Abstract LB-28: The IGF/insulin signaling axis TMPRSS2:ERG and prostate cancer survival.
Authors: Ahearn Thomas U. , Pettersson Andreas , Stack Edward C. , Ma Jing , Gerke Travis , Meisner Allison , Pollak Michael N. , Finn Stephen , Stampfer Meir J. , Loda Massimo , Giovannucci Edward L. , Mucci Lorelei A. 
Published: August 2014

Background: One half of prostate cancers harbor the TMPRSS2:ERG fusion, a somatic event that may reflect a distinct disease molecular subtype. TMPRSS2 is androgen regulated and ERG is a transcription factor that is part of the ETS family. Based on experimental evidence, we hypothesized that TMPRSS2:ERG tumors would be more sensitive to the insulin like growth factor (IGF)/insulin signaling axis in prostate cancer survival.

Methods: We studied participants in the prospective Physicians' Health Study (PHS) and the Health Professionals Follow-Up Study (HPFS) diagnosed with prostate cancer from 1982 - 2005. TMPRSS2:ERG was assessed in tumor tissue microarrays by immunohistochemical evaluation of ERG expression (n=1,236). Pre-diagnostic plasma concentrations of IGF1 (n=307), IGFBP3 (n=307), c-peptide (n=293), and adiponectin (n=120), and tissue expression of the IGF1 receptor (IGF1R; n=713), insulin receptor (IR; n=682), and adionectin receptor (AdipoR2; n=840) were available among men with measured ERG expression. Men have been followed for biochemical recurrence and cancer mortality through 2012. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CI) of associations between circulating biomarkers, TMPRSS2:ERG and prostate cancer outcomes.

Results: Mean follow-up for lethal prostate cancer was 12.8 years and for recurrence 11.1 years. The number of lethal and recurrence events among men with measured blood markers were: IGF1/IGFBP3 25 and 61, c-peptide 20 and 56, and adiponectin 9 and 17, respectively. Among ERG negative tumors, comparing high vs. low concentrations, the multivariable HR for recurrence was 0.4 (95% CI 0.2-1.1) for IGF1, 1.1 (95% CI 0.5-2.8) for IGFBP3, 1.6 (95% CI 0.7-3.6) for c-peptide, and 1.4 (95% CI 0.3-5.6) for adiponectin. The corresponding HRs among ERG positive tumors were 1.8 (95% CI 0.8-4.0; p interaction 0.04) for IGF1, 0.8 (95% CI 0.4-1.8; p interaction 0.61) for IGFBP3, 0.6 (95% CI 0.3-1.3; p interaction 0.16) for c-peptide, and 0.8 (95% CI 0.2-3.6; p interaction 0.53) for adiponectin. Among ERG negative tumors, comparing high vs. low concentrations of the blood markers, the multivariable HR for lethal disease was 0.7 (95% CI 0.2-3.2) for IGF1, 1.4 (95% CI 0.3-5.9) for IGFBP3, 3.64 (95% CI 0.6-20.9) for c-peptide, and 1.1 (95% CI 0.2-7.8) for adiponectin. The corresponding HRs among ERG positive tumors were 2.3 (95% CI 0.5-11.1; p interaction 0.53) for IGF1, 0.6 (95% CI 0.1-2.3; p interaction 0.86) for IGFBP3, 0.7 (95% CI 0.2-2.9; p interaction 0.37) for c-peptide, and 0.4 (95% CI 0.03-5.4; p interaction 0.44) for adiponectin. The expression of IR, IGF1R, and AdipoR2 were significantly (all p-values &lt;0.01) higher in ERG positive vs. negative tumors.

Conclusions: Although the number of events were relatively small, our results support the hypothesis that TMPRSS2:ERG fusion may modify the association between the IGF/insulin signaling axis and prostate cancer prognosis.

Citation Format: Thomas U. Ahearn, Andreas Pettersson, Edward C. Stack, Jing Ma, Travis Gerke, Allison Meisner, Michael N. Pollak, Stephen Finn, Meir J. Stampfer, Massimo Loda, Edward L. Giovannucci, Lorelei A. Mucci. The IGF/insulin signaling axis TMPRSS2:ERG and prostate cancer survival. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-28. doi:10.1158/1538-7445.AM2013-LB-28