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Julie R. Gralow, M.D. Director, Breast Medical Oncology, Seattle Cancer Care Alliance Professor, Medical Oncology, University of Washington School of Medicine.

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Presentation on theme: "Julie R. Gralow, M.D. Director, Breast Medical Oncology, Seattle Cancer Care Alliance Professor, Medical Oncology, University of Washington School of Medicine."— Presentation transcript:

1 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 Breast Cancer Systemic Therapy for Early Stage Disease

2 Adjuvant Systemic Treatment of Breast Cancer Breast cancer is most often curable when detected in early stagesBreast cancer is most often curable when detected in early stages Micrometastases exist at the time of diagnosis in many patients, leading to eventual recurrenceMicrometastases 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 patientsAdjuvant 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)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 FUTURETHE PRESENT AND FUTURE –Individualizing estimates of recurrence risk and chemotherapy benefit using genomic/molecular profiling –Many patients don’t need chemotherapy

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

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

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

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

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 INVASION Stromolysin 3 Cathepsin L2 HER2 GRB7 HER2 BAG1 GSTM1 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC CD68

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

11 Endocrine Therapy

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

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

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

15 Aromatase Inhibitors Adrenal Hormones CortisolAndrostenedioneAldosterone Estradiol TestosteroneEstrone Aromatase inhibitors block post-menopausal estrogen production AnastrozoleLetrozoleExemestane

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

17 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 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 Trials MA17 Trial: Letrozole vs. Placebo After Completing 5 Years of Tamoxifen Goss P et al, J Natl Cancer Inst 97: 1262-71, 2005 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

19 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

20 Chemotherapy

21 EBCTCG (Oxford Overview) 2000 Chemotherapy vs. Not: Deaths (Overall 14.8% +/- 2.1 reduction) Entry AgeEvents/Women Chemo Control Chemo Control < 40 293/960 335/908 (30.5%) (36.9%) (30.5%) (36.9%) 40-49 674/2480 783/2391 (27.2%) (32.7%) (27.2%) (32.7%) 50-59 1658/4880 1918/5143 (34.0%) (37.3%) (34.0%) (37.3%) 60-69 1851/4886 2000/4967 (37.9%) (40.3%) (37.9%) (40.3%) 70+ 210/570 264/610 (36.8%) (43.3%) (36.8%) (43.3%) Ratio annual deaths Chemo: Control Chemo: Control 1.00.51.5 26%+/-5 26%+/-5 29%+/-7 11%+/-11 7%+/-4 7%+/-4 15%+/-3 15%+/-3

22 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 0.9 1.0 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 5101520 Years after Mastectomy Disease-free survival Probability of Relapse-free Survival 5101520 Years after Mastectomy 0.9 1.0 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Overall survival Probability of Overall Survival 85% of dose <65% of dose Control 65-84% of dose

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

24 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 ACAC + T DFS (5 yrs)65%70% HR = 0.83, p=0.0023 OS77%80%HR = 0.82, p=0.0064 n=3,121 Adjuvant Taxanes BCIRG 001: TAC vs FAC in Breast Cancer Martin M, et al, N Engl J Med 2005 F 500 mg/m2T (Docetaxel) 75 mg/m2 A 50 mg/m2A 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 n=1,491vs

25 Biologic Therapy

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

27 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 yrsRisk of breast cancer recurrence reduced by 52% at 3 yrs Risk of death decreased by 33% at 2 yrsRisk 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!Clinical features, stage and biology all contribute to risk of recurrence! Endocrine therapy critical in ER+ breast cancerEndocrine therapy critical in ER+ breast cancer In chemotherapy-sensitive breast cancers, anthracycline and taxanes both add to disease controlIn chemotherapy-sensitive breast cancers, anthracycline and taxanes both add to disease control Many patients don’t need chemo!Many patients don’t need chemo! Trastuzumab significantly reduces breast cancer recurrence and death in HER2+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 cancerOngoing prospective trials are integrating traditional and novel markers of risk to better define tailored options for early-stage breast cancer


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