flares in patients on chemotherapy.  However, treatment with lamivudine once the patient has flared is not always successful, and fatalities have been reported (5). 

Lamivudine prophylaxis has been studied in breast cancer patients using case-control series from Hong Kong.  The largest series confined to HBsAg positive, breast cancer patients was reported in 2004(4) and involved 92 patients.  The lamivudine (case) group received prophylactic lamivudine 100mg/d starting the week before chemotherapy and continuing for 2 months after chemotherapy ended. The control group did not receive lamivudine prophylaxis. The majority of patients were treated in the adjuvant setting, received anthracycline chemotherapy, and also received steroids as part of the anti-emetic regimen.  In this series no deaths were reported.  Lamivudine prophylaxis reduced the number of HBV flares from 31.1% to 6.5%, and reduced the number of delays/premature terminations of chemotherapy from 21.3% to 3.2%.
 
A second report, using an identical study design from the same Hong Kong investigators (6) included 258 cancer patients of which 81 had breast cancer.  In this case-control series lamivudine reduced the number of HBV flares from 24.4% to 4.6%, and reduced the number of delays/premature terminations of chemotherapy from 14.5% to 0%.

From these two reports it appears that lamivudine prophylaxis reduces the number of HBV flares on chemotherapy from 30% to 5% (24-31% to 4¨C6%).  The number needed to treat to prevent one flare is between 4 and 5.  The number needed to treat to avoid 1 delay/disruption in chemotherapy is approximately 6 (5.5 ¨C 7.1).

Lamivudine

The prophylactic dose is 100mg/day starting the week before chemotherapy and is continued until 8 weeks after chemotherapy finishes.  Lamivudine is an expensive medication with 30 tablets costing approximately $145.  It is covered by most extended health plans, but not by basic MSP until a patient reaches their deductible.  A Special Access Form must be filled out so that the medication contributes to the patient' s deductible (see PharmaCare).

Hepatitis C

Hepatitis C is not associated with an appreciable risk for chemotherapy related flares. (10)  Lamivudine is not an effective method for suppression of hepatitis C. Thus, screening for hepatitis C, and the use of lamivudine are not recommended.

Recommendations

  • Patients known to be HBsAg positive should receive lamivudine prophylaxis 100mg/day starting the week before chemotherapy and continuing until 8 weeks after the chemotherapy finishes.
  • A Special Access Form must be completed for lamivudine to contribute to a patient's deductible. This is available at: Phar​maCare.

  • Decisions regarding baseline screening for HBsAg carrier status should take into account the patient's risk factors and the marked regional variation in HBsAg carrier rates.
  • Patients with identifiable risk factors should be screened for HBsAg.  Screening is optional for patients from regions with low HBsAg prevalence and without known risk factors.
  • Screening and the use of lamivudine for hepatitis C is not recommended

Refe​rences

  1. Lee WM. Hepatitis B virus infection. N Engl J Med 1997;337(24):1733-45.

  2. Dawar M, Patrick DM, Bigham M, Cook D, Krajden M, Ng H. Impact of universal preadolescent vaccination against hepatitis B on antenatal seroprevalence of hepatitis B markers in British Columbia women. Cmaj 2003;168(6):703-4.

  3. BC Centre for Disease Control:  2004 British Columbia Annual Summary of Reportable Diseases.

  4. Yeo W, Ho WM, Hui P, et al. Use of lamivudine to prevent hepatitis B virus reactivation during chemotherapy in breast cancer patients. Breast Cancer Res Treat 2004;88(3):209-15.

  5. Cainelli F, Longhi MS, Concia E, Vento S. Failure of lamivudine therapy for chemotherapy-induced reactivation of hepatitis B. Am J Gastroenterol 2001;96(5):1651-2.

  6. Yeo W, Chan PK, Ho WM, et al. Lamivudine for the prevention of hepatitis B virus reactivation in hepatitis B s-antigen seropositive cancer patients undergoing cytotoxic chemotherapy. J Clin Oncol 2004;22(5):927-34.

  7. Yeo W, Chan PK, Hui P, et al. Hepatitis B virus reactivation in breast cancer patients receiving cytotoxic chemotherapy: a prospective study. J Med Virol 2003;70(4):553-61.

  8. Yeo W, Zee B, Zhong S, et al. Comprehensive analysis of risk factors associating with Hepatitis  virus (HBV) reactivation in cancer patients undergoing cytotoxic chemotherapy. Br J Cancer 2004;90(7):1306-11.

  9. Shibolet O, Ilan Y, Gillis S, Hubert A, Shouval D, Safadi R. Lamivudine therapy for prevention of immunosuppressive-induced hepatitis B virus reactivation in hepatitis B surface antigen carriers. Blood 2002;100(2):391-6.

  10. Persico M, De Marino F, Russo GD, et al. Efficacy of lamivudine to prevent hepatitis reactivation in hepatitis B virus-infected patients treated for non-Hodgkin lymphoma. Blood 2002;99(2):724-5. 

5.0 Inflammatory Breast Cancer

​Updated: November 2004

Inflammatory breast cancer or T4d tumours present with rapid development of swelling, redness and peau d'orange (skin edema) which is often mistaken for an infection and treated with antibiotics before the correct diagnosis is made. A mass may be palpable or the breast may be diffusely involved. The mammogram may show a discrete mass, but often there is only diffuse increase in density and skin thickening. Although the diagnosis is primarily a clinical one, the distinctive pathological finding is the involvement of the dermal lymphatic vessels by tumour cells which results in the skin erythema and edema. A biopsy (either core or open)  to confirm the diagnosis should include skin for the examination of dermal lymphatics. More extensive surgery is not part of the initial management.

Inflammatory breast cancer is the most aggressive form of breast cancer with a median survival of 18 to 24 months, despite intensive combined modality treatment leading to a high initial response. Prompt initial referral to the BC Cancer Agency is suggested for these patients. Clinical trials are available and participation should be encouraged.

Inflammatory breast cancer should be managed like other inoperable locally advanced breast cancer (stage IIIB and C) (see Chemotherapy Protocols).

6.0 Phylloides Tumours of Breast (Cystosarcoma Phyloides)

​Updated: 25 August 2005

These uncommon sarcomas of the female breast arise from the stromal elements. Histologically they may be categorized to be benign or malignant. Adenocarcinoma may co-exist and therefore pathology review of these tumours is recommended. Wide local excision (at least 2 cm of histologically normal breast tissue margin and/or a clearly defined fascial boundary) is the treatment of choice for phylloides tumours. If the lesion is deep in the breast the excision must include fascia. Specimens should be inked so their margins can be assessed for involvement by tumour. A phylloides tumour should be suspected if a fibroadenoma is "recurrent." A pathology review at BCCA may be helpful. As lymph node metastases are rare, in the absence of adenocarcinoma elements, axillary node dissection is not recommended. Local recurrences may predict for development of metastases even in patients with "benign" disease. Metastases are generally to lung although bone and liver involvement may occur. Patients with more aggressive histology may be offered radiation therapy to improve local control rates. There is no known role for chemotherapy in the adjuvant setting.

7.0 Locoregional Recurrence

​Updated: November 2004

Locoregional recurrence may follow modified radical mastectomy or partial mastectomy, node dissection and irradiation therapy.

Locoregional recurrence following modified radical mastectomy carries a poor prognosis but some 15% of patients will be long term survivors after further locoregional therapy.

Recurrence in the breast following partial mastectomy is curable with much greater probability. The survival of patients under these circumstances is parallel to that of patients with new tumours of similar stage.

Tumours should be carefully assessed as some of these in breast 'recurrences' are not recurrences but new primary breast cancers which may require different treatment and may give a different prognosis. (i.e. the new tumour may be ER+ and the initial tumour ER-).

1) Locoregional Recurrence Following Modified Radical Mastectomy

These patients should have a biopsy to confirm recurrent disease and to assess estrogen receptor status.

A significant proportion of these patients will already have demonstrable metastatic disease and a full metastatic work-up should be performed. This should include a mammogram of the contralateral breast as well as a CBC, enzymes, bone scan and chest X-ray.

Surgery

If the recurrence is on a previously irradiated chest wall and is solitary, wide local excision may be advised. If the recurrence is in the axilla and the patient has not previously had an axillary node dissection then an axillary node dissection should be undertaken.

The patient may be referred to the BCCA for an opinion from the multi-disciplinary group at the Breast Conference.

Radiation Therapy

If the patient has not had previous radiation therapy then radiation should be given to the chest wall and the lymph node bearing areas with appropriate dose build-up at the site of the recurrence after it has been excised.

Chemotherapy

At present there is no defined role for chemotherapy under these circumstances, but it should be discussed in patients who have never received adjuvant systemic therapy and are otherwise well.

Hormone Therapy

Tamoxifen has been demonstrated to delay recurrence, but a statistically significant improvement in survival has not been demonstrated in randomized trials. If the initial tumour or the recurrent lesion is hormone receptor positive or unknown then an appropriate hormonal maneuver should be considered. This will usually be tamoxifen 20 mg po daily for five years or longer. An aromatase inhibitor is indicated if tamoxifen has been used.  For premenopausal women, as well as tamoxifen, there should be consideration of ovarian ablation by surgery or radiation therapy. Aromatase inhibitors have yet to be assessed in these specific circumstances. However, extrapolating from the metastatic setting, first line aromatase inhibitors are superior to tamoxifen in terms of time to disease progression and are therefore an appropriate first line option for post menopausal patients in this setting.

2) Local Recurrence After Previous Partial Mastectomy, Axillary Dissection and Radiation Therapy

Investigations

These patients should be fully investigated as above to search for the presence or absence of demonstrable metastatic disease, and for evidence of recurrence versus a new primary.

Surgery

Mastectomy is recommended for patients without demonstrable metastases. The cure rate will approach that of primary surgery on a similar lesion. The axilla will usually have been previously dissected so that a total mastectomy is the recommended procedure.

Radiation Therapy

If the recurrence is in the axilla or supraclavicular fossa and these lymph node areas have not previously been irradiated then radical radiation therapy should be offered to the axilla and supraclavicular node areas, with an appropriate blocking technique for the previously irradiated breast.

There will be some patients who initially refused or were not given radiation, but are prepared to accept it on recurrence. In these patients breast conservation is still possible and a repeat local excision can be carried out with radiation therapy.

Chemotherapy

The role of chemotherapy or hormonal therapy is not clearly defined. However, if the recurrence is in the axilla or if lymphatic, vascular or perineural invasion is identified, or if the invasive tumour is > 2 cms, any grade or >1 cm grade III, then adjuvant chemotherapy or hormone therapy may be considered, depending upon the patient's age, history of prior adjuvant treatment and estrogen receptor status. As yet, there are no data available to evaluate the benefit of systemic therapy in this setting. Referral to a medical oncologist is encouraged.

8.0 Stage I or II Tumours with Muscle, but Not Chest Wall, Fixation

​Updated: November 2004

Surgery

Fixation of the tumour to underlying muscle or fascia does not carry the same poor prognosis as had been previously thought. Presently it would seem appropriate that such patients, if they have otherwise operable disease, should be offered resection with an extension of the surgery to include the area of muscle involvement.

Radiation Therapy

Because of muscle involvement these patients should be offered postoperative radiation therapy.

Adjuvant Systemic Therapy

Adjuvant systemic therapy will be offered to those patients who are deemed to have risk factors for micrometastatic involvement (see Adjuvant Systemic Therapy).

9.0 Metastatic Breast Cancer

​Revised 04 January 2013

The BC Cancer Agency maintains current Chemotherapy Protocols.

1.0 GENERAL INFORMATION

1.1 BACKGROUND

The introduction of population based screening and adjuvant treatment are important contributors to declining breast cancer mortality rates observed in western countries over the last 4 decades (1). Despite these advances, metastatic breast cancer remains one of the leading causes of cancer related mortality in women. The majority of women with metastatic breast cancer have relapsed after curative-intent therapy for early breast cancer; a smaller proportion present with distant metastases at initial diagnosis. Breast cancer is distinctly uncommon in men, however treatment principles are similar to those described below.

1.2 PATTERNS OF SPREAD

Most patients with metastatic breast cancer have wide spread disease, with bone being the commonest site. Lung, liver, and soft tissue (nodes, skin) are also commonly involved. Parenchymal brain metastases are common during the course of metastatic her2+ breast cancer and triple negative (hormone receptor and her2 negative) breast cancers, less so among ER+ cancers. Lobular histology cancers frequently spread to the ovaries, peritoneal cavity, and pleura.

1.3 PROGNOSIS

Metastatic breast cancer is incurable with currently available therapies. The median survival is approximately 24 months. However, there is a wide range of survival, from several months in extreme cases, to 5 or more years. In general, patients with a long interval between early breast cancer diagnosis and metastatic relapse live longer than those with shorter disease free intervals. A small but significant fraction of patients achieves long-term disease control and survives more than 10 years. Survival patterns differ by type of breast cancer: patients with metastatic her2+ or metastatic ER+ cancers survive 4 to 5 years on average, while patients with metastatic ER-/her2- (triple negative cancers) typically survive a year or less.

2.0 MULTIDISCIPLINARY MANAGEMENT

2.1 ASSESMENT OF THE PATIENT

The initial investigation of a patient with metastatic disease should include:

  • Careful history with particular attention to symptoms, breast cancer history and prior treatments.
  • Complete physical examination and documentation of performance status.
  • Histological confirmation when possible and whenever the diagnosis is uncertain, with reassessment of ER/PR and HER2 status (up to 20% of cancers may change their ER,PR, and/or her2 expression at the time of metastatic recurrence, potentially opening up new treatment options).
  • Blood tests: CBC, liver and renal function, serum calcium and tumour markers CA15-3 and CEA
  • Imaging of symptomatic sites and assessment of the extent of disease; CT Chest/Abdomen, bone scan. Brain imaging in patients with neurological symptoms
  • PET-CT scan maybe helpful in patients when there is a high index of suspicion for metastatic disease but conventional imaging does not detect disease.

These are also useful for monitoring response to treatment and for identifying adverse disease progression and a need to change therapy.

2.2 MULTI-DISCIPLINARY APPROACH

The primary goal of treatment is to control cancer-related symptoms and to enhance survival where possible. The treatment of metastatic breast cancer requires a multidisciplinary approach (medical, radiation, surgical, specialists in pain and symptom management, and psychosocial support). Community home care and palliative support are important in later stages of the disease. There are a number of online websites which provide a range of resources, from chat lines to information and testimonials about particular treatments for breast cancer patients. Some useful links are listed below:

Patient Resources

BCCA Recommended Websites

Most improvements in survival and quality of life for patients with metastatic breast cancer have come from knowledge gained from successfully completed scientifically rigorous clinical trials. Patients should be given the opportunity to participate in clinical trials if available for their stage and type of breast cancer.

2.3 RADIATION

Metastatic breast cancer is moderately radiosensitive and worthwhile symptomatic relief can be expected from radiation to painful bony metastases. Radiation is commonly used in the treatment of:

  • Bony metastatic lesions
  • Cord compression in conjunction with steroids with or without surgical decompression
  • Symptomatic endobronchial lesions
  • Superior vena cava obstruction
  • Cerebral metastatic disease in conjunction with steroids with or without surgery.
  • Painful bulky soft tissue or ulcerating chest wall disease

2.4 SURGERY

There are a few well-defined indications for surgery. These include investigation of a solitary lesion which may be metastatic or a new primary disease, e.g., a solitary lung lesion; treatment of pathologic fracture; prophylactic instrumentation to prevent an impending fracture; surgical decompression for spinal cord compression and/or surgical stabilization of the spine with metal rods; and surgical resection of solitary and oligo brain metastasis. Radiation following surgical intervention to bone and brain is often indicated.

2.5 OTHER LOCAL THERAPY

  • Ascites: Patients developing symptomatic ascites may benefit from periodic therapeutic paracentesis.
  • Pleural Effusions: Symptomatic pleural effusions may be managed with thoracentesis, PleurX catheters, or pleurodesis.
  • Leptomeningeal disease is a poor prognostic sign, and is often a terminal event. However some patients achieve moderate duration of disease control with intrathecal methotrexate or ara-C. High dose iv methotrexate (link protocol) can also produce temporary relief of symptoms, as can craniospinal radiation in select cases.
  • Bowel Obstruction. Bowel obstruction resulting from peritoneal metastases from breast cancer is infrequently reversible. A trial of chemotherapy with TPN support may be indicated provided there are clear expectations about when futility will be declared and TPN will be withdrawn in the absence of resolution.
  • Uveal and periorbital soft tissue metastases. These are very uncommon in breast cancer and can be treated with radiation.

3.0 SYSTEMIC MANAGEMENT

The systemic management of invasive metastatic breast cancer is complex. At present, invasive breast cancer can be thought of as three broad entities that influence systemic treatment decisions: hormone receptor positive/Her2 negative cancers; Her2 positive cancers (regardless of hormone receptor status); and hormone receptor negative and Her2 negative (ie, triple marker negative) cancers. Within each of these entities, treatment recommendations are also influenced by patient age and comorbidities, personal preferences, extent of disease, and other histopathologic features of the cancer. For every patient, physicians must always weigh the benefits of treatment, particularly chemotherapy, against the potential risks of giving it.

3.1 HORMONE RECEPTOR POSITIVE BREAST CANCER

Hormonal therapy is generally the preferred initial treatment for hormone sensitive (ER and/or PR positive) disease which is

  • confined to non-visceral sites, or a low burden of visceral metastases (little/no organ dysfunction, low volume of the organ involved, minimal/no symptoms) and
  • Relatively indolent disease not likely to progress rapidly over the ensuing 3-4 months (e.g., one or two solitary pulmonary nodules or chest wall recurrence or skin involvement)

The choice of agent for optimal hormonal therapy in a given situation should reflect the best available evidence showing patient benefit, the likelihood of response and the associated side effects. One must also consider whether a patient is pre or postmenopausal, their co-morbidities and current performance status, what hormone therapies she was exposed to in the adjuvant setting, and whether the cancer relapsed on or sometime after they were discontinued. The probability of response is highest in patients with long disease-free interval predating relapse. Response to one hormonal agent often predicts for responses to other agents. Treatment with hormone therapy should be continued to progression unless there is significant toxicity.

Patients requiring chemotherapy as initial therapy for hormone receptor positive disease may benefit from the introduction of hormone therapy on completion of chemotherapy, as a means of maintaining longer remissions.

Hormonal therapy options in pre-menopausal women include:

  • Selective estrogen receptor modulator: BRAVTAM

  • Ovarian suppression with LHRH agonist, bilateral oophorectomy, or bilateral ovarian radiation
  • Ovarian suppression plus tamoxifen: BRAVLHRHT. Dual hormone inhibition may lead to longer survival than ovarian ablation alone (2,3).

  • Ovarian suppression plus an aromatase inhibitor is an option for premenopausal women who have a contraindication to tamoxifen, and for premenopausal women whose disease has progressed after tamoxifen. The combination of an LHRH agonist and an aromatase inhibitor requires a CAP approval.
  • Premenopausal women who have menopause induced may benefit from the same treatment options that are recommended for menopausal women.

Hormonal therapy options in post-menopausal women include:

  • Non-steroidal aromatase inhibitors: BRAVLET, BRAVANAS

  • Steroidal aromatase inhibitor: BRAVEXE

  • Steroidal AI plus everolimus: not presently funded by BCCA
  • Selective estrogen receptor modulator: BRAVTAM.

  • Selective estrogen receptor downregulator: fulvestrant: not presently funded by BCCA.
  • Occasional patients may still have hormone-sensitive disease after treatment with the above therapies and/or may have compelling reasons to avoid chemotherapy. In such cases older hormonal treatments such as megestrol (BRAVMEG) and testosterone enanthate (BRAVTEST) may provide some disease control.

Anastrozole and letrozole (BRAVLET, BRAVANAS) are generally the preferred first line hormone agent in menopausal metastatic breast cancer in patients who have not relapsed on either drug from the adjuvant setting. By inhibiting aromatase, they prevent peripheral conversion of androgens to estrogens, thus greatly reducing circulating estrogen levels in menopausal women. They have proven efficacy in both first and second line metastatic hormone receptor positive disease (4-6). They should not be used in sequence, as they have the same mechanism of action and very similar chemistry. A switch between letrozole and anastrozole can be considered if there are intolerable side effects, as sometimes there is a preference. They are not effective single agents in premenopausal women.

Tamoxifen (BRAVTAM) is a good first line choice in premenopausal women and in menopausal patients who have relapsed on an adjuvant aromatase inhibitor. It can also be used in second or third line if there was no prior tamoxifen use in the adjuvant setting, and in women with no relapse on or within one year of adjuvant Tamoxifen.

Exemestane (BRAVEXE) is an irreversible steroidal aromatase inactivator that has shown some activity after previous therapy with reversible aromatase inhibitors (7), and can be given as second line or third-line, provided the duration of disease control on anastrozole or letrozole is long enough to suggest possible continued hormone responsiveness of the cancer (generally at least 4-6 months). Combination of exemestane and everolimus after exposure to a non-steroidal AI results in longer disease control than exemestane alone, and may be an option for some patients (8). It is unclear at this time whether the addition of everolimus prolongs survival, however it does add some toxicity in the form of mucositis, diarrhea, and possible interstitial pneumonitis.

Fulvestrant is a pure anti-estrogen given by monthly intramuscular injection. It provides equivalent disease control to anastrozole in the first line setting and to exemestane after a non steroidal aromatase inhibitor (second line plus). It may be particularly effective in patients with no prior hormone therapy exposure (hormone therapy naive) (9,10).

Hormone Refractory Disease

At some point all hormone receptor positive cancers become unresponsive to hormone therapy and chemotherapy must be considered. As well, even among those cancers felt to retain hormone sensitivity, chemotherapy is generally preferred if the disease is locally-advanced (to achieve better local control), affects the function of visceral organs, or is causing the patient a high degree of symptoms. Chemotherapy is described under the “Hormone Receptor and Her2 Negative” section below.

3.2 HER2 POSITIVE BREAST CANCER

First line therapy

The standard of care first line therapy for metastatic her2+ disease, regardless of hormone receptor status, is anti-her2 therapy combined with chemotherapy (11). Anthracyclines should not be combined with trastuzumab due to synergistic cardiotoxicity. Unless patients are too frail or have prohibitive cardiac co-morbidity, a taxane combined with trastuzumab (BRAVTRAP, BRAVTRAD, BRAVTPCARB) should be the first choice of therapy (11-13). The chemotherapy drug(s) may be discontinued after 6-8 cycles to minimize cumulative toxicity, however trastuzumab should be continued (BRAVTR) until disease progression or prohibitive toxicity. Vinorelbine can be substituted for a taxane combination in patients who are frail due to disease, co-morbidity, or advanced age (BRAVTRVIN) (14). Some patients achieve a very long disease remission with first line therapy.

During the single agent trastuzumab phase, hormone therapy can be added if the cancer is hormone receptor positive.

All patients should have baseline left ventricular ejection fraction assessment with a MUGA scan or echocardiogram prior to initiating trastuzumab. There is no defined schedule for left ventricular ejection monitoring in the metastatic setting. Patients reporting symptoms or exhibiting signs of congestive cardiomyopathy should have anti-her2 therapy interrupted and cardiac assessment performed. Whether trastuzumab can be safely resumed later depends on the degree of recovery of cardiac function following discontinuation. Recommendations are further detailed in the BRAVTR protocol.

Relapse after adjuvant trastuzumab

A small fraction of patients receiving chemotherapy and trastuzumab for early breast cancer will experience a metastatic relapse. Patients relapsing 12 or more months after completion of adjuvant trastuzumab should be treated preferentially with chemotherapy / trastuzumab combination in first line, as described above. Patients relapsing on or within 6 months of completing trastuzumab may experience better disease control by substituting a different anti-her2 drug, such as lapatinib. It is unclear whether trastuzumab or lapatinib is better at controlling disease that recurs between 6 and 12 months after completing trastuzumab.

Concurrent ER+ disease:

Patients with hormone receptor positive and her2+ disease who refuse chemotherapy may experience a period of disease control with hormone therapy alone, although this is generally of shorter duration than with chemotherapy and trastuzumab, and of shorter duration than is seen in hormone receptor positive disease that is her2 negative (15). As such, it is not the preferred option. In extenuating circumstances where chemotherapy cannot be safely given, the combination of an aromatase inhibitor and lapatinib may provide longer disease control than an aromatase inhibitor alone (16). This requires CAP approval.

Second line therapy

At the time of disease progression, continuation of anti-her2 therapy and addition of chemotherapy is associated with the longest disease control and preservation of quality of life. Options include continuing trastuzumab or switching to lapatinib, and adding either vinorelbine or capecitabine (BRAVTRVIN, UBRAVTCAP, UBRAVLCAP) (14, 17, 18). Retreatment with a taxane/trastuzumab combination may be appropriate for patients who achieved a long period of disease control with initial treatment. After an appropriate period of combination therapy, the chemotherapy drug can be stopped to minimize toxicity, while the anti-her2 therapy is continued until disease progression.

Third line therapy and beyond

If available, continuation of anti-her2 therapy with chemotherapy in subsequent lines of therapy appears to be beneficial (19). At each time point that treatment change is required due to disease progression, consideration of whether or not to treat with further chemotherapy and which drug(s) to use must take into consideration the patient’s previous treatments, current performance status, extent of disease, likelihood of further disease control, and comorbidities. Options may include cytotoxic chemotherapy as described below, and hormonal therapy for the hormone receptor positive cancers.

Brain metastases

The majority (40-60%) of patients with metastatic her2 positive breast cancer develop brain metastases at some point in their disease course. One should maintain a low threshold for imaging the brain if a patient reports any neurologic symptoms, even if subtle. Oligometastases should be considered for surgical excision or radiotactic surgery followed by whole brain radiotherapy. Retreatment of progressive brain metastases with further radiation is sometimes feasible and beneficial, if the disease was controlled for an extended period (generally at least ten months) after initial radiotherapy. Several systemic drugs have some penetration into the blood brain barrier and may enhance control of brain metastases from breast cancer. These include capecitabine, lapatinib, anthracyclines, and cisplatin. While some other drugs have been used to treat primary brain tumors, their ability to control brain metastases of breast cancer origin has been disappointing.

Occasionally the brain may be the first and only apparent site of metastatic relapse. If isolated brain metastases occur during adjuvant therapy, they should be treated as described above and trastuzumab should be continued indefinitely as the chance of systemic metastases developing is high. If isolated brain metastases develop after completion of adjuvant trastuzumab, patients should be followed closely after treating them. Systemic treatment with chemotherapy and trastuzumab should be started at the time of eventual systemic metastases detection.

3.3 HORMONE RECEPTOR AND HER2 NEGATIVE (TRIPLE NEGATIVE) BREAST CANCER

Cytotoxic chemotherapy remains the standard of care for patients who have breast cancer that is negative for ER, PR, and Her2 expression. Patients with hormone receptor positive disease that is hormone refractory or who require chemotherapy, and patients with her2 positive disease that has progressed beyond available lines of anti-her2 therapy/chemotherapy combinations can be treated with chemotherapy using the same principles as for patients with triple negative disease.

There are several chemotherapeutic agents with activity against breast cancer, and choices should take into account the patient’s previous treatments, performance status, extent of disease, and other comorbidities. There is no single correct order for chemotherapy drug delivery. Unlike hormone therapy, chemotherapy has a narrow therapeutic index, requiring careful attention to toxicity. There should be a low threshold for dose modifications to minimize toxicity and patients should be advised to report side effects.

General indications for chemotherapy in MBC:

  • Rapidly progressive metastatic disease
  • Threatening metastatic disease e.g. involving the viscera, particularly the liver
  • Estrogen receptor negative primary tumours with symptomatic metastasis
  • hormone receptor positive tumors pretreated with and failing hormonal maneouvers.
  • Reasonable performance status (ECOG 0-2). Patients with ECOG-3-4 are unlikely to benefit and will very likely experience unacceptable toxicity

Response to chemotherapy should be evaluated after 2 or 3 cycles, and non-responding patients should have treatment changed. In responding patients, the optimal duration of therapy varies by drug and cumulative toxicity. In general, 6-8 cycles of therapy, or treatment for two cycles beyond best response affords optimal disease control. Longer therapy is an option for patients tolerating a drug well and without evidence of progression.

In general terms, anthracyclines, taxanes, and capecitabine should be considered for the first lines of therapy:

  • Anthracyclines: there is a maximum safe lifetime cumulative dose of anthracyclines beyond which the risk of cardiac toxicity is unacceptably high.
    • Single agent: BRAVA7

    • Combination: BRAVAC, BRAVCAF

  • Taxanes: the chief cumulative toxicity limiting therapy with taxanes is peripheral neuropathy.
    • Single agent: BRAVDOC, BRAVD7, BRAVTAX, BRAVT7, BRAVABR

    • Combination: BRAVDCAP, BRAVGEMD, BRAVGEMT

  • Capecitabine: palmar-plantar erythrodysesthesia is a cumulative toxicity which may limit duration of therapy or require dose modification over time.
    • Single agent: BRAVCAP

    • Combination: BRAVDCAP

Several chemotherapy combinations have shown modest gains in response rate and overall survival duration compared with single agent therapy, however generally combining several drugs results in increased toxicity (20-22). Combination chemotherapy should be considered in young fit patients and in patients in whom maximal disease shrinkage is optimal for symptom resolution.

Other/subsequent chemotherapy regimens include:

  • Gemcitabine: activity of gemcitabine is modest as a single agent. Results are better in combination.
    • Single agent: BRAVGEM

    • Combination: BRAVGEMP, BRAVGEMD, BRAVGEMT

  • Vinorelbine: BRAVNAV

  • Metronomic low-dose oral cyclophosphamide and methotrexate: BRAVCMPO

  • CMF regimens: BRAVCMFPO, BRAVCMF. Survival is better with the classic version of CMF (BRAVCMFPO) however toxicity is slightly better with the iv version (BRAVCMF)

Second and subsequent lines of therapy yield less rewarding results than first-line chemotherapy both in terms of degree and duration of tumour response. Toxicity can be greater due to prior therapy and more advanced disease state. The therapeutic gain is modest in many circumstances, but chemotherapy may relieve symptoms and therefore remains an important therapeutic tool. Chemotherapy can be safely and reasonably considered in patients with a performance status of 0-2, anticipated survival >3 months, and a previous response to at least one prior chemotherapy in metastatic disease.

3.4 TARGETED THERAPY

There is great interest in combining classic chemotherapy with target specific drugs. To date, targeting the ER receptor and the her2 receptor has resulted in the best survival and disease control benefit for metastatic breast cancer.

  • PARP inhibitors may have a particular role in cancers with BRCA1 or 2 mutations and are being explored in triple negative disease (23).
  • Targeting the EGFR and ER receptor simultaneously may result in longer disease control among cancers that are both ER and her2 positive, however this approach is not superior to the combination of anti-her2 therapy with chemotherapy (16).
  • Combining more than one anti-her2 therapy with chemotherapy in early treatment of metastatic her2+ disease appears to provide longer disease control (24)
  • The combination of mTOR inhibition and modulation of the ER target may restore or prolong hormone sensitivity in some ER+ cancers.
  • Although VEGF inhibition has enhanced the disease control achieved with chemotherapy for some metastatic cancers, the appropriate subtype of breast cancer to treat with this combination is not yet clear (25,26).

3.5 BONE MODIFYING AGENTS

Bone modifying drugs should be considered in women with metastatic breast cancer to bone, and/or presenting with hypercalcemia of malignancy. Patients should have necessary dental work done prior to initiating bone modifying agents to minimize the risk of osteonecrosis of the jaw.

Bisphosphonates have been shown to reduce the incidence of skeletal-related events in patients with metastatic breast cancer to bone. They reduce the rate and time to pathologic fracture, palliative radiation to bone, cord compression, and need for surgical intervention, however they have not been shown to increase survival however (27).

Oral clodronate (BRAVCLOD) and intravenous pamidronate (BRAVPAM) are funded by BCCA for bone metastases. For hypercalcemia, iv pamidronate is recommended, with zoledronic acid as a second line agent if hypercalcemia is resistant to pamidronate. Zoledronic acid and denosumab (a RANK-ligand inhibitor) are also active in slowing the development of skeletal related events (28, 29). The optimal duration of bisphosphonate therapy is not well defined (30), but the Breast Tumour Group recommends a treatment period of two to three years.

Acute pain syndrome

IV pamidronate 90-120 mg iv over 2-4 hours can also provide dramatic pain relief in cases of acute pain syndrome (31). It should be followed by appropriately dosed narcotic analgesics and treatment of underlying disease if possible. Repeat use of pamidronate may be considered if after 1 week there is clear but only partial relief of the pain despite aggressive analgesics.

4.0 REFERENCES:

  1. Chu KC, Tarone RE, Kessler LG, et al. Recent trends in US breast cancer incidence, survival, and mortality rates. J Natl Cancer Inst 1996;21:1571-1579

  2. Klijn JG, Beex LV, Mauriac L, et al. Combined treatment with buserelin and tamoixfen in premenopausal metastatic breast cancer: a randomized study. J Natl Cancer Inst 2000; 92(11):903-11

  3. Klijn JGM, Blamey RW, Boccardo F, et al. Combined Tamoxifen and Luteinizing Hormone-Releasing Hormone (LHRH) Agnosit versus LHRH Agonist alone in Premenopausal Advanced Breast Cacner: A Meta-Analysis of Four Randomized Trials. J Clin Onco 2001; 19 (2):343-53

  4. Nabholtz JM, Buzdar A, Pollak M, et al. Anastrozole is Superior to Tamoxifen as First-Line Therapy for Adavanced Breast Cancer in Postmenopausal Women: Results of a North American Multicenter Randomized Trial. J Clin Oncol 2000; 18:3758-3767

  5. Mourisden H, Gershanovich M, Sun Y, et al. Superior Efficacy of letrozole verus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 2001;19:2596-2606

  6. Paridaens RJ, Dirix LY, Beex LV et al. Phase III Study Comparing Exemestane With Tamoxifen As First-Line Hormonal Treatment of Metastatic Breast Cancer in Postmenopausal Women : The European Organisation of Research and Treatment of Cancer Breast Cancer Cooperative Group. J Clin Oncol 2008;26:1-8

  7. Lonning PE, Bajetta E, Murray R, et al. Activity of exemestane in metastatic breast cancer aftr failure of nonsteroidal aromatase inhibitors: A phase II trial. J Clin Oncol 2000; 18:2234-2244

  8. Baselga J, Campone M, Piccart M, et al. Everolimus in Postmenopausal Hormone-receptor-positive Advanced Breast Cancer. NEJM 2012;366:520-9

  9. Chia S, Gradishar W, Mauriac L, et al. Double-Blind, Randomized Placebo Controlled Trial of Fulvestrant Compared With Exemestane After Prior Nonsteroidal Armatase Inhibitor Therapy in Postmenopausal Women with Hormone receptor-Positive, Advanced Breast Cancer: Results From EFECT. J Clin Oncol 2008;26:1664-1670

  10. Robertson JFR, Llombart-Cussac A, Rolski J, et al. Activity of Fulvestrant 500mg versus Anastrozole 1mg as the first line treatment of Advanced Breast Cancer: Results from the FIRST trial. J Clin Oncol 2009;27: 4530-4535

  11. Slamon D, Leyland-Jones B, Shak S, et al. Use of Chemotherapy plus a Monoclonal Antibody for Metastatic Breast Cancer That Overexpresses HER2. NEJM 2001;344:783-92

  12. Marty M, cognetti F, Maraninchi D et al. Efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor recpetor 2 – positive metastatic breast cancer administered as first-line treatment: results of a randomized phase II trial by the M77001 study group. J Clin Oncol 2005;23:1-10

  13. Robert N, Leyland-Jones B, Asmar L, et al. Phase III comparative study of paclitaxel, trastuzumab and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 2006;24:2786-92

  14. Anderson M, Lidbink E, Bjerre K, et al. Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol 2011;29: 264-271

  15. Kaufman B, Mackey JR, Clemens M, et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast caner: results from the randomized phase III TAnDEM study. J Clin Onco 2009;27:5529-5537

  16. Johnston S, Pippen Jr J, Pivot X, et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol 2009;27:5538-5546

  17. von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer : a German Breast Group 26/Breast International Groups 03-05 study. J Clin Oncol 2009;27:1999-2006

  18. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355:2733-43

  19. Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 study. J Clin Oncol 2012;30:2585-92

  20. O’Shaughnessy J, Miles D, Vukekja S, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 2002;20:2812-2823

  21. Chan S, Romieu G, Huober J, et al. Phase III study of gemcitabine plus docetaxel compared with capecitabine plus docetaxel for anthracycline-pretreated patients with metastatic breast cancer. J Clin Oncol 2009;27:1753-1760

  22. Albain KS, Nag SM, Calderillo-Ruiz G, et al. Gemcitabine plus paclitaxel versus paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol 2006;25:3950-3957

  23. Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) plymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer : a proof of concept trial. The Lancet 2010;376:235-244

  24. Baselga J, Cortes J, Kim S, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012;366:109-19

  25. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007;357:2666-2676

  26. Miles DW, Chan A, Dirix LY, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor 2-negative metastatic breast cancer. J Clin Oncol 2010;28:3239-3247

  27. Pavlakis N, Schmidt RL, Stocker MR. Bisphosphonates for breast cancer. Cochrane Library online publication 16 Jul 2008

  28. Rosen LS, Gordon DH, Dugan Jr W, et al. Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 2004;100:36-43

  29. Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized double-blind study. J Clin Oncol 2010;28:5132-5139

  30. Van Poznak CH, Temin S, Yee GC, et al. American Society of Clinical Oncology Executive Summary of the Clinical Practice Guideline Update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol 2011;29:1221-7

  31. Portenoy RK, Lesage P. Management of cancer pain. The Lancet 1999;353:1695-1700

10. Breast Cancer in Pregnancy

Updated: November 2004

Since breast cancer is the most common tumour occurring in women during the reproductive years, carcinoma of the breast in pregnancy does occur and presents special management problems. It is, fortunately, relatively unusual and each case deserves consideration on its own merits. It is extremely important to assess the potential for cure in an individual patient. The welfare of the patient and the fetus needs to be evaluated. Diagnosis of breast cancer in pregnancy can be very difficult. New localized masses merit at least ultrasound examination and fine needle aspiration biopsy. For staging chest radiograph can be performed with abdominal and pelvic shielding.

1) Stage I or II

First Twelve Weeks

Definitive therapy of breast cancer during this phase of pregnancy may endanger the fetus and therefore a therapeutic abortion is usually recommended. The treatment of the malignancy will then proceed as in the non-pregnant state. Patients who decline termination should be treated by a modified radical mastectomy. No adjuvant radiation therapy should be given during pregnancy. Chemotherapy with AC chemo has been given in this situation, but is avoided if possible, unless the risks of withholding chemo outweighed the risks to the fetus. Referral is recommended to assess the need for further treatment after the baby has been delivered.

Twelve to Twenty-eight Weeks

During this interval the breast cancer can be adequately treated surgically without terminating pregnancy. Modified radical mastectomy is the treatment of choice. Adjuvant radiotherapy is contraindicated during pregnancy. The risk of recurrence should be estimated based on the pathology of the tumor. If the risk of relapse is high then adjuvant chemotherapy may be given.Cyclophosphamide and doxorubicin with or without 5-fluorouracil is the preferred combination during pregnancy. Epirubicin and taxanes should be avoided. Tamoxifen exposure in the first and second trimesters may be associated with genitourinary abnormalities and therefore should be avoided. Referral of these patients for assessment is recommended.

Twenty-eight Weeks to Term

Maturity of the fetus should be assessed. Consideration should be given to inducing labour as soon as obstetric advice indicates that the fetus is viable. Initial treatment by modified radical mastectomy is appropriate and as soon as the fetus has been delivered the patient should receive additional treatment as for the non-pregnant state. Chemotherapy may be given during pregnancy (see above)  but in most circumstances is delayed until after delivery.

Lactation

When a carcinoma arises during lactation, lactation should be terminated and therapy appropriate for the treatment of the malignancy instituted.

2) Locally Advanced or Inflammatory Breast Cancer

Patients with advanced disease pose a special problem. In the early weeks of pregnancy consideration has to be given to termination of the pregnancy. If the patient is in the second trimester and is still hoping to deliver a viable child then chemotherapy with drugs least likely to harm the fetus may be considered (see above). Referral to BCCA is recommended. Radiotherapy is contra-indicated except in exceptional circumstances.​

11. Cancer of the Male Breast

​Updated: November 2004

Cancer of the male breast is uncommon, about one percent of all breast cancers. Investigation of breast cancer in the male is identical to that of the female patient, including mammography as an initial investigation.

Because the male breast is very small, it is common for even small tumours to involve both skin and deep tissues with the result that the prognosis may be guarded. Surgery should be planned so that there will be wide margins on both the skin and deep tissues. This may require removal of some underlying muscle. Axillary dissection is also required and it is important to assess the hormone receptor status since most, but not all, carcinomas of the male breast contain hormone receptors.

Because of the small size of the male breast adjuvant radiotherapy is often recommended to reduce local recurrence. However the indications for post mastectomy radiation for males are essentially the same as those for females.

There are no series of male patients which have been adequately studied in regard to adjuvant systemic therapy. However, experience demonstrates that the clinical behaviour of male and female breast cancers are very similar. For the moment, adjuvant hormonal or chemotherapeutic recommendations are the same, stage-for-stage, as for a woman of the same age (see in situ disease). The role of aromatase inhibitors and fulvestrant in males has not been established. Orchiectomy or LHRH may provide a response after progression on tamoxifen in the metastatic setting.

12. Contraindications to Radiation Therapy

Updated: November 2004

Radiation Therapy may be relatively or absolutely contraindicated in the following circumstances:

  1. Significant pre-existing lung disease particularly where the diffusing capacity is reduced
  2. Pre-existing pulmonary tuberculosis
  3. Cardiomyopathy
  4. Connective tissue disorders (S.L.E., scleroderma, etc.) with significant vasculitis. The use of radiation may not be contraindicated with all connective tissue disorders. Referral to a radiation oncologist is advised.
  5. Prior radiation therapy to the same part.

In such situations partial mastectomy may therefore be inappropriate in that the radiation therapy may be precluded. With current anesthetic techniques a formal modified radical mastectomy with a therapeutic axillary dissection is usually tolerable and the treatment of choice for these patients.

13. Side Effects of Radiation Therapy

​Updated: November 2004

Side effects of radical radiation therapy are directly proportional to the volume of the irradiated tissues. Since radiation therapy (except whole body radiation) is essentially a localized treatment, the side effects depend also on the anatomic location irradiated.

The severity of side effects is directly related to the dose of radiation delivered and the time over which it is delivered.

  1. Skin - Mild to moderate erythema develops during the last days of treatment and will continue to progress for eight to ten days following treatment after which it will subside quickly. Moist desquamation may occur in the axilla or in the inframammary fold in large breasted women.

    If the reaction becomes uncomfortable the skin should be kept dry. It may be powdered with cornstarch and 0.5% hydrocortisone cream may be used over small areas where the reaction is particularly troublesome but without moist desquamation, e.g., the nipple.

    Read more about the care of radiation skin reactions.

  2. Esophagitis - If an en-face internal mammary field is used the esophagus is directly irradiated and esophagitis may develop during the third week but usually settles within two to three weeks of the completion of treatment. It is rarely troublesome unless there is a pre-existing hiatus hernia and in these patients cimetidine or a similar agent should be used. Symptomatic relief of the esophagitis in the absence of a hiatus hernia may be achieved by the use of acetaminophen or viscous local anaesthetics such as Xylocaine gel. These are rarely necessary.

  3. Lung - Some part of the lung is always included in the irradiated volume. It is least in the "breast only" tangent pair technique and is maximal when nodal areas are irradiated, particularly the apex of the lung. Late radiological changes of radiation fibrosis are common but symptomatic pneumonitis is uncommon. Patients with pre-existing pulmonary disease and who are symptomatic may need treatment with steroids (prednisone 30-50 mg daily for two weeks and then very slowly tapered over the next two weeks). In patients with a prior history of tuberculosis there is a possibility of reactivation and these patients should be seen in consultation by the physicians at the Willow Chest Clinic. Frequently prophylactic INH is advised.

  4. Heart - Symptomatic cardiac toxicity with these techniques is rare, but patients treated with regional radiation, especially the older techniques, have an increased risk of coronary artery disease.

  5. Fatigue - A variable amount of generalized tiredness may begin after the first one to two weeks of treatment and last for several months thereafter. The cause is not known. Getting adequate rest, reducing stress and having an afternoon "nap" are recommended.

All of the above reactions may be more severe if the patient is receiving chemotherapy especially Adriamycin. Patients who have received radiation therapy and subsequently need Adriamycin chemotherapy may have a "recall" of the radiation reaction.

14. Surgical Margins after Breast Conserving Surgery for Invasive Disease

Published: 10 July 2001

General Considerations

For most patients it is reasonable to try to achieve an ipsilateral breast tumour recurrence (IBTR) rate of <1% per year. The addition of a radiation boost to the tumour bed reduces the risk of IBTR. However, re-excision to obtain negative margins reduces IBTR more than using a radiation boost. The use of systemic therapy also reduces IBTR. For patients with a high systemic failure risk (for instance those with numerous positive axillary lymph nodes), it may be reasonable to accept a higher risk of IBTR. It may also be reasonable to accept a higher risk of IBTR in patients for whom further local breast surgery would result in an unacceptable cosmetic result, or where there is a strong desire to avoid a mastectomy, or if medical problems preclude surgery.

Guidelines for Re-excision and Radiation Boost following breast conserving surgery

  1. For patients with invasive disease, invasive or in situ disease at the margin will be treated in the same manner.
  2. The definition of a negative margin is tumour > 2 mm from an inked margin.
  3. A positive margin is defined as tumour touching ink.
  4. A close margin is anything in-between.
  5. Re-excision to obtain negative margins is recommended for patients with close or positive margins.
  6. If a margin is < 2 mm and re-excision is declined or inappropriate, a radiation boost to the tumour bed is recommended.
  7. Re-excision should be more strongly recommended where the risk of IBTR is high and systemic risk is low, for example:


    Margin < 2 mm and
    extensive intraductal component present
    age < 40
    lobular histology
    lymphatic invasion present
    no systemic therapy given
    margin close/positive at multiple sites
    Margin status unknown
    Tumour touching inked margin at any site

  8. When the deep margin is positive, and the surgeon has dissected down to fascia, then a boost should be given.

Patients with close or positive margins who decline re-excision should be advised that the risk of IBTR is increased. The relative risks/benefits of re-excision vs boost in the context of local control and cosmesis should be discussed.

Timing of Re-excision

Early consultation with a radiation oncologist is recommended if there is uncertainty about whether or not re-excision is recommended. This will facilitate a timely re-excision. Generally, re-excision should be carried out as part of the definitive surgery and prior to adjuvant systemic therapy and radiation.

Lobular Carcinoma In Situ

Lobular carcinoma in situ at the margins does not constitute a positive margin.

Pathology Reports

If a pathology report does not contain the necessary information to determine margin status, then a BCCA pathology review should be obtained. If, after this, it is still not possible to accurately determine the margins, then the margins should be treated as unknown in which case a re-excision (or radiation boost) is generally recommended.

15. Stage I and II Invasive Breast Cancer RT Section

Updated May 2013

Statement for the BC Cancer Agency’s Cancer Management Guidelines Management of Stage I and II invasive breast cancer (T1, T2; N0, N1; M0), RT section

Radiation Therapy following Breast Conserving Surgery (T1,T2;N0)

Patients treated with Breast Conserving Surgery (BCS; lumpectomy, partial or segmental mastectomy) for stage I or II breast cancer should have a consultation with a Radiation Oncologist regarding the role of radiation therapy (RT). If disease is within 2mm of or involves an inked surgical excision margin, then consideration should be given to a further breast excision.

RT to the breast following BCS reduces the risk of breast recurrence and lowers the risk of systemic recurrence and breast cancer death.(1-5) At 10 years after diagnosis, a 20% absolute reduction in the risk of breast recurrence (from 30% to 10%) translated into a 4-5% reduction in the chance of dying from breast cancer. RT should follow BCS unless contraindicated due to patient comorbidites, limited life span, the patient declining RT or in selected low recurrence risk situations (see below).

Timing of Adjuvant Radiotherapy:

  1. RT should optimally start once healing from the BCS is complete and generally within 10 weeks of BCS
  2. If post-operative problems occur, including hematoma, large seroma, infection, breast edema with erythema, or wound dehiscence occur, the start of RT may be delayed to allow resolution. In such cases or to accommodate patient convenience, there is no randomised trial evidence showing detriment to delay the start of RT until 16 weeks after BCS. Longer intervals may be associated with reduced RT efficacy and inferior local control.(6)
  3. If the patient receives adjuvant chemotherapy, then RT should follow the chemotherapy and start approximately four weeks after the last intravenous chemotherapy. Trastuzumab as a single agent may be delivered concurrently with radiation therapy. Adjuvant hormonal therapy may be commenced prior to or after RT.

Indications for supplemental boost dose of RT: (7-9)

  1. close or positive margins (less than or equal to 2 mm) post-BCS, without possibility of further excision
  2. age 50 years or younger, even if the margins are greater than 2 mm

Radiation Therapy Planning:

  1. Clinical Target Volume: Entire ipsilateral breast tissue. The lower axilla may be included if the patient has high risk features, particularly if an axillary node dissection has not been done.
  2. Dose:fractionation:
    1. Standard whole breast dose is 42.5 Gray (Gy) in 16 daily fractions
    2. Certain patients are at risk for inferior cosmetic outcome from the 16-fraction course.(10) Extended fractionation should be considered for patients with very large breast size, and those with significant post-operative induration, edema, erythema, hematoma or infection. Patients with these indications for extended fractionation should receive 45Gy in 25 daily fractions plus a boost dose of 10Gy in 5 fractions or 50.4 Gy in 28 daily fractions .
    3. If a boost is used, an additional dose of 6-16 Gy in 3-8 fractions is recommended.
  3. Technique: Ordinarily a tangential pair of fields to encompass the anatomic extent of the breast. Forward or inverse-planned IMRT (sometimes referred to as multi-leaf collimator (MLC) compensation) to improve dose homogeneity is recommended.
  4. Overall treatment time: Patients should be treated daily, Monday to Friday, for an interval of three to six weeks.
  5. Boost technique: The location of the boost may be guided by the presence of clips placed at the time of surgery or the post-operative seroma as contoured on the RT-planning CT scan. Boost may be treated with a direct electron field or conformal/mini-tangent photon fields.

Patients who might be spared radiation therapy after BCS

Radiation therapy consistently reduces the relative risk of local recurrence by 60-70%. Patients with a < 5% risk of local recurrence at 10 years are challenging to identify but might reasonably be considered for treatment with BCS alone. Women with all of the following factors likely have a 10 year risk of breast recurrence of 5% or less, especially if also prescribed adjuvant hormonal therapy: age >60 years, pN0, ER strongly positive, Grade 1 ductal carcinoma without lymphatic or vascular invasion and at least 5mm clear margins. Such women should be informed that RT will further decrease the risk of breast recurrence, but that the absolute benefit of RT on long-term survival is small.(11, 12)

The role of accelerated partial breast radiation therapy following BCS

Randomized trials of partial breast RT compared to whole breast RT have completed accrual but will not report cancer endpoints for several years. In the interim, the BCCA consensus is that:

  • Whole breast RT remains the standard local treatment following BCS.
  • Partial breast RT using 4-5 external 3-D conformal external beam RT may increase the risk of breast pain and induration at the primary site.
  • Where available, patients should be treated as part of a defined, clinical trial protocol.
  • Partial breast RT may be considered in particular circumstances, e.g. previous breast RT with refusal of mastectomy for local recurrence

Radiation therapy following mastectomy (T1,T2; N0)

Some patients treated with mastectomy with negative nodes may benefit from adjuvant therapy. Those with close or positive margins with 1-2 high risk features, i.e. grade 3 histology, lymphatic or vascular invasion, age<50 years, and T2 tumour size have a high risk of loco-regional recurrence and warrant a discussion of adjuvant radiotherapy.(13) Those with these high risk features should be referred for discussion of adjuvant radiation therapy with a radiation oncologist.

Radiation therapy following mastectomy or BCS (T1,T2; N1, and T3;N0)

Locoregional RT improves outcomes following mastectomy for patients with node-positive breast cancer or node-negative T3 breast cancer (increased 15 year overall survival by 10% p=0.015)(14-17). Subgroup analyses suggest this benefit is significant, even for patients with only a moderate risk (eg 1-3 nodes positive) of loco-regional recurrence)(18) . Regional RT also provides results in decreased risk of loco-regional recurrence and distant metastases and improved survival for patients with node-positive cancer.(5, 19)

Timing of Adjuvant Radiotherapy: Timing is as described above post BCS for node-negative patients

Radiation Therapy Planning:

  1. Clinical Target Volume: Entire chest wall or ipsilateral breast and regional nodes.


    The regional nodal volume should include the supraclavicular and level 3 axillary nodes medial to the coracoid process.The axillary contents lateral to the coracoid process should be included if fewer than 10 nodes were recovered, or if there are bulky or N2-3 disease or significant extranodal spread in the fat of the axilla.

    Inclusion of the internal mammary chain (IMC) node region is contraversial. Studies demonstrating a survival impact from regional RT consistently included the internal mammary lymph node region in the treatment volume,(14-16). Doing so increases the lung volume treated and for left-sided breast cancer, cardiac exposure. Treatment of the ipsilateral IMC nodal region including the first three inter-costal spaces should be considered when the supraclavicular or axillary nodes are to be treated.
  2. Dose:fractionation:
    1. Standard whole breast dose is 42.5 Gy in 16 daily fractions, chest wall dose is 40 Gy in 16 fractions, nodal dose is 37.5-40 Gy/16 fractions.
    2. Those at risk for increased toxicity post-BCS should be treated with the breast doses described above in the T1, T2, N0 section. Nodal dose should be 45 Gy/25 fractions.
    3. Those at risk for increased toxicity post-mastectomy, e.g. postoperative infection, and those undergoing reconstruction post-mastectomy should also be considered for extended fractionation. Patients with indications for extended fractionation post-mastectomy should receive 50.4 Gy in 28 daily fractions to the chest wall, and 45 Gy in 25 fractions to the nodal regions.
    4. For those with close or positive margins post-mastectomy, a higher chest wall dose (e.g. 42.5-44 Gy in 16 fractions) may be used, or a boost dose of 10Gy in 4 fractions or 16Gy in 8 fractions may be considered, if the anatomic area requiring the boost dose can be accurately delineated.
    5. For patients post-BCS with close or positive margins, or young age, supplemental boost is recommended as described above in the T1,T2 N0 Post BCS section.
  3. Technique: Ordinarily a mono-isocentric 4-field technique to encompass the anatomic extent of the breast/chest wall and regional nodes will be used. Forward or inverse-planned IMRT (sometimes referred to as multi-leaf collimator (MLC) compensation) to improve dose homogeneity is recommended. Specialized techniques, such as multi-field IMRT and Deep Inspiration Breath Hold techniques may be necessary to minimize dose to normal tissues in certain patients(20-22).
  4. Overall treatment time: Patients should be treated daily, Monday to Friday, for an interval of three to six weeks.
  5. Boost technique post-BCS: The location of the boost may be guided by the presence of clips placed at the time of surgery or the post-operative seroma as contoured on the RT-planning CT scan. Boost may be treated with a direct electron field or conformal/mini-tangent photon fields

References

1. Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans E, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet. 2005 Dec 17;366(9503):2087-106.

2. Fisher B, Bryant J, Dignam JJ, Wickerham DL, Mamounas EP, Fisher ER, et al. Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J Clin Oncol. 2002 Oct 15;20(20):4141-9.

3. Vinh-Hung V, Verschraegen C. Breast-conserving surgery with or without radiotherapy: Pooled-analysis for risks of ipsilateral breast tumor recurrence and mortality. J Natl Cancer Inst. 2004 Jan 21;96(2):115-21.

4. Veronesi U, Salvadori B, Luini A, Greco M, Saccozzi R, del Vecchio M, et al. Breast conservation is a safe method in patients with small cancer of the breast. long-term results of three randomised trials on 1,973 patients. Eur J Cancer. 1995 Sep;31A(10):1574-9.

5. Whelan TJ, Olivotto I, Ackerman I, Chapman JW, Chua B, Nabid A, et al. NCIC-CTG MA.20: An intergroup trial of regional nodal irradiation in early breast cancer. ASCO Meeting Abstracts. 2011 June 23;29(18_suppl):LBA1003.

6. Olivotto IA, Lesperance ML, Truong PT, Nichol A, Berrang T, Tyldesley S, et al. Intervals longer than 20 weeks from breast-conserving surgery to radiation therapy are associated with inferior outcome for women with early-stage breast cancer who are not receiving chemotherapy. J Clin Oncol. 2009 Jan 1;27(1):16-23.

7. Bartelink H, Horiot JC, Poortmans PM, Struikmans H, Van den Bogaert W, Fourquet A, et al. Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost versus no boost EORTC 22881-10882 trial. J Clin Oncol. 2007 Aug 1;25(22):3259-65.

8. Poortmans PM, Collette L, Horiot JC, Van den Bogaert WF, Fourquet A, Kuten A, et al. Impact of the boost dose of 10 gy versus 26 gy in patients with early stage breast cancer after a microscopically incomplete lumpectomy: 10-year results of the randomised EORTC boost trial. Radiother Oncol. 2009 Jan;90(1):80-5.

9. Romestaing P, Lehingue Y, Carrie C, Coquard R, Montbarbon X, Ardiet JM, et al. Role of a 10-gy boost in the conservative treatment of early breast cancer: Results of a randomized clinical trial in lyon, france. J Clin Oncol. 1997 Mar;15(3):963-8.

10. Olivotto IA, Weir LM, Kim-Sing C, Bajdik CD, Trevisan CH, Doll CM, et al. Late cosmetic results of short fractionation for breast conservation. Radiother Oncol. 1996 Oct;41(1):7-13.

11. Fyles AW, McCready DR, Manchul LA, Trudeau ME, Merante P, Pintilie M, et al. Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N Engl J Med. 2004 Sep 2;351(10):963-70.

12. Hughes KS, Schnaper LA, Berry D, Cirrincione C, McCormick B, Shank B, et al. Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med. 2004 Sep 2;351(10):971-7.

13. Truong PT, Olivotto IA, Speers CH, Wai ES, Berthelet E, Kader HA. A positive margin is not always an indication for radiotherapy after mastectomy in early breast cancer. Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):797-804.

14. Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. danish breast cancer cooperative group 82b trial. N Engl J Med. 1997 Oct 2;337(14):949-55.

15. Overgaard M, Jensen MB, Overgaard J, Hansen PS, Rose C, Andersson M, et al. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish breast cancer cooperative group DBCG 82c randomised trial. Lancet. 1999 May 15;353(9165):1641-8.

16. Ragaz J, Olivotto IA, Spinelli JJ, Phillips N, Jackson SM, Wilson KS, et al. Locoregional radiation therapy in patients with high-risk breast cancer receiving adjuvant chemotherapy: 20-year results of the british columbia randomized trial. J Natl Cancer Inst. 2005 Jan 19;97(2):116-26.

17. Truong PT, Olivotto IA, Kader HA, Panades M, Speers CH, Berthelet E. Selecting breast cancer patients with T1-T2 tumors and one to three positive axillary nodes at high postmastectomy locoregional recurrence risk for adjuvant radiotherapy. Int J Radiat Oncol Biol Phys. 2005 Apr 1;61(5):1337-47.

18. Overgaard M, Nielsen HM, Overgaard J. Is the benefit of postmastectomy irradiation limited to patients with four or more positive nodes, as recommended in international consensus reports? A subgroup analysis of the DBCG 82 b&c randomized trials. Radiother Oncol. 2007 Mar;82(3):247-53.

19. Whelan TJ, Julian J, Wright J, Jadad AR, Levine ML. Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis. J Clin Oncol. 2000 Mar;18(6):1220-9.

20. Beckham WA, Popescu CC, Patenaude VV, Wai ES, Olivotto IA. Is multibeam IMRT better than standard treatment for patients with left-sided breast cancer? International Journal of Radiation Oncology*Biology*Physics. 2007 11/1;69(3):918-24.

21. Wai ES, Wells DM, Bendorffe B, Beckham W, Popescu CC, McDonald RE, et al. Dosimetric benefit of deep inspiration breath hold (DIBH) and intensity modulated radiation therapy (IMRT) for women with left-sided breast cancer. Radiotherapy and Oncology. 2008 9;88, Supplement 1(0):S14.

22. Wai ES, Wells DM, Bendorffe B, Runkel J, Beckham WA, Popescu CC, et al. Phase II study of deep inspiration breath hold (DIBH) and intensity modulated radiation therapy (IMRT) treatment for women with left-sided breast cancer. Radiotherapy and Oncology. 2008 9;88, Supplement 1(0):S42.

A guide for people with advanced breast cancer

Published: 28 September 2005

Front cover 

 

Lymphedema

Updated: 27 August 2003

Definition

Lymphedema following treatment for breast cancer is caused by the interruption of axillary lymphatic drainage from the arm. To detect lymphedema, circumferential measurements of both extremities should be taken at the metacarpal-phalangeal joints, the wrists, 10 cm distal and 15 cm proximal to the lateral epicondyles. A difference of 2 cm or greater at any point is clinically significant.

Incidence

After axillary dissection alone, the risk of lymphedema has been reported to be 0 – 25% in different studies. The average rate without regional radiation was 3%. With axillary dissection plus regional radiation, the risk of lymphedema varied from 10 to 54%.  The average risk with regional radiation was 12%.  The addition of regional radiation, therefore, may increase the risk of arm swelling by 5 – 10%.

Lymphedema is likely to be permanent, transient lymphedema can develop in 7% of women. Most women who develop arm edema do so within 4 years of breast cancer treatment (1,2). (see References)

Recommendations

  • Treatment is most effective when physicians, physical therapists, nurses, massage therapists, and psychosocial counselors work together.
  • The early recognition of upper extremity lymphedema is essential because advanced lymphedema is more difficult to control (3). Limb girths should be monitored during follow-up visits.
  • Lymphedema treatment must begin with an assessment of severity and limb function. Tumour involvement of the axilla, infection or axillary vein thrombosis should be ruled out (4).
  • Avoidance of skin and soft tissue injury to the affected limb should be stressed (5).
  • Skin infections, which are usually streptococcal, should be promptly and aggressively treated with penicillin (6).
  • Elevation for early lymphedema may reduce swelling and can be used alone or as an adjunct to external compression and/or light massage (5).
  • Compression therapy, which includes graded compression garments and pneumatic compression pumps, is useful in controlling lymphedema and is currently the mainstay of lymphedema therapy in North America (5,8).
  • Complex Physical Therapy (CPT) or Complex Decongestive Physiotherapy (CDP), a comprehensive treatment regimen available in the US which includes meticulous skin hygiene, manual lymph drainage or treatment (MLD or MLT), bandaging, exercises, and support garments may offer some relief (4,9). MLD is available in Canada and may include bandaging and exercises after massage.
  • Pain and discomfort associated with lymphedema should be managed by controlling the lymphedema. Aggravating conditions, such as infection or axillary disease should be looked for and treated (10).
  • Exercise involving the affected upper extremity may be beneficial in controlling lymphedema (7). A compression sleeve is highly recommended for wear during exercise.
  • Maintenance of ideal body weight should be encouraged (2). Other than a weight reduction diet for obese patients, no nutritional or dietary restrictions are recommended for minimizing lymphedema.
  • Because of the psychological morbidity associated with lymphedema, psychosocial issues should be promptly recognized and addressed (11).
  • Surgery, apart from removing redundant skin folds after treatment, has had disappointing, inconsistent results and should be avoided (3).
  • Drugs, including diuretics and benzopyrones, should be avoided because of their toxicity profile and lack of benefit (12).
  • Other therapeutic modalities such as laser treatment, electrical stimulation, microwave and thermal therapy are based on clinical experience and have not been proven to be effective. These modalities need further study. Therapeutic ultrasound to potential metastatic sites is contraindicated because recent animal studies show it can enhance tumour growth (13). Diagnostic ultrasound is safe and can be an useful medical diagnostic tool.

Objective

To provide evidence-based guidelines for the management of lymphedema secondary to breast cancer treatments. The management of lymphedema in women with breast cancer is poorly addressed by practitioners. To identify the most effective treatment protocols, the Breast Tumour Group of the BC Cancer Agency recognized the need for practice guidelines.

Options

External compression, massage, elevation, exercise, psychosocial support, prompt treatment of infection, avoidance of factors which may aggravate lymphedema.

Outcomes

The outcomes considered were:

  • early detection of lymphedema to ensure more effective treatment
  • effective treatment of chronic lymphedema to improve the quality of life, ability to work, participate in leisure time activities, and perform activities of daily living

Evidence

To develop this guideline, a task force of the BC Cancer Agency, including physical therapists, women living with breast cancer, medical and surgical specialists, was set up by the Breast Tumour Group. After task force consensus was reached, the guidelines were sent for external review.

These guidelines are based on a review of published data and expert opinion from the Cancerlit and Medline databases 1966 -1997 and from recent breast cancer textbooks. Eighty-seven references were reviewed. The treatment guidelines are, whenever possible, evidence-based using Sackett's rules of evidence (14). The guidelines largely reflect case series evidence and often rely on consensus and common sense due to the paucity of clinical research in this area.

Values

The therapeutic nihilism associated with the treatment of lymphedema versus the multitude of empiric, costly and anecdotal remedies leave the health care provider and women living with lymphedema confused and frustrated. These guidelines attempt to address this confusion and try to provide the consumer and her health care provider with rational and potentially effective treatment for lymphedema.

Benefits, Harms and Costs

Safe reduction of lymphedema to restore and maintain function and cosmesis of the affected upper extremity are the primary benefits. Because of the lack of scientific evidence in this area, the time-honored 'Do No Harm' medical credo has been observed in developing these guidelines.

Treatment of lymphedema is costly for a woman and her health care insurers. The cost of a compression sleeve, which lasts about 6 months, is $60. Multiple treatments by a physical therapist to control the lymphedema are usually needed. A compression pump for home use costs well over $4000. Massage therapy (MLD) costs $60 a session and many sessions are required. CPT (complex physical therapy) costs about $7000 US for the recommended 4 week session. When infection occurs, intravenous antibiotics in an emergency department or hospitalization may be required. Early recognition of lymphedema and intervention may help to control some of these costs.

Validation

These guidelines were reviewed by clinical practitioners and by representatives of the College of Physician and Surgeons, the Registered Nurses Association of B.C., the College of Physical Therapists of B.C. and the B.C. Council on Clinical Practice Guidelines. The guidelines were then reviewed by the Breast Tumour Group at the B.C. Cancer Agency for final approval. These guidelines will be revised every two years to reflect new information.

Spo​nsors

This guideline was developed by a task force set up by the Breast Tumour Group of the BC Cancer Agency. The task force members included:
Sharon Allan (Medical Oncologist)
Carol Dingee (Breast Cancer Surgeon)
Faye Eddy (Physical Therapist)
Susan R.Harris, (Ph.D Physical Therapist, Task Force Co-editor and breast cancer survivor)
Brian Haylock (Radiation Oncologist)
Maria Hugi (Task Force Chair and Co-editor, Emergency Physician and breast cancer survivor with lymphedema)
Winkle Kwan (Radiation Oncologist)
Sherri Niesen (Physical Therapist and Ph.D. Candidate)
Cynthia Webster (Physical Therapist)

Refere​nces

  1. ​Kissin MW, Querci della Rovere G, Easton D et al. Risk of lymphedema following the treatment of breast cancer. Br J Surg 1986; 73: 580-584.
  2. Werner RS, McCormick B, Petrek J, et al. Arm edema in conservative management of breast cancer: obesity is a major predictive factor. Therapeutic Radiology 1991; 180 (1): 177-184.
  3. Petrek JA, Lerner R. Lymphedema. In Harris JR, Lippman ME, et al (eds): Diseases of the Breast, Lippincott-Raven, Philadelphia New York, 1996; 896-903
  4. Brennan MJ, DePompolo RW, Garden FH. Focused review: postmastectomy lymphedema. Arch Phys Med Rehab 1996; 77: S74-S79.
  5. Simon MS. Cellulitis after axillary lymph node dissection for carcinoma of the breast. Am J Med 1992; 93: 543-548.
  6. Consensus Document of the International Society of Lymphology Executive Committee. The diagnosis and treatment of peripheral lymphedema. Lymphology 1995; 28: 113-117.
  7. Kirshbaum M. The development, implementation and evaluation of guidelines for the management of breast cancer related lymphoedema. European Journal of Cancer Care 1996; 5: 246-251.
  8. Richmand DM, O'Donnell TF Jr, Zelikovski A. Sequential pneumatic compression for lymphedema: a controlled trial. Arch Surg 1985; 120: 1116-9.
  9. Casley-Smith JR. Modern treatment of lymphedema. Modern Medicine 1992; 35(5): 70-83.
  10. Brennan MJ. Incidence and sub-types of pain in lymphedema. Presented at the annual joint meeting of AAPM&R and ACRM. San Francisco, 1992.
  11. Tobin MB, Lacey HJ, Meyer L, Mortimer, PS. The psychological morbidity of breast cancer-related arm swelling. Cancer 1993; 72 (11): 3248-52.
  12. Minutes of the 178th (April 1995) Meeting of the Australian Drug Evaluation Committee. Sydney, Australia.
  13. Sicard-Rosenbaum L, Lord D, Danoff JV, et al. Effects of continuous therapeutic ultrasound on growth and metastasis of subcutaneous murine tumors. Physical Therapy 1995; 75 (1): 3/9-10/16.
  14. Sackett DL. Rules of evidence and clinical recommendations on the use of antithrombotic agents. Chest 1989; 95 (2) Supplement 2S-4S.

A complete report and list of references is available from the B.C.Cancer Agency through Dr. Karen Gelmon, Breast Tumour Group Chair, Vancouver Cancer Centre, 600 West 10th Ave., Vancouver, B.C., V5Z 4E6. Fax: (604)877-0585; e-mail: kgelmon@bccancer.bc.ca

* Because breast cancer occurs predominantly in women, the text addresses women, although the task force recognizes that breast cancer can also occur in men.​


Sentinel Node Biopsy (SNL)

​Updated: November 2004

Sentinel lymph node biopsy for breast cancer patients requires a multidisciplinary approach, coordinating the efforts of radiology, surgery and pathology divisions.  Appropriate training and skills development is mandatory.

In general, indications include women with T1 and T2, clinically N0 breast cancers.

Contraindications include patients with advanced breast cancer, multifocal cancers, previous disruptive breast procedures (surgery, radiation), palpable axillary nodes, adverse reactions to vital dyes.

All patients should undergo level 1 and level 2 axillary dissection if:

  1. the sentinel node(s) are reported positive for malignancy
  2. the surgeon is unable to identify a sentinel node or
  3. as part of the surgeon's training and validation process

 
Detailed guidelines  regarding appropriate patient selection.

Synoptic Report Form

(1 of 6)

In order to assist with optimal management of patients with breast cancer, the oncologists in British Columbia have requested the following information to be included in pathology reports. For the convenience of the reporting pathologist, the required information is presented in the form of a checklist. This information may be incorporated in the standard report format or may be listed in the form of a synoptic report.

Gross Assessment

SIDE : RIGHT/LEFT – (if bilateral please describe each side individually).

SPECIMEN TYPE: FNA, NEEDLE CORE BIOPSY, SURGICAL BIOPSY (incisional/excisional), WIDE EXCISION/PARTIAL MASTECTOMY, TOTAL MASTECTOMY +/- axillary dissection

MEASUREMENT OF SPECIMEN:

PRESENCE OR ABSENCE OF TUMOR:

NUMBER OF TUMORS: solitary/ multiple

SIZE OF TUMOR: please measure in 3 dimensions.

GROSS RELATIONSHIP OF TUMOR TO MARGINS: measurement to closest margin

GROSS INVOLVEMENT OF SKIN OR SKELETAL MUSCLE

Histological Assessment

HISTOLOGICAL DIAGNOSIS: state any specific type of carcinoma.

SIZE: check if greater than gross estimate; use a micrometer if possible.

GRADE: note - see below

LYMPHATIC INVASION OUTSIDE THE TUMOR: YES / NO

VENOUS INVASION: YES / NO

NEURAL INVASION: note - see below

MARGINS (Invasive ca.):
- STATE DISTANCE OF CLOSEST MARGIN

- STATE WHICH MARGIN, IF POSSIBLE SKELETAL MUSCLE:

STATE IF INVADED SKIN:
- ULCERATION
- DERMAL INVASION
- DERMAL LYMPHATIC INVASIONNIPPLE:
- PAGET'S DISEASE
- STROMAL INVASION

ESTROGEN RECEPTOR STATUS: (see below)

INTRADUCTAL COMPONENT: PRESENT/ABSENT
- PATTERN OF DCIS (Type)
- GRADE OF DCIS
- EIC PATTERN : YES/NO (see below)
-FOR DCIS ALONE, MEASUREMENT OF SIZE IS IMPORTANT
-MARGIN STATUS: measure distance of DCIS to closest margin

CALCIFICATION IN THE TUMOR (or DCIS): YES/NO

LYMPH NODES: TOTAL NUMBER

  NUMBER POSITIVE FOR ​METASTASES 
  SIZE OF BIGGEST METASTASIS 
  EXTRANODAL EXTENSION - measure distance from capsule  

 

HANDLING OF SPECIMENS

All specimens should be measured and margins inked. All wire-guided biopsies and wide excisions short of complete mastectomy should be processed in entirety.

Label all blocks separately and designate each block as to site in the gross description.(e.g. Block A = Nipple; B-E = Tumour; F = deep margin etc.). Blocks from wire-guided biopsies and wide excisions should be taken sequentially so the size of the DCIS component can be assessed.

Margin status:- State how the block is taken in relation to the margin. Usually blocks are taken perpendicular to the margin but if taken "en face" this must be recorded in the dictation or on a specimen diagram.

Submit all lymph nodes and state the number included in each cassette. In general the entire node should be processed.

Frozen sections should be avoided if possible - especially on lesions, which measure <1cm. in diameter.​

Synoptic Report Form (2 of 6)

Grading system for invasive carcinoma of the breast

General Guidelines:

  1. The system is applicable to all invasive carcinomas.   
  2. Special subtypes of breast carcinoma (lobular, tubulolobular, tubular, papillary, mucinous, cribriform, medullary, adenoid cystic, sarcomatoid (metaplastic), squamous, adenosquamous) should be noted separately but should also be assigned an overall grade. Strict criteria should be used to recognise these special types of breast cancer which have prognostic significance (Ellis 1992; Tavassoli 1992; Rosen 1993).   
  3. Since the term "differentiation" used in the context of breast carcinoma is an ambiguous term, it is recommended that grades 1,2 or 3 be used instead of, or at least in addition to, the terms "well, moderately, or poorly differentiated".   
  4. Grading cannot be performed adequately on material that has been frozen for the purposes of "frozen section" or "quick section". Well-fixed, well-cut, and optimally stained H&E sections are essential.   
  5. The Nottingham modification of the Bloom and Richardson method of grading is used most widely and is recommended for the BCCA. The system described below incorporates modifications suggested by Elston, Contesso, and Helpap. The three separate parameters are scored independently as follows :-

(I) NUCLEAR GRADE

Nuclear score 1: Nuclei are small to medium-sized, relatively uniform in size and shape, and lacking clumped chromatin or prominent nucleoli. Nuclei may have small, inconspicuous nucleoli. Uniformity of size and shape are the most important features.
Nuclear score 2: Nuclei are medium to large in size but exhibit only moderate variability in size, shape and intensity and pattern of staining. Nucleoli may be quite prominent as long as the nuclei are relatively monotonous in appearance. Nucleoli with irregular outlines, giant or "macronucleoli" are absent. Bizarre giant cells are absent.
Nuclear score 3: Nuclei are large and vesicular and/or contain coarse clumps of chromatin. There is considerable variation in the size and shape of nuclei. Typically, nucleoli are very large, often multiple and may have irregular outlines. Giant nuclei, polylobated nuclei and multinucleate tumour giant cells may be present. Karyorrhexis, karyolysis and pyknosis of nuclei are often encountered.

Note: The above descriptions are given as guidelines, which may be supplemented by study of illustrations of the different nuclear grades in the references, cited below. Furthermore, since there is a morphological continuum in the nuclear appearance in breast carcinomas, the extremes of the spectrum are easily recognised but, in some cases, the scoring of nuclei is to some extent subjective and differences of interpretation between pathologists are to be expected. It must be stressed that it is impossible to assign a nuclear score based on the frozen section or post-frozen paraffin embedded material.

(II) TUBULE FORMATION.

The assessment of tubular differentiation or tubule formation applies to the neoplasm overall and requires examination of several sections at scanning magnification. A reliable tubular score cannot be assigned when only needle biopsies or small pieces of the tumour are examined.

Tubule score 1: >75% of the neoplasm is composed of tubular structures with visible lumina. Solid trabeculae, vacuolated single cells, alveolar nests and solid sheets of cells comprise less than 25% of the tumour.
Tubule score 2: 10-75% of the tumour has a tubular pattern.
Tubule score 3: <10% tubule formation.

(III) MITOSIS SCORE

The mitosis score is assessed in the peripheral areas of the neoplasm and not the sclerotic central zone. The neoplasm is scanned at intermediate magnification to determine the area in which mitoses are most abundant (usually areas of poor tubule formation where cells are arranged in sheets or large nests). Only definite mitotic figures are counted with care to avoid including pyknotic nuclei in the count. Although the Nottingham grading system uses a scoring system based on the number of mitoses per 10HPF's, the Oncologic Standards Committee considers that a mitotic count per square millimetre is most accurate. Mitoses are only counted in the invasive component of the lesion.
Score 1: <4 mitoses per square mm.
Score 2: 4-7 mitoses per square mm.
Score 3: >7 mitoses per square mm.

Alternatively the number of mitoses in 10 high power fields (HPFs) is counted. Using a Nikon Labophot microscope with a 40X objective lens (i.e. X400) and a field surface area of 0.152mm2, the scores are as follows:
Score 1 : 0-5 mitoses
Score 2 : 6-10 mitoses
Score 3 : >10 mitoses

In practice, Contesso's method of scoring of mitoses is quicker and easier to perform especially on small biopsies (e.g. Core biopsies). At least 20HPF's of the same area as stated above are assessed and scored as follows:
Score 1: No field contains more than 1 mitosis.
Score 2: Two mitoses present in any one HPF.
Score 3: Three or more mitoses present in any one HPF.

COMPOSITE SCORE

The scores for the three separate parameters (tubules, nuclei and mitoses) are summated and the overall grade of the neoplasm is determined as follows:
Grade 1: 3-5 points.
Grade 2: 6-7 points.
Grade 3: 8 or 9 points.

Synoptic Report Form (3 of 6)

Grading of ductal carcinoma in situ (DCIS)

The following patterns of DCIS are recognised:

  1. Cribriform   
  2. Micropapillary - papillary structures lack fibrovascular cores.   
  3. Papillary - fibrovascular cores present within papillary structures.   
  4. Solid   
  5. Comedocarcinoma - defined as DCIS with extensive central necrosis (>2/3 the diameter of the duct). The latest consensus committee abandoned the requirement for high nuclear grade in combination with necrosis.   
  6. Others: ​
    • ​Clinging carc​inoma - not now recognised in the latest consensus statement but everyone knows that it exists
    • Apocrine DCIS
    • Signet ring cell DCIS
    • Low-grade endocrine DCIS

Grading of DCIS

Low Grade (Grade 1): Grade 1 nuclei and no necrosis.

Intermediate grade (Grade 2):

Grade 1 with associated necrosis.
Grade 2 nuclei without necrosis.
Grade 2 nuclei with necrosis but very few mitoses.

High grade (Grade 3):

Nuclear grade 2 with numerous mitoses and extensive necrosis.
Grade 3 nuclei with or without necrosis.
Signet-ring cell carcinoma in situ.
Comedocarcinoma in-situ with grade 2 or 3 nuclei.

Quantitation :- A rough estimate of the volume of DCIS relative to the overall tumour should be given as a percentage. "Extensive intraduct component (EIC)" is used to qualify invasive carcinomas with DCIS, which may take two forms as follows:

Prominent DCIS with in the invasive tumour mass (comprising 25% or more of the volume) AND  DCIS in adjacent breast ducts and/or lobules extending clearly beyond the boundaries of the invasive carcinoma.   
Widespread DCIS with microscopic stromal invasion is also placed in the EIC category.

This assessment is important because EIC carcinomas treated with breast conservation have a higher risk of local recurrence within the breast unless the margins are well clear (Schnitt 1984).

LOBULAR CARCINOMA

In general, it is possible to grade lobular carcinoma. Usually, classical lobular carcinoma will attain a total score of 5 (tubules 3; nuclei 1; mitoses 1) giving the tumour an overall grade 1. Although some of the data are somewhat inconclusive, histological variants of lobular carcinoma are thought to differ in their degree of aggressiveness as follows:

Good Prognosis (Grade 1):- Tubulolobular carcinoma. This variant features tubular structures that are lined by very uniform small cells resembling those of classical lobular carcinoma. Single-file strands of identical cells are also present. Some authorities would regard this variant as a ductal carcinoma (tubular type).
Fairly good Prognosis (Grade 1): (marginally better than that of ductal carcinoma NOS.) Classical lobular carcinoma.

Criteria include:

Small uniform cells; grade 1 nuclei
Single-file rows in a fibrous stroma.
Targetoid (concentric, "bull's-eye") pattern around pre-existing ducts.
Intermediate prognosis (Grade 2): Classical pattern with Grade 2 nuclei.
Alveolar variant - round and oval nests of uniform small cells.
Large cell variant
Mixed patterns of lobular carcinoma.
Poor prognosis patterns (Grade 3): Solid variant - large sheets of uniform small cells with round nuclei.
Pleomorphic lobular carcinoma - pattern resembles classical lobular carcinoma but the nuclei are grade 2-3, mitoses are easily identified, apocrine change is common, and ER is negative.
Signet-ring cell variant (>20% of cells should be signet-ring type)

Synoptic Report Form (4 of 6)

​ LYMPHATIC INVASION

Only invasion of lymphatics beyond the advancing edge of the tumour is important.

If in doubt call it negative.

Please state if there is extensive lymphatic/vascular invasion (>10 lymphatics involved).

VENOUS INVASION

Large calibre, thick-walled blood vessels containing tumour emboli either within the tumour in the surrounding tissue are included.

NEURAL INVASION

Only nerves with tumour cells within the perineurium are scored positive.

Non-invaded nerves entrapped within or surrounded by tumour are disregarded.

Only medium sized or large nerves sited at the advancing edge or outside of the tumour are important. Neural invasion has been shown not to be of prognostic significance in most studies. This is confirmed in a recent analysis of the BCCA data.

EXTRANODAL EXTENSION

Tumour cells must be outside the nodal capsule.

Please state if "minimal" extranodal spread (<1mm from capsule) or extensive infiltration of perinodal tissues with "matting" of nodes.

ESTROGEN RECEPTORS

Please select a block containing invasive carcinoma and normal breast tissue if possible.

Immunostains are graded subjectively on a scale 0-3+

0​​ Negative nuclear staining; positive internal control staining.
1+ >10% nuclei weakly positive.
2+ Intermediate staining intensity
3+ >70% nuclei strongly positive


DCIS is not submitted for immunostaining​

Synoptic Report Form (5 of 6)

​Pathological TNM Stage

TUMOR

pTXunable to assess size
pT1-mic<0.1 mm microinvasive
pT1aTumour diameter <5mm
pT1b6-10mm
pT1c11-20mm
pT221-50mm
pT3>50mm
pT4Extension of tumour (any size) to skin and/or chest wall (excluding pec. major muscle)


NODES

pNXNODAL STATUS UNKNOWN
pN0NEGATIVE NODES
pN1METASTASIS TO IPSILATERAL AXILLARY NODES - NOT MATTED
  ​N1a​​mi​crometastases <2mm diameter
  N1bmetastases >2mm diameter
    N1bi1-3 positive nodes
    N1bii4 or more positive nodes
    N1biiiextracapsular extension of tumour
    N1bivany nodal metastases >20mm diameter
pN2​IPSILATERAL NODE METASTASES MATTED
pN3IPSILATERAL INTERNAL MAMMARY METASTASES


DISTANT METASTASES

pMX​UNKNOWN STATUS
pM0NO DISTANT METASTASES
pM1DISTANT METASTASES PRESENT -INCLUDES SUPRACLAVICULAR LYMPH NODE METASTASES

Synoptic Report Form (6 of 6)

References

Processing, Reporting and Special Histological Types including Prognostic Factors

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  44. Bozzetti C, et al. Bcl-2 expression on fine needle aspirates from primary breast carcinoma: correlation with other biologic factors. Cancer 1999;87:224-230. 

  45. Holmqvist P, et al. Apoptosis and Bcl-2 expression in relation to age, tumour characteristics and prognosis in breast cancer. South-East Sweden Breast Cancer Group. Int J Biol Markers. 1999;14:84-91. 

  46. Carey LA, et al. Telomerase activity and prognosis in primary breast cancers. J Clin Oncol 1999;17:3075-3081. 

  47. Harbeck N, et al. Risk-group discrimination in node-negative breast cancer using invasion and proliferation markers: 6-year median follow-up. Brit J Cancer 1998;80:419-426 and Breast Cancer Res Treat 1999;54:147-157. 

  48. Jahkola T, et al. Cathepsin-D, urokinase plasminogen activator and type-1 plasminogen activator inhibitor in early breast cancer: an immunohistochemical study of prognostic value and relations to tenascin-C and other factors. Brit J Cancer 1999;80:167-174. 

  49. Soler AP, et al. P-cadherin expression in breast carcinoma indicates poor survival. Cancer 19999;86:1263-1272. 

  50. Tan DSP, et al. The biological and prognostic significance of cell polarity and E-cadherin in Grade I infiltrating ductal carcinoma of the breast. J Pathol 1999;189:20-27. 

  51. Gonzalez MA, et al. An immunohistochemical examination of the expression of E-cadherin, alpha- and beta/gamma- catenins and alpha2- and beta1- integrins in invasive breast cancer. J Pathol 1999;187:523-529. 

  52. Allred DC, et al. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 1998;11:155-168. 

  53. Jager JJ, et al. Loco-regional recurrences after mastectomy in breast cancer: prognostic factors and implications for postoperative irradiation. Radiotherapy and Oncology 1999;50:267-275.

Lobular carcinoma

  1. Dixon JM, et al. Infiltrating lobular carcinoma of the breast. Histopathology 1982;6:149-161. 

  2. DiCostanzo D et al. Prognosis of infiltrating lobular carcinoma. An analysis of "classical" and variant tumors. Am J Surg Pathol 1990;14:12-23. 

  3. Fechner RE. Histological variants of infiltrating lobular carcinoma of the breast. Hum Pathol 1975;6:373-378. 

  4. Fisher ER, et al. Tubulolobular invasive breast cancer: a variant of lobular invasive cancer. Hum Pathol 1977;8:679-683. 

  5. Weidner N, Semple JP. Pleomorphic variant of invasive lobular carcinoma of the breast. Hum Pathol 1992;23:1167-1171. 

  6. Eusebi V, et al. Pleomorphic lobular carcinoma of the breast: An aggressive tumour showing apocrine differentiation. Hum Pathol 1992;23:655-662. 

  7. Frost AR. The significance of signet-ring cells in infiltrating lobular carcinoma of the breast. Arch Pathol Lab Med 1995;119:64-68. 

  8. DCIS Grading 

  9. Schnitt SJ, et al. Developing a Prognostic index for ductal carcinoma in situ of the breast. Are we there yet? Cancer 1996;77:2189-2192. 

  10. Silverstein MJ, et al. A prognostic index for ductal carcinoma in situ of the breast. Cancer 1996;77:2267-2274. 

  11. Silverstein MJ, et al. Prognostic classification of breast ductal carcinoma in situ. Lancet 1995;345:1154-1157. 

  12. Fisher ER, et al. Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) protocol B-17. Intraductal carcinoma (ductal carcinoma in situ). Cancer 1995;75:1310-1319. 

  13. Holland R, et al. Microcalcification associated with ductal carcinoma in situ: mammographic-pathologic correlation. Semin Diagn Pathol 1994;11:181-192 

  14. Holland R, et al. Ductal carcinoma in situ: a proposal for a new classification. Semin Diagn Pathol 1994;11:167-180. 

  15. Leal CB, et al. Ductal carcinoma in situ of the breast; histological categorization and its relationship to ploidy, and immunohistochemical expression of hormone receptors, p54, and c-erbB-2 protein. Cancer 1995;75:2123-2131. 

  16. Sneige N, et al. Ductal carcinoma in situ treated with lumpectomy and irradiation: histopathological analysis of 49 specimens with emphasis on risk factors and long term results. Hum Pathol 1995;26:642-649. 

  17. Douglas-Jones AG, et al. A critical appraisal of six modern classifications od ductal carcinoma in situ of the breast (DCIS): correlation with grade of associated invasive carcinoma. Histopathology 1996;29:397-409. 

  18. Consensus conference on the classification of ductal carcinoma in situ. Human Pathology 1997;28:1221-1225.

Estrogen Receptors

  1. Pertschuk LP, et al. Immunocytochemical estrogen and progestin receptor assays in breast cancer with monoclonal antibodies. Histopathologic, demographic and biochemical correlations and relationship to endocrine response and survival. Cancer 1990;66:1633-1670. 

  2. Pertschuk LP, et al. Estrogen receptor immunocytochemistry in paraffin embedded tissues with ER1D5 predicts breast cancer endocrine response more accurately than H222Spgamma in frozen sections or cytosol-based ligand assays. Cancer 1996;77:2514-2519. 

  3. Andersen J, et al. Immunohistochemical estrogen receptor determination in paraffin-embedded tissue. Prediction of response to hormone treatment in advanced breast cancer. Cancer 1989;64:1901-1908. 

  4. Goulding H, et al. A new immunohistochemical antibody for the assessmnet of estrogen receptor status on routine formalin-fixed tissue samples. Human Pathol 1995;26:291-294.

7. Follow-up


Revised 18 January 2013

1) Follow Up of Early Breast Cancer

The follow up of patients who have been treated with curative intent for early breast cancer has four main goals:

  1. Detection of breast cancer recurrence
  2. Screening for a new breast cancer
  3. Enhancing adherence to hormone therapy (if applicable)
  4. Monitoring for and treating late or residual side effects of therapy

2) Second Cancers

In addition to the recognized increase in risk of developing a carcinoma of the contralateral breast, patients who have had breast cancer have a statistical increase in their risk of developing carcinoma of the colon, carcinoma of the endometrium and carcinoma of the ovary. The family physician should be aware of these possibilities in the follow up of patients with breast cancer.

3) Contraception

If permanent contraception is desired by the patient and her husband, then tubal ligation should be considered. For patients who are not yet ready to contemplate sterilization, a non-hormonal procedure such as barrier techniques or an IUD should be recommended.

7.1 Detecting Recurrences

Revised 18 January 18 2013

1A Detecting Recurrences

Patients should be seen by a physician every 3-6 months for the first 2 years from diagnosis, then every 6 months until 5 years, then annually for a careful history and physical examination including the nodal regions of the head, neck and axilla; breast/chest wall exam; heart, lung, and abdominal examination.1 Patients are encouraged to seek medical attention between scheduled visits if they develop unexplained and new symptoms. In the absence of concerning signs or symptoms, no lab or imaging tests are recommended to monitor for recurrence. Detection of asymptomatic metastases by periodic scheduled investigations has not been shown to increase survival or quality of life.2 Instead, clinicians should maintain a low threshold for promptly investigating any new concerning sign or symptom, even if the likelihood that breast cancer has recurred is low. Patients who have been discharged to their primary care physician for follow up can/should be referred back to their oncologist if concern or confirmation about recurrence arises.

Recurrences of triple negative cancer occur most frequently within the first five years following diagnosis and plateau at about 7 years. Hormone receptor breast cancers continue to recur over time, out to and beyond ten years. Her2 positive cancers that are hormone receptor negative appear to have a relapse pattern similar to triple negative cancers, and those that are hormone receptor positive behave more like their her2 negative, hormone receptor positive counterparts.

1B Location of Recurrence

The majority of recurrences from breast cancer are distant metastases (eg to bone, liver, or lung). These are generally treatable but not curable. Aggressive local therapy may improve long term survival in select cases with limited burden of metastases.

Selected recurrences have the potential to be cured with appropriate therapy. These include:

  1. Local recurrence in a breast which has previously treated by partial mastectomy and axillary node dissection [with or without radiation therapy].
  2. Local recurrence on the chest wall (and occasionally in the regional nodes) following mastectomy.
  3. Isolated solitary or oligo brain metastases following adjuvant therapy of her2+ breast cancer.

Such recurrences should be treated with surgical excision and radiotherapy (if applicable) for curative intent. A recent study suggests that chemotherapy following local management of local and regional recurrences may improve overall survival and cure rate.3

7.2 Screening for Contralateral Breast Cancer

​Revised 18 January 2013

Patients who have not undergone bilateral mastectomy should have annual screening mammography to facilitate early detection of any subsequent new breast cancer or in- breast recurrence. A new primary malignancy in the contralateral breast occurs at a rate of approximately 0.5% to 1% per year. The average 50 year old woman who has had breast cancer once carries approximately a 10-15% risk of a second contralateral breast cancer (invasive or DCIS) over the next 25 years.4 Adjuvant hormone therapy will reduce this risk (2C.Secondary Prevention) Women who have a confirmed BRCA2 and BRCA1 mutations and a prior breast cancer carry respectively about a 35% and 45% risk of a second breast cancer over 25 years if they do not have bilateral mastectomies or oophorectomy.5 They are also at increased risk of ovarian cancer. Women with confirmed BRCA1 and/or 2 mutations should be referred to the high risk hereditary cancer surveillance program for breast cancer screening with annual MRI followed every six months by mammography.

7.3 Hormone Therapy Compliance

Revised 18 January 2013

Numerous population based studies report poor longterm compliance with hormone therapy following early breast cancer, even when a patient does not have to pay for the drug.6,7 Lack of adherence is associated with poorer survival.6 Physicians should take the opportunity at each visit with a breast cancer patient to ask about adherence to hormone therapy, and explore reasons behind non-compliance. Patients should be reminded of the benefits of adherence in terms of risk reduction for recurrence and contralateral new disease. Means to reduce side effects should be explored when they are a hindrance to adherence.

7.4 Long Term Side Effects

Revised 18 January 2013

A number of late or chronic side effects are possible from chemotherapy, including early menopause, bone loss, chronic neuropathy, cognitive changes, congestive cardiomyopathy, and secondary leukemia. As a consequence of surgery and radiation, patients may experience long term intermittent breast or chest wall pain; shoulder pain and reduced range of motion; lymphedema; and chest wall dysesthesia. Hormone therapy can exacerbate depression, postmenopausal bone loss, joint pain, and hyperlipidemia. Many of these are amenable to therapeutic intervention.

7.5 References

Revised 18 January 2013

  1. Smith TJ, Davidson NE, Schapira DV, et al. American Society of Clinical Oncology 1998 update of recommended breast cancer surveillance guidelines. J Clin Oncol 1999; 17:1080-1082

  2. Grunefeld E, Mant D, Yudkin P, et al. Routine follow-up of breast cancer in primary care: randomized trial. BMJ 1996: 313: 665-669

  3. Aebi S, Gelber S, Lang I, et al. Chemotherapy prolongs survival for isolated local or regional recurrence of breast cancer: the CALOR trial (chemotherapy as adjuvant for locally recurrent breast cancer; IBCSG 27-02, NSABP B-37, BIG 1-02). Cancer Treatment 2012: 24 suppl 3: abstract S3-3

  4. Gao X, Fisher SG, and EMami B. Risk of second primary cancer in the contralateral breast in women treated for early stage breast cancer: a population based study. Int J Radiat Oncol Biol Phys 2003; 56:1038-45

  5. Metcalfe K, Lynch HT, Ghadirian P, et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2004; 22:2328-2335

  6. Hershman DL, Shao T, Kushi LH, et al. Early discontinuation and non-adherence to adjuvant hormonal therapy are associated with increased mortality in women with breast cancer. Breast Cancer Res Treat 2011; 126:529-537

  7. Partridge AH, LaFountain A, Mayer E, Tyalor S, Winer E, Asnis-Alibozek A. Adherence to initial adjuvant anastrozole therapy among women with early-stage brest cancer. J Clin Oncol 2008; 26: 556-562

Hormone Replacement Therapy After a Diagnosis of Breast Cancer

​The Breast Tumour Group of the BCCA has had a number of discussions regarding the use of hormone replacement therapy after a diagnosis of breast cancer. The traditional dogma has been that any use of hormones in patients with a personal history is contraindicated. This is based on the epidemiology of primary breast cancer, which reports an increased incidence of breast cancer in postmenopausal women exposed to long term estrogen replacement therapy (1). As well, a recent study has confirmed that HRT using a combination of progesterone and estrogen is also associated with an increased risk of developing breast cancer (2).

There is no direct evidence that estrogen causes recurrence in women with a previous history of cancer, but there is evidence of a decreased recurrence rate when women with a history of breast cancer are treated with Tamoxifen or after oophorectomy. Concerns about doing harm and contributing to incurable breast cancer recurrences have limited the use of estrogen replacement in these women. However, we are seeing an increased number of young women with early breast cancer and a relatively good prognosis, who are experiencing early menopause after adjuvant chemotherapy. As well, through screening mammography, we are identifying large numbers of older women with highly curable breast cancer.

At this time there is no good information on the risks of giving hormone replacement therapy to women after a diagnosis of breast cancer. There are a number of series reported in the literature which are not helpful because the studies are too small and have very short followup (3,4,5,6). Although there are plans for large randomized studies of women with a history of breast cancer to assess the risks and benefits of hormone replacement therapy, this data will not be available for many years.

Without evidence of safety our general policy has been to do no harm and therefore to not risk prescribing HRT to women with a previous history of any breast malignancy if there are other therapeutic options that can result in similar outcomes. Although there is evidence that HRT can improve bone health and conflicting evidence for cardiac health, there are often other therapies and lifestyle changes that can also be of benefit and should be considered as the first options in women with a history of breast cancer. In situations where there is a greater health risk from the non-breast cancer disease and there are no other options, the woman should be informed of the situation clearly and an individual decision to use HRT may be appropriate. Similarly, if there are symptoms that interfere significantly with a woman's quality of life (i.e. troublesome hot flashes, vaginal dryness, vaginal atrophy, dyspareunia, sleep disturbances, depression) and there are no other therapeutic options, HRT should be considered. For vaginal complaints topical estrogens may be considered. In all situations the woman must be fully informed about the risks, benefits, and areas where we are lacking in clear information, and the use of HRT monitored and for a limited duration.

There is some confusion about many of the new SERMS and their role in HRT and breast cancer. At this time, tamoxifen has been shown to be of benefit in decreasing relapse and new cancers in women with a history of in-situ and invasive breast cancer. Based on an individual risk assessment, tamoxifen may be prescribed for women for a duration of 5 years. Similarly there is evidence of tamoxifen being of benefit for the prevention of breast cancer in high risk women and it may be appropriate to prescribe tamoxifen for selected, informed high-risk women. Provincial guidelines for its use are available. Raloxifene is currently being studied in a large randomized study comparing it to tamoxifen for prevention of breast cancer in postmenopausal women. Information on this study is available at (604) 822-7997. It is not approved or proven for use in women with a history of breast cancer, nor is it approved for prevention. Both these drugs can cause hot flushes and dyspareunia and are not appropriate to treat these menopausal symptoms. Both drugs are effective in improving heart and bone outcomes, and Raloxifene is licensed for use in osteoporosis.

Laboratory and clinical work suggest that tamoxifen may begin exerting its pro-estrogen effects rather than its antagonistic, anti-estrogenic effects after a period of time. It is therefore recommended for 5 years, as that appears to be the optimal duration of use. As Raloxifene acts very similarly to tamoxifen, it is presumed that it too will exert an agonist effect after a period of time. Therefore its safety for prolonged periods and its safety after 5 years of tamoxifen in women with a previous diagnosis of breast cancer is not known and until there is data, should be avoided if there are treatment options. A recent study in animals suggested that tumours may become tamoxifen or raloxifene dependent after prolonged exposure suggesting as well that there may be clinical concerns about more than 5 years of use.

There is continued controversy in the use of progestins as single agents for postmenopausal symptoms and health. A number of research studies are ongoing to clarify safety and risks in breast cancer. In contrast to the well established role progestins have in decreasing uterine cancer when used in combination with estrogens, they are associated with an increased risk of breast cancer when used in combination HRT. At this time, however, in the woman with an intact uterus who is receiving HRT, combination therapy should remain standard.

As well, research is ongoing in the role of soy proteins for symptom control after a diagnosis of breast cancer. Many other treatments are also under investigation.

The role of HRT in women with a known genetic mutation in BRCA1 or BRCA2 causing an increased risk of breast or ovarian cancer is also unknown. There is evidence that oral contraceptives may be of value in decreasing the incidence of ovarian cancer (7). It is not clear if either oral contraceptives or HRT affects the incidence of breast cancer in carriers of BRCA1 or BRCA2 mutations. There is one study suggesting that early and multiple pregnancies are not protective in these women, so more research is needed.

In summary, the role of HRT in women with a history of breast cancer is unknown. If there are options for other therapies they should be used. In individual informed cases HRT may be appropriate for some women (see post-menopausal replacement therapy). Research may give us new insights in the next few years. If there are patients that need further assessment, please consult their oncologist. If HRT is used, it may be advisable to prescribe the lowest dose of estrogen to relieve symptoms and to monitor the patient carefully and to consider short term use until long term data is available.

References

  1. Collaborative Group on Hormonal Factors in Breast Cancer. Breast Cancer and hormone replacement therapy: collaborative re-analysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997; 350: 1047-1058.

  2. Schairer C, Lubin J, Troisi R, et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000; 283: 485-491.

  3. Powles TJ, Hickish T, Casey S; Hormone replacement after breast cancer. Lancet: 1993; 342: 60-61.

  4. Stoll BA. Hormone replacement therapy in women treated for breast cancer. Eur J Cancer 1995; 25: 1909-1913.

  5. Disaia PJ. Estrogen replacement therapy for the breast cancer survivor; A reappraisal. J Surg Oncol 1997: 64; 175-80.

  6. Eden JA. A case controlled study of combined continuous estrogen-progestin replacement therapy among women with a personal history of breast cancer. Menopause 1995; 2: 67-72.

  7. Narod SA, Risch H, Moslehi R et al Oral contraceptives and the risk of hereditary ovarian cancer. NEJM 1998; 339: 424-427.

Patient Guidelines for the Prevention of Osteoporosis in Women

​Revised 9 March 2011

Patient Guidelines for the Prevention of Osteoporosis in Women  Revised March 2011

Patient Guidelines for the Prevention of Osteoporosis in Women

Postmenopausal women have an increased risk of osteoporosis. As well, this risk can be increased further by factors such as family history, smoking, diet, early menopause, chemotherapy, long term corticosteroids and some hormonal therapies that lower estrogen.

The following guidelines are provided to reduce the risk of bone loss during and after treatment. If your bone density scan at the start of treatment indicates that you are at increased risk of osteoporosis you may be advised to use medications such as bisphosphonates (eg. alendronate (Fosamax®) in addition to following the guidelines below.

Calcium & Vitamin D:

Calcium and vitamin D are essential for strong bones. A daily dose is the sum of what you consume from food sources and from supplements. The recommended daily intake for calcium is 1200 mg. A daily supplement of 1000 IU of vitamin D is recommended for bone health and the prevention of cancer, in all women.

Food sources of Calcium:

Food Source Portion Size Calcium (mg)
Cheese (Swiss) 50 g (2 oz) 440
Cheese (Cheddar/Mozzarella) 50 g (2 oz) 390
Milk (skim,1 or 2% MF or whole) 250 mg(1 cup) 300
Buttermilk, or Chocolate milk 250 ml (1 cup) 300
Yogurt, plain 175 ml (3/4 cup) 300
Milk powder, dry 45 ml (3 Tbsp) 280
Fortified Beverages (soy, rice, orange juice) 250 ml (1 cup) 300
Blackstrap Molasses 15 ml (1 Tbsp) 180
Parmesan Cheese 15 ml (1 Tbsp) 90
Sardines, with edible bones 24 gm 90
Cottage cheese, 2% MF 125 ml (1/2 cup) 80
Figs, dried, uncooked 3 80
Orange, raw 1 medium 50
Broccoli, frozen, boiled, drained 250 ml (1 cup) 50

Adapted from the Manual of Clinical Dietetics, 6th Edition (p.746-747), by American Dietetic Association et al, 2000.

Calcium intake from all sources should not exceed 2000 mg per day.

Food sources of vitamin D:

Food Source Portion size Vitamin D (IU)
Fish, herring 100 gm (3 oz) 900
Fish, mackerel or salmon 100 gm ( 3 oz) 650
Fish, sardines or tuna 100 gm ( 3 oz) 250
Milk or Soy Beverage, fortified 250 ml (1 cup) 90
Margarine, fortified 5 ml (1 tsp) 55
Egg 1 large 25

Adapted from the Manual of Clinical Dietetics, 6th Edition (p.746-747), by American Dietetic Association et al, 2000.

Vitamin D intake from all sources should not exceed 4000 IU per day.

Vitamin and Mineral Supplements:

If you can't meet the recommended amounts with food alone, consider a supplement. Calcium carbonate is the least expensive calcium supplement and is well tolerated by most people when taken with food. The absorption of calcium from supplements is most efficient at doses of 500 mg or less. Some calcium supplements also include vitamin D (check the label for the exact amount). A standard multivitamin and mineral supplement provides approximately 175 mg of calcium and 400 IU of vitamin D and other nutrients.

Protein:

Adequate protein is required to maintain bone health. Include one of the following protein rich foods at each meal: meat, fish, poultry, beans, lentils, nuts, eggs, milk, yogurt and cheese.

Caffeine and salt:

Excess caffeine and salt can have a negative effect on bone. Caffeine is found in coffee and also tea, chocolate (cocoa) and some soft drinks. For optimal bone health limit coffee to less than 4 cups per day.

Foods high in salt generally include processed foods such as canned soups, snack foods, crackers, pastas and sauces. Check the nutrition label on processed foods and limit salt to less than 2100 mg per day.

Physical Activity:

Being physically active maintains optimal bone health and decreases the risk of a bone fracture by improving bone mass and increasing muscular strength, coordination and balance and thereby reducing falls. Physical activity that is weight bearing is best, examples include walking, dancing, aerobics, skating and weight lifting.

Smoking:

Smoking is related to poor bone and general health. If you smoke, ask your doctor for assistance to stop smoking.

Developed by BCCA Breast Tumour Group, 14 Oct. 2004; Revised March 2011

Post-menopausal Replacement Therapy

Updated 24 July 2006

We do not recommend routine replacement therapy. There are some postmenopausal symptoms which can cause considerable distress to patients and the issue of replacement therapy needs to be considered.

  1. Hot Flushes: initially try counseling, time. Avoidance of triggers for hot flushes may be helpful and include avoidance of caffeine (coffee or tea), chocolate, alcohol, colas, stress, hot weather. Medications that have been shown to be effective for some women include Effexor (lowest effective dose of 37.5 mg/day) clonidine (Dixarit 0.05 mg bid), Bellergal. If the symptoms are still severe after 6+ months, the lowest dose of combination estrogen and progesteron or progesterones alone (provera 5 mg or megace 40 mg) may be tried. They should be used at the lowest dose for the shortest duration after a full disclosure of the lack of evidence available for risk and benefit so a woman can make a choice related to quality of life issues.  
  2. Vaginal Irritation/Dyspareunia: try non-hormonal, water-soluble lubricants applied directly to the introitus and/or penis. If unsuccessful, using small amounts of estrogen cream (i.e., 1/4 manufacturer's recommended dose) applied topically to the introitus, intermittently, may be helpful. Estrogen used in this fashion is absorbed systemically. The potential risks and benefits should be discussed. Estring, an intravaginal estrogen releasing device, is another option. Serum levels of estrogen are only apparent for 24 hours after the initial use, so this may give a more local effect that may relieve symptoms and have less systemic absorption.  
  3. Osteoporosis. There are now a number of options for osteoporosis. Weight bearing exercise, calcium, vitamine D, and bisphosphonates all may improve osteopenia and osteoporosis. Raloxifene has also been licensed for this condition. For the majority of women entering menopause (without a diagnosis of breast cancer) estrogen therapy may be beneficial and carries only a small increased risk of developing breast cancer (1.5x after 10 to 15 years of use) and a small risk of developing endometrial cancer. For women with a diagnosis of breast cancer, tamoxifen may help prevent premature bone mineral loss. Treatment should be individualized.  
  4. Heart disease. There is controversy over the role of hormone replacement and the prevention of heart disease. Diet, exercise, avoidance of smoking and monitoring of hypertension, cholesterol etc. may be of major benefit.

Pregnancy Following Breast Cancer

The literature suggests that pregnancy after a carcinoma of the breast is not hazardous. It is however recommended that patients be advised to delay pregnancy. The length of the delay depends upon two factors, the initial stage of the disease and thus the probability of the development of metastatic disease and the age of the patient at the time of diagnosis.

The greatest incidence of both locoregional recurrence and distant metastases occurs within the first two years following diagnosis and treatment. It would appear that for women in their thirties desirous of a subsequent pregnancy a delay of two years should be recommended. For very young women with breast cancer a delay of five years may be more appropriate since the chance of developing metastatic disease is much reduced after such an interval and child bearing potential is probably not significantly adversely affected. This, however, is always a personal decision.

8. Upper Extremity Rehab after Axillary Dissection

Updated 5 March 2007

Limitation of shoulder mobility may occur in as little as two weeks following immobilization. Post-operative physiotherapy is useful for most patients.

This guideline applies to the provision of upper extremity rehabilitation, as well as hand and arm care, for women (or men) who have received axillary dissection as part of the management of breast cancer. Because breast cancer occurs predominantly in women, the remainder of the text will address women with breast cancer.

Recommendations

Upper Extremity Rehabilitation

  • Pre-operative, bilateral upper extremity function, e.g. active range of motion (ROM), strength, sensation, and limb circumference, should be assessed by the surgeon, family physician, or a physical therapist to provide a baseline prior to treatments (1-3).
  • Post-operative physical therapy should begin the first day following surgery. Gentle ROM exercises should be encouraged in the first week after surgery (1,2,4).
  • Active stretching exercises can begin 1 week after surgery, or when the drain is removed, and should be continued for 6-8 weeks or until full ROM is achieved in the affected upper extremity. Women should be instructed in scar tissue massage (1,2,3,5).
  • Post-operative assessments following surgery to include ROM, strength, sensation, limb circumference, and scar and chest wall tissue mobility (1,3,6).
  • Progressive resistive exercises, i.e. strengthening, can begin with light weights (1-2 lbs.) within 4-6 weeks after surgery. A compression sleeve should be worn during any resistive exercises or strenuous upper body athletic activity (2,3,4-7).

Hand and Arm Care

  • Careful hand and arm care, e.g. proper hygiene and avoiding trauma to the arm can minimize risks for infection and lymphedema (8-10).
  • Minimizing the extent of axillary dissection, preventing infection, and avoiding obesity may help prevent the development of lymphedema (9,11-13).
  • Generally, injections, vaccinations, venipuncture, and intravenous access in the axillary-dissected arms and shoulder have been contra-indicated (14-16).There is some evidence (Level V) that these restrictions can be relaxed (17).
  • Many suggestions regarding proper hygiene and trauma avoidance for the axillary-dissected upper extremity are sensible but there is little scientific literature to support these restrictions.

Electrotherapy Modalities

  • Laser treatment, electrical stimulation, microwave, and thermal therapy are not recommended at this time due to insufficient evidence to support their use as well as published precautions and contra-indications for their use in persons with neoplasms.(18-20).
  • Therapeutic ultrasound is contra-indicated over sites of possible metastasis in women with a history of breast cancer (19, 21-23).

Exercise for Cardiovascular Fitness:

Although these guidelines focus on upper extremity rehabilitation, women who have had breast cancer should be encouraged to engage in an ongoing, regular program of moderate, aerobic exercise (24-25). In a study published in 2005, women who exercised 3-5 hours per week (at an aerobic level equivalent to walking a 20-30 minute mile) significantly reduced their risk of recurrence as well as their risk of dying from breast cancer when compared to women who exercised less than 3 hours per week (26).

Objective

To provide evidence-based, clinical practice guidelines for choosing the most effective rehabilitation strategies and the most appropriate hand and arm care after axillary dissection for the management of breast cancer. Clinical practice guidelines are systematically developed to assist practitioners and consumers in making decisions about appropriate care in specific clinical circumstances. Rehabilitation of the upper extremity after axillary dissection in women with breast cancer is poorly addressed by practitioners. To identify the most effective rehabilitation protocols, the Breast Tumour Group at the B.C. Cancer Agency recognized the need for practice guidelines.

Options

Pre-operative assessment of upper extremity function, post-operative rehabilitation and reassessment of upper extremity function, and hand and arm care following axillary dissection.

Outcomes

Range of motion (goniometry), strength, functional mobility, return to pre-surgical activities of daily living and recreational activities.

Evidence

To develop the guidelines, a task force was set up by the Breast Tumour Group of the B.C. Cancer Agency. The task force included physical therapists, women living with breast cancer, medical and surgical specialists. Guideline authors were selected from the task force membership. After consensus was reached by the task force, the guidelines were sent out for external review.

These guidelines are based on a review of published data and expert opinion from the Cancerlit and Medline databases (1966-2000) and from recent breast cancer textbooks. Forty-seven references were reviewed. The treatment guidelines are, whenever possible, evidence-based using Sackett's rules of evidence(27). The guidelines largely reflect evidence at Levels III-V and sometimes rely on consensus and common sense, due to limited clinical research in this area. Where evidence exists, it will be parenthesized, e.g. (Evidence Level III).

Values

Early post-operative physical therapy has been shown to be both safe (Evidence Levels I-II) and effective in enhancing shoulder ROM and functional abilities in women recovering from breast cancer (Evidence Level III).

Benefits, Risks, and Costs

Benefits include functional and timely recovery of the upper extremity and avoidance of lymphedema and/or cellulitis. There may be increased wound drainage if exercises are initiated too early post-operatively (Day 1). However a number of recent studies (Evidence Levels I-II) have supported both the safety and effectiveness of early post-operative exercise. Stretching exercises during the early post-operative period may assist in breaking up of sclerosed lymphatic vessels (which appear as fine, cord-like structures along the medial surface of the upper arm and forearm). Exercises should provide slow, prolonged stretches, particularly to the shoulder abductors and flexors, with minimal pain or discomfort.

To locate a physical therapist in your area who has special expertise in working with women facing breast cancer surgery or recovering from surgery, ask your doctors or women who had breast cancer, or check with the Physiotherapy Association of B.C.. You do not need a doctor's referral to access physical therapy private clinics. The Medical Services Plan of B.C. no longer covers the cost of private physiotherapy treatments unless you meet low-income criteria. Prior to scheduling your first appointment, discuss the costs for the initial assessment, follow-up appointments and cancellation policy.

Recommendations included in these guidelines, for standard pre- and post-operative assessments and treatments under the direction of a physical therapist would likely require fewer than 12 visits. In cases where complications arise, e.g. post-treatment lymphedema, additional physical therapy visits would be necessary. There may also be costs of compression sleeves, compression pumps, and antibiotic therapy in cases of infection. Many of these costs are covered, at least in part, through extended health plans.

Validation

These guidelines were reviewed by clinical practitioners and by representatives of the B.C. College of Physicians and Surgeons, the Registered Nurses Association of B.C., the College of Physical Therapists of B.C., and the B.C. Council on Clinical Practice Guidelines. The guidelines were then reviewed by the Breast Tumour Group of the B.C. Cancer Agency for final approval. These guidelines will be revised every two years to reflect new information.

Sponsors

This guideline was developed by a task force set up by the Breast Tumour Group at the B.C. Cancer Agency. The task force members included:
Dr. Sharon Allan (Medical Oncologist)
Dr. Carol Dingee (Breast Cancer Surgeon)
Ms. Faye Eddy (Physical Therapist)
Dr. Susan R. Harris (Physical Therapist, Co-editor and breast cancer survivor)
Dr. Brian Haylock (Radiation Oncologist)
Dr. Maria Hugi (Task Force Chair, Co-editor, Emergency Physician and breast cancer survivor with lymphedema)
Dr. Winkle Kwan (Radiation Oncologist)
Ms. Sherri Niesen (Physical Therapist)
Ms. Cynthia Webster (Physical Therapist)

Additio​nal Resources

For more detailed information, refer to:

  1. Harris SR, Campbell KL, McNeely ML. Upper extremity rehabilitation for women who have been treated for breast cancer. Physiother Can. 2004;56:202-214.
  2. Harris SR, Hugi M, Olivotto IA, et al. Upper extremity rehabilitation after axillary dissection for the treatment of breast cancer: Clinical practice guidelines. Crit Rev Phys Med Rehabil. 2001;13:91-103.

Referen​ces

Updated on 5 March 2007

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  2. Wingate L, Croghan I, Natarajan N, Michalek AM, Jordan C. Rehabilitation of themastectomy patient: A randomized, blind, prospective study. Arch Phys Med Rehab 1989; 70: 21-24.

  3. Hladiuk M, Huchcroft S, Temple W, Schnurr BE. Arm function after axillary dissection for breast cancer: A pilot study to provide parameter estimates. J Surg Oncol 1992; 50: 57-52.

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  5. Miller LT. Postsurgery breast cancer outpatient program. Clinical Management 1992; 12: 50-56.

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  7. Stumm D. Recovering from Breast Surgery: Exercises to Strengthen your Body and Relieve Pain, Hunter House, Alameda, CA, 1995.

  8. Spratt JS, Donegan WL. Surgical management. In Donegan WL, Spratt JS (eds.), Cancer of the Breast, ed. 4, W.B. Saunders, Philadelphia, PA, 1995: 443-504.

  9. Petrek J, Lerner R. Lymphedema. In Harris JR, Lippman ME, et al (eds): Diseases of the Breast., Lippincott-Raven, Philadelphia New York, 1996; 896-903.

  10. Brennan MJ, DePompolo RW, Garden FH. Focused review: Post mastectomy lymphedema. Arch Phys Med Rehabil. 1996; 77: S74 - S80.

  11. Segerstrom K, Byerle P, Graffman S, Nystrom A: Factors that influence the incidence of brachial edema after treatment of breast cancer. Scand J Plast Reconstr Hand Surg 1992; 26: 223-227.

  12. Aitken D. Complications associated with mastectomy. Surg Clin N Am 1983; 63(6): 1331 - 1351

  13. Werner RS, McCormick B, Petrek J, et al. Arm edema in conservatively managed breast cancer: Obesity is a major predictive factor. Therapeutic Radiology 1991; 180: 177 - 184.

  14. Centers for Disease Control and Prevention: General recommendations on immunization: Recommendations of the Advisory Committee on Immunization Practices(ACIP). Morbidity and Mortality Weekly Report 1994; 43 (RR-1): 6.

  15. Procedures for the Collection of Diagnostic Blood Specimens by Venipuncture, ed 3. National Committee for Clinical Laboratory Standards (NCCLS). Villanova, PA, 1991: H3-A3.

  16. Koepke JA. Phlebotomy after mastectomy (Letter). Medical Laboratory Observer. 1992; 12-14.

  17. Dawson WJ, Elenz DR, Winchester DP, Feldman JL. Elective hand surgery in the breast cancer patient with prior ipsilateral axillary dissection. Ann Surg Oncol 1995; 2(2): 132 - 137.

  18. Lehmann JF, de Lateur BJ. Therapeutic heat. In Lehmann JF (ed.), Therapeutic Heat and Cold, 4th ed., Williams & Wilkins, Baltimore, MD, 1990: 417-581.

  19. The Chartered Society of Physiotherapy. Safety of Electrotherapy Working Group.Guide lines for the safe use of lasers in physiotherapy. Physiotherapy 1991; 77: 169-170.

  20. Snyder-Mackler L, Collender SL. Therapeutic uses of light in rehabilitation. In Michlovitz SL (ed.): Thermal Agents in Rehabilitation, 3rd ed., F.A. Davis, Philadelphia, PA, 1996: 255-277.

  21. Hogan RD, Burke KM, Franklin TD. The effect of ultrasound on microvascular hemodynamics in skeletal muscle: Effects during ischaemia. Microvascular Res 1982; 23: 370-379.22.

  22. Basford JR. Physical agents and biofeedback. In DeLisa JA (ed.), Rehabilitation Medicine: Principles and Practice, Philadelphia, PA, J.B. Lippincott, 1988: 261-263.

  23. Friedenreich CM, Courneya KS. Exercise as rehabilitation for cancer patients. Clin J Sport Med 1996; 6: 237-244.

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  25. Thune I, Brenn T, Lund E, Gaard M. Physical activity and the risk of breast cancer. New Eng J Med 1997; 336: 1269-1275.

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  27. Sackett DL. Rules of evidence and clinical recommendations on the use of anti-thrombotic agents. Chest 1989;95:2S-4S.

A complete report with complete list of references is available from the BC Cancer Agency through Dr. Karen Gelmon, Chair, Breast Tumour Group, Vancouver Cancer Centre, 600 West 10th Ave., Vancouver, B.C., V5Z 4E6. Fax: (604) 877-0585.mailto:kgelmon@bccancer.bc.ca


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