Abstract PD1-2: Impact of tumor-infiltrating B-cell clonal diversity on response to neoadjuvant therapy in triple negative and HER2+ breast cancer treated on CALGB (Alliance) 40601 and 40603

Background: Tumor infiltrating lymphocytes (TILs) are associated with improved outcomes in breast (BrCa) and ovarian cancer (OvCa). This benefit is largely restricted to the basal-like and HER2-enriched subtypes of BrCa and the immunoreactive subtype of OvCa. It is not known whether TILs respond to a small subset of antigens, similar to an antiviral or antibacterial response, or if the response is nonspecific. We developed a novel method to assess B-cell population diversity by analyzing B-cell receptor (BCR) sequence complexity in mRNA-seq datasets derived from tumor biopsies. B-cells in a subset of basal-like and HER2-enriched BrCa showed high expression of immunoglobulins coinciding with reduced BCR diversity consistent with a restricted epitope-driven immune response. Analysis of DNA patterns from B-cells in basal-like and HER2-enriched BrCa showed a greater prevalence of BCR somatic hypermutation (SHM) suggestive of an antigen-restricted response (Iglesia et al, CCR 2014). Here, we studied the impact of this adaptive immune response on treatment response. Methods: Using two neoadjuvant cooperative group trials in triple-negative (TNBC) and HER2-positive (HER2+) BrCa, we evaluated BCR diversity (as assessed by SHM diversity) as a continuous variable and as a binary variable (diverse/restricted) relative to BCR expression (the Restriction Index) in pre-treatment tumor samples from 265 patients with HER2+ BrCa treated on CALGB 40601, a randomized phase III trial of paclitaxel plus trastuzumab +/- lapatinib, and 443 patients with TNBC treated on CALGB 40603, a randomized phase II trial of standard chemotherapy +/- carboplatin and/or bevacizumab. We examined the relationship between a restricted immune response and pCR rate, the primary endpoint of both studies, overall and within molecular subtypes. Results: In HER2+ BrCa, the combination of high immunoglobulin expression and lower sequence diversity (high Restriction Index) was observed in 28% of the pre-treatment biopsies, and varied by intrinsic subtype, with the greatest prevalence in the HER2-enriched subset (n=80, 46% vs 20% in all others). BCR restriction predicted improved pCR rates in all patients (67% versus 37%, p Conclusions: The presence of a restricted diversity B-cell response in HER2+ breast cancer correlates with improved response to neoadjuvant chemotherapy plus HER2-targeted therapy, which may in part explain its impact on prognosis. We will determine if a similar correlation exists with chemotherapy response in TNBC. This suggests that immunomodulatory therapies supporting a B-cell response may be a promising therapeutic approach to targeting these tumors. Citation Format: Michael D Iglesia, Benjamin G Vincent, Jonathan S Serody, Lisa A Carey, William T Barry, William M Sikov, Clifford A Hudis, Eric M Winer, Charles M Perou. Impact of tumor-infiltrating B-cell clonal diversity on response to neoadjuvant therapy in triple negative and HER2+ breast cancer treated on CALGB (Alliance) 40601 and 40603 [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD1-2.