Prognostic markers on Breast Cancer
- 1. 1 Rev. 29 PROGNOSTIC MARKERS INPROGNOSTIC MARKERS IN BREAST CANCERBREAST CANCER
- 2. 2 OutlineOutline Introduction and Breast Cancer Statistics Prognostic Factors Tumor Grade and Type Lymph Node Status Distant Metastases Gene Markers Hormone Receptors Growth Factor Receptor Tumor Suppressor Gene Proliferation Marker Angiogenesis Marker Summary & Conclusion
- 3. 3 Breast Cancer - IntroductionBreast Cancer - Introduction Cells in the breast tissue divide and grow without control 80% of cases of breast cancer originate in the mammary ducts 20% cases arise in the lobules There are 2 main kinds of breast cancer: Invasive breast cancer carcinoma in situ
- 4. 4 OVERVIEWOVERVIEW BREAST CANCER FACTS & FIGURES New cases diagnosed in American women in 2002 : 203,500 New cases of invasive breast cancer in 2001: 192,200 Breast Cancer affects more than 1000 men in this country each year An estimated 40,200 deaths occurred in 2001 Overall survival rate is 18% if cancer has metastasized Early diagnosis is critical Overall 5-year survival rate: 96%
- 5. 5 PROGNOSTIC FACTORS Prognostic Factors are clinical, pathologic, and biological features of cancer patients and their tumors that forecast probable course and outcome of the disease. Predicts the likelihood of patient survival. Predicts recovery from cancer without additional or adjuvant systemic therapy after initial surgery.
- 6. 6 BREAST CANCERBREAST CANCER HIGHLY ELEVATED RISK FACTORS Female Age >50 North American or Northern European ancestry Personal history of prior breast cancer Family history of bilateral, pre-menopausal, or familial cancer Atypical proliferative breast disease with family history
- 7. 7 BREAST CANCERBREAST CANCER MODERATELY ELEVATED RISK FACTORS Any first degree relative with history of breast cancer Upper social / economic class Prolonged uninterrupted menses Postmenopausal obesity Proliferate benign breast disease
- 8. 8 BREASTBREAST CANCERCANCERSLIGHTLY ELEVATED RISK FACTORS Moderate alcohol intake Menarche: <12 years old Diet (?) Hormonal Replacement Therapy (?) Birth control pills (?)
- 9. 9 • T1 Tumour ≤2cm in greatest dimension • T2 Tumour 2-5 cm in greatest dimension • T3 Tumor >5 cm in greatest dimension • T4 Fixation to chest wall; edema; skin ulceration; inflammatory breast cancer; peau d’orange; satellite skin nodules PROGNOSTIC FACTORSPROGNOSTIC FACTORS PRIMARY TUMOR SIZE
- 10. 10 PROGNOSTIC FACTORSPROGNOSTIC FACTORS TUMOR GRADETUMOR GRADE Pathologists determine how close the cancer cells resemble normal tissue The more abnormal the cells, the higher the grade of the tumor High-grade tumors are more likely to spread to lymph nodes and other parts of the body Also determine the number of cancer cells in the process of dividing - assess the growth rate of the tumor The higher the grade of the tumor - the worse a woman’s prognosis
- 11. 11 • N0 No palpable regional lymph nodes • N1 Palpable ipsilateral axillary nodes, movable • N2 Palpable ipsilateral axillary nodes, fixed • N3 Metastases to ipsilateral mammary nodes PROGNOSTIC FACTORSPROGNOSTIC FACTORS LYMPHATIC SPREAD
- 12. 12 • Mx Distant metastases cannot be assessed • M0 No distant metastases • M1 Distant metastases present PROGNOSTIC FACTORSPROGNOSTIC FACTORS DISTANT METASTASES
- 13. 13 PROGNOSTIC FACTORSPROGNOSTIC FACTORS TNM STAGING STAGETNM0TisN0M0IT1N0M0IIAT0N1M0T1N1M0T2N0M0IIBT2N1M0T3N0M0IIIAT0N2M0T1
- 14. 14 HORMONE RECEPTORSHORMONE RECEPTORS ESTROGEN RECEPTOR (ER) Estrogen, by interacting with ER, plays a central role in regulating the proliferation and differentiation of normal breast epithelium Approximately 60-70% of breast cancers express ER ER is localized in the nucleus only Estrogen binds to its receptor (i.e. ER) and the complex then activates DNA synthesis Primary reason for measuring ER in breast cancer is the ability to predict response to endocrine therapy
- 15. 15 HORMONE RECEPTORSHORMONE RECEPTORS ESTROGEN RECEPTOR (ER) Survival statistics are improved in patients with receptor positive tumours Recurrence/survival benefit after diagnosis is 10% for patients with ER(+) tumors who did not receive adjuvant therapy There is a 20-30% average reduction in recurrence/mortality in ER(+) patients receiving adjuvant endocrine therapy There is a 60% overall clinical response rate in patients with ER(+) advanced breast cancer treated with endocrine therapy
- 16. 16 HORMONE RECEPTORSHORMONE RECEPTORS ESTROGEN RECEPTOR (ER) • Breast carcinoma stained with anti-ER MAb (ER88 / BioGenex) • This antibody stains human nuclear ER
- 17. 17 HORMONE RECEPTORSHORMONE RECEPTORS PROGESTERONE RECEPTOR (PgR) PgR is an ER-regulated gene product with many of the same prognostic/predictive implications as ER in breast cancer PgR is an estrogen-inducible protein, of which expression is indicative of an intact ER pathway. PgR may identify tumours that are hormonally responsive to estrogen, thereby improving the overall predictive value of steroid receptor IHC
- 18. 18 HORMONE RECEPTORSHORMONE RECEPTORS PROGESTERONE RECEPTOR (PgR) • PR88 (BioGenex) stains the nucleus of carcinoma cells but not surrounding connective tissue • Microwave pretreatment with Antigen Retrieval Citra solution of formalin-fixed, paraffin embedded breast tissue sections is recommended
- 19. 19 Receptor Content Incidence Response Rate ER(+) / PR(+) 50 77% ER(-) / PR(+) 5 46% ER(+) / PR(-) 20 27% ER(-) / PR(-) 25 11% • PR may be a more important predictor as there are more responders among patients with ER(-)/PR(+) compared to ER(+)/PR(-) tumours. STEROID RECEPTORSSTEROID RECEPTORS ER & PgR INCIDENCE & RESPONSE TO THERAPY
- 20. 20 GROWTH FACTOR RECEPTORGROWTH FACTOR RECEPTOR c-erbB-2 (Her-2/neu) c-erbB-2 (Her-2/neu) is a gene located on chromosome 17q12 - 21.32, encoding a 185 kDa protein c-erbB-2 (Her-2/neu) oncoprotein is a member of the tyrosine kinase receptor c-erbB-2 (Her-2/neu) oncoprotein is thought to function as a growth factor receptor, in addition to being involved in the regulation of cellular differentiation, adhesion, and motility
- 21. 21 GROWTH FACTORGROWTH FACTOR RECEPTORRECEPTORc-erbB-2 (Her-2/neu) c-erbB-2 (Her-2/neu) is amplified and/or overexpressed in 25 - 30% of invasive breast cancers c-erbB-2 (Her-2/neu) overexpression is correlated with an increased cell proliferation rate and poorer overall survival c-erbB-2 (Her-2/neu) overexpression is inversely related to Estrogen Receptor (ER) expression
- 22. 22 GROWTH FACTOR RECEPTORGROWTH FACTOR RECEPTOR c-erbB-2 (Her-2/neu) There is a direct correlation between c-erbB-2 (Her-2/neu) overexpression and resistance to cytoxan/methotrexate therapy c-erbB-2 (Her-2/neu) overexpression is also linked to tamoxifen resistance Increased levels of c-erbB-2 (Her-2/neu) might enhance response to adriamycin In certain situations, patients with an amplified c-erbB-2 status will qualify for specialized therapies, such as Herceptin
- 23. 23 GROWTH FACTOR RECEPTORGROWTH FACTOR RECEPTOR c-erbB-2 (Her-2/neu) • Breast carcinoma stained with anti-c-erbB-2 (Clone CB11 / BioGenex) • The specific binding of this MAb has been demonstrated by immunoprecipitation using c-erbB-2 protein from SKB-3 cells
- 24. 24 TUMOUR SUPPRESSOR GENETUMOUR SUPPRESSOR GENE p53 GENE p53 is a tumor suppressor gene whose protein product is a nuclear transcription factor with many functions, including arresting cell cycle progression p53 mutations lead to abnormal cell growth by failing to trigger cell suicide when DNA repair fails Mutant p53 are point mutations in conserved exons, resulting in a nonfunctional but more stable protein that accumulates to high levels in the nucleus
- 25. 25 TUMOUR SUPPRESSOR GENETUMOUR SUPPRESSOR GENE p53 GENE Mutant p53 correlates with more aggressive tumor behaviour, metastases, and lower 5-year survival rates p53 mutations have been found in more than 50 types of human tumours, including 70% of colorectal cancers, 50% of lung cancers, and 40% of breast cancers
- 26. 26 TUMOUR SUPPRESSOR GENETUMOUR SUPPRESSOR GENE p53 GENE Mutant p53 is a strong and independent prognostic factor that is very good at detecting high-risk patients, but not very good at defining patients with a low enough risk to alter standard therapy Oncologists still order p53 analysis on breast cancers and use the results to help make treatment decisions for patients whose outlook is borderline or complicated by other factors
- 27. 27 TUMOUR SUPPRESSOR GENETUMOUR SUPPRESSOR GENE p53 GENE • Breast carcinoma stained with anti-p53 (Clone BP53-12-1 / BioGenex) • Shows primarily a nuclear localization of mutant p53 protein
- 28. 28 PROLIFERATION MARKERPROLIFERATION MARKER Ki-67 Ki-67 is a 345-395 kD non-histone protein-protein complex The gene encoding Ki-67 is localized on chromosome 10 and organized in 15 exons Expression of human Ki-67 protein is strictly associated with cell proliferation
- 29. 29 PROLIFERATION MARKERPROLIFERATION MARKER Ki-67 Ki-67 expression is correlated with relapse-free survival, histologic grade, and mitotic figure count Ki-67 expression is inversely associated with the presence of ER and PR in breast carcinomas and the survival rate Ki-67 is more likely to be expressed in aneuploid tumours compared to diploid tumours
- 30. 30 PROLIFERATION MARKERPROLIFERATION MARKER Ki-67 • Malignant lymphoma stained with anti-Ki-67 (Clone Ki88 / BioGenex) • This MAb reacts with the Ki-67 antigen localized in nuclei of proliferating cells
- 31. 31 ANGIOGENESISANGIOGENESIS Factor VII RA Factor VIII RA remains a sensitive marker of benign blood vessels and has been used for the study of angiogenesis in neoplasms such as breast cancer Angiogenesis is the process leading to the formation of new blood vessels, necessary for tumour growth and metastasis
- 32. 32 ANGIOGENESISANGIOGENESIS Factor VII RA Factor VIII RA (Related Antigen) is more appropriately known as the von Willebrand factor Factor VIII is a glycoprotein and is complexed with factor VIII-RA in plasma Factor VIII RA is a useful marker for endothelial cell differentiation
- 33. 33 ANGIOGENESISANGIOGENESIS Factor VII RA • Blood vessels stained with anti-Factor VIII (Clone BGX016A / BioGenex) • Note the staining of endothelial cells
- 34. 34 SUMMARYSUMMARY FACTORS DEFINING POOR PROGNOSIS Histological Grade 3 Tumor Size: >5.0 cm Lymph Node Status: N>0 ER (-) and PR (-) p53 (+) c-erbB-2 (+) Ki-67: High Proliferation Rate Factor VIII RA: (+)
- 35. 35 CONCLUSIONCONCLUSION Tumor size and nodal status should be reported on all breast cancers, because they are currently the only prognostic factors that are comprehensively validated and powerful enough to identify a subset of patients whose predicted outcome is sufficiently favorable to justify withholding adjuvant chemotherapy. Hormone receptors should also be assessed in every case, because they are the only predictive factors with proven usefulness in selecting patients likely to respond to adjuvant endocrine therapy.
Editor's Notes
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