1. Carolina Breast Cancer Study: Breast cancer subtypes and race Robert Millikan University of North Carolina Chapel Hill, NC

2. Research Questions Could breast cancer represent more than one disease? Can different subtypes of breast cancer help to explain racial disparities?

3. 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?

4. Clinical and Pathologic Staging of Breast Cancer

5. 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.

6. New Paradigm “Biology trumps staging.” ASCO 2008 Differences in underlying biology of breast tumors determine clinical course and response to therapy.

7. 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

8. Histology TNM Staging Biology IHC / TMAsmRNA profiling

9. Histology Biology IHC / TMAsmRNA profiling TNM Staging

11. 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).

13. TNM staging TNM staging helps understand survival (prognosis). It does not tell us how to treat, what drugs to give (predict therapeutic response).

14. New paradigm: Use gene expression profiling and immunohistochemistry to understand the underlying biology

15. Histology Biology IHC / TMAsmRNA profiling TNM Staging

17. 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).

19. “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

20. HistologyClinical Staging Biology IHC / TMAsmRNA profiling

22. 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

23. Carolina Breast Cancer Study

24. 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

25. 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%

26. 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.

27. 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

28. 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.

29. 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

30. 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?

31. 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

32. 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.

33. 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%

34. Basal-like breast cancer in North Carolina (Carolina Breast Cancer Study)

35. 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

36. 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.”

37. 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