Sikov, Miriam Hospital and Alpert Medical School of Brown University, Providence, RI; Donald A. Berry, University of Texas MD Anderson Cancer Center, Houston, TX; Charles M. Perou and Lisa A. Carey, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill; Constance T.

Cirrincione, Alliance Statistical Center, Durham; Charles S. Kuzma, Southeast Cancer Control Consortium, Winston-Salem, NC; Baljit Singh, New York University Medical Center; Elisa R. Port, Mount Sinai Medical Center; Clifford A. Hudis, Memorial Sloan Kettering Cancer Center, New York, NY; Sara M. Tolaney, Mehra Golshan, Jennifer R.

Bellon, and Eric P. Winer, Dana-Farber Cancer Institute, Boston, MA; Timothy J.

Pluard, Washington University-St Louis Medical Center, St Louis, MO; George Somlo, City of Hope Comprehensive Cancer Center, Duarte; Deborah Collyar, Patient Advocates in Research, Danville, CA; and Olwen M. Hahn, University of Chicago Medical Center, Chicago, IL. Patients (N = 443) with stage II to III TNBC received paclitaxel 80 mg/m 2 once per week (wP) for 12 weeks, followed by doxorubicin plus cyclophosphamide once every 2 weeks (ddAC) for four cycles, and were randomly assigned to concurrent carboplatin (area under curve 6) once every 3 weeks for four cycles and/or bevacizumab 10 mg/kg once every 2 weeks for nine cycles.

Effects of adding these agents on pCR breast (ypT0/is), pCR breast/axilla (ypT0/isN0), treatment delivery, and toxicities were analyzed. Patients assigned to either carboplatin or bevacizumab were less likely to complete wP and ddAC without skipped doses, dose modification, or early discontinuation resulting from toxicity. Grade ≥ 3 neutropenia and thrombocytopenia were more common with carboplatin, as were hypertension, infection, thromboembolic events, bleeding, and postoperative complications with bevacizumab. Employing one-sided P values, addition of either carboplatin (60% v 44%; P =.0018) or bevacizumab (59% v 48%; P =.0089) significantly increased pCR breast, whereas only carboplatin (54% v 41%; P =.0029) significantly raised pCR breast/axilla. More-than-additive interactions between the two agents could not be demonstrated. Breast cancer (TNBC), characterized by absent or minimal expression of estrogen (ER) and progesterone receptors (PgRs) and human epidermal growth factor receptor 2 (HER2), accounts for 15% to 20% of invasive breast cancers diagnosed in the United States. It is more common in younger women, African Americans, Hispanics, and BRCA1-mutation carriers.

With no targetable characteristic molecular abnormalities yet identified, standard treatment for TNBC remains chemotherapy. In early-stage TNBC, recurrence-free (RFS) and overall survival (OS) are improved significantly with adjuvant chemotherapy, including dose-dense treatment, but overall prognosis remains inferior to that of other breast cancer subtypes, with higher risk of early relapse, often involving viscera or the CNS. Approximately one third of patients with stage II to III TNBC treated with anthracycline- and taxane-based (NACT) achieve a (pCR).

As in other aggressive cancers, pCR is associated with improved outcomes, whereas patients with residual disease have an increased risk of recurrence., Platinum analogs attack cancer cells by inducing double-stranded DNA breaks. As single agents, they have limited efficacy in heavily pretreated metastatic breast cancer, but greater activity has been seen in BRCA-mutation carriers, with pCR rates > 70% in small neoadjuvant trials., BRCA-mutated and sporadic TNBC have similar biologic characteristics and mRNA gene expression patterns, motivating further study of platinums in this subtype. Although single-agent cisplatin yielded few pCRs in sporadic TNBC, pilot studies of the addition of cisplatin or carboplatin to standard NACT have reported rates as high as 75%., binds and inactivates vascular endothelial growth factor 1, believed to support the growth and maintenance of tumor neovasculature necessary for survival and metastasis. In metastatic TNBC, addition of bevacizumab to once-per-week paclitaxel improves response rates and time to progression., Whether the addition of bevacizumab to NACT in TNBC could improve pCR rates and long-term outcomes was unknown. The CALGB (Cancer and Leukemia Group B) 40603 trial was designed to examine the impact of adding carboplatin and/or bevacizumab to conventional NACT in TNBC on clinical activity, measured by pCR rates, and toxicity.