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Highlights from the San Antonio Breast Cancer Symposium: Triple-Negative Breast Cancer

Highlights from the San Antonio Breast Cancer Symposium: Triple-Negative Breast Cancer. Debu Tripathy, MD Professor of Medicine University of Southern California Norris Comprehensive Cancer Center. Key SABCS Abstracts on Triple Negative Breast Cancer.

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Highlights from the San Antonio Breast Cancer Symposium: Triple-Negative Breast Cancer

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  1. Highlights from the San Antonio Breast Cancer Symposium:Triple-Negative Breast Cancer Debu Tripathy, MD Professor of Medicine University of Southern California Norris Comprehensive Cancer Center

  2. Key SABCS Abstracts on Triple Negative Breast Cancer • S5-01. CALGB 40603 -Addition of carboplatin to neoadjuvant weekly paclitaxel – impact on pCR • S1-06. GeparSixto: Impact of Carboplatin and Tumor infiltrating lymphocytes (TILs) • S1-01. TILs in TNBC: ECOG 2197 and 1199 • S5-02. Veliparib/carboplatin plus standard neoadjuvant therapy in TNBC: Results from the I-SPY 2 TRIAL • P2-09-02.BMN 673 in BRCA-mutation-related breast cancer • S6-01. JAK2 in Residual TNBC • S4-03. Sequencing of TNBC metastases – novel genes of specific ontogeny and association with outcome

  3. CALGB 40603: Neoadjuvant Paclitaxel ± Carboplatin ± Bevacizumab in TNBC Randomize Paclitax. 80 mg/m2 qw x 12 Paclitax. 80 mg/m2 qw x 12 Bevaciz.10 mg/kg q2w x 9 Stage II-III TNBC (N = 443) dd AC X 4 Paclitax.80 mg/m2 qw x 12 CarboAUC 6 q3w x 4 Paclitax. 80 mg/m2 qw x 12 CarboAUC 6 q3w x 4 Bevaciz.10 mg/kg q2w x 9 Surgery + Radiation as needed SikovWM, et al. SABCS 2013, Abstract S5-01

  4. CALGB 40603: Neoadjuvant Paclitaxel ± Carboplatin ± Bevacizumab in TNBC SikovWM, et al. SABCS 2013, Abstract S5-01

  5. CALGB 40603: Pathologic CR (ypT0/is N0) SikovWM, et al. SABCS 2013, Abstract S5-01

  6. CALGB 40603– Serious Adverse Events *1 death due to uncontrolled hypertension.

  7. CALGB 40603: Take Home Points • Carboplatin increases pCR rate • Bevacizumab show trend toward better pCR rate • No interaction between bevacizumab and carboplatin for efficacy • Bev leads to more Grade III HTN, febrile neutropenia, bleeding, thrombus, surgical complications • Carbo leads to more Gr III/IV neutropenia, thrombocytopenia and attenuates amount of paclitaxel delivered • Long-term impact on DFS, OS not known

  8. GeparSixto: Addition of Neo Adj Carboplatin Von Minckwitz G, et al ASCO 2013, Abstract # 1004

  9. GeparSixto: Carboplatin Impact on pCR Von Minckwitz G, et al ASCO 2013, Abstract # 1004

  10. Carboplatin Impact on pCR: HER+ vs. TNBC Von Minckwitz G, et al ASCO 2013, Abstract # 1004

  11. Incremental Improvements in TNBC pCR + Platinum + Bevacizumab Von Minckwitz G, et al ASCO 2013, Abstract # 1004

  12. pCR Rates: Based on Tumor-Infiltrating Lymphocytes (TILs) P<0.005 P=0.09 P<0.005 Denkert C, et al. SABCS 2013, Abstract S1-06

  13. GeparSixto: Impact of TILs for Carboplatin Neoadjuvant Tx for TN and HER2+ Early Breast Cancer Denkert C, et al. SABCS 2013, Abstract S1-06

  14. ECOG 2197 and 1199: Stromal TILs in Adjuvant Therapy for TNBC DDFS Probability OS Probability DFS Probability P=0.05 P=0.03 P=0.02 sTIL=0 sTIL=10 sTIL=20-40 sTIL=50-80 sTIL=0 sTIL=10 sTIL=20-40 sTIL=50-80 sTIL=0 sTIL=10 sTIL=20-40 sTIL=50-80 Years Years Years Adams S, et al. SABCS 2013, Abstract S1-07

  15. ECOG 2197 and 1199: sTILs in Adjuvant Therapy for TNBC • Stromal TILs associated with better prognosis (DFS, DRFI, OS) after standard adjuvant therapy in TNBC (multivariate model) • DFS HR: 0.84 (95% CI: 0.74-0.95; P = .005) • DRFI HR: 0.81 (95% CI: 0.68-0.97; P = .02) • OS HR: 0.79 (95% CI: 0.67-0.92; P = .003) • For every 10% incremental gain of stromal TILs: • 14% reduction of risk for recurrence/death (P = .02) • 18% reduction of risk for distant recurrence (P = .04) • 19% reduction of risk for death (P = .01) Adams S, et al. SABCS 2013, Abstract S1-07

  16. I-SPY 2 TRIAL Schema Learn, Drop, Graduate, and Replace Agents Over Time Paclitaxel+ Trastuzumab Key Paclitaxel + Trastuzumab* + New Agent A Randomize MRI HER 2 (+) AC Surgery Paclitaxel + Trastuzumab* + New Agent B Residual Disease (Pathology) Learn and adapt from each patient as we go along Paclitaxel + Trastuzumab* + New Agent F Paclitaxel + Trastuzumab* + New Agent C Eligible for NAC Paclitaxel Randomize Paclitaxel + New Agent F Paclitaxel + New Agent C HER 2 (–) AC Surgery Paclitaxel + New Agent GH Paclitaxel + New Agent D Paclitaxel + New Agent E Rugo H, et al. SABCS 2013, Abstract S5-02

  17. Agent Overview Rugo H, et al. SABCS 2013, Abstract S5-02

  18. I-SPY 2 Trial Adaptive Design • Adaptive randomization • Uses a pre-specified and automated algorithm • Randomization probabilities update as study proceeds • By signature, and based on MRI and pCR results • Algorithm triggers the decision to “graduate” when 60-120 patients are enrolled • 85% predicted likelihood of success in a randomized phase 3 neoadjuvant trial • N=300 patients • pCR is the endpoint Rugo H, et al. SABCS 2013, Abstract S5-02

  19. Veliparib/Carboplatin GRADUATES in the Triple Negative Signature Rugo H, et al. SABCS 2013, Abstract S5-02

  20. Safety Paclitaxel dose reductions in 27% Rugo H, et al. SABCS 2013, Abstract S5-02

  21. Response to PARP Inhibitor BMN 673 Phase I Study 9/18 patients with TNBC Mina LA, et al. SABCS 2013, Abstract P2-09-02

  22. BMN 673 Update • BMN 673 showed single-agent antitumor activity and favorable progression-free survival in BRCA-related advanced breast cancer • 72% clinical benefit rate in in BRCA-related breast cancer • 6% CR, 39% PR, 28% SD ≥ 24 wks • Generally well tolerated, with common drug-related toxicities seen in < 30% of patients and include myelosuppression, fatigue, nausea, and alopecia • Phase III trial of BMN 673 in combination with chemotherapy in patients with MBC and deleterious germline mutations of BRCA1 or 2 is ongoing and randomized trial compared to physicians choice is planned Mina LA, et al. SABCS 2013, Abstract P2-09-02

  23. Genomic Analysis of Residual TNBC After Neoadjuvant Therapy Deep Sequencing (Foundation Medicine) for 182 oncogenes in 72 evaluable cases with enough “coverage” JAK2 was novel and not seen in primary cases so far Balko JM, et al. SABCS 2013, Abstract S6-1

  24. JAK2 in TNBC • JAK2 is a receptor coupled TK that activates STAT proliferation and differentiation pathway is involved in stem cell maintenance • JAK2 mutations and amplification seen in TNBC, with amplification expansion seen upon treatment • JAK2 amplification associated with worse survival in TNBC • JAK2 inhibitor trials underway in breast cancer Balko JM, et al. SABCS 2013, Abstract S6-1

  25. Exome Sequencing of TNBC Metastases: Pathogenesis and Treatment TargetsGermline, Primary, Metastasis Comparisons Primary and Metastatic Mutations N=331 Metastatic-specific N=31 ABCA12, ADAM18 ARGHAP21, BRWD3, CCDC84, DCHS2, DLEC1, DOCK5, DYNCH1, FANCM, GRIN2C, TP53, MTOR, TRPM2, others 4/6 genes with PFS difference involved in macromolecule metabolism Blackwell K, et al. SABCS 2013, Abstract S4-03

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