Triple negative breast cancer (TNBC) is more common among African American (AA) women compared to other races and the survival rates are lower even after adjusting for socio- economic factors. Recently, we also demonstrated that response rates to preoperative (neoadjuvant) chemotherapy are also lower indicating lower chemotherapy sensitivity of TNBC in AA patients. The biological bases of these differences in treatment sensitivity and prognosis are currently unknown. Immune cell infiltration of TNBC has been shown to be associated with both prognosis and chemotherapy sensitivity across all races. High level of immune cell infiltration predicts for greater chemotherapy sensitivity and better survival. Laboratory studies also demonstrated that activation of anti-tumor immune cells in the cancer microenvironment during chemotherapy contribute to the cytotoxic effects of the treatment. Racial differences in immune infiltration of TNBC have not been studied. We hypothesize that the lower chemotherapy sensitivity of TNBC in AA patients may be due to lower immune cell presence in these cancers compared to non-AA patients. We also hypothesize that adding an immune ?boosting? drug to standard of care chemotherapy will increase the efficacy of treatment. The goals of this study are (i) to compare the immune environment of newly diagnosed, stage I- III, TNBC in AA and non-AA patients and (ii) test in a therapeutic clinical trial if addition of the anti-PDL1 antibody MEDI4736, to preoperative nab-paclitaxel and dose dense doxorubicin/cyclophosphamide chemotherapy could increase the rate of complete eradication of cancer from the breast and lymph nodes (i.e. pathologic complete response rate). This will be the first study to systematically examine the immune cell composition in TNBC in different racial groups and the first prospective clinical trial to test if adding immune checkpoint inhibitor therapy to neoadjuvant chemotherapy could improve response rates in AA patients and if the benefit from immune therapy differs by race. If our hypothesis is correct and TNBC in AA women have lower immune cell infiltration which translates into lower chemotherapy sensitivity and poorer survival, this would provide the basis for developing new immune targeted treatment strategies to eliminate the outcome difference. Our proposal will also assess one such therapeutic strategy, inclusion of the anti-PD-L1 antibody, MEDI4736, with standard-of-care neoadjuvant chemotherapy. Equally importantly, the immune profiling and genomic data that we will generate will also allow formulating new hypotheses of how one might increase the immunogenicity of TNBC in AA women, and test such strategies in future clinical trials. 1
This proposal brings together four different disciplines including medical oncology, breast surgery, pathology and Bioinformatics at Yale Cancer Center to investigate if there is an immune-biology related basis of race-associated differences in chemotherapy sensitivity of triple negative breast cancer (TNBC). Our project will address provocative question # 3 ?How do variations in tumor-associated immune responses contribute to differences in cancer risk, incidence, or progression?? We will test the hypothesis that the lower chemotherapy sensitivity and poorer prognosis of TNBC in African American (AA) women are due to lower anti-tumor immunity in the TNBC microenvironment in AA compared to non-AA patients. We will also test in a prospective clinical trial if inclusion of an immune checkpoint inhibitor (MEDI4736) with standard-of-care preoperative chemotherapy can increase chemotherapy sensitivity of TNBC in AA patients indicated by higher pathological complete response (pCR).