Association of HER2 amplification or overexpression with overall survival in advanced upper gastrointestinal adenocarcinomas.

Background: Advanced esophageal (EAC), gastroesophageal junction (GEJAC) and gastric (GAC) adenocarcinomas with HER2 amplification or overexpression (HER2+) are routinely treated with trastuzumab. However, it remains unclear if HER2+ is associated with superior overall survival (OS).

Methods: The cohort included recurrent or de novo metastatic GAC, GEJAC and EAC from Kaiser Permanente Northern California. We used Cox regression modelling to examine association between HER2+ and OS, adjusting for demographics, performance status, CCI, receipt of chemotherapy and p53 (mutp53), KRAS (mutKRAS), CDKN2A, PIK3CA co-mutations and MYC amplification.

Results: Of 875 total eligible patients, 173 had EAC, 276 had GEJAC and 426 had GAC. HER2+ was associated with better OS among the full cohort (HR = 0.74, 95% CI [0.60-0.93]), among EAC (HR = 0.62; [95% CI, 0.40-0.96]) and GEJAC (HR = 0.59; [95% CI, 0.38-0.87]), but not among GAC (HR = 0.89; [95% CI, 0.59-1.35]) patients. GEJAC had better OS than EAC (HR = 0.68, [95% CI, 0.54-0.86]). Trastuzumab treatment was associated with better OS (HR = 0.40, 95% CI [0.21-0.77]). In addition, HER2+ was associated with better OS across the molecular subgroups except that of KRAS mutation (mutKRAS). Our data also show that GEJAC, EAC and GAC were differentially associated with mutp53, mutKRAS and MYC amplification.

Conclusion: HER2+ and treatment with trastuzumab in HER2+ patients were associated with superior OS in upper gastrointestinal adenocarcinomas across molecular subgroups except that of mutKRAS. These results reaffirm the importance of anti-HER2 treatment in HER2+ patients and provide insight on the prognostic and biological divergence among these anatomically linked upper gastrointestinal adenocarcinomas.