Association between HER2 heterogeneity and clinical outcomes of HER2-positive gastric cancer patients treated with trastuzumab

Background The GASTHER1 study showed that re-evaluation of HER2 status rescued 8% of HER2-positive gastric cancer (GC) patients with initially HER2-negative GC. Since rescued HER2 positivity represents HER2 heterogeneity, we aimed to investigate this in a larger cohort with longer follow-up duration. Methods Data of 153 HER2-positive advanced GC patients who received first-line trastuzumab-based chemotherapy were analyzed. Repeat endoscopic biopsy was performed in patients with initially HER2-negative GC. Survival outcomes were analyzed according to the immunohistochemistry (IHC) score (IHC 2+ /in situ hybridization [ISH] + vs IHC 3+), HER2 status (initially vs rescued HER2 positive), and H-score. Results IHC 2+ /ISH + patients showed worse progression-free survival (PFS) and overall survival (OS) than those with IHC 3+ ( p < 0.05). Rescued HER2-positive patients showed worse PFS and OS than initially HER2-positive patients ( p < 0.05). Although survival outcomes were comparable according to HER2 status in IHC 2+ /ISH + patients, initially HER2-positive patients showed more favorable PFS and OS than rescued HER2-positive patients ( p < 0.05) among those with IHC 3+ . Among the subgroups determined by HER2 status and IHC score, the initially IHC 3+ subgroup had the highest H-score. The low H-score group (H-score ≤ 210) had significantly worse survival outcomes than the high H-score group (H-score > 210) ( p < 0.05). An H-score of ≤ 210 was independently associated with shorter OS (HR = 1.54, 95% CI 1.02–2.31, p = 0.04). Conclusions Rescued HER2-positive patients showed worse clinical outcomes than initially HER2-positive patients, especially those with IHC 3+ . This finding highlights the impact of HER2 heterogeneity, which can be quantified indirectly as an H-score.