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

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

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

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

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

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 A total of 115 breast cancer tumor tissues and 7 nonmalignant tissues were analyzed for characteristic patterns of gene expression measured by DNA microarrays applicable to classifying tumors into clinically relevant subgroups. Analysis was by hierarchical clustering based on patterns of expression of 534 “intrinsic” genes, delineated relative to 5 tissue subtypes: One basal-like, 1 ErbB2 (HER2)-overexpressing (ERBB2+), 2 luminal-like (subtypes A and B), and 1 normal breast tissue–like Slide shows the 5 recognized subgroups of coexpressed genes, with group C representing the ErbB2 (HER2)-overexpressing subgroup of genes. Expression of the HER2 gene cluster is most pronounced in the ERBB2+ tissue subtype of tumors, hence its designation. Results strongly support the contention that many breast cancer subtypes represent biologically distinct disease entities. Sorlie et al, Proc Natl Acad Sci 100:8418, 2003 Sørlie et al. Proc Natl Acad Sci U S A. 2003;100:8418.

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

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)

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 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC INVASION Stromolysin 3 Cathepsin L2 GSTM1 CD68 BAG1

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 The Recurrence Score has been correlated with Distant recurrence rate at 10 years assuming 5 years of tamoxifen treatment (the higher the score, the higher the distant recurrence rate) Hormone therapy benefit (the lower the score, the greater the impact of tamoxifen (given for 5) years on 10 year distant recurrence-free survival) Chemotherapy benefit (the higher the score, the greater the impact of chemotherapy on 10 year distant recurrence-free survival) Lower RS Less likelihood of recurrence Greater tamoxifen benefit No to minimal chemotherapy benefit Higher RS Greater likelihood of recurrence Less tamoxifen benefit Clear chemotherapy benefit

Endocrine Therapy

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

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

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

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

Adjuvant Aromatase Inhibitors Three Strategies AIs as Initial Therapy AIs After 2-3 Yrs of TAM AIs After 5 Years of TAM TAM X 5 Yrs TAM X 5 Yrs AI 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

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

42% decrease in breast cancer events Extended Adjuvant Hormonal Therapy Trials MA17 Trial: Letrozole vs. Placebo After Completing 5 Years of Tamoxifen Goss 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

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

Chemotherapy

EBCTCG (Oxford Overview) 2000 Chemotherapy vs. Not: Deaths (Overall 14 EBCTCG (Oxford Overview) 2000 Chemotherapy vs. Not: Deaths (Overall 14.8% +/- 2.1 reduction) Entry Age Events/Women Chemo Control < 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%) Ratio annual deaths Chemo: Control 29%+/-7 26%+/-5 15%+/-3 7%+/-4 11%+/-11 0.5 1.0 1.5

Survival Relative to Delivered Dose Adjuvant CMF Therapy - 20 Year Follow-up Milan 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 0.7 85% of dose 0.7 0.6 0.6 Probability of Overall Survival Probability of Relapse-free Survival 0.5 0.5 0.4 20-year follow-up in 386 women randomized to no treatment following radical mastectomy (control, n = 179) versus radical mastectomy followed by 12 monthly cycles of adjuvant CMF (n = 207) CMF = cyclophosphamide 100 mg orally days 1-14, methotrexate 40 mg/m2 IV days 1 and 8, fluorouracil 600 mg/m2 IV days 1 and 8. Cycles repeated every 4 weeks x 12 Reference: Bonadonna G, Valagussa P, Moliterni A, et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. N Engl J Med 332:901-906, 1995 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

Anthracyclines vs. CMF EBCTCG (Oxford Overview) 2006 Meta-Analysis Presented ASCO Educational Session 2007 Many studies with relatively low doses of anthracyclines included in analysis Magnitude of benefit probably underestimated

Adjuvant Taxanes CALGB 9344: AC +/- Paclitaxel in LN+ Breast Cancer Henderson IC et al, J Clin Oncol 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 AC AC + 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 TAC FAC DFS (55 months) 75% 68% HR = 0.72, p=0.001 OS 87% 81% HR = 0.7, p=0.008 vs n=1,491

Biologic Therapy

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

Adjuvant Chemotherapy +/- Trastuzumab: NSABP B-31 and N9831 Romond 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

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