Prediagnostic exposures, germline genetics, and triple negative breast cancer mutational and immune profiles - triple negative breast cancer (tnbc) are typically aggressive cancers with shorter median…

This $3.3 million project grant from the National Cancer Institute's Cancer Cause and Prevention Research program (CFDA 93.393) supports research to identify prediagnostic exposures, germline genetics, and immune and mutational profiles associated with triple negative breast cancer (TNBC). Joan & Sanford I Weill Medical College of Cornell University is the primary awardee and will perform whole exome sequencing of tumor and germline DNA from 400 TNBC patients across four prospective cohort studies. Sub-awardees include Harvard T.H. Chan School of Public Health, Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, the American Cancer Society, and The Ohio State University Office of Sponsored Programs.

Sub-awardees will extract DNA, manage data, generate mutation calls, develop immune signatures, and analyze associations between risk factors, mutations, and immune profiles. Results will provide insight into TNBC etiology and prognosis to support prevention strategies and targeted therapies for these aggressive cancers.

Prediagnostic exposures, germline genetics, and triple negative breast cancer mutational and immune profiles - triple negative breast cancer (tnbc) are typically aggressive cancers with shorter median time to relapse and death than other breast cancers. Because these cancers are defined by the absence of a target, identification of tailored therapies has been challenging. However, immune therapy shows important promise in tnbc, including the first FDA approval for immunotherapy in breast cancer and favorable response data for the addition of immunotherapy to neoadjuvant chemotherapy. Recent evidence suggests that tumor molecular characteristics may provide clues to both the different etiology and prognoses for tnbcs. Gene expression studies revealed that tnbcs are heterogeneous and composed of finer subtypes, defined in part by immune response signatures. IT has been hypothesized that the patients' immune response plays an important role in determining tumor progression. Further, sequencing studies have identified a set of genes that are frequently mutated in breast tumors and several mutational signatures that reflect distinct mutagenic processes, and may have etiologic implications. The mutational signatures that have been identified in tnbcs are distinct from the more common luminal breast cancers, highlighting the need for research specific to this subtype. We propose to perform whole exome sequencing (WES) of matched tumor and germline DNA samples from 400 tnbc patients from four prospective cohort studies, the nurses' health study, nurses' health study II, cancer prevention study II, and cancer prevention study 3. In combination with our existing rich database of germline gwas, breast cancer risk factors, and tumor immune signatures, we are well positioned to better understand how genetic and nongenetic risk factors influence breast tumor mutational signatures, immune response and prognosis. We will assess the association of genetic and nongenetic risk factors with tumor mutational profiles (aim 1), and tumor immune profiles (aim 2). We will also examine the association between immune response signatures and tumor mutation profiles (aim 3). In exploratory analyses, we will evaluate whether a possible joint effect of somatic mutational signatures and immune response signatures are associated with breast cancer-specific survival (aim 4). Knowledge from this study will be extremely valuable in developing prevention strategies and treatment targets for these aggressive tumors. To complete these aims, we have assembled a multidisciplinary team of experts in breast cancer epidemiology, genetic epidemiology, statistical genetics, bioinformatics, immuno-oncology, and tumor genomics. The principal investigators have extensive experience with the cohort resources and have worked collaboratively for over thirteen years. We have also partnered with the b-cast and amber consortia to create a large and diverse repository of WES data from tnbcs, which will enable US to both replicate our results and compare mutational profiles and their associations with prediagnostic and clinical factors in european-ancestry and african american women.