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
Authors: Iglesia Michael D , Vincent Benjamin G , Serody Jonathan S , Carey Lisa A , Barry William T , Sikov William M , Hudis Clifford A , Winer Eric M , Perou Charles M 
Published: May 2015

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 &lt;0.0001). It remained significant in the HER2-enriched subset (n = 82, p=0.0086). The impact of Restriction Index on response to chemotherapy in TNBC is being analyzed and will be presented along with multivariate models to adjust for other patient and disease characteristics and explore potential interactions.

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.