Comparison of actionable alterations in cancers with kinase fusion, mutation, and amplification

Abstract

AbstractKinase-related gene fusion and point mutations play pivotal roles as drivers in cancer, necessitating optimized targeted therapy against these alterations. The efficacy of molecularly targeted therapeutics varies depending on the specific alteration, with great success reported for such therapeutics in the treatment of cancer with kinase fusion proteins. However, the involvement of actionable alterations in solid tumors, especially in relation to kinase fusions, remains incompletely understood. This study aimed to compare the number of actionable alterations in patients with tyrosine or serine/threonine kinase domain fusions, mutations, and amplifications. We analyzed 613 patients with 40 solid cancer types who visited our division between June 2020 and April 2024. To detect alterations involving multiple-fusion calling, we performed comprehensive genomic sequencing using FoundationOne®companion diagnostic (F1CDx) and FoundationOne®Liquid companion diagnostic (F1LCDx). Patient characteristics and genomic profiles were analyzed to assess the frequency and distribution of actionable alterations across different cancer types. Of the 613 patients, 44 had fusions involving kinases, transcriptional regulators, or tumor suppressors. F1CDx and F1LCDx detected 13 with kinase-domain fusions. We identified 117 patients with kinase-domain mutations and 58 with kinase-domain amplifications. The number of actionable alterations in patients with kinase-domain fusion, mutation, or amplification (median [interquartile range; IQR]) was 2 (1–3), 5 (3–7), and 6 (4–8), respectively. Patients with kinase fusion had significantly fewer actionable alterations than those with kinase-domain mutations and amplifications. However, those cancers with fusion involving tumor suppressors tended to have more actionable alterations (median [IQR]; 4 [2–9]). Cancers with kinase fusions tended to exhibit fewer actionable alterations than those with kinase mutations and amplifications. These findings underscore the importance of detecting kinase alterations and indicate the pivotal role of kinase fusions are strong drivers of cancer development, highlighting their potential as prime targets for molecular therapeutics.