Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis
Publication Date
December 13, 2016
Authors
Tingting Jiang, Weiwei Shi, Vikram B. Wali, Lőrinc S. Pongor, et al
Volume
13
Issue
12
Pages
e1002193
DOI
https://dx.plos.org/10.1371/journal.pmed.1002193
Publisher URL
http://journals.plos.org/plosmedicine/article?id=10.1371%2Fjournal.pmed.1002193
Scopus
85007610185
Mendeley
http://www.mendeley.com/research/predictors-chemosensitivity-triple-negative-breast-cancer-integrated-genomic-analysis-1
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Mendeley | Further Information

{"title"=>"Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis", "type"=>"journal", "authors"=>[{"first_name"=>"Tingting", "last_name"=>"Jiang", "scopus_author_id"=>"56047751100"}, {"first_name"=>"Weiwei", "last_name"=>"Shi", "scopus_author_id"=>"56799550500"}, {"first_name"=>"Vikram B.", "last_name"=>"Wali", "scopus_author_id"=>"14057139500"}, {"first_name"=>"Lőrinc S.", "last_name"=>"Pongor", "scopus_author_id"=>"55889739900"}, {"first_name"=>"Charles", "last_name"=>"Li", "scopus_author_id"=>"57192718868"}, {"first_name"=>"Rosanna", "last_name"=>"Lau", "scopus_author_id"=>"36786537400"}, {"first_name"=>"Balázs", "last_name"=>"Győrffy", "scopus_author_id"=>"56009655800"}, {"first_name"=>"Richard P.", "last_name"=>"Lifton", "scopus_author_id"=>"7005891012"}, {"first_name"=>"William F.", "last_name"=>"Symmans", "scopus_author_id"=>"7003919463"}, {"first_name"=>"Lajos", "last_name"=>"Pusztai", "scopus_author_id"=>"7006477868"}, {"first_name"=>"Christos", "last_name"=>"Hatzis", "scopus_author_id"=>"6602077638"}], "year"=>2016, "source"=>"PLoS Medicine", "identifiers"=>{"issn"=>"15491676", "isbn"=>"1549-1676 (Electronic) 1549-1277 (Linking)", "pui"=>"613964658", "sgr"=>"85007610185", "doi"=>"10.1371/journal.pmed.1002193", "scopus"=>"2-s2.0-85007610185", "pmid"=>"27959926"}, "id"=>"d113fa06-1270-3670-9892-b3233fd51cee", "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. METHODS AND FINDINGS 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.", "link"=>"http://www.mendeley.com/research/predictors-chemosensitivity-triple-negative-breast-cancer-integrated-genomic-analysis-1", "reader_count"=>56, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Researcher"=>17, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>3, "Student > Master"=>7, "Other"=>4, "Student > Bachelor"=>3, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>1, "Professor"=>3}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Researcher"=>17, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>3, "Student > Master"=>7, "Other"=>4, "Student > Bachelor"=>3, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>1, "Professor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>4, "Biochemistry, Genetics and Molecular Biology"=>16, "Mathematics"=>2, "Agricultural and Biological Sciences"=>17, "Medicine and Dentistry"=>15, "Business, Management and Accounting"=>1, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>15}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>17}, "Computer Science"=>{"Computer Science"=>1}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>16}, "Mathematics"=>{"Mathematics"=>2}, "Unspecified"=>{"Unspecified"=>4}}, "reader_count_by_country"=>{"United Kingdom"=>2}, "group_count"=>1}

Scopus | Further Information

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