Survival Outcomes in ERBB2-Low vs ERBB2-Null Advanced Gastric Cancer.

Importance: ERBB2 (formerly termed HER2)-low gastric cancer (GC) has recently gained attention with the development of novel ERBB2-targeted therapies; however, its clinicopathologic features and prognostic significance compared with ERBB2-null disease remain unclear. Objective: To compare clinicopathologic characteristics of ERBB2-low and ERBB2-null advanced GC and assess whether ERBB2 status is independently associated with survival outcomes. Design, Setting, and Participants: This international, multicenter retrospective cohort study included patients aged 18 years or older diagnosed with advanced metastatic GC between January 2018 and June 2025 at 6 oncology centers across Turkey and Spain. Eligible patients were those with ERBB2-negative disease (ERBB2-low [immunohistochemistry (IHC) score of 1+ or IHC score of 2+ with negative in situ hybridization] or ERBB2-null [IHC score of 0]), consecutively identified from institutional databases. All eligible patients during the study period were included. Exposure: ERBB2 expression status, categorized as ERBB2-low or ERBB2-null. Main Outcomes and Measures: The primary outcomes were progression-free survival (PFS) and overall survival (OS). Factors associated with PFS or OS were evaluated using univariate and multivariable Cox proportional hazards regression models. Results: Among 522 patients with GC (median [IQR] age, 60 [51-69] years; 345 [66.1%] male), 222 (42.5%) had ERBB2-low tumors and 300 (57.5%) had ERBB2-null tumors. Patients with ERBB2-low GC were older (median [IQR], 62 [53-70] years vs 59 [50-67] years; P = .03) and more often male (159 [71.6%] vs 186 [62.0%]; P = .03) and had worse Eastern Cooperative Oncology Group (ECOG) performance status (39 [17.6%] vs 33 [11.0%] had ECOG score ≥2; P = .04). Liver metastases were more common in the ERBB2-low group (107 patients [48.2%] vs 98 [32.7%]; P < .001), as were elevated carcinoembryonic antigen levels (104 of 189 patients [55.0%] vs 89 of 234 [38.0%]; P < .001). Among patients receiving first-line therapy (488 [93.5%]), median PFS was shorter in the ERBB2-low than in the ERBB2-null group (7.2 months [95% CI, 6.2-8.3 months] vs 8.7 months [95% CI, 7.9-9.6 months]; HR, 1.36 [95% CI, 1.11-1.66]; P = .003), as was median OS (15.8 months [95% CI, 14.1-17.5 months] vs 23.1 months [95% CI, 19.4-26.8 months]; HR, 1.34 [95% CI, 1.09-1.64]; P = .006). However, ERBB2 status was not an independent factor associated with survival (PFS: HR, 1.16 [95% CI, 0.93-1.46]; P = .20; OS: HR, 1.13 [95% CI, 0.89-1.44]; P = .31). Conclusions and Relevance: In this cohort study of patients with advanced GC, ERBB2-low compared with ERBB2-null tumors were associated with inferior survival; however, ERBB2 status was not an independent factor associated with survival, indicating that survival differences may have been largely attributable to unfavorable baseline clinical characteristics rather than ERBB2 expression itself. These findings suggest that ERBB2-low status alone may be insufficient for prognostic stratification.