TY - JOUR
T1 - Sex hormones, insulin, and insulin-like growth factors in recurrence of high-stage endometrial cancer
AU - Merritt, Melissa A.
AU - Strickler, Howard D.
AU - Hutson, Alan D.
AU - Einstein, Mark H.
AU - Rohan, Thomas E.
AU - Xue, Xiaonan
AU - Sherman, Mark E.
AU - Brinton, Louise A.
AU - Yu, Herbert
AU - Miller, David S.
AU - Ramirez, Nilsa C.
AU - Lankes, Heather A.
AU - Birrer, Michael J.
AU - Huang, Gloria S.
AU - Gunter, Marc J.
N1 - Funding Information:
This work was supported by the NCI at the NIH [(1R01CA133010 to M.J. Gunter as well as intramural funds). G.S. Huang was supported by the Reproductive Scientist Development Program through the American Congress of Obstetricians and Gynecologists. This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office and Gynecologic Oncology Group Tissue Bank (U10 CA27469), the Gynecologic Oncology Group Statistical and Data Center (U10 CA180822), the Gynecologic Oncology Group Tissue Bank (U24 CA114796), the NRG Oncology Operations Center and the NRG Oncology Biospecimen Bank-Columbus (U10 CA180868), and the NRG Oncology Biospeci-men Bank-Columbus [U24 CA196067].
Funding Information:
The authors thank the study pathologists, Mona El-Bahrawy and Nesreen M. Magdy, who carried out the tissue microarray scoring and provided guidance on the interpretation of immunohistochemical staining data. We thank Robin Sgueglia for carrying out the serum estradiol and estrone assays. We are grateful to Jurriaan Brouwer-Visser and Maria Jose Cossio for their assistance with the acquisition of laboratory data for the tissue assays. We thank Dr. Joseph Rothwell for creating the forest plots. We acknowledge the use of the Albert Einstein Cancer Center Shared Resources (Analytical Imaging Facility, Biorepository and Histopathology) which is supported by the Cancer Center Support Grant (NCI P30 CA013330), and the Harold and Muriel Block Institute for Clinical and Translational Research (Biomarker Analytic Research Core) which is supported by the CTSA Grant UL1 TR001073, TL1 TR001072, KL2 TR001071 from the National Center for Advancing Translational Sciences (NCATS), a component of the NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Funding Information:
M.H. Einstein reports grants and other from Merck, PDS, Papivax, Asieris, grants from Inovio; grants from Johnson and Johnson, and grants from Iovance outside the submitted work. G.S. Huang reports grants from NIH/NCI, Reproductive Scientist Development Program, and grants from ACOG (American College of Obstetricians and Gynecologists) during the conduct of the study; personal fees from GSK/Tesaro and personal fees from Bristol-Myers Squibb outside the submitted work; in addition, G.S. Huang currently serves as a study co-chair for a clinical trial sponsored by the GOG Foundation/Partners and supported by Eli Lilly. No disclosures were reported by the other authors.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/4
Y1 - 2021/4
N2 - Background: The influence of sex hormone and insulin/insulinlike growth factor (IGF) axis signaling on endometrial cancer recurrence is unknown. We evaluated these pathways in a prospective cohort of Gynecologic Oncology Group (GOG)0210 trial endometrial adenocarcinoma patients. Methods: Stage II-IV patients (N = 816) were included in this study. Pretreatment specimens were tested for tumor mRNA and protein expression of IGF1, IGF2, IGF-binding proteins (IGFBP)-1 and -3, insulin (IR) and IGF-I receptors (IGF1R), phosphorylated IR/IGF1R (pIGF1R/pIR), and estrogen (ER) and progesterone receptors (PR) using qPCR and IHC. Serum concentrations of insulin, IGF-I, IGFBP-3, estradiol, estrone, and sex hormone binding globulin were measured. HRs and 95% confidence intervals (CI) for progression-free survival were calculated from Cox models adjusting for age, stage, and grade. Results: Recurrence occurred in 280 (34%) cases during a median of 4.6 years of follow-up. ER positivity (HR, 0.67; 95% CI, 0.47- 0.95), IR positivity (HR, 0.53; 95% CI, 0.29-0.98), and circulating IGF-I (highest vs. lowest quartile: HR, 0.66; 95% CI, 0.47-0.92) were inversely associated with recurrence risk. Circulating estradiol (highest vs. lowest tertile: HR, 1.55; 95% CI, 1.02-2.36) and pIGF1R/pIR positivity (HR, 1.40; 95% CI, 1.02-1.92) were associated with increased recurrence risk. Conclusions: Circulating estradiol and tumor tissue phosphorylated (activated) IGR1R/IR were independently associated with higher risk of recurrence in patients with endometrial cancer. Impact: This study may inform future clinical trials of endocrinetargeted adjuvant therapies in patients with endometrial cancer that could include baseline assessment of serum and tissue biomarkers of estradiol and insulin signaling pathways.
AB - Background: The influence of sex hormone and insulin/insulinlike growth factor (IGF) axis signaling on endometrial cancer recurrence is unknown. We evaluated these pathways in a prospective cohort of Gynecologic Oncology Group (GOG)0210 trial endometrial adenocarcinoma patients. Methods: Stage II-IV patients (N = 816) were included in this study. Pretreatment specimens were tested for tumor mRNA and protein expression of IGF1, IGF2, IGF-binding proteins (IGFBP)-1 and -3, insulin (IR) and IGF-I receptors (IGF1R), phosphorylated IR/IGF1R (pIGF1R/pIR), and estrogen (ER) and progesterone receptors (PR) using qPCR and IHC. Serum concentrations of insulin, IGF-I, IGFBP-3, estradiol, estrone, and sex hormone binding globulin were measured. HRs and 95% confidence intervals (CI) for progression-free survival were calculated from Cox models adjusting for age, stage, and grade. Results: Recurrence occurred in 280 (34%) cases during a median of 4.6 years of follow-up. ER positivity (HR, 0.67; 95% CI, 0.47- 0.95), IR positivity (HR, 0.53; 95% CI, 0.29-0.98), and circulating IGF-I (highest vs. lowest quartile: HR, 0.66; 95% CI, 0.47-0.92) were inversely associated with recurrence risk. Circulating estradiol (highest vs. lowest tertile: HR, 1.55; 95% CI, 1.02-2.36) and pIGF1R/pIR positivity (HR, 1.40; 95% CI, 1.02-1.92) were associated with increased recurrence risk. Conclusions: Circulating estradiol and tumor tissue phosphorylated (activated) IGR1R/IR were independently associated with higher risk of recurrence in patients with endometrial cancer. Impact: This study may inform future clinical trials of endocrinetargeted adjuvant therapies in patients with endometrial cancer that could include baseline assessment of serum and tissue biomarkers of estradiol and insulin signaling pathways.
UR - http://www.scopus.com/inward/record.url?scp=85103862406&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85103862406&partnerID=8YFLogxK
U2 - 10.1158/1055-9965.EPI-20-1613
DO - 10.1158/1055-9965.EPI-20-1613
M3 - Article
C2 - 33622671
AN - SCOPUS:85103862406
SN - 1055-9965
VL - 30
SP - 719
EP - 726
JO - Cancer Epidemiology Biomarkers and Prevention
JF - Cancer Epidemiology Biomarkers and Prevention
IS - 4
ER -
