Abstract GS6-03: Cisplatin versus doxorubicin/cyclophosphamide as neoadjuvant treatment in germline BRCA mutation carriers (BRCA carriers) with HER2-negative breast cancer: Results from the INFORM trial (TBCRC 031)
Authors: Tung Nadine , Arun Banu , Hofstatter Erin , Hacker Michele R. , Toppmeyer Deborah L. , Isakoff Steven J. , Borges Virginia , Legare Robert D. , Isaacs Claudine , Wolff Antonio C. , Marcom Paul K. , Mayer Erica L. , Lange Paulina B. , Goss Andrew J. , Krop Ian E. , Winer Eric P. , Schnitt Stuart J. , Garber Judy E. 
Published: March 2020

Abstract
Background: Single-agent platinum compounds have significant clinical activity in the neoadjuvant and metastatic settings for triple-negative breast cancer (TNBC) in BRCA mutation carriers. Limited data exist regarding activity in estrogen receptor (ER)-positive breast cancer among BRCA carriers. The INFORM trial is an investigator-initiated, randomized, multicenter, phase II study comparing pathologic complete response (pCR) rates with neoadjuvant single-agent cisplatin (CDDP) versus doxorubicin/cyclophosphamide (AC) in BRCA carriers with newly-diagnosed Stage I-III HER2-negative breast cancer.
Methods: BRCA carriers with cT1-3 (≥1.5 cm), cN0-3 HER2-negative breast cancer were randomized (stratified by site and ER status) 1:1 to preoperative CDDP (75mg/m2 every 3 wks x 4) or AC (doxorubicin 60 mg/m2; cyclophosphamide 600 mg/m2 every 2-3 wks x 4) followed by surgery. Prior chemotherapy was not allowed; subsequent adjuvant therapy was selected by treating clinicians. Baseline tumor features and pathologic responses were centrally determined. The primary endpoint was pCR (ypT0/is, N0). Based on a 2-sided α=0.1, a sample size of 170 provided 80% power to detect an improvement in pCR from 30% with AC to 50% with CDDP. Slow accrual led to early trial closure. We used an intent-to-treat approach and log-binomial regression to calculate risk ratios (95% confidence intervals (CI)), adjusting for ER status.
Results: We randomized 118 patients; 117 were included in outcome analyses. The mean age was 42 years (range: 24-73); 69% were BRCA1+, 30% BRCA2+, and 2% had both mutations. Clinical stage was I for 19%, II for 63%, and III for 18%; 45% of patients had nodal involvement at baseline. Most patients (70%) had TNBC (ER/PR &lt;10%). Histologic type and grade, clinical stage, lymphovascular invasion and tumor infiltrating lymphocytes were similar between treatment arms. Four patients did not complete protocol-assigned therapy and 7 received additional chemotherapy before surgery; all were assessed as not attaining pCR. The pCR rate was 18% in the CDDP arm and 26% in the AC arm, yielding a crude risk ratio of 0.70 (95% CI: 0.35-1.4); results were similar when adjusting for ER status. Table 1 shows pathologic responses.
Table 1: Intention-to-treat analysis comparing CDDP to ACCDDP n=60 n (%)AC* n=57 n (%)Crude Risk Ratio (95% CI)Adjusted Risk Ratio§ (95% CI)Pathologic complete responseResidual cancer burden score: 0All participants11 (18)15 (26)0.70 (0.35-1.4)0.67 (0.35-1.3)Triple negative (ER and PR &lt;10%)10 (23)11 (29)0.79 (0.37-1.6)–Hormone receptor positive (ER or PR ≥10%)1 (6)4 (21)0.30 (0.04-2.4)–Residual cancer burden¥Residual cancer burden score: 0 or 120 (33)26 (46)0.73 (0.46-1.2)0.72 (0.46-1.1)*One patient never received treatment, and is not included in the intent-to-treat analysis.§Adjusted for estrogen receptor status using 10% cutoff¥Residual cancer burden score of 0 or 1 could not be determined for 10 participants; they were assumed to have a residual cancer burden score greater than 1
Conclusion: While CDDP has single-agent activity in BRCA carriers with HER2-negative breast cancer, the pCR rate with CDDP is not higher than with standard AC chemotherapy. CDDP activity was notably lower in BRCA carriers with hormone-receptor positive breast cancer, though the sample size was small. Study-collected tumor and blood samples are being analyzed for biomarkers of response. Clinical information: NCT01670500.
Funding: Breast Cancer Research Foundation; Susan G. Komen for the Cure; Myriad Genetics, Inc.
Citation Format: Nadine Tung, Banu Arun, Erin Hofstatter, Michele R. Hacker, Deborah L. Toppmeyer, Steven J. Isakoff, Virginia Borges, Robert D. Legare, Claudine Isaacs, Antonio C. Wolff, Paul K. Marcom, Erica L. Mayer, Paulina B. Lange, Andrew J. Goss, Ian E. Krop, Eric P. Winer, Stuart J. Schnitt, Judy E. Garber. Cisplatin versus doxorubicin/cyclophosphamide as neoadjuvant treatment in germline BRCA mutation carriers (BRCA carriers) with HER2-negative breast cancer: Results from the INFORM trial (TBCRC 031) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS6-03.