TBCRC 030: A randomized phase II study of preoperative cisplatin versus paclitaxel in TNBC—Evaluating the homologous recombination deficiency (HRD) biomarker.
Authors: Erica L. Mayer, Vandana Gupta Abramson, Rachel Catherine Jankowitz, Carla Isadora Falkson, Paul Kelly Marcom, Tiffany A. Traina, Lisa A. Carey, Mothaffar F. Rimawi, Jennifer M. Specht, Kathy Miller, Vered Stearns, Charles M. Perou, Andrea L. Richardson, Nadine M. Tung, William Thomas Barry, Zhenying Tan-Wasielewski, Kirsten Timms, Anne-Renee Hartman, Antonio C. Wolff, Eric P. Winer
Journal: Journal of Clinical Oncology (2019)

507 Background: Cisplatin (C) and paclitaxel (T) have activity in TNBC, however predictive biomarkers are lacking. The HRD assay detects impaired dsDNA break repair and may identify BRCA1/2-proficient tumors for treatment with DNA targeting therapies. TBCRC 030 was designed to determine the association between HRD and response to preoperative chemotherapy (CT) in TNBC. Methods: This phase II study randomized patients (pts) with BRCA1/2-proficient/unknown stage I-III TNBC to 12 weeks (wks) of preoperative C or T, followed by surgery. HRD was performed on baseline tissue, with positive scores &gt; 33. Non-responders at 12 wks could crossover to alternative CT. The co-primary objectives were to detect a positive association of HRD with pathologic response (RCB 0-1) vs not (RCB 2-3) to C and a negative association to T. Target accrual of 160 pts was planned to yield 140 evaluable specimens for HRD, providing 90% power for the primary objectives. Analyses used logistic models and likelihood ratio tests with one-sided Type I errors of alpha = 0.05. Results: 140 pts initiated treatment, (72 Arm C, 68 Arm T; 81% T1-2, 62% node negative); 138 were evaluable for response at 12 wks. Post-enrollment testing showed 8 pts (5.8%) with germline DNA-repair pathway mutations. HRD results were available for 95 pts (68.8%, 23 inadequate tissue, 22 pending); 68 (71.6%) were HRD positive: 38 in Arm C, 30 in Arm T. In response-evaluable pts, 87 (63.0%) had surgery at 12 wks, and 51 (37.0%) crossed over. Response outcomes are shown in the Table. No association was seen between HRD score and RCB response to either neoadjuvant C (OR 2.78, [CI 0.61, 17.74]) or T (OR 0.98, CI [0.20, 5.06]). There was no evidence of an interaction between HRD and CT arms. Similarly, no association was observed between HRD score and pCR to either C (OR 1.47, CI [0.40, 5.59]) or T (OR 0.61, CI [0.14, 2.52]). There were no new safety signals. Conclusions: In this mostly BRCA1/2 proficient TNBC cohort, 12 wks of preoperative C or T led to a similar response rate of about 40%; baseline HRD was not predictive of response to preoperative CT, defined either by RCB 0-1 or pCR. Further data will be presented. Correlative analyses of research tissues for markers predictive of response to specific CT in TNBC is ongoing. Clinical trial information: NCT01982448. Outcome Arm C N = 71 Arm T N = 67 Total N = 138 RCB 0-1 27 (38.0%) 29 (43.3%) 56 (40.6%) -HRD + 15 (21.1%) 13 (19.4%) 28 (20.3%) -HRD - 3 (4.2%) 5 (7.5%) 8 (5.8%) RCB 2-3/crossover 44 (54.3%) 38 (46.3%) 82 (59.4%) -HRD + 23 (32.0%) 16 (23.9%) 39 (28.3%) -HRD - 13 (18.3%) 6 (9.0%) 19 (13.8%) pCR 15% 13%