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.

Trial registration: ClinicalTrials.gov NCT01670500.

FIG 1.

Schema of randomized phase II INFORM trial (TBCRC 031). (*) Granulocyte colony–stimulating factor (G-CSF) mandatory for dose-dense AC (once-every-2-weeks schedule). G-CSF optional for AC once every 3 weeks and cisplatin. AC, doxorubicin plus cyclophosphamide; BC, breast cancer; CDDP, cisplatin; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; LN, lymph node; T, tumor size; TNBC, triple-negative breast cancer.

FIG 2.

CONSORT diagram. (*) Two patients had residual disease at biopsy performed before additional chemotherapy or at definitive tumor resection after additional chemotherapy; for 3 patients, residual cancer was not seen at either biopsy before additional chemotherapy or tumor resection after additional chemotherapy. (**) Both patients had residual disease demonstrated by biopsy before additional nonstudy-assigned chemotherapy.

FIG 3.

(A) Pathologic complete response (pCR) breast/axilla (ypT0/is, N0); (B) residual cancer burden (RCB) 0 or 1; risk ratio with 90% CI for (A) pCR or for (B) RCB 0/1 with cisplatin (CDDP) compared with doxorubicin-cyclophosphamide (AC) is shown. ER, estrogen receptor; PR, progesterone receptor; TNBC, triple-negative breast cancer.

FIG 4.

The likelihood (risk ratio [RR]) of pathologic complete response with cisplatin compared with doxorubicin-cyclophosphamide is shown for various patient and tumor characteristics. ER, estrogen receptor; PR, progesterone receptor.