Central nervous system relapse in patients with untreated HER2-positive esophageal or gastroesophageal junction adenocarcinoma

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Although HER2-positive breast cancers demonstrate a propensity for central nervous system (CNS) metastasis, it is unknown whether other HER2-positive tumors, including adenocarcinomas of the esophagus/gastroesophageal junction (EAC), share this characteristic. Insight into this association may inform the development of HER2-targeted therapies that penetrate the blood-brain barrier. We examined HER2 overexpression and gene amplification in 708 patients with EAC who underwent curative-intent surgery during a time period (1980–1997) when no patient received HER2-targeted therapy. We identified patients whose site of first cancer recurrence was CNS and those who had a CNS relapse at any time. After a median follow-up of 61.2 months, 3.4% (24/708) of patients developed CNS relapse (all involved the brain). Patients with HER2-positive (vs -negative) primary tumors showed a higher 5-year cumulative incidence of CNS relapse as first recurrence (5.8% vs. 1.2%; p = 0.0058) and at any time (8.3% vs. 2.4%; p = 0.0062). In a multivariable model that included covariates previously associated with HER2 or with CNS relapse in breast cancer, HER2 positivity was the only variable that was statistically significantly associated with shorter time to CNS relapse as first recurrence (p = 0.0026) or at any time (hazard ratio 4.3 [95% confidence interval 1.8 to 10.3]; p = 0.001). These are the first data in a non-breast cancer to demonstrate an association between HER2 positivity and higher CNS relapse risk after surgery, and suggest that HER2-positive EACs have a predilection for CNS metastases.

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Breast cancers that overexpress HER2 tend to spread to the central nervous system (CNS). While this phenomenon can be influenced by targeted therapy, HER2-positive tumors may be biologically inclined toward CNS metastasis, though it is unknown whether this predilection extends to other HER2-positive cancers. In this study of patients with esophageal adenocarcinoma who had undergone curative-intent resection between 1980 and 1997, prior to the era of HER2-targeted therapy, HER2 overexpression/amplification was found to be independently associated with an increased risk of CNS relapse. The data suggest that HER2-positive esophageal adenocarcinomas have a biologic propensity for CNS metastasis.

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