Exceptional Response to Crizotinib With Subsequent Response to Cabozantinib in Metastatic, ROS1-GOPC Fusion–Mutated Breast Cancer

Abstract

ROS1 is a proto-oncogene that encodes a type I integral membrane protein with receptor tyrosine kinase (RTK) activity. 1 ROS1 arrangements are a well-recognized driver mutation present in up to 1%-2% of patients with non-small-cell lung cancer (NSCLC), with CD74-ROS1 fusion being the most common. 2 Actionable ROS1 mutations are exceptionally rare in breast cancer. Analysis of mutation profiles from 7,692 patients with breast cancer (cBioportal, 3 performed on July 11, 2022) revealed no hotspot-activating mutations and only four cases with ROS1 fusion.Crizotinib is an orally bioavailable multitargeted small-molecule tyrosine kinase inhibitor, targeting ALK, c-MET, and ROS1. 4 Crizotinib was originally developed as a c-MET inhibitor. The US Food and Drug Administration (FDA) granted fast-track approval of crizotinib on August 26, 2011, on the basis of the marked efficacy of crizotinib in patients with ALK-positive advanced NSCLC. 5 Crizotinib has demonstrated antitumor activity in patients with ALK-activating mutation-positive diseases, including anaplastic large cell lymphoma, inflammatory myofibroblastic tumors, and neuroblastoma, as well as with activating ROS1 gene mutations in NSCLC, activating MET gene mutations, MET amplifications in NSCLC, and others. 6 Cabozantinib is an orally bioavailable, small-molecule inhibitor of RTKs including VEGFR-1, VEGFR-2, VEGFR-3, KIT, TRKB, FLT-3, AXL, RET, MET, TIE-2, MER, TYRO3, and ROS1. 7 Cabozantinib is FDA-approved for the treatment of advanced renal cell carcinoma (RCC), hepatocellular carcinoma, and differentiated thyroid cancer. Cabozantinib has been shown to have efficacy in NSCLC in tumors with ROS1 mutations that develop resistance to crizotinib. 8 A recent case report has suggested clinical efficacy of cabozantinib in patients harboring CD74-ROS1 fusion mutations in advanced NSCLC after resistance to crizotinib. 9The clinical efficacy of crizotinib and cabozantinib in GOPC-ROS1 fusion mutations has not been well studied. GOPC-ROS1 mutations are seen at low frequency (approximately 0.95%) in NSCLC. 8 To date, we know of no reports demonstrating GOPC-ROS1 mutations in breast cancer. Here, we report a case of a woman with estrogen receptor (ER)-positive, progesterone receptor (PR)positive, and human epidermal growth factor receptor 2 (HER2)-negative breast cancer harboring a GOPC-ROS1 fusion. After an exceptional clinical response to crizotinib, a resistant ROS1 G2032R-mutant clone emerged, which then responded to cabozantinib. Case ReportA 69-year-old woman was found to have a left breast mass in the upper outer quadrant after undergoing screening mammography. Subsequently, the patient underwent diagnostic mammography and breast ultrasonography that confirmed a 2.1 3 1.5 3 1.0 cm hypoechoic irregular mass with spiculated margins. The patient underwent ultrasound-guided biopsy of the mass, and histopathology examination revealed an infiltrating mammary carcinoma, Nottingham grade 3, ER-positive, PR-positive, and HER2-negative. The patient underwent left breast lumpe...