Prostate Cancer Risk by Lipid Parameters

Cholesterol is a key building block of cells. It provides crucial support to cell membranes allowing signaling between the inside and outside of cells. Cholesterol makes up ~ 1/3 of the cell membrane. Also, cholesterol is the precursor for many hormones – including testosterone. Without cholesterol, life as we know it could not exist. However, there is such a thing as too much of a good thing. Specifically, high serum cholesterol levels have been linked with numerous conditions such as cardiovascular disease, stroke, and many cancers.

This has given rise to cholesterol-lowering drugs being some of the most widely used medicinal drugs in the world. Given all that background, it makes perfect sense that high cholesterol would be linked with prostate cancer.  However, the data to date have been mixed, potentially due to multiple reasons. As such, the report from Murtola et al. is very timely and important and sheds important light on this association.

Murtola and colleagues examined men enrolled in the Finnish Randomized Study of Screening for Prostate Cancer. They identified nearly 18,000 men who had cholesterol measurements.  Of these men, after a median follow-up of 17 years, there were over 2,400 cases of prostate cancer. They found that higher cholesterol was linked with a higher risk of overall prostate cancer. When broken down by stage and grade, the links with higher cholesterol were only seen for high-grade prostate cancer (Gleason 8-10 aka grade group 4-5) and patients with metastatic disease. Results were suggestively similar when LDL cholesterol was analyzed, but this did not reach statistical significance. No strong associations were seen for triglycerides or HDL.

The authors then undertook an interesting sub-analysis called a lag-time analysis. In short, a 3-year lag time analysis would exclude anyone who got prostate cancer within the next 3 years.  While the goal is to analyze the late-term effects of a risk factor, by excluding men who got the disease early, it creates some level of bias. For example, with a 20-year lag-time, as the authors did, it means the man had to be alive and not gotten prostate cancer within 20 years of his elevated cholesterol.  This is not necessarily the typical patient. In fact, I would argue someone who could survive 20 years after an elevated cholesterol without other major diseases (i.e. prostate cancer) was selected to be a healthy person. Whether this is due to genetics or other risk factors, to me, this sounds like a “healthy” person. As such, I would predict this person would be at lower risk of cancer and many other health conditions. Indeed, this is exactly what the authors found – the longer the lag time, the less cholesterol predicted increased cancer risk and actually started to predict lower cancer risk.

Key strengths of this study include the fact that this was nested within a large prospective trial and thus all men were (in theory) treated equally.  The quality of the data was high and follow-up in Finland due to the ability to track patients was excellent. The downside is the lack of data on other prostate cancer risk factors – namely diet and exercise. Thus, was high cholesterol simply a marker of poor diet and lack of exercise and it is diet and exercise that influenced prostate cancer risk or was it the cholesterol directly.

Ultimately, this study provides yet more data to support a growing link between high cholesterol and specifically aggressive prostate cancer. Key future questions that need answering are: 1) Does lowering serum cholesterol decrease these risks; 2) If so, are statins “good enough” or do we need more potent means to lower serum cholesterol; 3) Would dual targeting of serum and tumor cholesterol be even more effective than simply lowering serum cholesterol; 4) Ultimately, what are the molecular mechanisms linking cholesterol and aggressive prostate cancer. We look forward to furthering data from this group and others to move from interesting observations to better mechanistic understanding to ultimately interventions to negate the adverse effects of high cholesterol on aggressive prostate cancer.

Written by: Stephen Freedland, MD Editor-in-Chief, Prostate Cancer and Prostatic Diseases Cedars-Sinai Medical Center, Los Angeles, CA

Read the PCAN Full-Text Article
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