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Abstract
BackgroundThere is growing interest in the clinical significance of intratumoral HER2 heterogeneity. Its prognostic and predictive impacts on trastuzumab efficacy were demonstrated in breast cancer. However, its clinical significance in gastric cancer is still unclear.MethodsTwenty-eight HER2-positive gastric cancer patients who had gastrectomy prior to trastuzumab-based chemotherapy were consecutively enrolled. Intratumoral HER heterogeneity was evaluated using whole-tissue sections by immunohistochemistry. When all tumor cells overexpressed HER2 protein, the tumor was defined as homogeneously HER2 (Homo-HER2)-positive group. The others were defined as heterogeneously HER2 (Hetero-HER2)-positive group.ResultsThere was no significant difference in clinicopathological features between the two groups. The median progression-free survival (PFS) and overall survival (OS) in the Homo-HER2-positive group were significantly longer than those in the Hetero-HER2-positive group (PFS; 20.0 months [95% CI 17.8–22.2] vs. 6.0 months [95% CI 2.3–9.7]; HR 0.11; 95% CI 0.03–0.41; p < 0.001, OS; not reached vs. 14.0 months [95% CI 11.9–16.1]; HR 0.18; 95% CI 0.06–0.61; p = 0.003). In the multivariate analysis, these associations remained significant both in PFS (HR 0.12; 95% CI 0.03–0.46, p = 0.002) and OS (HR 0.21; 95% CI 0.06–0.72, p = 0.013). With respect to response rate, no statistical difference was found between two groups. However, deeper tumor shrinkage was obtained in the Homo-HER2-positive group compared with the Hetero-HER2-positive group (p = 0.046).ConclusionsIntratumoral HER2 heterogeneity may have robust clinical impact on trastuzumab efficacy in patients with HER2-positive gastric cancer. These findings should be validated by larger independent cohorts and further molecular correlative analyses are warranted.
Highlights
Gastric cancer is currently the third-most common cause of cancer-related deaths and the fifth-most common diagnosed cancer worldwide [1]
The median progression-free survival (PFS) and overall survival (OS) in the Homo-Human epidermal growth factor receptor 2 (HER2)-positive group were significantly longer than those in the Hetero-HER2-positive group
We carefully evaluated intratumoral HER2 heterogeneity using surgical specimens and examined predictive impact on trastuzumab efficacy
Summary
Gastric cancer is currently the third-most common cause of cancer-related deaths and the fifth-most common diagnosed cancer worldwide [1]. Trastuzumab, full humanized anti-HER2 antibody, has been successfully developed in HER2-positive breast cancer [12, 13]. The ToGA trial showed significant clinical benefits of the addition of trastuzumab to standard chemotherapy [14]. IHC 2?/FISH-positive groups benefited more from trastuzumab than the other groups, leading to different indications for trastuzumab use across the world. In Europe and Japan, trastuzumab use is limited in IHC 3? There is growing interest in the clinical significance of intratumoral HER2 heterogeneity. Its clinical significance in gastric cancer is still unclear. Methods Twenty-eight HER2-positive gastric cancer patients who had gastrectomy prior to trastuzumab-based chemotherapy were consecutively enrolled. The others were defined as heterogeneously HER2 (HeteroHER2)-positive group
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