Department of Surgery, Kitasato University School of Medicine, Kitasato 1-15-1, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.
Cancer Sci. 2014 Dec;105(12):1591-600. doi: 10.1111/cas.12556. Epub 2014 Dec 3.
Standard treatment in Japan for the 13th Japanese Gastric Cancer Association stage II/III advanced gastric cancer is postoperative adjuvant S-1 administration after curative surgery. High expression of receptor type tyrosine kinases (RTKs) has repeatedly represented poor prognosis for cancers. However it has not been demonstrated whether RTKs have prognostic relevance for stage II/III gastric cancer with standard treatment. Tumor tissues were obtained from 167 stage II/III advanced gastric cancer patients who underwent curative surgery and received postoperative S-1 chemotherapy from 2000 to 2010. Expression of the RTKs including EGFR, HER2, HER3, IGF-1R, and EphA2 was analyzed using immunohistochemistry (IHC). Analysis using a multivariate proportional hazard model identified the most significant RTKs that represented independent prognostic relevance. When tumor HER3 expression was classified into IHC 1+/2+ (n = 98) and IHC 0 (n = 69), the cumulative 5-year Relapse Free Survival (5y-RFS) was 56.5 and 82.9%, respectively (P = 0.0034). Significant prognostic relevance was similarly confirmed for IGF-1R (P = 0.014), and EGFR (P = 0.030), but not for EphA2 or HER2 expression. Intriguingly, HER3 expression was closely correlated with IGF-1R (P < 0.0001, R = 0.41), and EphA2 (P < 0.0001, R = 0.34) expression. Multivariate proportional hazard model analysis identified HER3 (IHC 1+/2+) (HR; 1.53, 95% CI, 1.11-2.16, P = 0.0078) as the sole RTK that was a poor prognostic factor independent of stage. Of the 53 patients who recurred, 40 patients (75.5%) were HER3-positive. Thus, of the RTKs studied, HER3 was the only RTK identified as an independent prognostic indicator of stage II/III advanced gastric cancer with standard treatment.
在日本，对于第 13 期日本胃癌协会（Japanese Gastric Cancer Association）的 II/III 期进展期胃癌，标准治疗是根治性手术后辅助 S-1 给药。受体酪氨酸激酶（receptor type tyrosine kinases，RTKs）的高表达已反复表明癌症预后不良。然而，尚未证明 RTKs 是否与标准治疗的 II/III 期胃癌具有预后相关性。
从 2000 年至 2010 年接受根治性手术并接受术后 S-1 化疗的 167 例 II/III 期进展期胃癌患者获得肿瘤组织。使用免疫组织化学（immunohistochemistry，IHC）分析 RTKs（包括 EGFR、HER2、HER3、IGF-1R 和 EphA2）的表达。使用多变量比例风险模型分析确定具有独立预后相关性的最重要 RTKs。
当将肿瘤 HER3 表达分为 IHC 1+/2+（n=98）和 IHC 0（n=69）时，累积 5 年无复发生存率（Relapse Free Survival，5y-RFS）分别为 56.5%和 82.9%（P=0.0034）。IGF-1R（P=0.014）和 EGFR（P=0.030）也同样证实了具有显著的预后相关性，但 EphA2 或 HER2 表达则没有。有趣的是，HER3 表达与 IGF-1R（P<0.0001，R=0.41）和 EphA2（P<0.0001，R=0.34）表达密切相关。多变量比例风险模型分析确定 HER3（IHC 1+/2+）（HR；1.53，95%CI，1.11-2.16，P=0.0078）是独立于分期的唯一不良预后因素的 RTK。在 53 例复发患者中，有 40 例（75.5%）为 HER3 阳性。因此，在所研究的 RTKs 中，HER3 是唯一被确定为具有标准治疗的 II/III 期进展期胃癌独立预后指标的 RTK。
