Abstract

BackgroundTriple negative breast cancer (TNBC) is a highly heterogeneous and aggressive disease, and although no effective targeted therapies are available to date, about one-third of patients with TNBC achieve pathologic complete response (pCR) from standard-of-care anthracycline/taxane (ACT) chemotherapy. The heterogeneity of these tumors, however, has hindered the discovery of effective biomarkers to identify such patients.Methods and FindingsWe performed whole exome sequencing on 29 TNBC cases from the MD Anderson Cancer Center (MDACC) selected because they had either pCR (n = 18) or extensive residual disease (n = 11) after neoadjuvant chemotherapy, with cases from The Cancer Genome Atlas (TCGA; n = 144) and METABRIC (n = 278) cohorts serving as validation cohorts. Our analysis revealed that mutations in the AR- and FOXA1-regulated networks, in which BRCA1 plays a key role, are associated with significantly higher sensitivity to ACT chemotherapy in the MDACC cohort (pCR rate of 94.1% compared to 16.6% in tumors without mutations in AR/FOXA1 pathway, adjusted p = 0.02) and significantly better survival outcome in the TCGA TNBC cohort (log-rank test, p = 0.05). Combined analysis of DNA sequencing, DNA methylation, and RNA sequencing identified tumors of a distinct BRCA-deficient (BRCA-D) TNBC subtype characterized by low levels of wild-type BRCA1/2 expression. Patients with functionally BRCA-D tumors had significantly better survival with standard-of-care chemotherapy than patients whose tumors were not BRCA-D (log-rank test, p = 0.021), and they had significantly higher mutation burden (p < 0.001) and presented clonal neoantigens that were associated with increased immune cell activity. A transcriptional signature of BRCA-D TNBC tumors was independently validated to be significantly associated with improved survival in the METABRIC dataset (log-rank test, p = 0.009). As a retrospective study, limitations include the small size and potential selection bias in the discovery cohort.ConclusionsThe comprehensive molecular analysis presented in this study directly links BRCA deficiency with increased clonal mutation burden and significantly enhanced chemosensitivity in TNBC and suggests that functional RNA-based BRCA deficiency needs to be further examined in TNBC.

Highlights

  • Triple negative breast cancer (TNBC) disproportionately affects younger women and women of African ancestry, contributing to health disparities

  • Our analysis revealed that mutations in the androgen receptor (AR)- and FOXA1-regulated networks, in which BRCA1 plays a key role, are associated with significantly higher sensitivity to ACT chemotherapy in the MD Anderson Cancer Center (MDACC) cohort and significantly better survival outcome in the The Cancer Genome Atlas (TCGA) TNBC cohort

  • Our analysis revealed that, mutations in single genes were not individually predictive, TNBC tumors bearing mutations in genes involved in the androgen receptor (AR) and FOXA1 pathways were much more sensitive to chemotherapy

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Summary

Introduction

Triple negative breast cancer (TNBC) disproportionately affects younger women and women of African ancestry, contributing to health disparities. One-third of patients achieve pathologic complete response (pCR) and have excellent survival, but the remaining patients relapse and eventually die of the disease [3,4,5] Identifying those TNBC patients who might benefit from ACT chemotherapy and directing the remaining patients to novel targeted therapies may be an effective strategy with near-term clinical impact for managing TNBC. Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive disease, and no effective targeted therapies are available to date, about one-third of patients with TNBC achieve pathologic complete response (pCR) from standard-of-care anthracycline/taxane (ACT) chemotherapy. The heterogeneity of these tumors, has hindered the discovery of effective biomarkers to identify such patients

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