Koichiro Yoshino, Manabu Takamatsu, Akira Ooki, Keisho Chin, Daisuke Takahari, Hiroki Osumi, Mariko Ogura, Mikako Tamba, Koshiro Fukuda, Keitaro Shimozaki, Shohei Udagawa, Shota Fukuoka, Eiji Shinozaki, Kensei Yamaguchi, Takeru Wakatsuki
BACKGROUND: Intratumoral HER2 heterogeneity has been associated with poor response to trastuzumab-based chemotherapy in HER2-positive gastric cancer. However, its clinical significance in patients treated with trastuzumab deruxtecan (T-DXd) remains unclear. METHODS: Patients with advanced HER2-positive gastric cancer who received T-DXd as second-line or later therapy were enrolled. HER2-positive proportion was defined as the percentage of tumor cells with immunohistochemical score ≥ 2 + in diagnostic specimens obtained before first-line therapy. The cutoff value was determined using time-dependent receiver operating characteristic analysis. RESULTS: Forty-three patients were enrolled. Median progression-free survival (PFS) and overall survival (OS) were 4.7 and 8.1 months, respectively. With an optimal cutoff of 79%, 20 patients (47%) were in the HER2-homogeneity group and 23 (53%) in the HER2-heterogeneity group. The HER2-homogeneity group showed significantly longer PFS (6.3 vs. 3.1 months, p = 0.002) and OS (9.8 vs. 6.0 months, p = 0.006) with higher overall response rate (79% vs. 19%, p < 0.001). In Cox proportional hazards model, HER2-homogeneity was an independent prognostic factor for both PFS (hazard ratio (HR) 0.37, 95% confidence interval (CI) 0.18–0.76, p = 0.007) and OS (HR 0.41, 95% CI 0.21–0.82, p = 0.01). CONCLUSIONS: Intratumoral HER2 heterogeneity in pre-treatment diagnostic specimens was associated with T-DXd efficacy and may represent a potential prognostic factor.