Hypercholesterolemia, ADT & CRPC

[pjoshea13]

New Korean study [1] below.

The study found that hypercholesterolemia shortens the time to ADT failure in men with bone mets.

I don't know how high cholesterol has to be to meet the definition of "hypercholesterolemia". But perhaps a cutoff would mislead. One way that PCa uses to escape ADT, is to create androgen from cholesterol. & so a sufficiency of circulating cholesterol is all that's required. Cholesterol is carried by lipoproteins, & my understanding is that only very-low density lipoprotein cholesterol [VLDL cholesterol (VLDL-C)] gets into PCa cells. If so, total or LDL cholesterol would only approximate risk.

I know from experience that going from high-normal testosterone [T] to castrate T, alters one's lipid profile. VLDL-C is significantly increased.

Hypercholesterolemia is associated with other morbidities, & it's possible that one of those explains the shortened time to CRPC.

Regardless, the accumulation of cholesterol in PCa cells is an early event, and this is common for other cancers - a fact that was noted almost a hundred years ago.

Looking at past papers:

[2] from Australia (2015):

"Recent studies suggest that hypercholesterolemia increases intratumoral androgen signaling in prostate cancer, but it is unclear whether androgen-independent mechanisms also exist. Since hypercholesterolemia is associated with advanced, castrate-resistant prostate cancer, in this study, we aimed to determine whether and how hypercholesterolemia affects prostate cancer progression in the absence of androgen signaling."

"Taken together, our data show that hypercholesterolemia promotes prostate cancer metastasis independent of the androgen pathway, in part by increasing IQGAP1 and caveolin-1."

[3] from the Pokhara valley, Nepal (2011):

"The percentage of {PCa} cases with HDL normal limits (40 to 60 mg/dl) was 72% which did not show much variation when compared to 79% in controls. However, the percentage of cases with LDL borderline high (150-190 mg/dl) was 30% ands markedly increased when compared to the 5% in controls."

So, "borderline high" LDL represents a significant risk. Too bad that VLDL levels were not noted.

[4] from Fargo, ND (2008):

"Hypercholesterolemia was defined as total cholesterol greater than 5.17 (mmol/l)."

"A significant association was found between low HDL and prostate cancer" 57% increase in risk.

"High LDL was associated with a 60% increased risk for prostate cancer"

These are the only hits on PubMed for: <prostate[title] hypercholesterolemia[title]>, & cholesterol is implicated at every stage: (i) initiation, (ii) metastasis & (iii) CRPC.

There are 52 other PCa studies that give hypercholesterolemia a mention, but I'll end with:

[5] from Fred Hutchinson Cancer Research Center, Seattle (2012) {in vivo LNCaP PCa xenograft model}:

"we ... demonstrate that circulating cholesterol levels are significantly associated with tumor size ... and intratumoral levels of testosterone"

"We demonstrate tumoral expression of cholesterol uptake genes as well as the spectrum of steroidogenic enzymes necessary for androgen biosynthesis from cholesterol. Moreover, we show that circulating cholesterol levels are directly correlated with tumoral expression of CYP17A, the critical enzyme required for de novo synthesis of androgens from cholesterol"

I have to say that I am the most unlikely advocate for statin drugs - I wouldn't use one if I didn't have PCa. Dr Myers has come around to the idea that men with PCa should use Metformin - my guess is that statins will be next!

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/271...

Hypercholesterolemia Is Associated with a Shorter Time to Castration-Resistant Prostate Cancer in Patients Who Have Undergone Androgen Deprivation Therapy.

Jeon JC1, Park J1, Park S1, Moon KH1, Cheon SH1, Park S1.

Author information

Abstract

PURPOSE:

The goal of this study was to investigate the association between hypercholesterolemia and the time required for progression to castration-resistant prostate cancer (CRPC) in patients who have undergone androgen deprivation therapy (ADT).

MATERIALS AND METHODS:

Data from 154 patients with prostate cancer between 2005 and 2012 were reviewed retrospectively. ADT was employed as a treatment modality for these patients either due to multiple bone metastases at the time of diagnosis or due to old age in combination with other morbidities. Serum cholesterol levels and statin use were reviewed. We analyzed the factors associated with the development of CRPC after ADT treatment. The mean follow-up period was 34.8 months.

RESULTS:

The mean age of the patients was 71.3 years old and their mean prostate-specific antigen level was 141.8±212.6 ng/mL. Their mean cholesterol level was 175.9±37.7 mg/dL, and 14 patients (9.1%) were statin users. CRPC developed in 44 patients (28.6%), and the mean duration from ADT treatment to CRPC was 24.1 months. In a multivariate analysis, hypercholesterolemia was associated with the development of CRPC (hazard ratio [HR]=1.017, p<0.001), depending on clinical T stage (p=0.005) and the presence of bone metastasis (p<0.001). A subanalysis showed that hypercholesterolemia was associated with the development of CRPC in patients with bone metastasis (HR=1.032, p<0.001), but not in patients without bone metastasis.

CONCLUSIONS:

Hypercholesterolemia may be associated with the development of CRPC after ADT in patients with bone metastasis. Further studies with longer follow-up periods and larger samples are needed to validate this finding.

KEYWORDS:

Cholesterol; Prognosis; Prostatic neoplasms

PMID:

27169126

[PubMed]

[2] ncbi.nlm.nih.gov/pubmed/259...

[3] ncbi.nlm.nih.gov/pubmed/222...

[4] ncbi.nlm.nih.gov/pubmed/187...

[5] ncbi.nlm.nih.gov/pubmed/222...