Characterization Of High-Grade Serous Ovarian Carcinoma By Measuring Functional Signal Transduction Pathway Activity.

Abstract Introduction: The majority of advanced stage high-grade serous ovarian carcinoma (HGSC), the most common subtype of ovarian cancer, recurs within the first 24 months despite complete remission after initial treatment. Yet there are remarkable differences in disease-free (DFS) and overall survival (OS). We hypothesize that differences in signal transduction pathway (STP) activity may relate to survival and may also improve targeted therapy selection. We investigate the STP activity in relation to survival in patients diagnosed with advanced stage HGSC, as well as identify STPs that may be targeted in alternative treatment strategies. Methods: We included 85 HGSC patients (DFS <12 months, n=52 and DFS >24 months, n=33) who achieved complete remission after treatment with debulking surgery and chemotherapy. Total mRNA was extracted, and RT-qPCR was performed to determine expression levels of pathway-specific target genes in primary HGSC samples taken prior to start of chemotherapy. OncoSignal pathway assays were used to quantitatively measure functional STP activity of the androgen and estrogen receptor (ER), PI3K, Hedgehog, TGF-β and Wnt pathways. Survival analysis in relation to STP activity was performed by means of Cox regression analysis and differences between groups were analyzed with Mann-Whitney U tests. Results: Differences in PI3K, Hedgehog and TGF-β pathway activity were observed across the HGSC cohort, suggesting unique tumor activation patterns. Median STP activity was not discernably different between the short and long DFS groups. Significantly higher ER pathway activity was found in premenopausal women (n=16) compared to postmenopausal women (n=67) (p=0.002). Cox regression analysis in postmenopausal women (n=67) showed that ER pathway activity was positively associated with DFS (HR=0.943, p=0.033) and OS (HR=0.930, p=0.041) in univariate analysis. None of the pathways were significantly related to DFS or OS in premenopausal women (n=16). Conclusion: We observed a positive association between ER pathway activity and survival in postmenopausal women but not in premenopausal women. Also, differences in activation levels of the other STPs were observed in individual patients. STP analysis may be used to aid targeted therapy selection, such as anti-hormonal therapy, in HGSC patients. Citation Format: Phyllis van der Ploeg, Laura van Lieshout, Yvonne Wesseling-Rozendaal, Anja van de Stolpe, Diederick Keizer, Steven Bosch, Marjolein Lentjes-Beer, Caroline Vos, Joanne de Hullu, Ruud Bekkers, Jurgen Piek. Characterization of high-grade serous ovarian carcinoma by measuring functional signal transduction pathway activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 741.