Gene Variants May Predict Prostate Cancer Progression on ADT

Inherited variants in an androgen transporter gene may determine the time to progression (TTP) for men with prostate cancer receiving androgen deprivation therapy (ADT).

In a cohort of 616 men with prostate cancer treated with ADT, one of three single nucleotide polymorphisms (SNP) within the SLCO2B1 gene tested-the risk allele-was associated with TTP using two types of statistical analyses (P = .0187 and P = .0489).

The median overall survival from the start of ADT was 6.5 years for all 1,094 patients included in the original and validation cohort.

A different SNP was significantly associated with overall survival (OS) after initiation of ADT using two types of statistical analyses (P = .0091 and P = .014). The difference of median OS was 18 months.

The results were presented by Philip Kantoff, MD, leader of the Dana-Farber/Harvard Cancer Center Prostate Cancer Program in Boston, at the 2015 Genitourinary Cancers Symposium held February 26-28, in Orlando, Fla.

In normal prostate tissue, the predominant SNP linked to OS resulted in lower expression of SLCO2B1 compared to tissue expressing the risk allele (P-trend = .0193). According to the study authors, this suggests that the association between the predominant allele and OS may be linked to the expression levels of the SLCO2B1 protein.

SLCO2B1 functions as a transporter of steroids including testosterone and other forms of androgens. The risk allele of the SLCO2B1 gene was previously shown by these authors to result in more efficient import of androgen precursors--dehydroepiandrosterone (DHEA) and the sulfated form, DHEAS-which boosts androgen receptor signaling and cell growth, and in turn, results in shorter TTP. Both DHEA and DHEAS are important precursors for testosterone production in the tumor microenvironment, and DHEA alone has been shown to bind to mutated forms of the androgen receptor found in prostate tumors.

“DHEAS is a precursor of testosterone and dihydrotestosterone, which are potent androgens. SLCO2B1 is the mechanism by which DHEAS gets taken up by cells,” explained Kantoff.

In the current study, in vitro knockdown of SLCOB1 results in decreased uptake of androgens and decreased prostate tumor cell growth.

From both the patient and in vitro data, the authors conclude that germline variants in the SLCO2B1 transporter can affect expression of this protein and the uptake of androgen precursors, which can affect outcomes for prostate cancer patients treated with ADT.

“Germline variants determine the activity of SLCO2B1 and thereby, the uptake of DHEAS by cells including prostate cancer cells,” said Kantoff.

The study also showed that statins interfere with the uptake of DHEAS into cells, as statins are also substrates of SLCO2B1. This increases the time to progression on androgen deprivation therapy, according to Kantoff. “This highlights the need to understand the complex interactions of cancer therapies and the other agents that patients are taking.”

The authors are currently planning further validation studies. With further validation, it may be possible to use this gene as a prognostic tool of response to ADT in prostate cancer patients. It may also be possible to inhibit the activity of this androgen transporter to improve patients’ responses to ADT.