Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
National Center for Tumour Diseases (NCT), Dresden, Germany.
Mol Oncol. 2021 Sep;15(9):2491-2503. doi: 10.1002/1878-0261.12939. Epub 2021 Apr 7.
The tyrosine kinase mesenchymal-epithelial transition (cMET) is typically overexpressed in up to 75% of patients with ovarian cancer, and cMET overexpression has been associated with poor prognosis. The proteolytic release of the soluble cMET (sMET) ectodomain by metalloproteases, a process called ectodomain shedding, reflects the malignant potential of tumour cells. sMET can be detected in the human circulation and has been proposed as biomarker in several cancers. However, the clinical relevance of sMET in ovarian cancer as blood-based biomarker is unknown and was therefore investigated in this study. sMET levels were determined by enzyme-linked immunosorbent assay in a set of 432 serum samples from 85 healthy controls and 86 patients with ovarian cancer (87% FIGO III/IV). Samples were collected at primary diagnosis, at four longitudinal follow-up time points during the course of treatment and at disease recurrence. Although there was no significant difference between median sMET levels at primary diagnosis of ovarian cancer vs. healthy controls, increased sMET levels at primary diagnosis were an independent predictor of shorter PFS (HR = 0.354, 95% CI: 0.130-0.968, P = 0.043) and shorter OS (HR = 0.217, 95% CI: 0.064-0.734, P = 0.014). In the follow-up samples, sMET levels were prognostically most informative after the first three cycles of chemotherapy, with high sMET levels being an independent predictor of shorter PFS (HR = 0.245, 95% CI: 0.100-0.602, P = 0.002). This is the first study to suggest that sMET levels in the blood can be used as an independent prognostic biomarker for ovarian cancer. Patients at high risk of recurrence and with poor prognosis, as identified based on sMET levels in the blood, could potentially benefit from cMET-directed therapies or other targeted regimes, such as PARP inhibitors or immunotherapy.
酪氨酸激酶间质-上皮转化（cMET）通常在多达 75%的卵巢癌患者中过度表达，cMET 过表达与预后不良有关。金属蛋白酶对可溶性 cMET（sMET）细胞外结构域的蛋白水解释放，这一过程称为细胞外结构域脱落，反映了肿瘤细胞的恶性潜能。sMET 可以在人体循环中被检测到，并已被提议作为几种癌症的生物标志物。然而，sMET 作为卵巢癌基于血液的生物标志物的临床相关性尚不清楚，因此本研究对此进行了调查。在一组 432 份来自 85 名健康对照者和 86 名卵巢癌患者（87%FIGO III/IV）的血清样本中，通过酶联免疫吸附试验测定 sMET 水平。样本在原发性诊断时、治疗过程中的四个纵向随访时间点以及疾病复发时采集。虽然卵巢癌患者的 sMET 水平在原发性诊断时与健康对照组之间没有显著差异，但原发性诊断时 sMET 水平升高是 PFS 较短（HR=0.354，95%CI：0.130-0.968，P=0.043）和 OS 较短（HR=0.217，95%CI：0.064-0.734，P=0.014）的独立预测因子。在随访样本中，sMET 水平在化疗前三个周期后最具预后意义，高 sMET 水平是 PFS 较短（HR=0.245，95%CI：0.100-0.602，P=0.002）的独立预测因子。这是第一项表明血液中的 sMET 水平可作为卵巢癌独立预后生物标志物的研究。根据血液中的 sMET 水平识别的具有高复发风险和预后不良的患者，可能受益于 cMET 定向治疗或其他靶向治疗，如 PARP 抑制剂或免疫疗法。
