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6.3 Early Invasive Breast Cancer (T1T2; N0N1; T3N0)

Updated February 2016

Management of Invasive Breast Cancer

Invasive breast cancer requires multimodality management that is specific to the stage of the disease. The majority of patients with invasive breast cancer have ductal breast cancer and, less commonly, lobular breast cancer. While there is a slight difference in the natural history of lobular and ductal breast cancer, patients with these two different pathologies are treated in the same way. The management sections that follow, aside from the section about less common histologies, refer in particular to those with invasive ductal or lobular breast cancer.

6.3.1 Locoregional Management

6.3.1.1 Surgical Treatment

Breast Surgery

Definitive treatment of early invasive breast cancer is surgery. Typically, the primary tumor is excised and axillary lymph nodes are removed for staging. The decision of when to proceed to surgery and which procedure is best for an individual patient has become more complicated with the options of neoadjuvant chemotherapy and immediate breast reconstruction, and with changing recommendations for radiotherapy and chemotherapy. Sequencing of breast cancer treatment is more commonly done with multidisciplinary input.
A general overview of breast cancer surgery is outlined below and additional information on special circumstances, such as young women, elderly patients, pregnant patients, and male breast cancer are found in following sections.

Breast Conserving Surgery

Breast conserving surgery (BCS, lumpectomy, partial mastectomy or segmental mastectomy) or breast conserving surgery plus radiotherapy has been shown in multiple randomized control studies to be equivalent to mastectomy in terms of survival and breast cancer outcomes for patients with early-stage disease1,2.  It is recommended that most patients with early stage disease be offered BCS3,4,5 as long as the tumor to breast ratio would give a reasonable cosmetic outcome following the procedure. Additional strategies such as oncoplastic lumpectomy resections and tumor shrinkage with Neoadjuvant Chemotherapy (NAT) can increase the number of patients eligible for BCS. 

MRI is not recommended in the routine assessment of unilateral breast cancer as there has been no improvement in survival or repeat surgery rates by using MRI and the additional investigations and findings can result in delay or overtreatment to the known cancer.6,7

Patients with a positive margin should be evaluated for further surgery.8

Patients having BCS should be referred to radiation oncology as radiotherapy significantly lowers the risk of in-breast recurrence in the setting of BCS. However, there is a group of patients felt to be at low risk of recurrence with BCS alone who may be spared radiotherapy.9 Patients in remote communities who have traditionally opted for mastectomy to avoid travel for radiotherapy might be eligible for BCS alone and if this is considered, a preoperative discussion with radiation oncology is recommended.  

Surgical Margins after Breast Conserving Surgery for Invasive Disease

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 may reduce IBTR more than using a radiation boost. The use of systemic therapy also minimally reduces IBTR. 

Those with positive margins have double the risk of IBTR compared to those with negative margins. There is conflicting data regarding the risk of IBTR with close margins. Most of the randomized trials of breast conservation with radiation vs mastectomy were in the context of no tumour seen at ink at pathologic examination of the resection specimen, although retrospective studies demonstrate an increased IBTR with both positive or close margins. 

There is no evidence that re-excision alters survival compared to radiotherapy boost. The degree of survival impact of either, in the setting of close margins in particular, is expected to be small, or negligible, particularly in the absence of other risk factors. 

For patients with a high systemic failure risk (e.g. 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, but for whom there is a strong desire to avoid a mastectomy, or if medical problems preclude further surgery. In these situations, a radiation boost would likely be used, albeit this can also affect the cosmetic outcome.

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 no tumour at the inked margin.  A positive margin is defined as tumour touching ink. In British Columbia, a close margin is currently defined as less than 2 mm margin. 
  3. Re-excision to obtain negative margins is recommended for patients with positive margins.
  4. If a margin is close (< 2 mm), a re-excision is not routinely recommended but could be considered if the risk of IBTR is high and systemic risk is low, for example. A radiotherapy boost is usually recommended in the setting of a close margin.

    Re-excision may be considered for close margins in the following circumstances:

    Margin < 2 mm and
    extensive intraductal component present
    Age < 40
    No systemic therapy planned or the patient declines systemic therapy
    Margin close at multiple sites
    Margin status unknown
  5. When the deep margin is positive, and the surgeon has dissected down to fascia, then a radiotherapy boost should be given instead of re-excision
  6. When the anterior margin is positive, and the surgeon has removed the breast tissue underlying the skin, then a radiotherapy boost should be given instead of re-excision.
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 re-excision is recommended. This will facilitate a timely re-excision. Re-excision should be carried out prior to adjuvant radiation but does not need to occur prior to systemic therapy.

Lobular Carcinoma In Situ at margin

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

Pathology Report Reviews

If a pathology report does not contain the necessary information to determine margin status, then the reading pathologist should be consulted or a BC Cancer 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.

Mastectomy

Total mastectomy (TM) is defined as the removal of entire breast. "Mastectomy requires the elevation of skin flaps sufficiently thin to remove all of the breast tissue, and extended to the anatomic limits of the breast (the sternal border medially, the clavicle superiorly, the latissimus laterally, and the rectus sheath/inframammary fold inferiorly)."10

Skin sparing mastectomy (SSM) is used in conjunction with immediate breast reconstruction and studies have shown no increased recurrence risk with use of this technique10. Nipple sparing mastectomy (NSM) is a viable option by the properly trained surgeon in women with small to moderate sized breasts, minimal ptosis, and favorable tumour features11  Evidence is accumulating that there is a low recurrence risk in properly selected patients.  When assessing a patient for a NSM, considerations include location of the tumor, nodal status and need for radiotherapy, and tumor biology.11 A nipple margin (core) should be taken when a NSM is performed.11

Total Mastectomy (TM, SSM, NSM) is an option for patients with early stage breast cancer particularly for patients with contraindications to radiotherapy or desire to avoid radiotherapy, patients who would have a poor cosmetic outcome with breast-conserving therapy or those with multicentric disease or associated diffuse, extensive DCIS. Mastectomy should also be considered in those who continue to have positive margins of invasive disease after multiple breast-conserving surgeries.

Axillary Surgery

Axillary surgery provides important prognostic information and can improve regional control for some patients with invasive breast cancer. Traditionally, level I and II axillary node dissection (ALND) had been the standard of care for all patients with invasive breast cancer. ALND has now been replaced by Sentinel Lymph Node biopsy (SLNB) for most patients with clinically N0 breast cancer12,13.  Sentinel lymph node biopsy is associated with less morbidity than ALND12 and similar staging accuracy and oncologic outcomes in early breast cancer12,13,14,15 and should be offered to all eligible patients. 

Axillary lymph node dissection is recommended12,13,14,15,16,17 (Surgical Breast Tumor group consensus 2016) in the following situations:

  1. Inflammatory breast cancer
  2. Occult breast cancer presenting as axillary node metastasis
  3. Clinically node positive axilla, confirmed by FNA or core biopsy in a patient for whom neoadjuvant chemotherapy is not planned
  4. Axillary nodes that remain positive after neoadjuvant chemotherapy
  5. Axillary recurrence following previous breast cancer treatment.  
Axillary lymph node dissection should be considered12,13,14,15,16,17 (Surgical Breast Tumor group consensus 2016):

  1. Failed Sentinel node mapping in invasive cancer with high risk features
  2. Positive sentinel lymph nodes not meeting eligibility criteria for Z0011 study15* (multidisciplinary discussion recommended)
  3. Node positive disease prior to NAT (evidence evolving around the role of SLNB, multidisciplinary discussion recommended)
  4. Axillary staging required in the setting of previous mastectomy
Axillary lymph node dissection not recommended12,13,14,15,16,17 (Surgical Breast Tumor group consensus 2016):

  1. Clinically T1-T2 N0 breast cancer (sentinel node biopsy should be offered)
  2. Positive sentinel nodes meeting criteria for Z0011 study15*
  3. DCIS
* Z0011 Eligibility criteria: T1T2 Invasive breast cancer, no palpable axillary nodes, 1-2 Sentinel nodes positive, treated with BCS with clear margins (no tumour at ink), no matted nodes / gross extranodal disease / neoadjuvant hormonal or chemotherapy 

Level 1 and 2 axillary dissection is generally recommended for those with three or more pathologically positive sentinel nodes and those at high risk for gross residual nodal disease after sentinel node procedure (e.g. those with three or more pathologically positive sentinel nodes, or gross extracapsular extension) to improve regional control, although the elevated risk of lymphedema of axillary dissection in the setting of regional radiotherapy must also be considered in the absence of a proven survival advantage. 

Synoptic Reporting for Breast Cancer Surgery

The Surgical Breast Tumor group developed a Breast Cancer Checklist (Synoptic Report) in conjunction with medical and radiation oncology. It is recommended that surgeons report breast cancer procedures using this template to facilitate communication of relevant details to other care providers.
  
Pathology considerations for Partial and Modified Radical Mastectomy

The specimen removed at partial mastectomy must be oriented by the surgeon. 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). 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, 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.

Contralateral Prophylactic Mastectomy

Patients who require a mastectomy to treat unilateral breast cancer often enquire about contralateral prophylactic mastectomy (CPM). A detailed history and family history is required to assess the risk of a contralateral breast cancer (CBC). For the average woman the risk of CBC is less than 0.7% per year. CBC rate is increased in higher risk populations (eg BRCA mutation carriers). CPM reduces the risk of CBC but never eliminates it completely. Systemic treatments also reduce the risk of CBC. Rates of CPM are rising at more then 1% per year and have been known to almost double the risk of complications after surgery. CPM in an average risk woman does not improve cancer outcomes.  

As such, CPM is not recommended for women with unilateral breast cancer. CPM may be considered in selective cases when a patient is deemed to be of moderate risk of CBC (e.g.very young age, strong family history of breast cancer, non-BRCA mutations, other high risk features such as atypical ductal hyperplasia or lobular carcinoma in-situ), or  when issues arise surrounding asymmetry after unilateral mastectomy (with or without breast reconstruction).

High risk populations (BRCA mutation carriers, history of mantle field radiation) with unilateral breast cancer should be counseled on the risk of CBC and often CPM is recommended.  

A Canadian expert consensus statement on this issue is a work in progress. The link will be posted here once it is available. Other groups, including the American Society of Breast Surgeons18 and Choosing Wisely19, have similar consensus statements discouraging the routine use of CPM.   

Breast Reconstruction

All women undergoing mastectomy should be offered a reconstruction and referral to a plastic surgeon if they are clinically candidates. Reconstruction can be performed at the time of mastectomy (immediate reconstruction) or as a second procedure (delayed reconstruction). Options for reconstruction include autologous tissue vs implant reconstruction.20

Current review of breast reconstruction is found in the Surgical Oncology Network Newsletter Spring 2016.

References

  1. Fisher B, Anderson S, Bryant J et al Twenty year follow up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer.  N Engl J Med 2002;347:1233-41
  2. Veronesi U, Cascinelli N Mariani L et al.  Twenty year follow up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer.  N Engl J Med 2002; 1227-32. 
  3. Eusoma  http://www.eusoma.org/Engx/Guidelines/Other/OtherMT.aspx?cont=MT
  4. ACS breast centers:  https://www.facs.org/~/media/files/quality%20programs/napbc/2014%20napbc%20standards%20manual.ashx
  5. https://www.breastsurgeons.org/new_layout/about/statements/PDF_Statements/PerformancePracticeGuidelines_Breast-ConservingSurgery-PartialMastectomy.pdf
  6. Peters NH1, van Esser S, van den Bosch MA, Storm RK, Plaisier PW, van Dalen T, Diepstraten SC, Weits T, Westenend PJ, Stapper G, Fernandez-Gallardo MA, Borel Rinkes IH, van Hillegersberg R, Mali WP, Peeters PH. Preoperative MRI and surgical management in patients with nonpalpable breast cancer: the MONET - randomised controlled trial. Eur J Cancer. 2011 Apr;47(6):879-86. doi: 10.1016/j.ejca.2010.11.035. Epub 2010 Dec 30.
  7. Turnbull L1, Brown S, Harvey I, Olivier C, Drew P, Napp V, Hanby A, Brown J. Comparative effectiveness of MRI in breast cancer (COMICE) trial: a randomised controlled trial. Lancet. 2010 Feb 13;375(9714):563-71. doi: 10.1016/S0140-6736(09)62070-5.
  8. Meena S. Moran, Stuart J. Schnitt, Armando Giuliano et al. Society of Surgical Oncology–American Society for Radiation Oncology Consensus Guideline on Margins for Breast-Conserving Surgery With Whole-Breast Irradiation in Stages I and II Invasive Breast Cancer.  March 2014, Volume 21, Issue 3, pp 704–716
  9. Hughes KS, Schnaper LA, Berry D, 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;351: 971: l
  10. https://www.breastsurgeons.org/new_layout/about/statements/PDF_Statements/PerformancePracticeGuidelines_Mastectomy.pdf
  11. Headon HL, Kasem A, Mokbel K.The Oncological Safety of Nipple-Sparing Mastectomy: A Systematic Review of the Literature with a Pooled Analysis of 12,358 Procedures.  Arch Plast Surg. 2016 Jul;43(4):328-38. doi: 10.5999/aps.2016.43.4.328. Review.
  12. https://www.breastsurgeons.org/statements/QM/ASBrS_Management_of_Axilla.pdf
  13. https://www.breastsurgeons.org/new_layout/about/statements/PDF_Statements/PerformancePracticeGuidelines_SLN.pdf
  14. Krag DN, Anderson SJ, Julian TB et al.  Sentinel lymph node resection compared with conventional axillary lymph node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomized phase 3 trial.  Lancet Oncol 2010;11:927-33.
  15. Giuliano A, Ballman K, McCall L.  Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases.  Long term follow up from the ACOSOG Z0011
  16. https://www.breastsurgeons.org/new_layout/about/statements/PDF_Statements/PerformancePracticeGuidelines_ALND.pdf
  17. Lyman et al. Sentinel lymph node biopsy for patients with early-stage breast cancer:  American society of clinical oncology clinical practice guideline update.  JCO.  http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2013.54.117. Accessed April 21, 2016
  18. Judy C. Boughey, Deanna J. Attai, Steven L. Chen et al. Contralateral Prophylactic Mastectomy (CPM) Consensus Statement from the American Society of Breast Surgeons: Data on CPM Outcomes and Risk. Annals of surgical oncology.  October 2016, Volume 23, Issue 10, pp 3100–310
  19. https://www.breastsurgeons.org/docs/2016_asbrs_cw_recommendations.pdf. Accessed Sept 14, 2016
  20. Joon Y Choi, MD, Amy K Alderman, MD, Lisa Ann Newman, MD, MPH, FACS. Aesthetic and Reconstruction Considerations in Oncologic Breast Surgery. JACS 2006; 202:943-952.

6.3.1.2 Radiation Therapy (RT)

Updated November 2017

Radiation Therapy following Breast Conserving Surgery (pT1T2;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).

RT to the breast following BCS reduces the risk of breast recurrence and lowers the risk of systemic recurrence and breast cancer death.1,2,3,4,5 At 10 years after diagnosis, a 20% absolute reduction in the risk of breast recurrence (from 30% to 10%) translates into a 4-5% reduction in the chance of dying from breast cancer. RT should follow BCS unless contraindicated due to patient comorbidites, limited patient life expectancy, patient desire to avoid RT, or in selected low recurrence risk situations (see below). In addition to breast RT, regional RT may be indicated in select node-negative patients, such as those with a number of high-risk features including large tumour, high grade, lymphovascular involvement, central/inner quadrant location, or those with triple-negative (i.e. ER/PR negative, her-2-neu negative) disease.

Timing of Adjuvant Radiotherapy

  • I. RT should optimally start once healing from the BCS is complete and generally within 10 weeks of BCS
  • II. 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 20 weeks after BCS. Longer intervals may be associated with reduced RT efficacy and inferior local control6
  • III. If the patient receives adjuvant chemotherapy, then RT should follow the chemotherapy and start approximately 3-4 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.
Boost Radiotherapy

Randomised trials have shown improved local control with a boost of RT to the surgical bed following tangential RT for selected patients.7,8,9

Indications for supplemental boost dose of RT: 

  • I. close or positive margins (less than or equal to 2 mm) post-breast conserving surgery, without possibility of further excision
  • II. age 50 years or younger, even if the margins are greater than 2 mm
Patients who might be spared radiation therapy after breast conserving surgery

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, 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.11,12,13

Accelerated partial breast radiation therapy following breast conserving surgery

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 BC Cancer consensus is that:

  • Whole breast RT remains the standard local treatment following breast conserving surgery.
  • Partial breast RT using 4-5 external 3-D conformal external beam RT has been shown to increase the risk of breast pain and induration at the primary site.
  • Where available, patients undergoing accelerated breast radiation therapy 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 (pT1,T2;N0)

Some patients treated with mastectomy with negative nodes may benefit from adjuvant RT. Those with close or positive margins with T2 tumour size plus other high risk features, such as grade 3 histology, lymphatic or vascular invasion, age<50 years, and central or inner quadrant tumours have a higher risk of locoregional recurrence and warrant a discussion of adjuvant radiotherapy.14 Adjuvant locoregional RT may benefit select node-negative patients with clear margins post-mastectomy or breast conserving therapy, such as those with central/inner quadrant tumours, or those with T2 tumour size with other high risk features, e.g. high grade, lymphovascular involvement, or triple-negative (i.e. ER/PR negative, her-2-neu negative) disease.15 Those with these high-risk features should be referred after mastectomy for discussion of adjuvant RT with a radiation oncologist. 

Radiation therapy following mastectomy or breast conserving surgery (pT1,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)15,16,17,18,19,20.  This benefit is significant, even for patients with only a moderate risk (e.g. 1-3 nodes positive) of loco-regional recurrence.16,17 Regional RT results in decreased risk of loco-regional recurrence and distant metastases and improved survival for patients with node-positive cancer.

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

Details of radiotherapy planning and prescription in the post-breast conserving surgery and post-mastectomy setting are described separately.

References

  1. EBCTCG (Early Breast Cancer Trialists' Collaborative Group), McGale P, Taylor C, Correa C, Cutter D, Duane F, Ewertz M, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet. 2011 Nov 12;378(9804):1707-16. doi: 10.1016/S0140-6736(11)61629-2. Epub 2011 Oct 19. Review. PMID: 22019144
  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 IA, Parulekar WR, Ackerman I, Chua BH, Nabid A, et al.  Regional Nodal Irradiation in Early-Stage Breast Cancer. N Engl J Med. 2015 Jul 23;373(4):307-16. doi: 10.1056/NEJMoa1415340.
  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. Bartelink H1, Maingon P2, Poortmans P3, Weltens C4, Fourquet A5, Jager J, et al. Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for earlybreast cancer: 20-year follow-up of a randomised phase 3 trial. Lancet Oncol. 2015 Jan;16(1):47-56. doi: 10.1016/S1470-2045(14)71156-8. Epub 2014 Dec 9.
  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. Kunkler IH, Williams LJ, Jack WJ, Cameron DA, Dixon JM; PRIME II investigators. Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breastcancer (PRIME II): a randomised controlled trial. Lancet Oncol. 2015 Mar;16(3):266-73. doi: 10.1016/S1470-2045(14)71221-5. Epub 2015 Jan 28
  14. 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.
  15.  Poortmans PM., Collette S, Kirkove C., Van Limbergen, E, Budach V, Struikmans H, et al. Internal Mammary and Medial Supraclavicular Irradiation in Breast Cancer.  N Engl J Med 2015; 373:317-327July 23, 2015DOI: 10.1056/NEJMoa141536
  16. 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.
  17. 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.
  18. 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.
  19. EBCTCG (Early Breast Cancer Trialists' Collaborative Group), McGale P, Taylor C, Correa C, Cutter D, Duane F, Ewertz M, et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-yearbreast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials.  Lancet. 2014 Jun 21;383(9935):2127-35. doi: 10.1016/S0140-6736(14)60488-8. Epub 2014 Mar Erratum in: Lancet. 2014 Nov 22;384(9957):1848.
  20. 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.

6.3.2 Systemic Management 

6.3.2.1 Introduction

Revised 18 January 2013

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. BC Cancer maintains current Chemotherapy Protocols.

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:

  • hormone receptor positive/her2 negative cancers;
  • her2 positive cancers;
  • 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.

6.3.2.2 Hormone Receptor Positive Breast Cancer

Revised 18 January 2013

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 Breast Tumour group recommends the following:

Table 1. BC Cancer 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 cancerAbsolute
Patients 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 (Prozac), or paroxetine (Paxil)Relative
These 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 osteoporosisRelativeAromatase 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 BC Cancer specific patient and professional education information.

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.

The BC Cancer 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 Assay Ineligible for funded Oncotype Dx Assay
§ 80 years of age or younger, and

Fit for chemotherapy, and fit for chemotherapy, with hormone receptor positive (ER+ and/or PR+) and HER-2 negative

1.  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 and T1b or larger

OR

§ Any Grade 1-2 cancers (any size) in women 40 years of age and younger

2.  Node-postive (pN1mi only) (0.3-2mm micrometastases in ONE lymph node)
§ 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 T1b 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 volume1,2,3 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. 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 (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

6.3.2.3 HER2 Positive

Revised 18 January 2013

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 BC Cancer protocol (BC Cancer 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 BC Cancer 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.

References

  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

6.3.2.4. Triple Negative Breast Cancers

Revised 18 January 2013

Triple negative breast cancers (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.

Reference

  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

6.3.2.5 Neoadjuvant Therapy

Updated October 2015

Neoadjuvant therapy (NAT) has been studied in multiple settings, tumour subtypes, and with many different types of agents. NAT may be considered in certain patients with early stage breast cancer.

In British Columbia, in patients with early stage breast cancer, most 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).

Details of NAT are further described below

6.3.2.6 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.1 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. If chemotherapy is given prior to surgery, clinically/radiologically suspicious lymph nodes should be biopsied prior to delivery of chemotherapy to aid in planning of radiotherapy after chemotherapy and surgery. 

2. Bone Modifying Agents

There is insufficient evidence to routinely recommend bisphosphante therapy as adjuvant therapy for 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.2,3 Studies with earlier generation bisphosphonates did not show a benefit, however. Data from longer follow up and corroborating evidence from ongoing trials are anticipated. While not funded by BC Cancer, Oncologists may recommend intermittent zoledronic acid for three years in selected early breast cancer patients based on existing evidence.

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

6.3.2.7 Hepatitis B Screening & Prophylaxis in Setting of Adjuvant Systemic Therapy

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 20044 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 included 258 cancer patients of which 81 had breast cancer.6 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 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
References

  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. 

SOURCE: 6.3 Early Invasive Breast Cancer (T1T2; N0N1; T3N0) ( )
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