Prognostic relevance of longitudinal HGF levels in serum of patients with ovarian cancer

Abstract

The pleiotropic protein hepatocyte growth factor (HGF) is the only known ligand of the tyrosine kinase mesenchymal-epithelial transition (cMET) receptor. The HGF/cMET pathway mediates invasion and migration of ovarian cancer cells, and upregulation of HGF/cMET pathway components has been associated with poor prognosis. This study investigated the clinical relevance of circulating HGF in serum of patients with ovarian cancer. Serum HGF (sHGF) was determined by enzyme-linked immunosorbent assay in a total of 471 serum samples from 82 healthy controls and 113 patients with ovarian cancer (88.5% with ≥ FIGO III). Patient samples were collected at primary diagnosis and at four follow-up time points throughout treatment and at disease recurrence. Patients with ovarian cancer showed elevated median sHGF levels at primary diagnosis, and sHGF levels transiently increased after surgery and normalized in the course of chemotherapy, even dropping below initial baseline. Higher levels of sHGF were an independent predictor for shorter overall survival (OS) (a) at primary diagnosis (HR = 0.41, 95% CI: 0.22-0.78, P = 0.006), (b) at longitudinal follow-up time points (after surgery and before/during/after chemotherapy), (c) along the patients' individual dynamics (HR = 0.21, 95% CI: 0.07-0.63, P = 0.005), and (d) among a subgroup analysis of patients with BRCA1/2 wild-type ovarian cancer. This is the first study proposing sHGF as an independent prognostic biomarker for ovarian cancer at primary diagnosis and in the course of platinum-based chemotherapy, irrespective of the postoperative residual disease after surgical debulking. sHGF could be implemented into clinical diagnostics as a CA125 auxiliary tumor marker for individualized prognosis stratification and sHGF-guided therapy monitoring.

Keywords: HGF; biomarker; cMET; ovarian cancer; prognosis.

Fig. 1

sHGF levels from primary diagnosis, surgery, and platinum‐based chemotherapy to relapse. Scatter plot showing sHGF levels in healthy controls (n = 82), in ovarian cancer patients at primary diagnosis (n = 100) and among five subsequent follow‐up samples, obtained (a) within 1 week after primary surgery (postoperative, n = 56), (b) before platinum‐based chemotherapy (before Ctx, n = 74), (c) after the third cycle of chemotherapy (n = 56), (d) after completion of chemotherapy (after Ctx, n = 75), and (e) at disease relapse (n = 28). The black horizontal lines indicate the median sHGF level in each group with error bars, showing the interquartile range. P‐values, according to the nonparametric, two‐tailed Mann–Whitney U‐test, are indicated.

Fig. 2

Association of sHGF level with clinicopathological parameters of ovarian cancer. (A) ROC analysis to determine the diagnostic ability of sHGF level to distinguish between patients with a primary diagnosis of ovarian cancer and healthy controls. Ovarian cancer patients, n = 100; healthy individuals, n = 82. The respective AUC value and the 95%CI are indicated. (B) Scatter plots comparing sHGF level at primary diagnosis between FIGOI‐IIIA (n = 20) vs. FIGO IIIB‐IV (n = 80) ovarian cancer patients. The black horizontal lines indicate the median sHGF level with error bars, showing the interquartile range. P‐value, according to the nonparametric, two‐tailed Mann–Whitney U‐test, is indicated. (C, D) Spearman’s correlation analysis of sHGF at primary diagnosis and (C) the patients’ age, n = 100 ovarian cancer patients; or (D) baseline CA125 log values, n = 97 ovarian cancer patients with available matching CA125 values at primary diagnosis.

Fig. 3

Prognostic relevance of sHGF at primary diagnosis, surgery, and throughout platinum‐based chemotherapy. The Kaplan–Meier analyses comparing progression‐free survival (PFS) and OS of patients with high sHGF level vs. patients with low sHGF level (A) at primary diagnosis, n _(PFS) = 96 and n _(OS) = 100; (B) after primary surgery, n _{(OS and PFS)} = 56; (C) before initiating chemotherapy, n _(PFS) = 73 and n _(OS) = 74; (D) after three cycles of chemotherapy, n _{(PFS and OS)} = 56; and (E) after chemotherapy, n _{(PFS and OS)} = 75. P‐values, HR, and 95%CI were calculated, as described in Materials and methods section.

Fig. 4

Prognostic relevance of the patients` individual sHGF dynamics. Patients’ dynamic curves showing the progression of sHGF levels in the time between primary diagnosis and after the completion of chemotherapy. (A) Example of a patient with a high AUC and (B) the Kaplan–Meier analyses comparing progression‐free survival and OS (n _{(PFS and OS)} = 56) of ovarian cancer patients with a high AUC value vs. patients with a low AUC value. P‐values, HR, and 95%CI were calculated, as described in Materials and methods section.