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Study Links microRNA Signature to Prostate Cancer Patient Response to Salvage Therapy

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NEW YORK (GenomeWeb) – While prostate cancer is one of the most curable forms of the disease given its typically early detection, identifying the optimal treatment regimens remains a challenge given the limitations of current methods to differentiate aggressive from indolent tumors.

However, a new study by researchers from Ohio State University suggests that microRNA signatures may be able to help clinicians identify which patients would be the best candidates for radiation therapy immediately following surgical removal of the prostate and those who should be monitored before such follow-on treatment.

Prostatectomy is a common treatment for men diagnosed with prostate cancer, including ones with early-stage disease, while in high-risk patients, surgical removal of the prostate will be followed by adjuvant radiation therapy.

In some cases, patients who undergo prostatectomy alone will experience what is known as a biochemical recurrence or failure — a rise in prostate-specific antigen (PSA) levels, which indicates that there is residual prostate tissue or cancer remaining — and require salvage radiation therapy. And a subset of these patients will eventually experience a second biochemical failure even after salvage therapy.

According to OSU researcher Erica Bell, at present there are no sure-fire methods for differentiating prostatectomy patients who will respond to salvage therapy from those who could benefit from adjuvant therapy or may require another form of therapy right after initial treatment.

"It's really a quality-of-life issue," Bell told GenomeWeb, citing the toxicities associated with radiation.

To address this issue, Bell and colleagues at OSU set out to identify prostate biomarkers that may help identify salvage radiation therapy responders from non-responders, focusing on miRNAs given their stability in formalin-fixed, paraffin-embedded (FFPE) tissue and the growing body of data pointing to their prognostic and diagnostic potential.

In collaboration with investigators from University Medical Center Freiburg in Germany, the OSU team obtained 43 FFPE specimens from prostate cancer patients who had undergone radical prostatectomy followed by salvage radiation therapy between 2005 and 2011.

Total RNA was isolated and then analyzed on Nanostring Technologies' nCounter system using the company's human v2 array, which contains 800 miRNA probes. Bell noted that the nCounter platform offered a whole-genome approach, which is particularly important in a discovery study, and does not require an amplification step, which limits added variability.

"In addition, NanoString has shown to be a better technique than qRT-PCR for FFPE specimens and correlates more with its paired fresh-frozen counterpart than qRT-PCR," she and the study's other authors wrote in their paper, which appeared in PLOS One.

Importantly, Nanostring's technology has been approved by the US Food and Drug Administration for use in assessing a breast cancer patient's risk of distant recurrence of disease, "so we know it is able to be clinically implemented," Bell said.

In total, 88 miRNAs were found to be significantly associated with biochemical failure after prostatectomy by multivariate analysis. They also clustered into two groups that correlated with either early and late recurrence. Notably, 15 of these 88 have been reported to be a part of a prostate cancer prognostic signature or model by other groups.

Meantime, nine miRNAs were significantly associated multivariate analysis with bio-chemical failure after salvage radiation therapy. All except one have been reported as associated with cancer in general, and six linked to prostate cancer specifically.

The OSU team also wanted to see if miRNA biomarkers could be used in combination with other clinical factors to improve the sensitivity and selectivity of existing prediction models.

To do so, they included lymph node status and scores from the so-called Gleason system of grading prostate cancer tissue based on microscopy analysis on top of the nine miRNAs from the initial experiments.

Two miRNAs — miR-601 and miR-4516 — alone and together with Gleason score and lymph node status stood out for their predictive capability.

According to Bell, this is the first study to use miRNA expression to predict a biochemical recurrence in prostatectomy patients following salvage radiation therapy and its findings are encouraging.

With a combination of the miRNA signatures and other clinical factors, physicians may be able to know which patients respond well to salvage therapy and therefore should not receive radiation until PSA levels rise.

Still, the study has some limitations, she cautioned. First, the miRNA model proposed does not indicate which prostatectomy patients will respond to adjuvant radiation therapy. "That is something we're going to need to find out" with additional experimentation, Bell said.

Additionally, the study involved a fairly small sample size, more than 50 percent of the patients involved experienced biochemical failure after salvage radiation therapy, and a small subset of patients received androgen deprivation therapy.

"Although hormonal therapy does not appear to be a confounding variable in the study, further validation using larger samples sizes, as well as patients who received adjuvant and observation after prostatectomy, will be required to determine the clinical usefulness of the identified predictive models," the OSU researchers wrote in PLOS One.

Bell said that she and the study's other authors are currently working to validate their findings in a larger number of patient samples, preferably ones obtained from multiple clinical sites and from patients with more diverse ethnicities as recent studies have shown that race can influence the usefulness of miRNA biomarkers.

She also hopes to be able to identify additional miRNAs that can be used to increase the predictive capacity of miR-601 and miR-4516.