Enrichment of kinase fusions in ESR1 wild-type, metastatic breast cancer revealed by a systematic analysis of 4854 patients Journal Article
| Authors: | Ross, D. S.; Liu, B.; Schram, A. M.; Razavi, P.; Lagana, S. M.; Zhang, Y.; Scaltriti, M.; Bromberg, J. F.; Ladanyi, M.; Hyman, D. M.; Drilon, A.; Zehir, A.; Benayed, R.; Chandarlapaty, S.; Hechtman, J. F. |
| Article Title: | Enrichment of kinase fusions in ESR1 wild-type, metastatic breast cancer revealed by a systematic analysis of 4854 patients |
| Abstract: | Background: Kinase fusions are rare and poorly characterized in breast cancer (BC). We aimed to characterize kinase fusions within a large cohort of advanced BC. Patients and methods: 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. Results: 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. Conclusion: 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. © 2020 European Society for Medical Oncology |
| Keywords: | adult; controlled study; human tissue; aged; middle aged; unclassified drug; gene mutation; cancer growth; nonhuman; animal cell; animal tissue; breast cancer; epidermal growth factor receptor 2; molecular dynamics; animal experiment; animal model; cohort analysis; protein tyrosine kinase; fibroblast growth factor receptor 3; cancer resistance; hormonal therapy; metastatic breast cancer; protein ret; b raf kinase; fibroblast growth factor receptor 1; fibroblast growth factor receptor 2; resistance; fulvestrant; endocrine therapy; scatter factor receptor; braf gene; anaplastic lymphoma kinase; lamin a; estrogen receptor alpha; ret gene; met gene; erbb2 gene; mapk signaling; alk gene; fgfr1 gene; fgfr3 gene; ros1 gene; dna sequencing; human; female; priority journal; article; ceritinib; rna sequencing; kinase fusion; larotrectinib; fgfr2 gene; ntrk1 gene; esr1 gene; neurotrophic receptor tyrosine kinase 1 |
| Journal Title: | Annals of Oncology |
| Volume: | 31 |
| Issue: | 8 |
| ISSN: | 0923-7534 |
| Publisher: | Oxford University Press |
| Date Published: | 2020-08-01 |
| Start Page: | 991 |
| End Page: | 1000 |
| Language: | English |
| DOI: | 10.1016/j.annonc.2020.04.008 |
| PUBMED: | 32348852 |
| PROVIDER: | scopus |
| PMCID: | PMC7396305 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 September 2020 -- Source: Scopus |
