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Weill Cornell Study Finds Gene Fusion Could Predict Prognosis in Prostate Cancer Precursor Lesions

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In a study of samples from patients with high–grade prostatic intraepithelial neoplasia — a prostate cancer precursor lesion — researchers from Weill Cornell Medical College have shown that a cancer-associated gene fusion can predict which patients with HGPIN are more likely to have cancer in subsequent biopsies.

The group published its results, based on analysis of samples from a large HGPIN clinical trial, in the Journal of Clinical Oncology last month.

In the study, the team used immunohistochemistry to measure ERG gene expression as a surrogate for the presence of a fusion of the promoter region of the TMPRSS2 gene and coding region of the ERG gene in 461 patients from a trial of 1,590 men with biopsy-diagnosed HGPIN.

More than half of the men in the trial whose ERG expression indicated the presence of this gene fusion developed prostate cancer, while only 35 percent of those without this expression showed the same progression.

According to Weill Cornell's Mark Rubin, the senior author of the study, this difference in risk is enough to make stratifying patients based on this translocation an attractive tool for clinical decision-making.

"It's important because currently, urologists taking care of men with abnormal biopsies, especially high grade PIN, don’t know what is the best indication to perform another biopsy," he told PGx Reporter this week.

"Ten years ago the standard of care was to always biopsy if someone had this abnormality, but now the standard of care is not to biopsy unless there are other abnormalities like elevated PSA," he added. "The question is, is this a tipping point to say some [men with HGPIN] are at this elevated 50 percent risk."

In the study, Rubin and his colleagues used samples from a Phase II clinical trial testing the efficacy of toremifene citrate in preventing prostate cancer in men with HGPIN. The group evaluated 663 biopsy cores from 461 patients for ERG expression using immunohistochemistry.

According to Rubin, measuring ERG expression as a surrogate for the presence of a TMPRSS2:ERG fusion is a technique his team developed in earlier work investigating the biology of the alteration and its role in prostate cancer progression.

The idea that the presence of TMPRSS2:ERG fusions mark a distinct molecular subset of HGPIN is not new, Rubin explained. After describing the fusion for the first time in 2005, Rubin said his group went on to discover its association with the male hormone androgen and its occurrence early in prostate cancer development.

Based on this biological information, the researchers then wanted to address whether the fusion might confer higher risk of developing cancer for patients with HGPIN.

Evaluating samples from the toremifene citrate trial, the researchers found that among samples positive for ERG, more than fifty percent developed prostate cancer during the trial period. For those negative for ERG expression, only 35 percent progressed to cancer.

According to the study authors, the hazard ratio for cancer development among ERG-negative patients relative to ERG-positive patients was 0.58. ERG expression status was also independent of other factors, including age, baseline PSA, Gleason score, or tumor volume.

By showing that this subclass of patients with TMPRSS2:ERG fusions has a significantly higher risk of developing prostate cancer, the team has opened up the possibility that this molecular marker could serve as a tool to guide treatment, Rubin said.

While other studies have shown different cancer development rates in ERG-positive and -negative patients, Rubin said, the newer study, having been conducted on samples from such a large clinical trial, provides much more powerful evidence that this is a clinically relevant observation.

According to Rubin, the finding will need to be confirmed in a prospective study to establish firmly that ERG status is important enough to change the way patients are managed. He said his team is preparing to do this follow up research now.

IP around the fusion was licensed initially to Gen-Probe, which sublicensed it to Roche's Ventana Medical Systems in 2012, Rubin said.

He said Gen-Probe (now part of Hologic) has developed a urine-based ERG assay, while Ventana is working on tissue-based applications.

"The indications for use are still being defined," Rubin said, "But we believe this is one of the very first indications for this as a clinical test."

Additional research has also suggested the marker could be used as both a predictor of prostate cancer and more specifically of higher-grade cancer, he added.

A team of University of Michigan researchers also involved in the initial TMPRSS2:ERG discovery also launched a clinical trial earlier this year to study whether patients harboring TMPRSS2:ERG fusions respond better to treatment with a PARP inhibitor combined with hormone therapy or to hormone therapy alone.

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