Enrichment of Kinase Fusions in ESR1 Wild Type, Metastatic Breast Cancer Revealed by a Systematic Analysis of 4,854 Patients.
Kinase fusions are rare and poorly characterized in breast cancer. We aimed to characterize kinase fusions within a large cohort of advanced breast cancer.4854 patients with breast cancer were analyzed by 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 (5 FGFR2, 3 FGFR3, 3 FGFR1), 5 BRAF, 4 NTRK1, 2 RET, 2 ROS1, 1 ALK, 1 ERBB2, and 1 MET. A history of endocrine therapy was present in 15 (56%) of fusion-positive breast cancers; eight of the 15 cases had available pre-treatment samples, of which 6 were fusion negative. None of the fusion-positive breast cancer samples harbored ESR1 hotspot mutations. Two patients with acquired LMNA-NTRK1 fusions and metastatic disease received larotrectinib and demonstrated clinical benefit.Kinase fusions in breast cancers 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 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.