ASPO Abstracts
A Prospective Study of Intra-tumoral Cholesterol Synthesis Enzyme Expression and Lethal Prostate Cancer.
Category: Molecular Epidemiology & Environment
Conference Year: 2023
Abstract Body:
Purpose of the study: Cholesterol has been implicated in prostate cancer progression via varied mechanisms. Cholesterol can be produced de novo in tumor cells via the mevalonate (MVA) pathway. 3- hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) is the first rate-limiting enzyme in the MVA pathway and is the target of statin therapy. This study examined whether HMGCR expression in prostate tumors is associated with lethal disease. Methods: The study population included men diagnosed with primary prostate cancer during prospective follow-up of the Health Professionals Follow-up Study and the Physicians' Health Study for whom archival tumor samples were available. Tissue microarrays were constructed from tumors and stained with a polyclonal anti-HMGCR antibody. HMGCR expression intensity was scored as 1) weak/none, 2) moderate or 3) strong. Lethal prostate cancer was defined as development of distant metastases or death from prostate cancer. Results: 1098 men with prostate cancer were included. 16% of tumors showed strong HMCGR expression. Among 1082 men without metastases at diagnosis, 96 lethal events occurred over a follow-up of 31 years (median 16.7 years). Compared with weak/no HMGCR expression, tumors with strong HMGCR expression had higher rates of lethality (hazard ratio [HR] 2.20, 95% confidence interval [CI] 1.41- 3.44), adjusting for age at diagnosis and Gleason score. Tumors with moderate HMGCR expression tended to have a better prognosis (HR 0.51, 95% CI 0.27-0.95) compared to those with weak/no expression. Examining whether statin use (pre- or post-diagnosis) modified the association between HMGCR expression and lethality was limited by a small number of lethal events among statin users (total n = 26), but estimates were not strongly suggestive of differential associations. Conclusions: High intra-tumoral cholesterol synthesis, indicated by the expression of HMGCR, was associated with higher risk of lethality in prostate cancer. These findings align with research suggesting active cholesterol synthesis in prostate cancer may be a feature of aggressive disease. Non-linear associations of lower expression levels and the potential impact of interventions with statins requires further study.
Keywords: Prostate Cancer, Lethality, Cholesterol, HMGCR.