Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-sayama, Osaka, 589-8511, Japan.
Research Institute for Disease of the Chest, Kyushu University Faculty of Medicine, Fukuoka City, Fukuoka, 812-8582, Japan.
Sci Rep. 2019 Dec 20;9(1):19501. doi: 10.1038/s41598-019-55939-5.
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard therapy for EGFR-mutant non-small cell lung cancer (NSCLC). Preclinically, HER3 ligand heregulin induces resistance to EGFR-TKIs, whereas the pan-human EGFR family inhibitor afatinib remains effective. Here, we examined whether soluble heregulin levels have clinical implications for EGFR-mutant NSCLC treated with EGFR-TKIs. Soluble heregulin was immunologically measured in plasma from EGFR-mutant NSCLC patients. Cutoff values were determined by 1-year PFS ROC curve. The relationship between soluble heregulin and PFS following EGFR-TKI therapy was analyzed by Cox proportional hazards model. Seventy-three patients were enrolled: 44 were treated with 1-generation and 29 with 2-generation EGFR-TKIs. Soluble heregulin levels varied (range: 274-7,138 pg/mL, median: 739 pg/mL). Among patients treated with 1-generation EGFR-TKIs, those with high heregulin (n = 20, >800 pg/mL) had a tendency for shorter PFS than those with low heregulin (n = 24, <800 pg/mL), with median PFS of 322 and 671 days, respectively. Cox proportional hazards model also indicated a trend toward resistance against 1-generation EGFR-TKIs (HR: 1.825, 95% CI: 0.865-4.318) but not against 2-generation EGFR-TKIs. Soluble heregulin potentially correlates with resistance to EGFR-TKIs but not 2-generation EGFR-TKIs in patients with EGFR-mutant NSCLC.
表皮生长因子受体酪氨酸激酶抑制剂 (EGFR-TKIs) 是治疗表皮生长因子受体突变型非小细胞肺癌 (NSCLC) 的标准疗法。在临床前研究中，HER3 配体人表皮生长因子受体 3 配体 (heregulin) 诱导 EGFR-TKIs 耐药，而泛人表皮生长因子受体家族抑制剂阿法替尼仍然有效。在这里，我们研究了 EGFR 突变型 NSCLC 患者接受 EGFR-TKIs 治疗时，可溶性人表皮生长因子受体 3 配体水平是否具有临床意义。使用 EGFR 突变型 NSCLC 患者的血浆通过免疫测定法测量可溶性人表皮生长因子受体 3 配体。通过 1 年 PFS ROC 曲线确定截断值。通过 Cox 比例风险模型分析 EGFR-TKI 治疗后可溶性人表皮生长因子受体 3 配体与 PFS 的关系。共纳入 73 例患者：44 例接受 1 代 EGFR-TKI 治疗，29 例接受 2 代 EGFR-TKI 治疗。可溶性人表皮生长因子受体 3 配体水平存在差异（范围：274-7138pg/mL，中位数：739pg/mL）。在接受 1 代 EGFR-TKI 治疗的患者中，可溶性人表皮生长因子受体 3 配体高（n=20，>800pg/mL）的患者 PFS 短于可溶性人表皮生长因子受体 3 配体低（n=24，<800pg/mL）的患者，中位 PFS 分别为 322 天和 671 天。Cox 比例风险模型也表明对 1 代 EGFR-TKI 存在耐药趋势（HR：1.825，95%CI：0.865-4.318），但对 2 代 EGFR-TKI 没有耐药趋势。可溶性人表皮生长因子受体 3 配体可能与 EGFR-TKIs 耐药相关，但与 EGFR 突变型 NSCLC 患者的 2 代 EGFR-TKIs 耐药无关。
