Daniel Martin Klotz

The prognostic influence of hospital type, method of first histological confirmation and time to chemotherapy in patients with advanced primary ovarian cancer

Abstract Purpose Ovarian cancer is the fifth most common cancer in women and the leading cause of death of all gynecological malignancies. Prognosis is determined by optimal surgical outcome (macroscopic complete resection) most commonly achieved in tertiary hospitals. We investigated whether tertiary versus non-tertiary hospital as the location of an initial diagnostic intervention for histological confirmation before cytoreductive surgery versus immediate primary debulking surgery impacts outcome in patients with advanced ovarian cancer. Methods We analyzed 115 patients who underwent cytoreductive surgery at a German tertiary center: 60 patients underwent primary debulking surgery (PDS) and 55 patients had a diagnostic intervention for histological confirmation before debulking surgery (PHC). Results Although there was no prognostic difference between the two subgroups, the median time to chemotherapy was longer in the PHC group (46 days) compared to the PDS group (26 days; p < 0.0001), equally seen comparing non-tertiary versus tertiary PHC groups (p: 0.0001), its impact confirmed in a multivariate analysis (PFS: HR: 1.03, 95%CI: 1.01–1.05, p: 0.007; OS: HR: 1.04, 95%CI: 1.02 –1.06, p: < 0.001) of the PHC group only. In total, 9/10 patients with port-site metastases after diagnostic laparoscopy were initially treated at non-tertiary hospitals, resulting in a lower PFS compared to patients without port-site metastases after laparoscopy (HR 0.21, 95%CI 0.06–0.733, p: 0.014). Conclusions In conclusion, patients with ovarian cancer undergoing treatment solely at a tertiary center have some clinical benefits and improved outcome, given the shorter time to chemotherapy and potential impact of port-site metastases. This supports centralization of oncological treatment.

A predictive and prognostic model for surgical outcome and prognosis in ovarian cancer computed by clinico-pathological and serological parameters (CA125, HE4, mesothelin)

Abstract Objectives Numerous prognostic models have been proposed for ovarian cancer, extending from single serological factors to complex gene-expression signatures. Nonetheless, these models have not been routinely translated into clinical practice. We constructed a robust and readily calculable model for predicting surgical outcome and prognosis of ovarian cancer patients by exploiting commonly available clinico-pathological factors and three selected serum parameters. Methods Serum CA125, human epididymis protein 4 (HE4) and mesothelin (MSL) were quantified by Lumipulse® G chemiluminescent enzyme immunoassay (Fujirebio) in a total of 342 serum samples from 190 ovarian cancer patients, including 152 paired pre- and post-operative samples. Results Detection of pre-operative HE4 and CA125 was the optimal marker combination for blood-based prediction of surgical outcome (AUC=0.86). We constructed a prognostic model, computed by serum levels of pre-operative CA125, post-operative HE4, post-operative MSL and surgical outcome. Prognostic performance of our model was superior to any of these parameters alone and was independent from BRCA1/2 mutational status. We subsequently transformed our model into a prognostic risk index, stratifying patients as “lower risk” or “higher risk”. In “higher risk” patients, relapse or death was predicted with an AUC of 0.89 and they had a significantly shorter progression free survival (HR: 9.74; 95 % CI: 5.95–15.93; p<0.0001) and overall survival (HR: 5.62; 95 % CI: 3.16–9.99; p<0.0001) compared to “lower risk” patients. Conclusions We present a robust predictive/prognostic model for ovarian cancer, which could readily be implemented into routine diagnostics in order to identify ovarian cancer patients at high risk of recurrence.

Overcoming PARP inhibitor resistance in ovarian cancer: what are the most promising strategies?

Abstract Purpose Ovarian cancer is the most lethal gynaecological malignancy. Despite the introduction of bevacizumab, standard chemotherapy has remained largely unchanged and the vast majority of patients will relapse within the first two years of diagnosis. However, results from recent clinical trials demonstrating clinical benefits of PARP inhibitor treatment are rapidly changing therapeutic options for many patients with ovarian cancer. Methods Given the introduction of new therapeutic options in the treatment of ovarian cancer, we critically review key clinical trials, areas of scientific research and its clinical relevance. Results Most notably, patients with BRCA1/2 mutant ovarian cancer benefit from maintenance treatment with PARP inhibitors after (complete or partial) response to platinum-based chemotherapy. Here, we discuss the mechanism of PARP inhibition, multiple drug resistance mechanisms, including BRCA reverse mutations, altered PARP expression, changes in DNA repair pathways, kinase activation and additional drug targets that may augment PARP inhibition. Conclusion Although the use of PARP inhibitors is a huge step forward, it is apparent that patients, both with and without BRCA-mutant ovarian cancer, will eventually become resistant to PARP inhibitors. Therefore, novel combination therapies may enhance PARP inhibitor efficacy and overcome resistance mechanisms.

Evaluation of circulating Dickkopf-1 as a prognostic biomarker in ovarian cancer patients

Abstract Objectives Dickkopf-1 (DKK1) is a secreted protein, known for suppressing the differentiation and activity of bone-building osteoblasts by acting as an inhibitor of Wnt-signalling. Soluble DKK1 (sDKK1) has been proposed as prognostic biomarker for a wide range of malignancies, however, clinical relevance of sDKK1 as potential blood-based marker for ovarian cancer is unknown. Methods sDKK1 levels were quantified in a cohort of 150 clinically documented ovarian cancer patients by a commercially available DKK1 ELISA (Biomedica, Vienna, Austria). Results Median sDKK1 level was significantly elevated at primary diagnosis of ovarian cancer compared to healthy controls (estimated difference (ED) of 7.75 ng/mL (95% CI: 3.01–12.30 ng/mL, p=0.001)). Higher levels of sDKK1 at diagnosis indicated an increased volume of intraoperative malignant ascites (ED 7.08 pmol/L, 95% CI: 1.46–13.05, p=0.02) and predicted suboptimal debulking surgery (ED 6.88 pmol/L, 95% CI: 1.73–11.87, p=0.01). sDKK1 did not correlate with CA125 and higher sDKK1 levels predicted a higher risk of recurrence and poor survival (PFS: HR=0.507, 95% CI: 0.317–0.809; p=0.004; OS: HR=0.561, 95% CI: 0.320–0.986; p=0.044). Prognostic relevance of sDKK1 was partly sustained in wtBRCA patients (PFS: HR=0.507, 95% CI: 0.317–0.809; p=0.004). Conclusions This is the first study demonstrating the prognostic relevance of sDKK1 in ovarian cancer patients, including those with wtBRCA 1/2 status. Our data encourage further evaluation of sDKK1 in ovarian cancer patients, possibly in terms of a therapy monitoring marker or a response predictor for sDKK1-directed targeted therapies.

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

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.

The levels of soluble cMET ectodomain in the blood of patients with ovarian cancer are an independent prognostic biomarker

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 cancervs. 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.