Michael Offin1,2, Daniel Feldman1, Ai Ni3, Mackenzie L Myers1, W Victoria Lai1,2, Elena Pentsova2,4, Adrienne Boire2,4,5, Mariza Daras2,4, Emmet J Jordan6, David B Solit2,5,7, Maria E Arcila8, David R Jones2,9, James M Isbell2,10, Kathryn Beal11, Robert J Young2,12, Charles M Rudin1,2, Gregory J Riely1,2, Alexander Drilon1,2, Viviane Tabar2,13, Lisa M DeAngelis2,4, Helena A Yu1,2, Mark G Kris1,2, Bob T Li1,2. 1. Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. 2. Weill Cornell Medical College, New York, New York. 3. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York. 4. Neurology Service, Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York. 5. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. 6. Medical Oncology, University Hospital Waterford, Waterford, Ireland. 7. Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. 8. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. 9. Thoracic Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. 10. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. 11. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. 12. Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York. 13. Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, New York.
Abstract
BACKGROUND: Mutations in human epidermal growth factor receptor 2 (HER2; also known as ERBB2) are found in approximately 2% of lung adenocarcinomas. The frequency and clinical course of brain metastases in this oncogenic subset are ill defined. METHODS: Baseline and subsequent development of brain metastases was evaluated in consecutive patients with HER2-mutant (n = 98), epidermal growth factor receptor (EGFR)-mutant (n = 200), and KRAS-mutant lung cancers (n = 200). RESULTS: At metastatic diagnosis, the odds ratio (ORs) for brain metastases was similar for patients whose tumors harbored HER2 mutations (19%) in comparison with patients with KRAS mutations (24%; OR for HER2 vs KRAS, 0.7; P = .33) but lower compared to patients with EGFR mutations (31%; OR for HER2 vs EGFR, 0.5; P = .03). Patients with lung cancer and HER2 mutations developed more brain metastases on treatment than patients with KRAS mutations (28% vs 8%; hazard ratio [HR], 5.2; P < .001) and trended more than patients with EGFR mutations (28% vs 16%; HR, 1.7; P = .06). Patients with HER2 YVMA mutations also developed more brain metastases on treatment than patients with KRAS mutations (HR, 5.9; P < .001). The median overall survival (OS) was shorter for patients with HER2-mutant (1.6 years; P < .001) or KRAS-mutant lung cancers (1.1 years; P < .001) than patients with EGFR-mutant lung cancers (3.0 years). Brain metastases occurred in 47% of patients with HER2-mutant lung cancers, which imparted shorter OS (HR, 2.7; P < .001). CONCLUSIONS: These data provide a framework for brain imaging surveillance in patients with HER2-mutant lung cancers and underpin the need to develop HER2-targeted agents with central nervous system activity.
BACKGROUND: Mutations in humanepidermal growth factor receptor 2 (HER2; also known as ERBB2) are found in approximately 2% of lung adenocarcinomas. The frequency and clinical course of brain metastases in this oncogenic subset are ill defined. METHODS: Baseline and subsequent development of brain metastases was evaluated in consecutive patients with HER2-mutant (n = 98), epidermal growth factor receptor (EGFR)-mutant (n = 200), and KRAS-mutant lung cancers (n = 200). RESULTS: At metastatic diagnosis, the odds ratio (ORs) for brain metastases was similar for patients whose tumors harbored HER2 mutations (19%) in comparison with patients with KRAS mutations (24%; OR for HER2 vs KRAS, 0.7; P = .33) but lower compared to patients with EGFR mutations (31%; OR for HER2 vs EGFR, 0.5; P = .03). Patients with lung cancer and HER2 mutations developed more brain metastases on treatment than patients with KRAS mutations (28% vs 8%; hazard ratio [HR], 5.2; P < .001) and trended more than patients with EGFR mutations (28% vs 16%; HR, 1.7; P = .06). Patients with HER2 YVMA mutations also developed more brain metastases on treatment than patients with KRAS mutations (HR, 5.9; P < .001). The median overall survival (OS) was shorter for patients with HER2-mutant (1.6 years; P < .001) or KRAS-mutant lung cancers (1.1 years; P < .001) than patients with EGFR-mutant lung cancers (3.0 years). Brain metastases occurred in 47% of patients with HER2-mutant lung cancers, which imparted shorter OS (HR, 2.7; P < .001). CONCLUSIONS: These data provide a framework for brain imaging surveillance in patients with HER2-mutant lung cancers and underpin the need to develop HER2-targeted agents with central nervous system activity.
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