Tsuji Takahiro, Sakamori Yuichi, Ozasa Hiroaki, Yagi Yoshitaka, Ajimizu Hitomi, Yasuda Yuto, Funazo Tomoko, Nomizo Takashi, Yoshida Hironori, Nagai Hiroki, Maeno Ken, Oguri Tetsuya, Hirai Toyohiro, Kim Young Hak
Department of Respiratory Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Oncotarget. 2017 May 16;8(42):71805-71816. doi: 10.18632/oncotarget.17895. eCollection 2017 Sep 22.
Activation of c-MET through hepatocyte growth factor (HGF) increases tumorigenesis, induces resistance, and is associated with poor prognosis in various solid tumors. However, the clinical value of serum HGF (sHGF) in patients with advanced non-small cell lung cancer (NSCLC), especially those receiving cytotoxic chemotherapy, remains unknown. Here, we show that sHGF may be useful to predict tumor response and progression-free survival (PFS) in patients with advanced NSCLC. A total of 81 patients with NSCLC were investigated. sHGF levels were evaluated using ELISA at 4 time-points: at pre-treatment, at response-evaluation (1-2 months after treatment initiation), at the best tumor response, and at disease progression. As a control biomarker, CEA was also evaluated in lung adenocarcinoma. Positive-sHGF at response-evaluation predicted poor PFS compared with Negative-sHGF in both first-line (median, 153.5 vs. 288.0; < 0.05) and second-line treatment (87.0 vs. 219.5; = 0.01). In 55 patients that received cytotoxic chemotherapy, multiple Cox proportional hazards models showed significant independent associations between poor PFS and Positive-sHGF at response-evaluation (hazard ratio, 4.24; 95% CI, 2.05 to 9.46; < 0.01). Lung adenocarcinoma subgroup analysis showed that in patients receiving second cytotoxic chemotherapy, there were no significant differences in PFS between patients with low-CEA compared with those with high-CEA, but Positive-sHGF at pre-treatment or at response-evaluation predicted poor PFS (35.0 vs. 132.0; < 0.01, 50.0 vs. 215.0; < 0.01, respectively). These findings give a rationale for future research investigating the merit of sHGF as a potential clinical biomarker to evaluate HGF/c-MET activity, which would be useful to indicate administration of c-MET inhibitors.
通过肝细胞生长因子（HGF）激活c-MET会增加肿瘤发生、诱导耐药，并与多种实体瘤的不良预后相关。然而，血清HGF（sHGF）在晚期非小细胞肺癌（NSCLC）患者，尤其是接受细胞毒性化疗患者中的临床价值仍不清楚。在此，我们表明sHGF可能有助于预测晚期NSCLC患者的肿瘤反应和无进展生存期（PFS）。共调查了81例NSCLC患者。在4个时间点使用酶联免疫吸附测定（ELISA）评估sHGF水平：治疗前、反应评估时（治疗开始后1 - 2个月）、最佳肿瘤反应时和疾病进展时。作为对照生物标志物，还在肺腺癌中评估了癌胚抗原（CEA）。在一线治疗（中位数，153.5对288.0；P < 0.05）和二线治疗（87.0对219.5；P = 0.01）中，反应评估时sHGF阳性与sHGF阴性相比，预测PFS较差。在55例接受细胞毒性化疗的患者中，多个Cox比例风险模型显示反应评估时sHGF阳性与PFS较差之间存在显著独立关联（风险比，4.24；95%置信区间，2.05至9.46；P < 0.01）。肺腺癌亚组分析显示，在接受第二次细胞毒性化疗的患者中，低CEA患者与高CEA患者之间的PFS无显著差异，但治疗前或反应评估时sHGF阳性预测PFS较差（分别为35.0对132.0；P < 0.01，50.0对215.0；P < 0.01）。这些发现为未来研究sHGF作为评估HGF/c-MET活性的潜在临床生物标志物的价值提供了理论依据，这将有助于指导c-MET抑制剂的给药。
