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Carolina Breast Cancer Study: Breast cancer subtypes and race Robert Millikan University of North Carolina Chapel Hill, NC
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Research Questions Could breast cancer represent more than one disease? Can different subtypes of breast cancer help to explain racial disparities?
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Research Question #1 A major problem in breast cancer research is tumor heterogeneity: Patients do not respond uniformly to treatment. Could breast cancer represent more than one disease?
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Clinical and Pathologic Staging of Breast Cancer
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Traditional Staging Breast cancer patients receive a clinical stage at initial diagnosis. The definitive stage is based upon pathologic information obtained at the time of surgical removal of the primary tumor and regional lymph nodes. TNM system.
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New Paradigm “Biology trumps staging.” ASCO 2008 Differences in underlying biology of breast tumors determine clinical course and response to therapy.
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How do we get at the underlying biology of breast cancer? How do we apply this knowledge to: Prognosis Predicting therapeutic response Understanding disease causation Prevention
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Histology TNM Staging Biology IHC / TMAsmRNA profiling
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Histology Biology IHC / TMAsmRNA profiling TNM Staging
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TNM staging T stands for tumor (its size and how far it has spread within the breast and to nearby organs). N stands for spread to lymph nodes (the number of nodes where cancer is detected). M is for metastasis (spread to distant organs).
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TNM staging TNM staging helps understand survival (prognosis). It does not tell us how to treat, what drugs to give (predict therapeutic response).
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New paradigm: Use gene expression profiling and immunohistochemistry to understand the underlying biology
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Histology Biology IHC / TMAsmRNA profiling TNM Staging
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Identification of Breast Cancer Subtypes DNA microarray-based gene expression profiling. Perou and colleagues (UNC Chapel Hill) 8,102 genes →1,753 genes→ 496 genes “intrinsic” Nature 406: 747-52 (2000).
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“Intrinsic” breast cancer subtypes Basal-like ER- PR- HER2- ck5/6+ and /or HER1+ Luminal A ER+ and/or PR+ HER2- Luminal B ER+ and/or PR+ HER2+ HER2+ / ER – ER- PR- HER2+ “Unclassified” Negative for all five markers
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HistologyClinical Staging Biology IHC / TMAsmRNA profiling
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Algorithm for breast cancer subtypes HER2 +HER2 - EGFR + or CK5/6 + EGFR - CK5/6 – UnclassifiedBasal-like All cases ER - PR - ER+ or PR + HER2 -HER2 + HER2+/ER-Luminal BLuminal A
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Carolina Breast Cancer Study
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The Carolina Breast Cancer Study (CBCS) is an ongoing population-based epidemiologic study examining the causes of breast cancer in African American and white women. The study began in 1993 and continued enrolling participants until 2001 (Phase 1 and 2). We are opening the study again from 2008 to 2012 (Phase 3). Carolina Breast Cancer Study
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Distribution of IHC subtypes in invasive breast cancer (Phase 1 CBCS) Luminal A (ER+ PR+ HER2-) 51% Luminal B (ER+ PR+ HER2+) 16% Basal-like (ER- PR- HER2- ck5/6+ and/or HER1+) 20% HER2+, ER- (HER2+,ER-, PR-) 7% Unclassified (negative for all five IHC markers) 6%
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Basal-like subtype Increased proliferation (P < 0.0001) Higher grade (P < 0.0001) Poor differentiation (P < 0.003) P53 mutation positive (P< 0.001) JAMA 2006, 295: 2492-2502.
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Breast Cancer Specific Survival Mean survival Percent (years)survival Luminal A 7.6 84% Luminal B7.7 87% Basal-like4.9 75% HER2+/ER-6.752% Log-rank test P < 0.0001
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Luminal A Luminal B Unclassified Basal-like HER2+/ER- P <0.0001 Breast Cancer Specific Survival Time in Years Note: Prior to introduction of herceptin.
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Basal-like subtype of breast cancer No proven therapeutic targets ER negative, PR negative: Can’t use Tamoxifen or anti-estrogens HER2 negative: Can’t use Herceptin
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Tailored Therapy ER positiveER negative HORMONAL THERAPY HERCEPTIN EGFR C-kit BRCA1 defective Gefitinib, erlotinib Lapatinib CI-1033 DNA damage PARP inhibitors Imatinib/Gleevec Luminal A Luminal B HER2 BASAL-LIKE BASAL THERAPEUTIC TARGETS?
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Research Question #2: Why is breast cancer mortality higher among African American women compared with white women? Younger white women 6.3 deaths / 100,000 per year Younger African American women 11.0 deaths / 100,000 per year
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Basal-like breast cancer is more common in younger African American women. Our observation may help to explain why breast cancer mortality is higher among younger African American women.
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Distribution of subtypes according to race and menopausal status (CBCS Phase 1) Premenopausal African American Postmenopausal African American Premenopausal Whites Postmenopausal Whites Luminal A 36%59%51%58% Luminal B 9%16%18%16% Basal-like 39%14%16% HER2+ / ER- 9%7%6% Unclassified Chi square P = 0.0001 6%4%10%4%
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Basal-like breast cancer in North Carolina (Carolina Breast Cancer Study)
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Latest CBCS results Younger African American women have a higher risk of basal-like breast cancer because they have a higher prevalence of risk factors for the disease: Higher waist hip ratio Higher parity Lower breastfeeding Several of these risk factors are modifiable. Breast Cancer Res Trt 2008, 109: 123-139
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Public Health Significance These results stand in stark contrast to recent news commentaries (NY Times, AP, Science) suggesting that basal-like breast cancer represents: The “exclusive property” of a specific age and racial group. A disease caused solely by “genetic inheritance.”
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Summary Breast cancer appears to be more than one disease Younger African American women have a higher frequency of basal-like breast cancer, which could contribute to higher breast cancer mortality Basal-like breast cancer may be preventable
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