Department of Gastroenterology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
Department of Pathology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
J Gastroenterol. 2018 Nov;53(11):1186-1195. doi: 10.1007/s00535-018-1464-0. Epub 2018 Apr 9.
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.
Twenty-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.
There 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).
Intratumoral 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.
肿瘤内 HER2 异质性的临床意义越来越受到关注。其对曲妥珠单抗疗效的预后和预测影响已在乳腺癌中得到证实。然而，其在胃癌中的临床意义尚不清楚。
连续纳入 28 例接受曲妥珠单抗为基础化疗前胃切除术的 HER2 阳性胃癌患者。采用免疫组织化学方法对全组织切片进行肿瘤内 HER 异质性评估。当所有肿瘤细胞均过度表达 HER2 蛋白时，肿瘤被定义为均一性 HER2（Homo-HER2）阳性组。其余的被定义为异质性 HER2（Hetero-HER2）阳性组。
两组患者的临床病理特征无显著差异。Homo-HER2 阳性组的中位无进展生存期（PFS）和总生存期（OS）明显长于 Hetero-HER2 阳性组（PFS：20.0 个月[95%CI 17.8-22.2] vs. 6.0 个月[95%CI 2.3-9.7]；HR 0.11；95%CI 0.03-0.41；p<0.001；OS：未达到 vs. 14.0 个月[95%CI 11.9-16.1]；HR 0.18；95%CI 0.06-0.61；p=0.003）。多变量分析显示，在 PFS（HR 0.12；95%CI 0.03-0.46，p=0.002）和 OS（HR 0.21；95%CI 0.06-0.72，p=0.013）中，这些相关性仍然显著。关于缓解率，两组间无统计学差异。然而，Homo-HER2 阳性组的肿瘤退缩更深（p=0.046）。
肿瘤内 HER2 异质性可能对曲妥珠单抗治疗 HER2 阳性胃癌患者的疗效有显著的临床影响。这些发现需要更大的独立队列验证，并需要进一步的分子相关性分析。
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