Crizotinib is FDA approved in lung cancers with alterations in MET, ROS1 or ALK. Alterations in these genes are also reported in breast cancer, but are very rare and not routinely evaluated. Here we describe two heavily pre-treated patients with metastatic breast cancer treated with off-label single-agent crizotinib following NGS panel detection of alterations in MET and ROS1 in their tumors. Both patients had strong responses to crizotinib. Patient I was 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. A NGS assay detected a 30-fold amplification of MET. MET amplification, overexpression and hyperactivity was confirmed by FISH and by IHC 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. NGS revealed a MET D1228N mutation, previously reported in crizotinib resistant lung cancer. This mutation was not detected in the pre-crizotinib biopsy (locus sequenced at 6300x) suggesting de novo acquisition in response to crizotinib. Mechanistic studies in HEK393 cells indicated that this mutation is sufficient to confer crizotinib (Type I MET inhibitor) resistance but remains sensitive to cabozantinib (Type II MET inhibitor). Transition to 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. Patient II had ER+ PR+ HER2- breast cancer in 2014 and developed metastatic disease in 2017. She was subsequently treated with fulvestrant/palbociclib before an NGS panel revealed a GOPC-ROS1 fusion. She had a brisk response to crizotinib, documented by both imaging and reduction in circulating CA27-29. After experiencing crizotinib-related pneumonitis, she switched to ceritinib (an alternative ROS1 inhibitor) and continues to have an excellent response following six months of anti-ROS1 treatment. Together, these cases underline the value of NGS panel sequencing in patients with metastatic breast cancer. Although alterations in crizotinib-sensitive pathways are quite rare in breast cancer, very substantial clinical responses may be observed if these patients can be identified.

Citation Format: Benjamin M. Parsons, David R. Meier, Sreeja Sreekumar, Craig S. Richmond, Kyle J. Ernzen, Kristopher A. Lofgren, Jake A. Deviley, Grzegorz T. Gurda, Paraic A. Kenny. Exceptional responses to crizotinib in breast cancer patients with somatic MET and ROS1 alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1317.