Reference Detail

Ref Type

Journal Article

PMID

(32348852)

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	Vol	Issue	Date	Pages	Journal Short Title
Annals of oncology : official journal of the European Society for Medical Oncology			2020 Apr 26	991-1000	Ann Oncol

URL

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.

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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