Clinical and Genomic Characterization of Esophageal Cancer Brain Metastases

Purpose/Objective(s)Brain metastases from esophageal cancer are a rare and understudied form of metastatic spread with limited treatment options. We characterized the clinical and genomic features of esophageal cancer brain metastases.Materials/MethodsWe identified 129 patients who were diagnosed with brain metastases secondary to esophageal cancer at a single institution between 2002 and 2020. Survival analysis was performed using multivariable Cox proportional hazards regression. Results of targeted next-generation sequencing (NGS) panels were obtained for 56 patients representing 62 adenocarcinoma samples and compared to a cohort of 1344 esophageal adenocarcinoma samples identified from the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) v11.0. ERBB2/HER2 amplified/overexpressed (HER2+) status was determined using routine clinical assays and/or NGS results.ResultsMedian age at the time of esophageal cancer diagnosis was 63 years (interquartile range 58-68 years). 14% of the cohort (n=18) was female, 93% (n=120) had adenocarcinoma, and 98% (n=126) of primary tumors involved the distal esophagus and/or gastroesophageal junction. 50% (n=64) of patients had distant metastases at presentation, including 18 patients with brain metastases. 51% (n=66) underwent resection for brain metastases, and 84% (n=108) underwent radiation therapy (n=26 for whole brain, n=55 for partial brain or stereotactic, and n=27 for both). With median follow-up of 19 months for the entire cohort, median overall survival following primary cancer diagnosis was 22 months and significantly higher for HER2+ disease (31 vs 19 months, hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.47-0.87, P=0.004). For patients without brain metastases initially, the median time between initial diagnosis and brain metastasis diagnosis was 13 months and significantly higher for patients without distant metastasis initially (14 vs 12 months, HR 0.59, 95% CI 0.39-0.89, P=0.012). Median overall survival after brain metastasis diagnosis was 7 months and significantly higher for HER2+ disease (14 vs 4 months, HR 0.60, 95% CI 0.45-0.82, P=0.001). NGS results were notable for an enrichment of HER2 high amplification events (42% vs 19%, P<0.0001), HER2 mutations (10% vs 4%, P=0.036), and TP53 mutations (97% vs 73%, P<0.00001; all with Fisher's exact test) compared to the GENIE cohort.ConclusionEsophageal cancer brain metastases are associated with a poor prognosis and have a distinct molecular profile. Further efforts are necessary to elucidate the drivers of this unique and aggressive entity in order to develop novel treatment strategies.