Triple Negative Breast cancer New treatment options arenowhere? Ofer Rotem, M.D., B.Sc. Breast Unit, Davidoff center Rabin Medical center October 2017
Case 6/2013 - M.D., 38 years old woman, healthy, no family Hx Palpated mass in her right breast O/E & Imaging 3cm mass in Rt breast UOQ and a 2cm mobile LN in the right axilla. CNBx Rt breast & axilla IDC Grade 2-3, LN-Pos ER/PR/HER2-Neg, Ki67-40% Systemic work-up no evidence of Met disease TNBC Stage II T2N1M0
Case After consulting with her surgeon, the Mrs. D refers to your clinic for Preoperative treatment. Mrs. D is married + 3, works as a pilot in EL-AL.
Which regimen would you prefer? 1- DD AC Weekly Taxol 2- DD AC Taxol-Carbo 3- DD AC-Bev Taxol-Carbo-Bev 4- AC Weekly Taxol
GeparSixto: Study Design Randomized phase IIb study in 51 German centers Pts with centrally confirmed TNBC* or HER2+ BC with ct2 - T4a-d or ct1 with N+ disease (N = 588) PMCb Myocet 20 mg/m² Q1W + Paclitaxel 80 mg/m² Q1W Carboplatin AUC 2 Q1W q.18w (n = 295) PM Myocet 20 mg/m² Q1W + Paclitaxel 80 mg/m² Q1W q.18w (n = 293) Surgery Primary endpoint: pcr Secondary endpoints: RFS, DFS, OS *TNBC pts also received bevacizumab 15 mg/kg IV Q3W. HER2+ BC pts also received trastuzumab 8 mg/kg IV (initial dose), then 6 mg/kg IV Q3D (subsequent doses) and lapatinib 750 mg QD. Dose reduced to AUC 1.5 after 330 pts enrolled. von Minckwitz G, et al. SABCS 2015. Abstract S2-04.
GeparSixto: pcr Outcomes SABCS 2015 pcr, % ypt0/is ypn0 PMCb PM Odds Ratio P Value All pts (n = 588) 43.7 36.9.107* HER2+ BC (n = 273) 32.8 36.8 0.84.6 TNBC (n = 315) gbrca wild type (n = 241)* gbrca mutant (n = 50)* *Level for significance = 0.2 Test for interaction, P =.015 53.2 55 65.4 36.9 36.4 66.7 1.94 2.14 0.94.005.004 0.92 * Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast Cancer Secondary Analysis of the GeparSixto Randomized Clinical Trial Eric Hahnen. JAMA Oncology, Oct 2017. von Minckwitz G, et al. SABCS 2015. Abstract S2-04. von Minckwitz G, et al. Lancet Oncol. 2014;15:747-756. von Minckwitz G, et al. ASCO 2014. Abstract 1005.
Pts With DFS (%) GeparSixto: DFS by gbrca Status and Regimen in TNBC 100 80 60 BRCA wt PM BRCA wt PMCb BRCA mt PM BRCA mt PMCb BRCA wt PM BRCA wt PMCb BRCA mt PM BRCA mt PMCb 40 20 3yDFS (%) 85.3 Vs 73.5 86.3 Vs 82.5 HR, CI 0.53, 0.29-0.96 Non-Significant 0 0 12 24 36 48 121 120 24 26 104 107 23 25 WT Mos 88 95 19 20 BRCA1/2 Mut 43 40 6 7 0 0 0 0
CALGB 40603
CALGB 40603 pcr breast/axilla No Carbo Carbo 41% 54% OR-1.71, p-0.0029 No Bev Bev 44% 52% OR-1.36, p-0.057 Control With Bev With Carbo With Bev & Carbo 39% 43% 49% 60% William M. Sikov, et al. JCO, Jan 2015
San Antonio Breast Cancer Symposium, December 8-12, 2015 CALGB 40603 EFS and OS by Factor Carboplatin Bevacizumab Yes No Yes No EFS OS 3-year 76% 71% 75% 72% HR 0.84 (0.58-1.22) 0.80 (0.55-1.17) 3-year 81% 85% 85% 81% HR 1.15 (0.74-1.79) 0.76 (0.49-1.19)
ESMO Guidelines. 2015: Addition of carboplatin to neoadj chemotherapy in TNBC - For BRCA 1/2 or RAD mutations it is acceptable to add a platinum compound, after discussion with the patient. NCCN Guidelines version 2.2017: The NCCN panel does not recommend addition of carboplatin to neoadj standard chemotherapy for patients with TNBC outside a clinical trial setting.
ASCO 2017: I-SPY 2 Trial: Combination of Pembrolizumab Plus Standard Neoadjuvant Therapy in High-Risk Breast Cancer
ASCO 2017: I-SPY 2 Trial 69 pts were randomized to Pembro (HER2- subsets only) from Dec 2015 until it graduated in Nov 2016. 46 pts (25 HR+, 21 TN) have undergone surgery.
Case cont Mrs. D decided she wants it all! 6-11.2013 - DD AC Carbo-Taxol + Bev 12.2013 - Rt Breast Lumpectomy + ALND Pathology report: IDC Grade II, 0.5cm, LN-3/17
Next step? 1- Adj xeloda 2- RTx and cont FU 3- NGS 4- Clinical trial OlympiA (In case of Germline BRCA Mut)
CREATE-X NEJM, Jun 2017 Stratified by ER status, age, neoadjuvant chemotherapy, use of 5-FU, institution, node status Wk 24 Pts 20-74 yrs of age with stage I-IIIB HER2- BC and residual disease (non-pcr, N+) after neoadjuvant chemotherapy* and surgery; ECOG PS 0 or 1; no previous oral fluoropyrimidines Japan & South Korea (N = 910) Capecitabine 2500 mg/m²/day PO Days 1-14 Q3W for 8 cycles Hormonal therapy if ER/PgR+ (n = 455) Hormonal therapy if ER/PgR+ No further therapy if ER/PgR- (n = 455) *Anthracycline/taxane, anthracycline containing, or docetaxel/cyclophosphamide. 25 pts were removed from treatment (n = 10) and control (n = 15) arms due to failure to meet eligibility criteria. IDMC recommended extension to 8 cycles following interim safety analysis of first 50 pts receiving 6 cycles. [2] 1. Toi M, et al. SABCS 2015. Abstract S1-07. 2. Ohtani S, et al. SABCS 2013. Abstract P3-12-03.
CREATE X PEP DFS SEP OS, time from first day of preoperative chemotherapy to recurrence or death, safety, cost-effectiveness The result of the prespecified interim analysis met the PEP, so the trial was terminated.
CREATE X - TN Pts 5yDFS 70% Vs 56% 5yOS 79% Vs 70%
Case cont Mrs. D was found to be BRCA1/2 WT, and decided to get Capecitabine. 10.2014 - Lower back pain, fatigue. PET scan - metastatic dis Bones, liver. ECOG 1 Blood test Normal
WWUD? 1- NGS 2- Chemotherapy (+/- Bev) 3- PARPi 4- Immunotherapy
Immunotherapy
Somatic mutation prevalence (number of mutations per megabase) Somatic mutations in cancers Breast Cancer and mutations: Lower median rate detected compared to the most immune-sensitive cancers but wide range of mutations detected 1,000 100 10 1.0 0.1 0.01 0.001 Alexandrov L,B. Nature 2013
TNBC - The best of what s left... Luen, The Breast, 2016
1L 2L
Results<br />BOR per RECIST v1.1 by line of therapy
KEYNOTE 150 - An Open-Label, Single-Arm Multicenter Phase 1b/2 Study to Evaluate the Efficacy and Safety of Eribulin Mesylate in Combination With Pembrolizumab in Subjects With Metastatic Triple-Negative Breast Cancer (mtnbc) SABCS 2016
Case Cont 11.2014 Single agent Pembrolizumab. 11.2015 Clinical and radiographic PD. NGS: Somatic BRCA1 Mut
OlympiAD ASCO 2017 NEJM 8.2017
OlympiAD
OlympiAD
OlympiAD No crossover
Case Cont 12.2015 Olaparib 9.2016 Clinical and radiographic PD. New Liver Biopsy TN, AR > 10%
11%
TNBC subtypes comparison with intrinsic PAM50 subtypes (Unsupervised Vs supervised clustering) 374 TNBC GE profiles were subtyped using PAM50 or TNBCtype
Anti Androgen therapy Bicalutamide Enzalutamide Abiraterone acetate
RR-0-8%
Triple Negative Breast cancer New treatment options arenowhere/arenowhere?