Stromal PDGFR-beta expression is a prognostic factor in high-grade serous ovarian cancer patients but is it also predictive for response to antiangiogenic treatment?

In advanced ovarian cancer, the majority of patients receive anti-angiogenic treatment with bevacizumab. However, its use is often associated with severe side effects, and not all patients benefit from the therapy. Currently, there are no reliable biomarkers to predict response to treatment. Given their role as key regulators of angiogenesis, platelet-derived growth factor receptor-beta (PDGFR-beta) and vascular endothelial growth factor receptor-2 (VEGFR-2) are promising candidates for predictive biomarkers. This study evaluates their potential. PDGFR-beta and VEGFR-2 expression was evaluated using immunohistochemistry in a tissue microarray assay including 391 ovarian tissue samples. Correlation analyses with clinical and histopathological parameters were performed in a homogeneous cohort of 199 high grade serous ovarian cancer samples (HGSOC). In HGSOC, strong stromal PDGFR-beta expression was associated with significantly shorter overall survival compared to weak/moderate expression. The impact of stromal PDGFR-beta expression on patient survival was however not restricted to the subgroup of patients receiving therapy with bevacizumab, and therefore cannot be considered as a predictive factor. For VEGFR-2, no or weak protein expression was found in the majority of the tumor samples. Survival analyses showed a more favorable prognosis with no or weak VEGFR-2 expression. High stromal expression levels of PDGFR-beta correlate with shorter overall survival in HGSOC. Thus, stromal PDGFR-beta might serve as a prognostic biomarker. No predictive effect in response to bevacizumab therapy could be attributed.

Volk A ，von Bülow C ，Stern A ，Simon R ，Burandt E ，Sauter G ，Schmalfeldt B ，Oliveira-Ferrer L ... -  《-》

Vascular endothelial growth factor receptor 2 (VEGFR2) correlates with long-term survival in patients with advanced high-grade serous ovarian cancer (HGSOC): a study from the Tumor Bank Ovarian Cancer (TOC) Consortium.

Guan J ，Darb-Esfahani S ，Richter R ，Taube ET ，Ruscito I ，Mahner S ，Woelber L ，Prieske K ，Concin N ，Vergote I ，Van Nieuwenhuysen E ，Achimas-Cadariu P ，Glajzer J ，Woopen H ，Stanske M ，Kulbe H ，Denkert C ，Sehouli J ，Braicu EI ... -  《-》

Contrasting prognostic implications of platelet-derived growth factor receptor-β and vascular endothelial growth factor receptor-2 in patients with angiosarcoma.

Yonemori K ，Tsuta K ，Ando M ，Hirakawa A ，Hatanaka Y ，Matsuno Y ，Chuman H ，Yamazaki N ，Fujiwara Y ，Hasegawa T ... -  《-》

High expression of Tie-2 predicts poor prognosis in primary high grade serous ovarian cancer.

Sopo M ，Sallinen H ，Hämäläinen K ，Kivelä A ，Ylä-Herttuala S ，Kosma VM ，Keski-Nisula L ，Anttila M ... -  《PLoS One》

Tumor Microvessel Density as a Potential Predictive Marker for Bevacizumab Benefit: GOG-0218 Biomarker Analyses.

Combining bevacizumab with frontline chemotherapy statistically significantly improved progression-free survival (PFS) but not overall survival (OS) in the phase III GOG-0218 trial. Evaluation of candidate biomarkers was an exploratory objective. Patients with stage III (incompletely resected) or IV ovarian cancer were randomly assigned to receive six chemotherapy cycles with placebo or bevacizumab followed by single-agent placebo or bevacizumab. Five candidate tumor biomarkers were assessed by immunohistochemistry. The biomarker-evaluable population was categorized into high or low biomarker-expressing subgroups using median and quartile cutoffs. Associations between biomarker expression and efficacy were analyzed. All statistical tests were two-sided. The biomarker-evaluable population (n = 980) comprising 78.5% of the intent-to-treat population had representative baseline characteristics and efficacy outcomes. Neither prognostic nor predictive associations were seen for vascular endothelial growth factor (VEGF) receptor-2, neuropilin-1, or MET. Higher microvessel density (MVD; measured by CD31) showed predictive value for PFS (hazard ratio [HR] for bevacizumab vs placebo = 0.40, 95% confidence interval [CI] = 0.29 to 0.54, vs 0.80, 95% CI = 0.59 to 1.07, for high vs low MVD, respectively, P interaction = .003) and OS (HR = 0.67, 95% CI = 0.51 to 0.88, vs 1.10, 95% CI = 0.84 to 1.44, P interaction = .02). Tumor VEGF-A was not predictive for PFS but showed potential predictive value for OS using a third-quartile cutoff for high VEGF-A expression. These retrospective tumor biomarker analyses suggest a positive association between density of vascular endothelial cells (the predominant cell type expressing VEGF receptors) and tumor VEGF-A levels and magnitude of bevacizumab effect in ovarian cancer. The potential predictive value of MVD (CD31) and tumor VEGF-A is consistent with a mechanism of action driven by VEGF-A signaling blockade.

Bais C ，Mueller B ，Brady MF ，Mannel RS ，Burger RA ，Wei W ，Marien KM ，Kockx MM ，Husain A ，Birrer MJ ，NRG Oncology/Gynecologic Oncology Group ... -  《-》