TBCRC 031: Randomized Phase II Study of Neoadjuvant Cisplatin Versus Doxorubicin-Cyclophosphamide in Germline BRCA Carriers With HER2-Negative Breast Cancer (the INFORM trial)

Abstract

PURPOSE Platinum compounds have activity in triple-negative breast cancer (TNBC) in germline BRCA mutation carriers ( BRCA carriers). Limited data exist for estrogen receptor (ER)–positive (+) breast cancer among BRCA carriers. INFORM is a randomized, multicenter, phase II trial comparing pathologic complete response (pCR) rates (ypT0/is, N0) after neoadjuvant single-agent cisplatin (CDDP) versus doxorubicin-cyclophosphamide (AC) in BRCA carriers with stage I-III human epidermal growth factor receptor 2 (HER2)–negative breast cancer. Secondary objectives included residual cancer burden scores (RCB) of 0 or 1 (combined) and toxicity. The goal was to determine whether pCR was ≥ 20% higher with CDDP than AC. PATIENTS AND METHODS BRCA carriers with cT1-3 (≥ 1.5 cm), cN0-3 HER2-negative breast cancer were randomly assigned to preoperative CDDP (75 mg/m2 every 3 weeks × 4 doses) or AC (doxorubicin 60 mg/m2; cyclophosphamide 600 mg/m2 every 2-3 weeks × 4 doses) followed by surgery. Pathologic responses were confirmed by central review. RESULTS A total of 118 patients were randomly assigned; 117 were included in outcome analyses. Mean age was 42 years (range, 24-73 years); 69% were BRCA1+, 30% were BRCA2+, and 2% had both mutations. Clinical stage was I for 19%, II for 63%, and III for 18%; 45% had nodal involvement at baseline. Seventy percent had TNBC. Clinical and tumor characteristics were well matched between treatment arms. The pCR rate was 18% with CDDP and 26% with AC, yielding a risk ratio (RR) of 0.70 (90% CI, 0.39 to 1.2). The risk of RCB 0 or 1 (RCB 0/1) was 33% with CDDP and 46% with AC (RR, 0.73; 90% CI, 0.50 to 1.1). Both regimens were generally well tolerated without unexpected toxicities. CONCLUSION pCR or RCB 0/1 is not significantly higher with CDDP than with AC in BRCA carriers with stage I-III HER2-negative breast cancer for both TNBC and ER+/HER2-negative disease.

Clinical outcome of breast cancer in carriers of BRCA1 and BRCA2 mutations according to molecular subtypes

“…Several studies have shown that among ovarian cancer patients, BRCA1 and especially BRCA2 carriers respond better than non-carriers to platinum-based chemotherapy and have prolonged survival [20][21][22] . We hypothesized that BRCA germline mutations would lead to prolonged survival in breast cancer patients treated by DNA-damage agents such as alkylating agents and/or anthracylines 23 . We conducted a multicentric retrospective study with the primary objective of assessing the prognostic value of BRCA germline mutation on survival among stage I-III breast cancer patients treated with chemotherapy.…”

Neoadjuvant Treatment for Triple Negative Breast Cancer: Recent Progresses and Challenges

“…In addition to studies with carboplatin, cisplatin 75 mg/m 2 , every three weeks × 4 was evaluated in a randomized phase II study of neoadjuvant cisplatin vs. AC in germline BRCA carriers with HER2-negative (TBCRC 031) [46]. The pCR rate was 18% with cisplatin and 26% with AC, yielding a risk ratio (RR) of 0.70 (90% CI, 0.39 to 1.20).…”

Platinum-Based Neoadjuvant Chemotherapy for Breast Cancer With BRCA Mutations: A Meta-Analysis

“…All the studies included early breast cancer patients, two studies included Stage I-III patients (9,14), and the other three included Stage II-III patients (10,11,13). Three studies included only TNBC (10,13,14) and one study included HER2-patients (11). For study design, study by Hahnen et al, Loible et al, and Tung et al were randomized controlled trial (RCT) (10,11,13), and the other two were prospective cohort studies (PCS) (9,14).…”

“…Three studies included only TNBC (10,13,14) and one study included HER2-patients (11). For study design, study by Hahnen et al, Loible et al, and Tung et al were randomized controlled trial (RCT) (10,11,13), and the other two were prospective cohort studies (PCS) (9,14). Two studies involved merely BRCA1 mutated patients (9,14), while the other three involved both BRCA1 or 2 mutated patients (10,11,13).…”

“…Study by Byriski et al reported extremely high pCR rate (83.3%) with single agent cisplatin (9). On the contrary, GeparSixto trial and recently published INFORM trial demonstrated the pCR rate of BRCA mutation carriers was not further improved with the application of platinum (10,11). Therefore, we conducted this meta-analysis to evaluate the therapeutic effect of platinum in neoadjuvant therapy for breast cancer with BRCA mutations.…”