Abstract 1822: Emergence of MET D1228N mutation as a resistance mechanism following an exceptional response to crizotinib in a MET-amplified triple-negative breast cancer patient

Abstract

Abstract The MET proto-oncogene encodes a receptor tyrosine kinase which is activated by Hepatocyte Growth Factor binding. Recent reports have described single agent activity for crizotinib in MET-amplified or mutant lung adenocarcinoma, squamous cell carcinoma and papillary renal cell carcinoma. Here we describe a stage IV triple-negative breast cancer patient in her early forties, previously treated with doxorubicin/cyclophosphamide, carboplatin/paclitaxel and with capecitabine. PET/CT imaging after progression on capecitabine revealed extensive metastatic disease including a large left pleural effusion, bilateral hypermetabolic nodular pleural implants, innumerable bilateral lung nodules and widespread mildly hyper-metabolic skeletal metastases in the ribs, spine and pelvis. A next-generation sequencing assay detected a 30-fold amplification of MET. MET amplification, overexpression and hyperactivity was confirmed by FISH and by immunohistochemistry for total MET and phospho-MET, respectively. Single agent crizotinib (250 mg, twice daily) was well-tolerated. Immunostaining of a biopsy taken after 9 days of treatment showed elimination of active phosphorylated MET, demonstrating in-tumor crizotinib efficacy at the clinical dose. CT imaging at 10 weeks showed a resolution of her metastatic disease, meeting RECIST 1.1 criteria for a complete response. This response was sustained at 22 weeks. At 37 weeks, the patient progressed in the pleura. An ultrasound guided biopsy revealed a robust resurgence of MET phosphorylation while still taking crizotinib, suggesting an alteration rendering MET recalcitrant to crizotinib. Next generation sequencing revealed a MET D1228N mutation, previously implicated in crizotinib resistance in lung cancer. This mutation was not detected in the pre-crizotinib biopsy (locus sequenced at 6300x) suggesting de novo acquisition in response to crizotinib. Transition from this type I MET inhibitor to a type II inhibitor (cabozantinib, initially 60 mg/day, later 100 mg/day) resulted in clinically stable disease for a period of 7 weeks, at which point the patient again progressed. Although MET-amplification is rare in breast cancer (~0.6% of cases), these data indicate that substantial clinical benefit may be achieved using single agent MET inhibition however the optimal selection of second-line agents to use upon progression will be critical. Citation Format: Benjamin M. Parsons, David R. Meier, Grzegorz T. Gurda, Kristopher A. Lofgren, Paraic A. Kenny. Emergence of MET D1228N mutation as a resistance mechanism following an exceptional response to crizotinib in a MET-amplified triple-negative breast cancer patient [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1822.