Abstract P3-07-31: Immune activation signatures identify a subset of ER+ breast cancers with increased pathologic complete response to neoadjuvant chemotherapy

Abstract

Background: Proliferation is the strongest predictor of response to neoadjuvant chemotherapy in estrogen receptor-positive (ER+) breast cancer. Evidence of immune activation has also been associated with improved response to neoadjuvant chemotherapy in breast cancer. We hypothesized that immune signatures may be associated with response independent of proliferation in ER+ breast cancers. Approach: We compiled microarray expression data from breast cancer biopsies obtained prior to neoadjuvant chemotherapy on 465 ER-positive/HER2-negative patients by reported pathologic receptor status. We evaluated the association of 118 published gene expression signatures with response to neoadjuvant chemotherapy, based on study-defined pathologic complete response (pCR) versus residual disease (RD). Results: Overall, 42 of 118 signatures were significantly associated with response to neoadjuvant chemotherapy in ER+ breast cancer (FDR-corrected p<0.05, simple logistic regression). Of those signatures that achieved significance, 52% (22/42) of signatures were proliferation-associated based on correlation to the 11-gene PAM50 proliferation index (Pearson's R2>0.30, p<1e-10). Among signatures that were NOT proliferation-associated, 50% (10/20) were immune-related. Using unsupervised hierarchical clustering of all 118 signatures, these ten immune signatures formed a distinct cluster. Of the 10 signatures, nine were designed to reflect "immune activation" and were highly correlated with each other in ER+ tumors (R2>0.4, p<0.001). The mean of each of these nine signatures was significantly higher in patients with pCR versus RD (FDR-corrected p<0.05, t-test). Patients with higher "immune activation" signatures had increased likelihood of pCR within multiple subgroups of ER+ breast cancer, including luminal B and non-luminal PAM50 subgroups, as well as intermediate- and high-proliferation ER+ breast cancers. For luminal A or low-proliferation breast cancers, "immune activation" signatures were not significantly associated with response, though very few patients achieved pCR in these two subgroups. Conclusions: Gene expression signatures associated with "immune activation" identify a subset of ER+ breast cancers with higher rates of pCR to neoadjuvant chemotherapy. These "immune activation" signatures appear to be proliferation-independent and may provide additional predictive information to existing gene expression-based approaches for ER+ breast cancer. Citation Format: Stover DG, Waks AG, Erica ML, Brugge JS, Winer EP, Selfors LM. Immune activation signatures identify a subset of ER+ breast cancers with increased pathologic complete response to neoadjuvant chemotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-31.