1. Use of prognostic and predictive factors for breast cancer
2. Definition of menopause
3. Staging system for breast cancer
4. Limitations of the current staging systems for breast cancer
5. Early breast cancer
6. Tests for staging an early breast cancer
7. Review of breast pathology reports by BC Cancer Agency pathologists

1. Use of prognostic and predictive factors for breast cancer

Breast cancer is a heterogeneous disease. This means that it presents in very different ways and in patients who have very different clinical, biological, social and human characteristics. Therefore, the approach to breast cancer treatment must be individualized for every patient.

Prognostic factors predict outcomes (relapse or progression) and are independent of treatment effects. Predictive factors predict response to a specific therapy. Some markers are thought to be purely prognostic and some purely predictive, and some are both.¹

• Patient age and menopausal status: Pre-menopausal women younger than 35 tend to have worse clinical outcomes than older post-menopausal women. Younger women tend to have a higher prevalence of adverse histological features, increased tumour size, node involvement, ER negativity, and higher proliferation rates
• Tumour size (Table 1): The larger the tumour, the more likely it is to spread. Breast cancers that have grown into the skin, muscle or chest wall (locally advanced) have a higher risk of recurring or spreading.

Table 1. Tumour Size - Three spheres measuring 1 cm, 3 cm, and 5 cm.

Table content sourced with permission from www.breastcancer.org

• Histological grade: Cancers can be graded as low grade (score 1 out of 3, or 3-5 out of 9), moderate grade (score 2 out of 3, or 6-7 out of 9), or high grade (score 3 out of 3 or 8-9 out of 9). They can also be referred to as well, moderately, or poorly differentiated. The higher the grade, the higher the risk
• Axillary lymph node status: Node status is the most powerful prognostic factor for primary breast cancer. The risk of recurrence increases with the number of involved nodes, the amount of cancer contained in them, and if extranodal extension is present. Oncologists prefer to have 5-10 nodes in order to do appropriate staging
• HER-2/neu level of expression: HER-2/neu is a cancer gene that is overexpressed in some breast cancers (15-20%). HER-2 positive breast cancer behaves in a more aggressive manner. Her-2/neu status is also a predictive factor for the use of trastuzumab and may also predict the added benefit to anthracycline or taxane-containing chemotherapy regimes
• Histological subtype: Some invasive cancers, such as tubular, mucinous, and colloid cancers, tend to be less aggressive, whereas medullary and inflammatory cancers have a higher risk of recurrence
• Lymphatic or vascular invasion (Table 2): If cancer cells are found in the lymph channels or blood vessels in the breast, the prognosis is similar to having one to three positive lymph nodes.

Table 2. Vascular and Lymphatic Invasion
Normal breast with cancer cells invading the lymph channels and blood vessels in the breast tissue. A: blood vessels B: lymphatic channels Enlargement: A: normal duct cells B: cancer cells C: basement membrane D: lymphatic channel E: blood vessel F: breast tissue

Table and image sourced with permission from www.breastcancer.org

• Presence or absence of metastatic disease: once a cancer has spread, it is no longer considered curable
• Hormone receptor status: Most breast cancers are receptive to hormones (estrogen and/or progesterone). When stimulated with these hormones, tumour cells will grow and divide. These receptors are predictive factors as to whether the tumour will respond to anti-estrogen therapy (e.g. tamoxifen, Aromatase Inhibitors)
  • About 75% of breast cancers are estrogen-receptor-positive ("ER-positive")
  • About 65% of breast cancers are progesterone-receptor-positive ("PR-positive")
  • About 25% of breast cancers are ER-negative and PR-negative or "unknown"
  • About 10% of breast cancers are ER-positive and PR-negative
  • About 5% of breast cancers are ER-negative and PR-positive⁷

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2. Definition of menopause

A woman's menopausal status affects the adjuvant systemic treatments that will be beneficial for her. Menopause is the permanent cessation of menses, and as the term is utilized in breast cancer management includes a profound and permanent decrease in ovarian estrogen synthesis. Reasonable criteria for determining menopause include any of the following:²

• Prior bilateral oopherectomy
• Age greater than or equal to 60 years
• Age less than 60 years and amenorrheic for 12 or more months in the absence of chemotherapy, tamoxifen, or ovarian suppression and FSH and estradiol in the postmenopausal range
• If taking tamoxifen, and age less than 60 years, then FSH and plasma estradiol level in postmenopausal ranges

It is not possible to assign menopausal status to women who are receiving an LH-RH agonist or antagonist. In women premenopausal at the time of adjuvant chemotherapy, amenorrhea is not a reliable indicator of menopausal status.²

3. Staging system for breast cancer

Staging systems are used to provide a common language to describe the extent of a breast cancer, to understand prognosis and to guide treatment decisions.There are several systems for classifying the extent or stage of breast cancer. The two most common are the Stage I, II, III, IV system and the TNM system. These systems provide an approximate idea of the extent of the disease to help plan the treatment strategy. They do not determine specific outcomes or prognosis for any one particular woman. The TNM classification system is more useful for cancer specialists to communicate with each other.

Please refer to the American Joint Committee on Cancer (AJCC) TNM staging system.

4. Limitations of the current staging systems for breast cancer

The present pathological staging system was largely developed to determine surgical resectability. Modern day decisions involve both the need to establish surgical resectability, and whether or not the tumour will recur and hence the need for adjuvant systemic therapy. To better estimate the risk of recurrence, additional features such as grade and lymphovascular invasion (LVI) have been incorporated with tumour size and nodal status. There is major research focusing on trying to develop better prognostic factors and scientists are are looking at biomarkers. Biomarkers are molecular/ genetic expressions of a breast cancer which might better predict outcomes.

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5. Early stage breast cancer

Early stage breast cancer refers to DCIS or Stage I, IIA, IIB, or IIIA breast cancer. (Stages IIIB, IIIC and IV are considered advanced breast cancers.)

6. Tests for staging an early breast cancer ³

Pre-operative Investigations: The goal of pre-operative investigations is to determine the presence or absence of blood borne metastatic disease prior to definitive management. These tests can be arranged by the general practitioner, surgeon or oncologist:

• History and physical exam, including supraclavicular nodes, lungs, liver and bones, to assess any physical symptoms which may suggest metastatic disease
• Bilateral mammography
• CBC
• Liver enzymes and alkaline phosphatase
• Chest X-ray
• Add abdominal ultrasound if liver enzymes are elevated
• Add bone scan for:
  • tumours greater than 5 cm;
  • palpable axillary nodes; or
  • elevated alkaline phosphatase

Note: Bone scans are 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.

Post-op Investigations: Major information for breast cancer staging post-op is the pathology report. Other recommended work-up and staging of invasive breast cancer includes:

• History and physical exam, including supraclavicular nodes, lungs, liver and bones, to assess any physical symptoms which may suggest metastatic disease
• Complete blood cell count
• Platelet count
• Liver function tests
• Chest imaging
• Bilateral diagnostic mammography
• Add bone scan for:
  • locally advanced disease; or
  • node positive disease
• Tumour markers: Tumour markers (CEA, CA15-3) 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.⁴

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7. Review of breast pathology reports by BC Cancer Agency pathologists

Breast cancer pathology reports are reviewed in cases where there is a need to further clarify specific aspects of the tumour where it may impact treatment (e.g. margins). These reviews are prompted by the treating oncologist.⁵

References

1. Harris JR, Lippman ME, Morrow M, Osbourne CK. Diseases of the breast. 3rd ed. Philadelphia, PA. Lippincott Williams & Wilkins; 2004, pg.675-682.

2. Breast cancer: practice guidelines in oncology, Version 2.2006, 12-05-05 © 2005, National Comprehensive Cancer Network, Inc.

3. breastcancer.org (http://www.breastcancer.org). Narberth (PA): breastcancer.org; c2000-06. (cited Sep 22, 2006). Available from: http://www.breastcancer.org/tre_sys_hrt_role.html

4. BC Cancer Agency (http://www.bccancer.bc.ca). Vancouver (BC): 2006. (cited Sep 22, 2006). Available from: http://www.bccancer.bc.ca/HPI/CancerManagementGuidelines/Breast/Staging.htm

5. BC Cancer Agency (http://www.bccancer.bc.ca). Vancouver (BC): 2006. (cited Sep 22, 2006). Available from: BC Cancer Agency's cancer Management Guidelines -> Breast -> Diagnosis