Background: In the EXPAND study adding cetuximab to first-line capecitabine and cisplatin chemotherapy (CT) failed to improve clinical outcome in patients (pts) with advanced gastric or gastroesophageal junction cancer. This analysis assessed treatment outcome according to tumor HER2 status (a pre-defined subgroup) and EGFR expression in EXPAND study pts. Methods: Tumor HER2 status was determined primarily by immunohistochemistry (IHC), HER2 +ve tumors were IHC 3+ or IHC 2+ and fluorescence in situ hybridization (FISH) +ve. EGFR expression was assessed by IHC. A continuous scoring system (scale of 0–300) was used to determine the level of EGFR expression. Biomarker status was correlated with clinical outcome. Results: In both treatment arms, pts with HER2 +ve tumors (n=144) vs HER2 -ve tumors (n=535) had a longer median overall survival (OS): 13.3 (95% CI 10.9–15.5) vs 9.2 (95% CI 8.1–10.5) months in the CT + cetuximab arm and 14.0 (95% CI 11.3–17.1) vs 9.7 (95% CI 8.6–11.0) months in the CT arm, and a better overall response rate, 51.4 (95% CI 39.3–63.3) vs 27.0 (95% CI 21.9–32.6) % and 37.5 (95% CI 26.4–49.7) vs 26.4 (95% CI 21.1–32.3) % respectively. In stepwise multivariable models, pts with HER2 -ve vs HER2 +ve tumors showed an increased risk of death (adjusted hazards ratio 1.552, 95% CI 1.244–1.936) and reduced odds of response (adjusted odds ratio 0.477, 95% CI 0.316–0.720). EGFR tumor expression was evaluable in 774 pts from the intent to treat population (n=904). The EGFR IHC score was low (median 0, range 0–300). No discriminating threshold for the IHC score was identified. However in pt subgroups defined by a series of cut-off points from an IHC score of 10 upwards (rising incrementally by 10), there was a tendency for improved OS, progression-free survival, and tumor response when adding cetuximab to CT in pts with high tumor EGFR IHC scores. Conclusions: In this analysis of EXPAND study pts, those with HER2 +ve tumors were associated with better outcome irrespective of the treatment arm compared with pts with HER2 -ve tumors. Tumor EGFR expression was generally low. Adding cetuximab to CT failed to improve outcome overall, but may benefit a small proportion of pts with high EGFR tumor expression. Clinical trial information: 2007-004219-75.