Association between intratumoral HER2 heterogeneity (IHH) and trastuzumab (T-mab) efficacy in HER2 positive–gastric cancer (GC).

Abstract

92 Background: ToGA study showed superiority of adding T-mab to standard chemotherapy and a positive correlation between HER2 expression levels and the T-mab efficacy. In gastric cancer IHH is frequently recognized but its clinical impact on T-mab efficacy is unclear. Methods: Patients who were treated with T-mab and had surgical specimens available for IHC test were retrospectively examined. When all tumor cells overexpressed HER2 protein by IHC, the tumor was defined as non-HER2-heterogeneous. The others were defined as HER2-heterogeneous. Progression-free survival (PFS) and overall survival (OS) were estimated using by Kaplan-Meier methods and compared by the log-rank test. The level of significance was set to p<0.05 and all statistical tests were two-sided. Results: 23 patients were enrolled. Their median age was 68 years and 83% were male. PS 0, GEJ cancer, intestinal type histology, visceral metastasis (lung or liver), and previous chemotherapy were found in 57%, 35%, 83%, 57%, and 57% of them, respectively. After a median follow-up of 11.3 months, the median OS, PFS, and overall response rate were 14.4 months, 10.8 months, and 62.5%, respectively. All tumors were IHC3+, and 13 were non-HER2-heterogeneous and 10 were HER2-heterogeneous. There was no significant difference in clinicopathological features between the two groups. Median PFS in non-HER2-heterogeneous group (21.9 months) was significantly longer than that in HER2-heterogeneous group (8.6 months), (HR: 0.24 [0.06-0.91], P=0.024). Median OS in non-HER2-heterogeneous group was not reached while that in HER2-heterogeneous group was 12.9 months (HR: 0.29 [0.06-1.42], P=0.102). A higher rate of response to T-mab was seen in non-HER2-heterogeneous group than in HER2-heterogeneous group, though the difference was not statistically significant (75% vs. 50%, p=0.608). Conclusions: IHH might have robust clinical impact on T-mab efficacy for HER2 positive GC. These findings should be validated by independent large cohorts and further molecular correlative analyses are warranted.