Expression of immunologic genes in triple-negative and HER2-positive breast cancer in the neoadjuvant GEPARSIXTO trial: Prediction of response to carboplatin-based chemotherapy.

Abstract

510 Background: We have recently described tumor-infiltrating lymphocytes (TILs) as predictors of pathological complete response (pCR = ypT0ypN0) to neoadjuvant carboplatin-based chemotherapy in the GeparSixto breast cancer (BC) trial. To further dissect the immunological status in tumor tissue we have evaluated a total of 12 immunologically relevant genes, including T-cell markers, B-cell markers, chemokines and immunoregulatory factors, in 481 pretherapeutic FFPE samples. Methods: GeparSixto investigated the addition of carboplatin to a doxorubicin/taxane combination in HER2-positive (HER2+) or triple-negative (TN) primary BC. Trastuzumab and lapatinib were added for HER2+ disease and bevacizumab for TN disease. Expression of 12 immunologically relevant genes (CXCL9, CCL5, CD8A, CD80, CXCL13, IGKC, CD21, IDO1, PD-1, PDL1, CTLA4, FOXP3) was evaluated by quantitative RT-PCR in 481 core biopsies. Results: All immune mRNA markers showed a strong positive correlation with each other and with the stromal lymphocyte infiltrate. Hierarchical clustering revealed three different immune-subtypes of tumors with different expression of immunological genes and different amounts of tumor infiltrating lymphocytes. In the GeparSixto cohort all 12 immune markers were significantly linked to increased pCR rates in univariate analysis. 11 of the markers were also significant in multivariate analysis including clinical parameters. Some markers, such as CCL5, IDO1 and PDL1 provided predictive information even if controlled for TILs. CCL5, CD8A, CTLA4, IDO1 and PD1 showed a significant interaction with treatment (carboplatin vs. control) in the complete cohort. In TN disease CCL5 and CD8A provided predictive information for carboplatin response even after adjustment for TILs. Conclusions: Expression of immune marker mRNAs in BC is predictive for response to neoadjuvant chemotherapy. In GeparSixto, these immunological parameters can be used in addition to TILs to identify patients with increased response rates to carboplatin. The results should be validated in other breast cancer trials evaluating carboplatin therapy.