Assessment & Prognostic Factors In Breast CancerWHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers.
Educational grant provided by Women's Health and Education Center (WHEC).
Few breast cancer risk factors are prevalent in more than 10% to 15% of the population, although some associated with very large relative risks (eg, mutated genes, cellular atypia). Estimates of the summary population attributable risk for breast cancer range from only 21% to 55%, leaving most of the population attributable risk for the disease unexplained. Age is one of the most important risk factors for breast cancer. Although age-adjusted incidence rates continue to rise, breast cancer mortality has fallen in the past decade in the United States.
The purpose of this document is to explain various classification schemes and staging of breast cancer. It is useful for determining the extent of the disease, predicting overall survival, and providing guidance for therapy. Clinically established prognostic factors in breast cancer and concepts and mechanisms of breast cancer metastasis are also discussed. We hope our forums help the clinicians better understanding of the disease process and the patient management.
Natural History of Breast Cancer:
It has been possible to use the large, population-based, randomized breast cancer screening trials to study a broader range of questions about the biology of breast cancer. During the asymptomatic pre-clinical phase of breast cancer growth, there is a time when the prevalent cancer has reached a size that is detectable with screening mammography. The time point is determined by a number of variables, including the rate of tumor cell growth, the suitability of the breast for optimal imaging, the sensitivity of equipment used, and the skill of the physician interpreting the results. The interval between the time of detection by screening and the time when the cancer becomes clinically incident (incident cancer) is defined as the lead-time. Thus the longer the lead-time is, the better the prognosis is. Lead-time, of course, depends on how long a breast cancer is in the pre-clinical or asymptomatic phase but is detectable with screening. The longer this pre-clinical phase of detectable cancer is, the longer is the lead-time.
Studies of a large group of breast cancer patients at the Institute Gustave-Roussy divided cancers according to their volume at surgical excision and plotted for each subset of volumes the actuarial cumulated proportion of patients with metastases as a function of time from treatment up to 25 years. From their extensive analysis of these data, the investigators concluded that the capacity of lymphatic spread is acquired much earlier than the capacity for hematogenous spread. In rapidly growing tumors, initial axillary node invasion was estimated in their model to have occurred when the primary tumor was 2 to 3 mm in diameter, and distant metastasis was estimated to have occurred with tumor diameter smaller than 1.5 cm (1).
It is now possible to determine the patient's risk for occult metastases by assessing tumor growth rate, histologic grade, receptor content, the presence or absence of specific gene markers, and DNA-ploidy. From such a profile it will be possible to predict the patient's position on the risk curve and thus select the appropriate surgical and adjuvant therapy. Certain genetic markers may even provide guidelines that will further increase the benefit of specific screening.
Breast Cancer Staging - Past, Present, and Future:
Classification schemas and staging of cancers are useful for determining the extent of disease, predicting overall survival, and providing guidance for therapy. This process requires objective analysis of pertinent, well-organized clinical and pathologic data. In the past, the cancer staging system was quite simplistic. Neoplasms were staged on the basis of clinical evaluation alone as operable or inoperable and classified as local, regional, or metastatic. However, there were limitations of clinical staging in accurately predicting the outcome in patients, and therefore the importance of deriving a more sophisticated staging system has been put in the practice. Future staging systems will likely include new technologies and in-depth molecular and pathologic analysis of the tissue specimen. The introduction of the sentinel lymph node technique has the potential of allowing more accurate staging with much less morbidity to the patients compared with complete axillary node dissection. Human Genome Project has provided a large number of molecular tools that may prove valuable in the evaluation of tumor progression. Central to any staging system are identifiable objective tumor and host characteristics that are prognostic of tumor regression.
Current Staging System:
Currently, the most popular staging system is the TNM system, based on the American Joint Committee on Cancer (AJCC) and the American College of Surgeons (ACS). Although TNM system lacks simplicity, its gains in prognostic power and accuracy have never been surpassed. The current staging system requires microscopic confirmation and histologic typing of the tumor before attempting any stage classification. Any patient with documented breast cancer may then be staged by clinical (per-operative) or pathologic criteria (post-operative, designated by a "p" prefix). The clinical-diagnostic staging process requires a complete physical examination, with determination of the extent of ipsilateral and contralateral neoplasic involvement of skin, breast tissue, regional and distant lymph nodes, and underlying muscles. The microscopic diagnosis of breast cancer must be confirmed by examination of breast tissue. Routine laboratory examination, chest X-ray films, and bilateral mammograms are also recommended.
The current TNM staging system based on the sixth edition of the AJCC staging manual is summarized below (2):
T Stage (Tumor Size) - clinical tumor state is the size of the tumor (reported in centimeters) based on the physical examination and various imaging modalities (eg, mammogram, ultrasound, CT scans, MRI scans). The pathologic T stage is based on the tumor size on the final pathologic specimen measuring only the invasive component. For multiple synchronous ipsilateral primary carcinomas, the largest tumor is used for the T classification and the physician should document that there are multiple primaries with their corresponding sizes and characteristics. Bilateral synchronous breast cancers are staged separately as separate primaries.
N Stage - clinical nodal staging is based on physical examination or imaging studies, including CT scans and ultrasound but excluding lynphoscintigraphy. Pathologic staging of lymph nodes is based on biopsies taken from sentinel lymph node or complete axillary lymph node dissections. If the regional lymph nodes cannot be assessed pathologically (previously removed or not removed for pathologic examination), they are designated pNx. One of the major changes in the revised staging system was to sub-classify internal mammary nodal metastasis.
M Stage - distant metastatic disease is designated as M1 disease. Ipsilateral supraclavicular lymph node disease is no longer considered distant metastatic disease but rather locally advanced disease (N3). Evidence of metastatic disease may be based on clinical history and physical examination, with or without the assistance of various imaging modalities and biochemical markers.
Stage Grouping:There are five stage groupings (0, I, II, III, IV) in the new TNM system, with stage II being sub-divided into A and B and stage III into A, B, and C.
|Stage I||T1(includes T1 mic.)N0M0|
|Stage IIA||T0N1M0 ; T1(T1 mic)N1M0 ; T2N0M0|
|Stage II B||T2N1M0; T 3N0M0|
|Stage IIIA||T0N2M0; T1(T1 mic)N2M0 ; T2N2M0 ; T3N1M0 ; T3N2M0|
|Stage IIIB||T4N0M0 ; T4N1M0 ; T4N2M0|
|Stage IIIC||Any TN3M0|
|Stage IV||Any T Any NM1|
Prognostic Factors for Breast Cancer:
Clinically established prognostic factors are those that meet the following criteria:
- Are reproducibly associated with a better or worse prognosis at a level of clinical utility.
- Provide independent information not available by more easily measured parameters (this requires multivariate analysis with other established factors).
- Are reproducible in multiple clinics or laboratories.
- Have demonstrated prognostic value in prospective trials.
Standard prognostic factors are: lymph node status; tumor size; histologic grade; and age. Predictive factors are: estrogen and/or progesterone receptor status; HER2 overexpression.
Axillary lymph nodes - the degree of involvement by metastatic tumor cells is the dominant prognostic factor for later systemic disease (3). Oncologists believe that virtually all women with axillary lymph node involvement should receive adjuvant systemic therapy. The potential for metastatic spread also depends on interaction with host resistance. Axillary lymph node status reflects actual end-results data on the interaction between aggressiveness and host defense mechanisms. Therefore it is not surprising that it provides the most important prognostic measure available in clinical decision- making. The adoption of sentinel lymph node has, however, introduced other areas of controversy in prognostic factor research. The first issue concerns the additional values of the number of involved lymph nodes in planning adjuvant systemic therapy. If a patient has a clinically node positive, the risk of systemic failure is roughly 70% at 10 years. Micro-metastases to axillary lymph nodes, defined as metastases less than 2 mm in diameter, have been found to have the same prognostic significance as negative nodes (3).
Tumor size - it is the most important single, secondary prognostic factor for risk of recurrence and consequent benefit from systemic therapy in axillary node-negative breast cancer. Tumor size also affects axillary node involvement: Axillary nodes are involved in 15% of patients with tumors smaller than 1.1 cm in diameter and in 60% of those with tumors 5.5cm in diameter or larger. Small tumors associated with positive nodes have better prognosis than large tumors with positive nodes. Survival decreases with increasing tumor size in all node categories according to this large study (4). Patients with tumors larger than 2 cm benefit significantly from adjuvant therapy, and those with tumors measuring 1 to 2 cm should be evaluated for risks and benefits based on careful examination of other prognostic factors.
Histologic grading system - histopathologic analysis is based on individual characteristics such as nuclear grade, gland formation, or the clustering of various cytologic and histologic features into special types of breast carcinoma. Breast cancers generally arise from the two major functional units of the breast: lobules and ducts. Invasive ductal and invasive lobular histologies behave similarly, and the differentiation has no particular prognostic significance. They are further classified as non-invasive or carcinoma-in-situ if the malignant cells fail to traverse the basement membrane and as infiltrating or invasive if the malignant cells do invade the basement membrane. The three special types of invasive breast cancer are tubular, mucinous (or colloid), and medullary. Tubular carcinomas have excellent prognosis and its accounts for some 3% to 5% of all breast cancers but may be the most prevalent of the special breast cancers. Colloid carcinoma is a glandular papillary or glandular cystic tumor that demonstrates a high degree of maturity and prominent mucin surrounding the cellular aggregates. A favorable prognosis is associated with colloid carcinoma only when it occurs in the pure form. It accounts for 2% to 4% of all invasive breast cancers and usually affects older women. Medullary carcinoma is a parenchyma-rich tumor with little stroma that shows a marked lymphoid infiltrate and it accounts for 5% to 7% of all breast cancers. These tumors have a favorable prognosis despite a high degree of cellular pleomorphism and a high mitotic rate. Generally, medullary tumors are well circumscribed and may be large, but size does not seem to affect prognosis adversely (5).
Pure infiltrating - papillary carcinomas are rare; it accounts for only 0.3% to 1.5% of all breast cancers. Intraductal papillary growth is a common component of breast cancer of many other histologic types, and like colloid carcinoma, unless the papillary carcinoma is present in the pure form, it is not associated with a more favorable prognosis. Adverse histologic features such as lymphatic vessel or blood vessel invasion may be noted at the time of diagnosis. These findings are strongly related to the presence of lymph node metastases and are consequently of moderate prognostic significance. Despite their association with increased risk, they are not of independent significance sufficient for them to influence clinical decision-making regarding such things as systemic therapy.
Age - younger age is a major risk factor for bad outcome in breast cancer. A multivariate analysis of more than 4,000 women younger than 50 demonstrated that the hazard ratio set at 1.0 for women 40 to 44 and 45 to 49, was 1.8 for those younger than 30 years, 1.7 for women 30 to 34, and 1.5 for those 35 to 39. These differences are highly statistically significant (6).
Steroid Receptors - the measurement of estrogen-receptors (ERs) and progesterone-receptors (PRs) has become standard of practice in the evaluation of patients with primary breast cancer. Although there is modest prognostic effect of receptor status, it disappears by 5 years. Much data on the prognostic significant of hormone receptor assays is confounded by the predictive value of receptor positivity. Data from both the National Surgical Adjuvant Breast Project (NSABP) and the National Cancer Institute (NCI) Breast Intergroup have been confirmed by the Early Breast Cancer Trialists' Collaborative Overview of all randomized trials. These all show that the benefit of tamoxifen, the most potent therapy in preventing systemic failure of breast cancer, is confined to patients with receptor-positive tumors. Thus the treatment benefits prediction confounds the prognostic value except when it is measured in patients who have not received systemic therapy (7).
Epidermal Growth Factor Receptor Family - over the last decade, many growth factors and their receptors have been found to be expressed in primary breast cancers. Some of these are estrogen regulated, some are prognostically important, and the role of many remains unknown. Epidermal growth factor receptors are upregulated in approximately 25% to 40% of breast cancers, usually ER-negative cases. Overexpression of epidermal growth factor receptor is associated with poor prognosis and hormone resistance, in lymph-node-positive and lymph-node-negative cases. Another member of the family, ERB2, or HER2, is overexpressed in 20% to 30% of cases, usually as a result of gene amplification (8). Controversy reigns over the role of HER2 overexprssion as a predictive factor for tamoxifen resistance, sensitivity to certain cytotoxic agents, or dose density of chemotherapy.
Recurrence after breast conservative surgery and radiation:
The results of radiation on the local control of triple receptor-negative breast cancer (negative estrogen [ER], progesterone [PR], and HER-2/neu receptors) were studied. ER- and PR-negative patients were statistically significantly more likely to be black, have T2 disease, have tumors detectable on both mammography and physical examination, have grade 3 tumors, and receive chemotherapy. There were no significant differences noted with regard to ER- and PR- patients by HER-2 status. There was a significant difference noted in rates of first distant metastases (3%, 12%, and 7% for Groups 1, 2, and 3, respectively; P = .009). However, the isolated 5-year loco-regional recurrence (LRR) was not significantly different (2.3%, 4.6%, and 3.2%, respectively; P = .36) between the 3 groups. Conservative surgery and radiation were used in 753 patients with T1-T2 breast cancer. Three groups were defined by receptor status: Group 1: ER or PR (+); Group 2: ER and PR (-) but HER-2 (+); and Group 3: triple-negative (TN). Factors analyzed were age, menopausal status, race, stage, tumor size, lymph node status, presentation, grade, extensive in situ disease, margins, and systemic therapy. The primary end-point was 5-year loco-regional recurrence (LRR) isolated or total with distant metastases. Patients with triple negative (TN) breast cancer do not appear to be at a significantly increased risk for isolated LRR at 5 years and therefore remain appropriate candidates for breast conservation (9).
Published reports provide level-III evidence in support of the hypothesis that distant metastatic breast cancer (MBC) might be curable in up to 3% of cases through a multidisciplinary approach including combination chemotherapy regimens in selected patients, usually young, and with limited metastases. This study evaluates the rate and characteristics of long-term survivors based on a non-selective study cohort. Five patients (3.4%) were long-term survivors (9-14 years after initial diagnosis of MBC) without any clinical evidence of disease. They had a 2-peaked distribution of age: 3 were 41-57 years old at the diagnosis of MBC and 2 were much older (76 and79 years). Median survival time after diagnosis of MBC was 152 (range, 109-172) months. Three patients had isolated metastatic lesions, although 1 patient had multiple organ metastases and another extensive bone metastases. In 4 of 5 cases, long-term survival was achieved without the administration of chemotherapy. Long-term survivors in MBC comprise a relatively heterogeneous group, and the factors which lead to the quite rare situation of long-term survival can hardly be evaluated systematically. Aggressive chemotherapy regimens appear not to be a key factor for survival. Furthermore, in a non-selective study cohort, some patients clearly are not only alive but also disease-free more than 12 years after initial relapse. This fraction may be small, but the chance for survival, and even for cure, truly exists (10).
Metastasis of breast cancer is a highly selective process, which depends on both unique tumor cell phenotypes and normal host factors. In breast and other cancers the contribution of regional lymph nodes and distant organ sites to the pathogenesis of metastasis has been well documented. Clinical and experimental data indicate that specific cellular mechanisms exist for tumor cell arrest and implantation, invasion, survival, and growth of metastatic cells in different organs.
How can all of these various prognostic factors be used to make rational treatment decisions? The first step in the process is to determine recurrence probability for the sub-population of patients with a similar profile of the established prognostic factors. Oncologists agree that axillary nodal metastasis mark a population of breast cancer patients who should receive adjuvant systemic therapy. Within this group of patients the number of involved axillary lymph nodes remains the most powerful predictor of prognosis, overwhelming the results of the other factors. In the absence of nodal metastases, tumor size and grade or proliferative index, together with the possibility of special histologies, allow patients to be sorted into groups of extremely low risk or increasing risk. Some oncologists have suggested that adjuvant systemic therapy is appropriate for all patients with invasive breast cancer, regardless of prognostic factors. If prognostic factors can identify the populations at risk, predictive factors can identify therapies that will not be effective for certain subgroups. Hormone receptor-negative tumors will not respond to tamoxifen, and tumors that do not overexpress HER2 will not respond to the anti-erbB2 drug trastuzumab (Herceptin).
- Li CI, Malone KE, Porter PL et al. Relationship between menopausal hormone therapy and risk of ductal, lobular, and ductal-lobular breast carcinomas. Cancer Epidemiol Biomarkers Prev 2008;17:43-50
- Bland & Copeland. The Breast (third edition) 2004. The American Joint Committee of Cancer (AJCC) report on staging for breast cancer. pp. 438-439. Publisher: Saunders.
- Reeves GK, Beral V, Green J et al. Women Study Collaborators. Hormonal therapy for menopause and breast-cancer risk by histological type: a cohort study and meta-analysis. Lancet Oncol 2006;7:910-918
- Silva OE, Zurrida S. Breast Cancer: a practical guide. 3rd ed. New York (NY): Elsevier; 2005. P. 26-63
- Santiago RJ, Wu L, Harris E et al. Fifteen-year results of breast-conserving surgery and definitive irradiation for Stage I and II breast carcinoma: the University of Pennsylvania experience. Int J Radiat Oncol Biol Phys 2004;58:233-240
- National Comprehensive Cancer Network. NCCN Practice Guidelines in Oncology. Breast Cancer. v. 1.2008. Available at: http://www.nccn.org/professionals/physician_gls/PDF/breast-screening.pdf Retrieved 12 July 2009
- Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 2005;97:1652-1662
- National Cancer Institute. The study of tamoxifen and raloxifene (STAR): questions and answers. Available at: http://www.cancer.gov/newscenter/pressreleases/STARresultsQandA Retrieved 20 August 2009
- Freedman GM, Anderson PR, Li T et al. Locoregional recurrence of triple-negative breast cancer after breast-conserving surgery and radiation. Cancer 2009;115:946-951
- Guth U, Huang DJ, Dirnhofer S et al. Distant metastatic breast cancer as an incurable disease: a tenet with a need for revision. Cancer J 2009;15:81-86
The Editors are deeply indebted to the authors and their co-authors who have contributed to the series on the Breast Cancer to give you a comprehensive overview and better understanding of the disease process.
Finally, to all who are involved in preparing the text for gynecologic-oncology section and the friends who expressed interest and encouragement, we are greatly appreciative of your support in helping us to prepare this section.
Dedicated to Women's and Children's Well-being and Health Care Worldwide