Systemic Therapy for Early-Stage Breast Cancer: Current Trends and Future Directions

1. Breast Cancer Systemic Therapy for Early Stage Disease Julie R. Gralow, M.D. Director, Breast Medical Oncology, Seattle Cancer Care Alliance Professor, Medical Oncology, University of Washington School of Medicine Member, Clinical Division, Fred Hutchinson Cancer Research Center

2. Adjuvant Systemic Treatment of Breast Cancer • Breast cancer is most often curable when detected in early stages • Micrometastases exist at the time of diagnosis in many patients, leading to eventual recurrence • Adjuvant systemic therapy has been found to prolong both overall and disease-free survival in breast cancer patients

3. Systemic Therapy for Breast Cancer Endocrine Therapy Chemotherapy Biologically-targeted Therapy New Strategies: Individualizing treatment to the cancer and the patient

4. Systemic Treatment of Early Stage Breast Cancer • THE PAST (2000 NCI Consensus Development Conference on Adjuvant Breast Cancer) • Chemotherapy should be offered to the majority of women with early stage breast cancer regardless of size, lymph node, menopausal or hormone receptor status • THE PRESENT AND FUTURE • Individualizing estimates of recurrence risk and chemotherapy benefit using genomic/molecular profiling • Many patients don’t need chemotherapy

5. Genetic change Genetic change The Genomic EraUnderstanding the Genetic Changes in Each Individual Tumor Testing the acquired genetic makeup of the tumor can lead to more effective treatment strategies normal cell atypical cell cancer cell

6. Genomics of Breast Cancer: Breast Cancer is NOT One Disease! Luminal Subtype A Luminal Subtype B Basal Subtype Normal Breast–like HER-2+ • Subtypes vary with respect to: • Likelihood of recurrence • Sites of metastases • Response to treatment Sorlie et al, Proc NatlAcadSci 100:8418, 2003

7. Agendia Mammaprint 70-Gene Prognostic Signature Assay Clinically Available Molecular Profiling Assays in Breast Cancer Genomic Health OncotypeDx 21-Gene Recurrence Score Assay

8. Who Doesn’t Need Chemotherapy? Oncotype Dx 21-Gene Recurrence Score Assay Developed to help define which “low risk” patients do not need chemotherapy, and which may benefit Fixed (stored) tissue Extract tumor RNA Surgical removal of tissue Tumor evaluated for 21 genes Recurrence score results • In lymph node negative, ER+ breast cancer: • 20% recurrence with tamoxifen only (may benefit from chemo) • 80% won’t recur with tamoxifen only (won’t benefit from chemo)

9. 21 Gene Recurrence Score (RS) Assay: 16 Cancer Genes and 5 Reference Genes PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 ESTROGEN ER PR Bcl2 SCUBE2 HER2 GRB7 HER2 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC INVASION Stromolysin 3 Cathepsin L2 GSTM1 CD68 BAG1

10. 21-Gene Recurrence Score Assay Results (Oncotype DX) Recurrence Score in LN-, ER+ if 5 Years Tamoxifen RS of 39 = 27% 10 yr distant relapse rate despite tamoxifen • Higher RS • Greater likelihood of recurrence • Less tamoxifen benefit • Clear chemotherapy benefit • Lower RS • Less likelihood of recurrence • Greater tamoxifen benefit • No to minimal chemotherapy benefit

11. Endocrine Therapy

12. Estrogen and Breast Cancer Aromatase inhibitors, ovarian suppression SERMS, SERDS Cell Growth and Division Estrogen Estrogen Receptor

13. Endocrine Therapy in Breast Cancer • Selective Estrogen Receptor Modulators • tamoxifen • toremifene • raloxifene • Aromatase inhibitors (postmenopausal) • anastrozole • letrozole • exemestane • Medical or surgical oophorectomy (premenopausal) • Selective Estrogen Receptor Downregulators • fulvestrant • Others: Progestins, Estrogens, Androgens

14. Selective Estrogen Receptor ModulatorsEarly Breast Cancer Trialists’ Collaborative Group 2000 (Oxford Overview) Tamoxifen vs. Nil: Disease-free Survival ER Negative ER Positive tamoxifen nil 5 years of adjuvant tamoxifen became standard in ER+ patients ER status matters!!

15. Aromatase Inhibitors Anastrozole Letrozole Exemestane Adrenal Hormones Cortisol Androstenedione Aldosterone Estrone Testosterone Aromatase inhibitors block post-menopausal estrogen production Estradiol

16. Adjuvant Aromatase Inhibitors Three Strategies AIs After 2-3 Yrs of TAM AIs as Initial Therapy AIs After 5 Years of TAM AI X 5 Yrs TAM X 5 Yrs TAM X 5 Yrs TAM X 5 Yrs PLAC X 5 Yrs AI X 5 Yrs TAM X 2-3 AI X 2-3 ATAC and BIG1-98 studies Reduction in recurrences Survival benefit for AI arm

17. Upfront Use of Aromatase Inhibitors vs. TamoxifenATAC Trial: Anastrozole vs. Tamoxifen Howell A et al, Lancet 365:60-62, 2005BIG 1-98 Trial: Letrozole vs. Tamoxifen Thurlimann B et al, NEJM 353: 2747-57, 2005 68 months follow-up: 17% relative reduction in events for A vs T (3% absolute difference) No difference in overall survival • 26 months follow-up: • 19% relative reduction in events for L vs. T • (3% absolute difference) • No difference in overall survival

18. Extended Adjuvant Hormonal Therapy TrialsMA17 Trial: Letrozole vs. Placebo After Completing 5 Years of TamoxifenGoss P et al, J Natl Cancer Inst 97: 1262-71, 2005 30 months of follow-up: 42% decrease in breast cancer events Node positive patients show statistically significant improvement in survival

19. Ovarian Ablation in Early Stage Breast CancerEarly Breast Cancer Trialists’ Collaborative Group 2000 (Oxford Overview) Overall Survival Ablation vs. Not Chemo/Ablation vs. Chemo ablation No ablation

20. Chemotherapy

21. EBCTCG (Oxford Overview) 2000 Chemotherapy vs. Not: Deaths(Overall 14.8% +/- 2.1 reduction) Ratio annual deaths Chemo: Control Entry AgeEvents/Women ChemoControl < 40 293/960 335/908 (30.5%) (36.9%) 40-49 674/2480 783/2391 (27.2%) (32.7%) 50-59 1658/4880 1918/5143 (34.0%) (37.3%) 60-69 1851/4886 2000/4967 (37.9%%) (40.3%) 70+ 210/570 264/610 (36.8%) (43.3%) 29%+/-7 26%+/-5 15%+/-3 7%+/-4 11%+/-11 0.5 1.0 1.5

22. Survival Relative to Delivered DoseAdjuvant CMF Therapy - 20 Year Follow-upMilan Study (N = 386) Bonadonna G et al, N Engl J Med 1995 Disease-free survival Overall survival Control 1.0 1.0 <65% of dose 0.9 0.9 65-84% of dose 0.8 0.8 85% of dose 0.7 0.7 0.6 0.6 Probability of Overall Survival 0.5 0.5 Probability of Relapse-free Survival 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0.0 0.0 5 10 15 20 5 10 15 20 Years after Mastectomy Years after Mastectomy

23. Anthracyclines vs. CMFEBCTCG (Oxford Overview) 2006 Meta-AnalysisPresented ASCO Educational Session 2007 • Many studies with relatively low doses of anthracyclines included in analysis • Magnitude of benefit probably underestimated

24. Adjuvant Taxanes CALGB 9344: AC +/- Paclitaxel in LN+ Breast CancerHenderson IC et al, J ClinOncol 2003 A 60 vs 75 vs 90 mg/m2 + T 175 mg/m2 q3 wks x 4 C 600 mg/m2 q3 wks x 4 No T ACAC + T DFS (5 yrs) 65% 70% HR = 0.83, p=0.0023 OS 77% 80% HR = 0.82, p=0.0064 n=3,121 BCIRG 001: TAC vs FAC in Breast Cancer Martin M, et al, N Engl J Med 2005 F 500 mg/m2 T (Docetaxel) 75 mg/m2 A 50 mg/m2 A 50 mg/m2 C 500 mg/m2 q3 wks x 6 C 500 mg/m2 q3 wks x 6 TACFAC DFS (55 months) 75% 68% HR = 0.72, p=0.001 OS 87% 81% HR = 0.7, p=0.008 vs n=1,491

25. Biologic Therapy

26. HER-2 as a Target for Therapy HER-2 Oncogene: amplified and overexpressed in 20-25% of breast cancer HER-2 Trastuzumab (Herceptin) Anti-HER-2 Antibody cancer cell nucleus Lapatinib (Tykerb) Dual HER-1/HER-2 Tyrosine Kinase Inhibitor cell division

27. Adjuvant Chemotherapy +/- Trastuzumab: NSABP B-31 and N9831Romond E et al, N Engl J Med 353, 2005 Number of patients • Risk of breast cancer recurrence reduced by 52% at 3 yrs • Risk of death decreased by 33% at 2 yrs

28. Adjuvant Therapy in Breast Cancer: The Future • Clinical features, stage and biology all contribute to risk of recurrence! • Endocrine therapy critical in ER+ breast cancer • In chemotherapy-sensitive breast cancers, anthracycline and taxanes both add to disease control • Many patients don’t need chemo! • Trastuzumab significantly reduces breast cancer recurrence and death in HER2+ • Ongoing prospective trials are integrating traditional and novel markers of risk to better define tailored options for early-stage breast cancer