KITgenetic alterations in breast cancer

Abstract

AimsActivating somatic mutations or gene amplification ofKITresult in constitutive activation of its receptor tyrosine kinase, which is targetable in various solid tumours. Here, we sought to investigate the presence ofKITgenetic alterations in breast cancer (BC) and characterise the histological and genomic features of these tumours.MethodsA retrospective analysis of 5,575 BCs previously subjected to targeted sequencing using the FDA-authorised Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Targets (MSK-IMPACT) assay was performed to identify BCs withKITalterations. A histological assessment ofKIT-altered BCs was conducted, and their repertoire of genetic alterations was compared with that of BCs lackingKITgenetic alterations, matched for age, histological type, oestrogen receptor/HER2 status and sample type.ResultsWe identified 18 BCs (0.32%), including 9 primary and 9 metastatic BCs, with oncogenic/likely oncogenic genetic alterations affectingKIT, including activating somatic mutations (n=4) or gene amplification (n=14). AllKIT-altered BCs were of high histological grade, although no distinctive histological features were observed. When compared with BCs lackingKITgenetic alterations, no distinctive genetic features were identified. In two metastaticKIT-altered BCs in which the matched primary BC had also been analysed by MSK-IMPACT, theKITmutations were found to be restricted to the metastatic samples, suggesting that they were late events in the evolution of these cancers.ConclusionsKITgenetic alterations are vanishingly rare in BC.KIT-altered BCs are of high grade but lack distinctive histological features. Genetic alterations inKITmight be late events in the evolution and/or progression of BC.

Spatial molecular profiling of mixed invasive ductal-lobular breast cancers reveals heterogeneity in intrinsic molecular subtypes, oncogenic signatures, and mutations

“…Development of robust mutational signature analysis tools such as Signature Multivariate Analysis (SigMa) have allowed accurate identification of mutational signatures associated with such HRD and APOBEC defects from targeted sequencing panels such as MSK-impact [80][81][82][83][84] .…”

c-Kit Receptors as a Therapeutic Target in Cancer: Current Insights

“…142 On the other hand, Vahdatinia et al concluded that c-KIT mutation is a rare event in BC (0.32%) and that the c-KIT-altered BC patients showed high-grade tumors with poor outcomes. 143 Many TKIs are commercially available for blocking c-KIT functions, such as imatinib, sorafenib, sunitinib, nilotinib, and dasatinib; however, the only approved TKI for treating BC patients is lapatinib, especially for those with HER2-positive BC, as it also targets epidermal growth factor receptors (EGFRs). 53,54 Colorectal Carcinoma (CRC)…”