Clinical impact of intratumoral HER2 heterogeneity on trastuzumab deruxtecan efficacy in patients with HER2-positive gastric cancer

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.