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Purpose    FBXW7  is a tumor suppressor gene responsible for the degradation of several proto-oncogenes. Preclinical data suggest that  FBXW7  mutations sensitize cells to mTOR inhibitors. Clinicopathologic characteristics of cancer patients with  FBXW7  mutations and their responses to mTOR inhibitors remain unknown.    Methods  Using multiplex gene panels we evaluated how the  FBXW7  mutation affected the cancer phenotype of patients referred to a phase I clinic starting January 2012. Whenever possible patients positive for FBXW7 mutation were treated with regimens containing an mTOR inhibitors and their outcomes were reviewed.    Results    FBXW7  mutations were detected in 17 of 418 patients (4.0%). Among tumor types with more than 10 patients tested,  FBXW7  mutations occurred in colorectal cancer (7/49; 14.3%), squamous cell cancer of head and neck (2/18; 11.1%), liver (1/13; 7.7%), and ovarian cancers (1/40; 2.5%). No one clinical, pathological or demographic feature was characteristic of the  FBXW7 -mutated patient population. The mutation occurred in isolation in only 2/17 (12%) patients, and  KRAS  was frequently found as a concomitant mutation, especially in patients with colorectal cancer (6/7; 86%). Ten patients were treated on a protocol containing an mTOR inhibitor, with a median time to treatment failure of 2.8 months (range, 1.3–6.8). One patient with liver cancer (fibrolamellar subtype) continues to have a prolonged stable disease for 6.8+ months.    Conclusion  In patients with advanced cancers, somatic mutations in  FBXW7  usually occur with other simultaneous molecular aberrations, which can contribute to limited therapeutic efficacy of mTOR inhibitors.

FBXW7 Mutations in Patients with Advanced Cancers: Clinical and Molecular Characteristics and Outcomes with mTOR Inhibitors