Lipids & aggressive PCa in the PRACTICAL consortium

New study below [1].

A large study, involving 10 countries & 22,249 cases.

"We found weak evidence that higher LDL and {triglyceride} levels increase aggressive prostate cancer risk, and that a variant in HMGCR (that mimics the LDL lowering effect of statin drugs) reduces risk."

"Weak evidence" but entirely plausible. The LDL cholesterol that is taken up by PCa is cholesterol carried by the smaller protein, VLDL, so the finding might have been more robust if VLDL had been measured.

Unfortunately, ADT tends to increase VLDL & triglycerides. Can exercise help?

In a recent "2-year home-based endurance training intervention" study [2], "PSADT increased in the training group from 28 to 76 months." "The training group showed significant improvements in plasma triglycerides". The study included some men with "biochemical recurrence following radical prostatectomy", but there is no mention of how many, in this small study, were on ADT.

From a 2011 Australian paper [3]:

"A total of 50 men 55 to 84 years old undergoing androgen suppression therapy for nonbone metastatic prostate cancer completed a progressive resistance and cardiovascular exercise program for 12 weeks, including 16 with acute {less than 6 months} and 34 with chronic {6 months or greater} androgen suppression therapy exposure."

"Triglycerides decreased in the chronic group and increased in the acute group". (!)

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/269...

Cancer Med. 2016 Mar 19. doi: 10.1002/cam4.695. [Epub ahead of print]

Blood lipids and prostate cancer: a Mendelian randomization analysis.

Bull CJ1,2,3,4, Bonilla C1,2,3, Holly JM3,4, Perks CM3,4, Davies N1,2,3, Haycock P1,2,3, Yu OH5, Richards JB5,6, Eeles R7,8, Easton D9, Kote-Jarai Z7, Amin Al Olama A9, Benlloch S9, Muir K3,10,11, Giles GG12,13, MacInnis RJ12,13, Wiklund F14, Gronberg H14, Haiman CA15, Schleutker J16,17, Nordestgaard BG18, Travis RC19, Neal D20,21, Pashayan N9,20,21,22, Khaw KT23, Stanford JL24,25, Blot WJ26, Thibodeau S27, Maier C28,29, Kibel AS30,31, Cybulski C32, Cannon-Albright L33, Brenner H34,35,36, Park J37, Kaneva R38, Batra J39, Teixeira MR40,41, Micheal A42, Pandha H42, Smith GD1,2, Lewis SJ1,2,3, Martin RM1,3,43; PRACTICAL consortium.

Abstract

Genetic risk scores were used as unconfounded instruments for specific lipid traits (Mendelian randomization) to assess whether circulating lipids causally influence prostate cancer risk. Data from 22,249 prostate cancer cases and 22,133 controls from 22 studies within the international PRACTICAL consortium were analyzed. Allele scores based on single nucleotide polymorphisms (SNPs) previously reported to be uniquely associated with each of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels, were first validated in an independent dataset, and then entered into logistic regression models to estimate the presence (and direction) of any causal effect of each lipid trait on prostate cancer risk. There was weak evidence for an association between the LDL genetic score and cancer grade: the odds ratio (OR) per genetically instrumented standard deviation (SD) in LDL, comparing high- (≥7 Gleason score) versus low-grade (<7 Gleason score) cancers was 1.50 (95% CI: 0.92, 2.46; P = 0.11). A genetically instrumented SD increase in TGs was weakly associated with stage: the OR for advanced versus localized cancer per unit increase in genetic risk score was 1.68 (95% CI: 0.95, 3.00; P = 0.08). The rs12916-T variant in 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) was inversely associated with prostate cancer (OR: 0.97; 95% CI: 0.94, 1.00; P = 0.03). In conclusion, circulating lipids, instrumented by our genetic risk scores, did not appear to alter prostate cancer risk. We found weak evidence that higher LDL and TG levels increase aggressive prostate cancer risk, and that a variant in HMGCR (that mimics the LDL lowering effect of statin drugs) reduces risk. However, inferences are limited by sample size and evidence of pleiotropy.

© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

KEYWORDS:

Cholesterol; Mendelian randomization; prostate cancer; statins

PMID: 26992435 [PubMed - as supplied by publisher]

[2] ncbi.nlm.nih.gov/pubmed/265...

Cancer Causes Control. 2016 Feb;27(2):165-74. doi: 10.1007/s10552-015-0694-1. Epub 2015 Nov 16.

Effect of a 2-year home-based endurance training intervention on physiological function and PSA doubling time in prostate cancer patients.

Hvid T1, Lindegaard B1, Winding K1, Iversen P2, Brasso K2, Solomon TP1,3, Pedersen BK1, Hojman P4.

Author information

Abstract

AIM:

Physical activity after prostate cancer diagnosis has been shown to reduce the risk of disease progression. Here, we aimed to evaluate the effect of a 2-year home-based endurance training intervention on body composition, biomarkers levels, and prostate-specific antigen (PSA) doubling time as a surrogate end-point for progressing disease.

METHODS:

Out-clinic patients with either biochemical recurrence following radical prostatectomy or patients managed on active surveillance were randomized to either 24 months (3 times/week) of home-based endurance training or usual care. Aerobic fitness, body composition, insulin sensitivity, and biomarkers were measured at 0, 6, and 24 months of intervention. PSA doubling time (PSADT) was calculated based on monthly PSA measurements.

RESULTS:

Twenty-five patients were enrolled, and 19 patients completed the study. PSADT increased in the training group from 28 to 76 months (p < 0.05) during the first 6 months and was correlated with changes in VO2max (p < 0.01, r (2) = 0.41). The training group lost 3.6 ± 1.0 kg (p < 0.05) exclusively as fat mass, yet the changes in body composition were not associated with the increased PSADT. The training group showed significant improvements in plasma triglycerides, adiponectin, IGF-1, IGFBP-1, and fasting glucose levels, but no changes in insulin sensitivity (measured as Matsuda index), testosterone, cholesterols, fasting insulin, plasma TNF-alpha, IL-6, or leptin levels. The control group showed no changes in any of the evaluated parameters across the 2-year intervention.

CONCLUSION:

In this small randomized controlled trial, we found that improvements in fitness levels correlated with increasing PSADT, suggesting a link between training and disease progression.

KEYWORDS:

Exercise; Insulin sensitivity and body composition; PSA; PSA doubling time

PMID: 26573844 [PubMed - in process]

[3] ncbi.nlm.nih.gov/pubmed/218...

J Urol. 2011 Oct;186(4):1291-7. doi: 10.1016/j.juro.2011.05.055. Epub 2011 Aug 17.

Acute versus chronic exposure to androgen suppression for prostate cancer: impact on the exercise response.

Galvão DA1, Taaffe DR, Spry N, Joseph D, Newton RU.

Author information

1Edith Cowan University Health and Wellness Institute, School of Exercise, Biomedical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia. d.galvao@ecu.edu.au

Abstract

PURPOSE:

Exercise has been proposed as an effective countermeasure for androgen suppression therapy induced side effects. Since the magnitude of fat gain and muscle loss is most pronounced during the early phases of androgen suppression therapy, the exercise response may differ by the duration of androgen suppression therapy. We investigated whether the exercise response varied by the prior duration of exposure to androgen suppression therapy, that is acute--less than 6 months vs later--6 months or greater.

MATERIALS AND METHODS:

A total of 50 men 55 to 84 years old undergoing androgen suppression therapy for nonbone metastatic prostate cancer completed a progressive resistance and cardiovascular exercise program for 12 weeks, including 16 with acute and 34 with chronic androgen suppression therapy exposure. We assessed fat and lean mass by dual energy x-ray absorptiometry as well as muscle strength, functional performance, quality of life and blood biomarkers.

RESULTS:

Patients on acute androgen suppression showed an increase in total body fat compared to those on chronic androgen suppression (0.9 kg, p = 0.018). Each group experienced increased appendicular skeletal muscle (about 0.5 kg, p <0.01). Triglycerides decreased in the chronic group and increased in the acute group (p = 0.027). Change in triglycerides were associated with the change in total body fat (r = 0.411, p = 0.004). There were no differences between the groups in prostate specific antigen, testosterone, glucose, insulin, total cholesterol, low and high density lipoprotein, cholesterol, C-reactive protein, homocysteine or quality of life. The 2 groups showed similar improvement in muscle strength and function, and cardiovascular fitness.

CONCLUSIONS:

Apart from differences in body fat and triglycerides the beneficial effects of exercise are similar in patients on acute or chronic androgen suppression therapy.

Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

PMID: 21849187 [PubMed - indexed for MEDLINE]

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