Abstract 1537: Tumor stroma in serous ovarian cancer; inter and intra patient heterogeneity and impact on survival
Authors: Corvigno Sara , Wisman Bea , Van der Zee Ate G.J. , Nijman Hans W. , Mezheyeuski Artur , Åvall Lundkvist Elisabeth , Östman Arne , Dahlstrand Hanna 
Published: August 2015

Purpose of the study: This study subjected primary tumors and matched metastasis of serous ovarian cancer to a multi-parametric analysis of tumor stroma characteristics. The aims were to explore potential co-regulation of these characteristics, analyze their concordance in primary and metastatic lesions and define their correlation to survival. The impact of tumor microenvironment in serous ovarian cancer is largely unexplored and new prognostic tools for this tumor are strongly needed Experimental procedures: A retrospective consecutive study was performed, including 321 patients at primary surgery of ovarian cancer. Patients with serous ovarian cancer (N = 186) were included in the current study, 91 with matched primary and metastatic tissue. A tissue microarray (TMA) was built from the pre-treatment paraffin-embedded samples and was subjected to immunohistochemistry double staining with CD34 (endothelial cell marker) together with the fibroblast and pericyte markers alpha smooth muscle actin (α-SMA), platelet-derived growth factor receptor beta (PDGFβR), and the pericyte marker desmin. The images were digitally analyzed to yield thirteen “tumor-stroma metrics” related to the vasculature and the fibroblast-rich stroma. Spearman two-tails test was used for correlation estimates. Log Rank test and Cox proportional hazards models were used to estimate the overall survival (OS) with uni and multivariate analysis.

Results: Within the ovarian primary site, we found a strong association between expression of PDGFβR in perivascular cells and in fibroblasts. Similar findings were made concerning α-SMA-positive fibroblasts and perivascular cells. Most stroma characteristics except PDGFβR expression in fibroblast stroma and in perivascular cells, showed large variations when matched primary tumors and metastasis were compared. Large PDGFβR-positive stroma fraction, as well as high PDGFβFR positive perivascular intensity, was significantly associated with worse survival in uni and multivariate analysis (HR 1.7, Cl 95% 1.1-2.5 and HR 1.7, Cl 95% 1.1-2.7, respectively).

Conclusions: The study identified previously unrecognized co-regulation patterns of PDGFβR-positive perivascular cells and fibroblasts, and α-SMA-positive perivascular cells and fibroblasts; it revealed that status of stromal markers, except PDGFβR, differs between matched primary tumors and metastases. Moreover analyses identified PDGFβR expression in perivascular cells and in fibroblasts as novel prognosis markers. This prognosis association is in agreement with previous findings from breast and prostate cancer and suggests that PDGFβR could be explored as a target for personalized tumor microenvironment-targeted treatments.

Citation Format: Sara Corvigno, Bea Wisman, Ate G.J. Van der Zee, Hans W. Nijman, Artur Mezheyeuski, Elisabeth Åvall Lundkvist, Arne Östman, Hanna Dahlstrand. Tumor stroma in serous ovarian cancer; inter and intra patient heterogeneity and impact on survival. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1537. doi:10.1158/1538-7445.AM2015-1537