TY - JOUR
T1 - Survival Is Related to Estrogen Signal Transduction Pathway Activity in Postmenopausal Women Diagnosed with High-Grade Serous Ovarian Carcinoma
AU - van Lieshout, L.
AU - van der Ploeg, P.
AU - Wesseling-Rozendaal, Y.
AU - van de Stolpe, A.
AU - Bosch, S.
AU - Lentjes-Beer, M.
AU - Ottenheijm, M.
AU - Meriaan, A.
AU - Vos, C.
AU - de Hullu, J.
AU - Massuger, L.
AU - Bekkers, R.
AU - Piek, J.
N1 - Funding Information:
This study was financially supported by the Ruby and Rose foundation (project number R0004286), the Catharina Research Fund (reference number OFC16/02) and Molecular Pathway Diagnostics, Philips. We are grateful for the provision of patient data by the IKNL. Furthermore, we want to express our gratitude to Judith Jeuken, Wendy Pellis-van Berkel and Hans Bulten for their valuable assistance and guidance in this work. In addition, the authors would like to thank Eveline den Biezen-Timmermans, Diederick Keizer, Sieglinde Neerken, Dianne van Strijp, Saskia Vermeer-van de Laar, Paul van de Wiel, Danielle Willemen-Clout, Janneke Wrobel and Martijn van Zelst for their contribution to the conceptualization of this project and the data analysis.
Funding Information:
Conflicts of Interest: L.v.L., S.B., M.L.-B., M.O., A.M., C.V., J.d.H., L.M., and R.M. have nothing to disclose. P.v.d.P. is employed by Catharina Hospital, where her research work is co-funded by Molecular Pathway Diagnostics, Philips and the Catharina research fund. Y.W.-R. and A.v.d.S. are employed by Molecular Pathway Diagnostics, Philips. J.P. co-retrieved funds from Molecular Pathway Diagnostics, Philips and the Catharina research fund, and received a Ruby and Rose research grant.
Funding Information:
Funding: This study was financially supported by the Ruby and Rose foundation (project number R0004286), the Catharina Research Fund (reference number OFC16/02) and Molecular Pathway Diagnostics, Philips.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/10/1
Y1 - 2021/10/1
N2 - Simple Summary:& nbsp;All cells have a complex internal network of 'communication chains' called signal transduction pathways (STPs). Through interaction of different proteins in STPs, they are partly responsible for the behavior of a cell. In our study, we investigated the activity of six STPs in 85 women with advanced stage high-grade serous ovarian cancer (HGSC). To investigate the relation between and differences in survival and STP activity, women with a short disease-free survival (below 12 months) and a long disease-free survival (above 24 months) were included. We found no differences in mean STP activity between short-term survivors (52 women) and long-term survivors (33 women). However, when we analyzed postmenopausal women, we found that both disease-free and overall survival were related to estrogen receptor (ER) pathway signaling. This indicates that a better survival outcome was related to a more active ER pathway in this subgroup.High-grade serous ovarian carcinoma (HGSC), the most common subtype of ovarian cancer, has a high mortality rate. Although there are some factors associated with survival, such as stage of disease, there are remarkable differences in survival among women diagnosed with advanced stage disease. In this study, we investigate possible relations between survival and signal transduction pathway (STP) activity. We assessed the functional activity of the androgen receptor (AR), estrogen receptor (ER), phosphoinositide-3-kinase (PI3K), Hedgehog (HH), transforming growth factor beta (TGF-beta) and canonical wingless-type MMTV integration site (Wnt) pathway in 85 primary tumor samples of patients with FIGO stage IIIC to IVB HGSC and disease-free survival (DFS) below 12 (n = 52) or over 24 months (n = 33). There were no significant differences in median pathway activity between patients with a short and long DFS. In univariate Cox proportional hazards analysis, ER pathway activity was related to a favorable DFS and overall survival (OS) in postmenopausal women (p = 0.033 and p = 0.041, respectively), but not in premenopausal women. We divided the postmenopausal group into subgroups based on ER pathway activity quartiles. Survival analysis revealed that postmenopausal women in the lowest ER quartile had a shorter DFS and OS (log-rank p = 0.006 and p < 0.001, respectively). Furthermore, we were able to form subgroups of patients based on an inverse relation between ER and PI3K pathway activity. In conclusion, in postmenopausal patients with advanced stage HGSC, a poorer survival outcome was associated with low functional ER pathway activity.
AB - Simple Summary:& nbsp;All cells have a complex internal network of 'communication chains' called signal transduction pathways (STPs). Through interaction of different proteins in STPs, they are partly responsible for the behavior of a cell. In our study, we investigated the activity of six STPs in 85 women with advanced stage high-grade serous ovarian cancer (HGSC). To investigate the relation between and differences in survival and STP activity, women with a short disease-free survival (below 12 months) and a long disease-free survival (above 24 months) were included. We found no differences in mean STP activity between short-term survivors (52 women) and long-term survivors (33 women). However, when we analyzed postmenopausal women, we found that both disease-free and overall survival were related to estrogen receptor (ER) pathway signaling. This indicates that a better survival outcome was related to a more active ER pathway in this subgroup.High-grade serous ovarian carcinoma (HGSC), the most common subtype of ovarian cancer, has a high mortality rate. Although there are some factors associated with survival, such as stage of disease, there are remarkable differences in survival among women diagnosed with advanced stage disease. In this study, we investigate possible relations between survival and signal transduction pathway (STP) activity. We assessed the functional activity of the androgen receptor (AR), estrogen receptor (ER), phosphoinositide-3-kinase (PI3K), Hedgehog (HH), transforming growth factor beta (TGF-beta) and canonical wingless-type MMTV integration site (Wnt) pathway in 85 primary tumor samples of patients with FIGO stage IIIC to IVB HGSC and disease-free survival (DFS) below 12 (n = 52) or over 24 months (n = 33). There were no significant differences in median pathway activity between patients with a short and long DFS. In univariate Cox proportional hazards analysis, ER pathway activity was related to a favorable DFS and overall survival (OS) in postmenopausal women (p = 0.033 and p = 0.041, respectively), but not in premenopausal women. We divided the postmenopausal group into subgroups based on ER pathway activity quartiles. Survival analysis revealed that postmenopausal women in the lowest ER quartile had a shorter DFS and OS (log-rank p = 0.006 and p < 0.001, respectively). Furthermore, we were able to form subgroups of patients based on an inverse relation between ER and PI3K pathway activity. In conclusion, in postmenopausal patients with advanced stage HGSC, a poorer survival outcome was associated with low functional ER pathway activity.
KW - BETA
KW - CANCER
KW - estrogen signaling
KW - ovarian cancer
KW - signal transduction pathways
U2 - 10.3390/cancers13205101
DO - 10.3390/cancers13205101
M3 - Article
C2 - 34680250
SN - 2072-6694
VL - 13
JO - Cancers
JF - Cancers
IS - 20
M1 - 5101
ER -