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

Abstract

Background There 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.Electronic supplementary materialThe online version of this article (10.1007/s00535-018-1464-0) contains supplementary material, which is available to authorized users.

Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance

“…Such tumor heterogeneity increased the risk of a false positive result on HER2 testing, potentially leading to a reduced survival benefit for HER2-tageted therapy in clinical trials. Two retrospective studies in Japan indeed detected a poorer outcome of trastuzumab-based therapy in AGC patients with heterogeneity of HER2 expression than in those with homogeneity of such expression [30,31]. A recent study analyzed gene alterations by next-generation sequencing in 50 patients with HER2-postive metastatic esophagogastric cancer, who received first-line trastuzumab therapy [32].…”

HER2 and BRAF mutation in colorectal cancer patients: a retrospective study in Eastern China

“…HER2 gene, which is located on chromosome 17q21, is a tyrosine kinase receptor and encodes for a 185-kDa transmembrane protein (Salvia, Lopez-Gomez & Garcia-Carbonero, 2018). HER2 gene has been evidenced as a proto-oncogene and identified in many cancer types, including breast, gastric and CRC (Calhoun & Collins, 2015;Sartore-Bianchi et al, 2016;Wakatsuki et al, 2018). HER2 gene amplification plays a pivotal role in tumor growth and metastasis.…”

Chimeric Antigen Receptor T Cells: Extending Translation from Liquid to Solid Tumors

“…40 Comparison of the anti-HER2 antibody trastuzumab in gastric cancer patients whose tumors homogenously expressed HER2 with those whose tumors heterogeneously expressed HER2 showed deeper tumor shrinkage and longer median progression-free and overall survival in the homogenously expressing group. 41 As the main mechanism of tumor control for CAR T cells is based upon tumor cell antigen recognition, tumor heterogeneity is also expected to limit CAR T-cell efficacy. In spite of these challenges, some promising advances using CAR T-cell therapy in solid tumor settings have been achieved.…”