title: Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis.
abstract: BACKGROUND
  Triple 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Department of Medicine, Yale School of Medicine, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Tingting
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Department of Medicine, Yale School of Medicine, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Shi
authors.affiliation: Department of Medicine, Yale School of Medicine, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Vikram B
authors.initials: VB
authors.lastname: Wali
authors.affiliation: MTA TTK Lendulet Cancer Biomarker Research Group, Research Center for Natural Sciences, Budapest, Hungary.|2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Lőrinc S
authors.initials: LS
authors.lastname: Pongor
authors.affiliation: Department of Genetics, Yale School of Medicine, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Charles
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Lau
authors.affiliation: MTA TTK Lendulet Cancer Biomarker Research Group, Research Center for Natural Sciences, Budapest, Hungary.|2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Győrffy
authors.affiliation: Department of Medicine, Yale School of Medicine, Yale University, New Haven, Connecticut, United States of America.|Department of Genetics, Yale School of Medicine, Yale University, New Haven, Connecticut, United States of America.|Yale Cancer Center, New Haven, Connecticut, United States of America.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: William F
authors.initials: WF
authors.lastname: Symmans
authors.affiliation: Department of Medicine, Yale School of Medicine, Yale University, New Haven, Connecticut, United States of America.|Yale Cancer Center, New Haven, Connecticut, United States of America.
authors.forename: Lajos
authors.initials: L
authors.lastname: Pusztai
authors.affiliation: Department of Medicine, Yale School of Medicine, Yale University, New Haven, Connecticut, United States of America.|Yale Cancer Center, New Haven, Connecticut, United States of America.
authors.forename: Christos
authors.identifier: http://orcid.org/0000-0002-8120-2290
authors.initials: C
authors.lastname: Hatzis
mesh_terms: D018943:Anthracyclines / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015415:Biomarkers; D001952:Bridged-Ring Compounds / Q000627:therapeutic use*; D015331:Cohort Studies; D019008:Drug Resistance, Neoplasm; D059472:Exome; D005260:Female; D023281:Genomics; D006801:Humans; D043823:Taxoids / Q000627:therapeutic use*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*
chemical_list: D018943:Anthracyclines; D015415:Biomarkers; D001952:Bridged-Ring Compounds; D043823:Taxoids; C080625:taxane