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

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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 > 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%