Looking to the Genome for Prostate Cancer Biomarkers

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Researchers are trying to develop prostate cancer biomarkers that can predict treatment effects, to spare patients toxicities associated with unhelpful regimens.
Researchers are trying to develop prostate cancer biomarkers that can predict treatment effects, to spare patients toxicities associated with unhelpful regimens.

Oncologists cannot yet predict which men with castration-resistant prostate cancer (CRPC) will benefit from taxane therapy, and which will benefit from the androgen-receptor signaling inhibitors abiraterone acetate and enzalutamide.

An investigational liquid biopsy that made headlines earlier this year detects circulating prostate tumor cells' androgen-receptor splice variant 7 (AR-V7), which is involved in tumor resistance to next generation androgen-receptor antagonist, enzalutamide (Xtandi).  But more study is needed and, to date, there are no approved molecular biomarkers for prostate cancer.

It is “unfortunate” that there is no predictive biomarker for the second leading cause of cancer deaths among men in the US (advanced prostate cancer), said associate professor of oncology Neeraj Agarwal, MD, of the University of Utah School of Medicine in Salt Lake City.

“It's not that people haven't tried. Investigators are trying all over,” he said. “Challenge number one is that prostate cancer is a very heterogeneous disease that occurs in the backdrop of varied genetic and epigenetic changes.”

That means that advanced prostate cancer in a given individual is a target-rich environment with many different mutations. 

Noting that germline predisposition is a piece of the puzzle, Dr Agarwal and colleagues are among those who have turned to the search for predictive germline prostate cancer biomarkers in a patient's own genome.  

“If we can study germline DNA that you're born with from a simple blood draw, an advantage is that we don't need tumor biopsy,” Dr Agarwal said. That's important from the perspective of regular clinical practice, because many patients with metastatic CRPC (mCRPC) have metastasis in the bones only, which can be “very difficult” to biopsy, he added. Although liquid biopsies are going to change this in the near future, “we are not there yet,” he said.

A recent study reported that an inherited variant of the HSD3B1 gene (1245C) in men with prostate cancer is associated with prostate tumor resistance to androgen deprivation therapy (ADT).1 HSD3B1 encodes an androgen-synthetic enzyme that converts androgen precursors into dihydrotestosterone, which in turn stimulates androgen receptor signaling. If validated, HSD3B1 (1245C) could be used as a predictive biomarker with clinical benefit for androgen suppression, and as a prognostic tool for spotting men whose cancers are likely to prove aggressive, the authors noted. Those patients could then be considered for escalated therapy.

Dr Agarwal's lab is also looking for prostate cancer biomarkers in patients' genes. 

Using blood samples from Caucasian men with metastatic, castration-refractory prostate cancer, Dr Agarwal's team genotyped boundary regions for 61 genes thought to participate in the androgen metabolic pathway, and compared these data to time to treatment failure (TTF) on abiraterone acetate.2 They found single-nucleotide polymorphisms (SNPs) in the SULT1E1 estrogen sulfotransferase enzyme gene that correlated with TTF on abiraterone acetate.

This enzyme is implicated in the regulation of estrogen-related signaling, including estrogen-mediated regulation of cell-growth. It might also affect mRNA expression in several genes.

RELATED: Prostate Biopsy Rates Drop Post-USPSTF 2012 PSA Screening Guidelines

“We found that patients who have a rare allele were less likely to respond to treatment with abiraterone, one of the most commonly used drugs in the mCRPC setting,” Dr Agarwal said.

That could mean that inferior responses to abiraterone can be predicted using a blood test. The team is following up with a larger, prospective validation cohort study.

“I think simple germline variations in these genes in the steroid metabolic pathways can predict response to androgen deprivation therapy or abiraterone—and that's very encouraging,” Dr Agarwal said. 

References

  1. Hearn JW, Abu Ali G, Reichard CA, et al. HSD3B1 and resistance to androgen-deprivation therapy in prostate cancer: a retrospective, multicohort study. Lancet Oncol. 2016;17(10):1435-1444. doi: 10.1016/S1470-2045(16)30227-3
  2. Agarwal N, Alex AB, Farnham JM, et al. Inherited variants in SULT1E1 and response to abiraterone acetate by men with metastatic castration refractory prostate cancer. J Urol. 2016;196(4):1112-6. doi: 10.1016/j.juro.2016.04.079

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