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Adjuvant Therapy for Early Breast Cancer Subtypes Joyce O’Shaughnessy, MD Baylor Sammons Cancer Center Texas Oncology, P

Adjuvant Therapy for Early Breast Cancer Subtypes Joyce O’Shaughnessy, MD Baylor Sammons Cancer Center Texas Oncology, PA US Oncology Dallas, TX. Encouraging…. Peto, SABCS 2006. Sites of breast cancer metastases . CNS, brain meninges eyes (>20%). bones (>60%). lungs (>60%).

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Adjuvant Therapy for Early Breast Cancer Subtypes Joyce O’Shaughnessy, MD Baylor Sammons Cancer Center Texas Oncology, P

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  1. Adjuvant Therapy for Early Breast Cancer SubtypesJoyce O’Shaughnessy, MDBaylor Sammons Cancer CenterTexas Oncology, PAUS OncologyDallas, TX

  2. Encouraging….. Peto, SABCS 2006

  3. Sites of breast cancer metastases CNS, brain meninges eyes (>20%) bones (>60%) lungs (>60%) lymph nodes (>50%) liver (>60%) GI, peritoneum (>20%) adrenals (~40%) bones (>60%)

  4. ER-, PR- HER-2- Basal-like Virulent ER+ Luminal B Virulent ER++ Luminal A Indolent HER-2+ Virulent Traditional approach Node positive Node negative New Approach

  5. Advances in Early Breast Cancer • Adjuvant Herceptin for HER2+ disease • Less adjuvant chemotherapy for indolent, strongly ER+ disease • Prolonged anti-estrogen therapy for indolent, strongly ER+ disease • Improving therapy for virulent ER, PR, HER2-negative disease

  6. HER2-Driven Breast Cancer

  7. Fluorescence In Situ Hybridization (FISH) HER-2

  8. AC  T+ H(n=1,989; 222 events) 92.3% 87.9% 85.9% 1,854 1,347 868 522 202 4 Adjuvant Herceptin + Chemotherapy 100 80 86.4% 77.6% 73.1% 60 AC  T (n=1,979; 397 events) Alive and disease-free (%) N=619 events HR*adj = 0.48 (95% CI: 0.41-0.57) 40 P < 0.00001 20 Numberat risk 1,800 1,235 753 460 168 8 0 0 1 2 3 4 5 6 7 Follow-up (yrs) Despite 21% crossover! Perez E, et al. PASCO 2007

  9. Indolent ER and PR-Positive Breast Cancer E2 • Breast Cancer • Tamoxifen and Aromatase Inhibitor- responsive ER P PR

  10. More Virulent ER+ Breast Cancer TAM IGFR Her-1 Her-2 ER + AIB1 An estrogen response coactivator PR Schiff R, J Natl Cancer Inst 2003;95:353 - 361

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

  12. 95% CI Recurrence Score in Node Negative, ER+ Patients Paik S et al NEJM 2005

  13. NCI Cooperative Groups TAILORx Node-Negative, ER-Positive Breast Cancer Register Specimen banking 21-Gene Recurrence Score Assay RS 11-25 Randomize Hormone Rx vs Chemotherapy + Hormone Rx RS <10 Hormone Therapy Registry RS >25 Chemotherapy + Hormone Rx Primary study group

  14. Annual Risk of Recurrence For ER+ Patients N=2257 10% 9% 9% 8% 7% 7% 6% 6% 5% 5% 4% 3% Adapted from Saphner et al, JCO 1996

  15. Benefit from Tamoxifen over 15 Years Early Breast Cancer Trialists (Lancet 2005)

  16. Adjuvant Trials of AIs in Postmenopausal Women(Arimidex, Femara, Aromasin) Tamoxifen x 5 years Upfront AI vs Tamoxifen AI x 5 years Tamoxifen x 5 years Sequential AI vs Tamoxifen Tamoxifen AI Placebo x 5 years Tamoxifen x 5 years AI x 5 years

  17. Tamoxifen Tamoxifen + ovarian suppression Extended Treatment Options in ER+ Premenopausal Women IF POSTMENOPAUSAL, AI X 5 YEARS

  18. Extended Treatment Options in ER+ Premenopausal Women TAMOXIFEN x 5 YEARS +/- Ovarian Suppression Still Premenopausal ??????????? Continued tamoxifen Oophorectomy or Ovarian Suppression + AI

  19. Basal-like Tumors Basal-Like Breast Cancer (ER, PR, HER2-Negative) Courtesy of Charles Perou, PhD

  20. Breast Cancer Subtypes, Race and Age P=0.0001 Carey LA et al, JAMA. 2006;295:2492-502

  21. Chemotherapy Advances and ER-Negative Breast Cancer ER-negative tumors = Basal-like and HER2+/ER- Reduction in Breast Cancer Recurrence 63% 36% 32% 25% 23% 14% 12% 10% CALGB Trial Berry DA et al, JAMA 2006

  22. Adriamycin/Cytoxan vs Taxotere/Cytoxan 89% 86% 86% 80% DFS 94% 90% 93% 87% OS Jones et al, J Clin Oncol 2006

  23. Preoperative ChemoRx in Basal-like Breast Cancer P<0.001 P=0.003 1 Rouzier et al, Clin Cancer Res 2005; 2 Carey LA et al, SABCS 2004

  24. pCR (no residual disease in breast after preoperative chemotherapy) defines risk of recurrence high-risk & pCR (34) 1.0 0.8 0.6 high-risk & no-pCR (125) Prob Survival 0.4 Candidates for clinical trials for novel therapies after surgery 0.2 0.0 Time (months) 0 20 40 60 80 100 Time (months) Paik NCI Preoperative Conference March 2007

  25. Basal-like Tumors Basal-Like Breast Cancer Courtesy of Charles Perou, PhD

  26. Cancer stem cells: are we missing the target? Jones et al. JNCI 96:583, 2004 Courtesy of Jenny Chang, MD

  27. Cancer stem cells: are we missing the target? Jones et al. JNCI 96:583, 2004

  28. Cancer stem cells: are we missing the target? Jones et al. JNCI 96:583, 2004

  29. Breast Stem Cell Survival Hedgehog family Notch family TGFβ family Wnt family Growth Hormone /Insulin-like GF EGF family Estrogen Progesterone Self-renewal FGF family Stem Cell Prolactin Modified from Clarke et al 2005

  30. VEGF: Survival Factor for Vasculature -- Avastin Tumor vessels Normal vessels

  31. PARP Inhibitor + DNA-Damaging Chemotherapy Basal Breast Cancer: Deficits in DNA Repair Yap T ASCO 2007

  32. Women’s Intervention Nutrition Study (WINS) Evaluating Dietary Fat Reduction and Breast Cancer Outcomes Eligibility Criteria: • Women 48-79 years • Early breast cancer • Primary surgery ± RTx • Systemic therapy (ER+: tamoxifen/chemotherapy; ER–: chemotherapy) • Dietary fat intake > 20% of calories RANDOMIZE Dietary intervention: reduced fat intake to about 35 fat grams/day (15% kcals) (n = 975) Control (n = 1462) (n = 2437) Primary Endpoint: Relapse-free survival Randomization 60:40 within a year from primary surgery Chlebowski RT, et al. Breast Cancer Res Treat 2006; 100(suppl 1):S16 (abstract 32).

  33. Change in BMI and Weight by Group All values, P < .005 versus control BMI = Body Mass Index All values for weight, P = .005, intervention versus control Information on weight and BMI was available for all 975 and 1462 women in the dietary intervention group and the control group, respectively, at baseline; for 854 and 1310 at year 1; 698 and 1044 at year 3; and 386 and 998 at year 5. Chlebowski RT, et al. Breast Cancer Res Treat 2006; 100(suppl 1):S16 (abstract 32).

  34. Relapse-Free Survival (ER+, PgR+) HR 0.92; 95% CI, 0.71-1.19 Dashed line ---- Control Solid line – Diet ;

  35. Relapse-Free Survival (ER–, PgR–) HR 0.46; 95% CI, 0.26-0.80 Dashed line ---- Control Solid line – Diet

  36. Fasting Insulin and Outcome in Early Breast Cancer Patients Goodwin, P, et al. J Clin Oncol 20:42-51, 2002

  37. Goodwin, P. ASCO 2005

  38. Body Mass Index and Outcome in Early Breast Cancer Patients Goodwin, P, et al. J Clin Oncol 20:42-51, 2002

  39. Breast Cancer Lab Report of the Future Jones, Mary A. DOB: 4/22/47 MR#:555690 Dx: Breast cancer Receptor status: ER-, Her2-, PR-, AR- Activated pathway: Insulin-like growth factor receptor, AKT, mTOR Basal-like Breast Cancer Percentage of patients that have had this pathway activated in breast cancer: 16% Potential therapies: RAD0001 Imatinib Anti-IGFR antibody Metformin Exercise, low fat diet

  40. Breast Cancer MortalityWill the Progress Continue? Queen- size panty Hose – one size does not fit all ! Clinical Trials in Breast Cancer Subtypes 2030 2010 2020

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