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|Ref Type||Journal Article|
|Authors||Ross DS, Liu B, Schram AM, Razavi P, Lagana SM, Zhang Y, Scaltriti M, Bromberg JF, Ladanyi M, Hyman DM, Drilon A, Zehir A, Benayed R, Chandarlapaty S, Hechtman JF|
|Title||Enrichment of kinase fusions in ESR1 wild-type, metastatic breast cancer revealed by a systematic analysis of 4854 patients.|
|Journal||Annals of oncology : official journal of the European Society for Medical Oncology|
|Date||2020 Apr 26|
|Abstract Text||Kinase fusions are rare and poorly characterized in breast cancer (BC). We aimed to characterize kinase fusions within a large cohort of advanced BC.A total of 4854 patients with BC were analyzed by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) targeted DNAseq and MSK-Fusion targeted RNAseq during the study time period.Twenty-seven of 4854 (0.6%) patients harbored fusions: 11 FGFR (five FGFR2, three FGFR3, three FGFR1), five BRAF, four NTRK1, two RET, two ROS1, one ALK, one ERBB2, and one MET. A history of endocrine therapy was present in 15 (56%) of fusion-positive BC; eight of the 15 cases had available pre-treatment samples, of which six were fusion-negative. None of the fusion-positive BC samples harbored ESR1 hotspot mutations. Two patients with acquired LMNA-NTRK1 fusions and metastatic disease received larotrectinib and demonstrated clinical benefit.Kinase fusions in BC are extremely rare, and appear to be enriched in hormone-resistant, metastatic carcinomas and mutually exclusive with ESR1 mutations. The present study expands the spectrum of genetic alterations activating mitogen-activated protein kinase (MAPK) signaling that can substitute for ESR1 mutations in this setting. Molecular testing at progression after endocrine therapy should include fusion testing, particularly in the absence of ESR1 hotspot alterations, in an effort to identify additional therapeutic options which may provide substantial clinical benefit.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|EML4 - ALK||breast cancer||sensitive||Ceritinib||Preclinical - Cell culture||Actionable||In a preclinical study, breast cancer cells expressing EML4-ALK were sensitive to treatment with Zykadia (ceritinib) in culture, demonstrating inhibition of cell growth (PMID: 32348852).||32348852|
|EML4 - ALK||breast cancer||resistant||Fulvestrant||Preclinical - Cell culture||Actionable||In a preclinical study, breast cancer cells expressing EML4-ALK demonstrated resistance to treatment with Faslodex (fulvestrant) in culture (PMID: 32348852).||32348852|
|EML4 - ALK||breast cancer||predicted - sensitive||Ceritinib + Fulvestrant||Preclinical - Cell culture||Actionable||In a preclinical study, the addition of Zykadia (ceritinib) to Faslodex (fulvestrant) treatment in breast cancer cells expressing EML4-ALK restored growth inhibition in culture (PMID: 32348852).||32348852|