Duke Researchers Identify a Relationship Between Prostate Cancer Recurrence and Lipid Levels

In a retrospective study, investigators found that increases in total cholesterol and triglycerides were associated with an increased risk of biochemical recurrence in prostate cancer.

According to researchers at the Duke University School of Medicine in Durham, North Carolina, total cholesterol and triglyceride levels in men with prostate cancer are associated with an increased risk of disease recurrence. The research, which was published in the journal Cancer Epidemiology, Biomarkers & Prevention on October 10, 2014, innovates on previous studies that found mixed results in population-based analysis of a link between cholesterol levels and prostate cancer aggressiveness.^1,2

According to researcher Emma Allott, PhD, a postdoctoral associate at Duke University, "Our findings suggest that normalization, or even partial normalization, of serum lipid levels among men with dyslipidemia [abnormal lipid profile] may reduce the risk of prostate cancer recurrence.”^1,2

The association was identified in 843 men, all of whom had received a prostate cancer diagnosis and underwent radical prostatectomy. None of the patients involved in the study had received lipid-lowering therapy with a statin prior to surgery. Of these qualifying individuals identified in records from 6 Veterans Affairs Medical Centers, 41% of were of African descent.

Abnormal cholesterol levels were identified in more than one-third (39%) of men, abnormal triglyceride levels were identified in nearly one-third (31%) of men, and more than one-third (35%) of men experienced biochemical recurrence of prostate cancer as defined by rising levels of prostate-specific antigen.^1,2

Triglyceride levels of 150 mg/dL or higher versus levels lower than 150 mg/dL were associated with a 35% increase in the risk for recurrence of prostate cancer. A relationship between total cholesterol levels emerged in patients with a total cholesterol of 200 mg/dL or greater. For each 10-mg/dL increase above this mark, the risk of prostate cancer recurrence jumped 9 percentage points. Conversely, every 10-mg/dL increase in high-density lipoprotein cholesterol levels was associated with a 39% reduction in the risk of prostate cancer recurrence.^1,2

According to Allott, this relationship between cardiovascular disease markers and a common cancer has important public health implications.

In a press release, Allott stated, "Given that 45 percent of deaths worldwide can be attributed to cardiovascular disease and cancer, with prostate cancer being the second most common cause of male cancer deaths in the United States, understanding the role of dyslipidemia as a shared, modifiable risk factor for both of these common causes of mortality is of great importance.”^1,2

The hypothesis that reductions in triglyceride levels using triglyceride-lowering medications could reduce the risk of biochemical recurrence in prostate cancer is refuted by recently published research from investigators based in The Netherlands and Japan. In the Dutch alpha omega trial, over 40 months, daily consumption of margarine containing 2 grams of ALA or an unsupplemented margarine product in 1622 patients with a history of myocardial infarction aged 60 to 80 years of age with an initial PSA concentration <4 ng/mL led to no significant improvement in the rate of PSA level increase.³

Similarly, researchers in Japan found that EPA supplementation (2.4 grams per day) for 2 years in 62 patients who had undergone prostatectomy did not have any preventive effect in terms of time to biochemical recurrence in prostate cancer.⁴

However, statins may be of some utility. Finnish researchers identified a cytostatic effect of simvastatin in prostate cancer, potentially linking statin use with improved outcomes, as has been observed in previous epidemiologic studies.⁵ In addition, Allott and colleagues identified a 36% reduction in the risk of recurrence in patients over 6 years in patients with prostate cancer who received statins after prostate resection versus comparable patients not receiving statins after the procedure.⁶

Other researchers found that caveolin-1, a biomarker secreted by metastatic prostate cancers, may enter the circulation through lipid raft formation in prostate cancer cells that affect the function of the endoplasmic reticulum organelles, and increase the rate of caveolin-1 secretion. This data suggests lipids play a role in releasing the caveolin-1 biomarker, which is associated with metastasis of prostate cancer.⁷

Further complicating the research outlook with regard to lipid levels and prostate cancer, androgen-deprivation therapy, which is known to extend time to recurrence, is also known to adversely affect lipid levels, triglyceride levels, and fasting glucose levels.⁸

The relationship between lipid levels and prostate cancer progression appears to be somewhat more complex than suggested by initial retrospective analyses. More research will be necessary to fully understand and leverage this finding, especially with regard to the clinical utility of simvastatin and the relationship between intratumoral lipid levels and caveolin-1 expression.

References:

• American Association for Cancer Research. Elevated Cholesterol and Triglycerides May Increase the Risk for Prostate Cancer Recurrence [press release].
• Allott EH, Howard LE, Cooperberg ME, et al. Serum Lipid Profile and Risk of Prostate Cancer Recurrence: Results from the SEARCH Database [published online October 10, 2014]. Cancer Epidemiol Biomarkers Prev.
• Brouwer IA, Geleijnse JM, Klaasen VM, et al. Effect of alpha linolenic acid supplementation on serum prostate specific antigen (PSA): results from the alpha omega trial. PLoS One. 2013;8(12):e81519.
• Higashihara E, Itomura M, Terachi T, et al. Effects of eicosapentaenoic acid on biochemical failure after radical prostatectomy for prostate cancer. In Vivo. 2010;24(4):561-565.
• Murtola TJ, Syvälä H, Pennanen P, et al. Comparative effects of high and low-dose simvastatin on prostate epithelial cells: the role of LDL. Eur J Pharmacol. 2011;673(1-3):96-3):96-100.
• Statin Use Associated with Reduced Risk of Prostate Cancer Recurrence [press release]. http://corporate.dukemedicine.org/news_and_publications/news_office/news/statin-use-associated-with-reduced-risk-of-prostate-cancer-recurrence. Accessed October 10, 2014.
• Inder KL, Zheng YZ, Davis MJ, et al. Expression of PTRF in PC-3 Cells modulates cholesterol dynamics and the actin cytoskeleton impacting secretion pathways. Mol Cell Proteomics. 2012.
• Yannucci J, Manola J, Garnick MB, Bhat G, Bubley GJ. The effect of androgen deprivation therapy on fasting serum lipid and glucose parameters. J Urol. 2006;176(2):520-525.