The prognostic value of HER2 in gastroesophageal adenocarcinoma - a meta-analysis

HER2 amplification and overexpression are predictive markers for HER2-targeted therapies in gastroesophageal adenocarcinoma. However, unlike in breast cancer, the prognostic significance of HER2 status in this disease remains uncertain, with conflicting evidence across studies.

We conducted a systematic review and meta-analysis of studies reporting hazard ratios (HRs) for overall survival (OS) based on HER2 status, identified through PubMed, Scopus, and Web of Science. Eligible studies included HER2-positive and HER2-negative patients with gastroesophageal adenocarcinoma, using IHC and/or ISH diagnostics. Pooled HRs were calculated using random-effects models. Subgroup analyses and meta-regressions were performed by stage, treatment, and covariates. A novel statistical framework was applied to contextualize HER2's prognostic role.

Eighty studies encompassing 30,574 patients were included. HER2 positivity was associated with poorer OS in univariate analyses for stage I-III (HR 1.29, 95% CI: 1.02-1.61) and stage I-IV disease (HR 1.58, 95% CI: 1.14-2.20), and remained significant in multivariate analyses (HR 1.46 and HR 1.52, respectively). In metastatic disease, HER2 positivity was associated with poorer survival in untreated cohorts (multivariate HR 1.37, 95% CI: 1.01-1.85; p = 0.043), but with improved survival in trastuzumab-treated cohorts in univariate analysis (HR 0.73, 95% CI: 0.61-0.88; p = 0.0007) and borderline multivariate analysis (HR 0.71, 95% CI: 0.50-1.00; p = 0.047).

HER2 positivity was independently associated with poorer overall survival in gastroesophageal adenocarcinoma. In metastatic disease, pooled estimates differed according to trastuzumab exposure, with more favorable outcomes observed in trastuzumab-treated HER2-positive cohorts. These findings support an adverse prognostic association of HER2 positivity and further investigation of HER2-directed therapy in earlier-stage disease.