Urine gene expression assay may noninvasively diagnose prostate cancer

A novel urine exosome gene expression assay added to standard-of-care assessments improved the identification of high-grade prostate cancers among men with elevated PSA levels, according to the results of a prospective study.

“The test has the potential to be a significant improvement over PSA alone in distinguishing between low- and high-grade prostate cancer, especially in the PSA gray zone patient,” James McKiernan, MD, John K. Lattimer professor and chair of urology at Columbia University Medical Center, said in a press release. “It could reduce hundreds of thousands of invasive biopsies each year.”

The overdiagnosis and overtreatment of indolent and low-grade prostate cancer is a health issue in most developed countries, according to study background. The development and implementation of a noninvasive, easily administered diagnostic assay to determine whether a prostate biopsy is needed remains an unmet clinical need.

McKiernan and colleagues sought to observe the performance of the addition of a urine exosome gene expression assay (ExoDx Prostate[IntelliScore], Exosome Diagnostics) to standard-of-care assessments — which include PSA level, age, family history, race and ethnicity — for discriminating between high-grade (Gleason score 7) and low-grade (Gleason score 6 or benign disease) disease on initial biopsy.

The researchers used a reverse-transcriptase polymerase chain reaction to compare the gene expression assay with biopsy outcomes in a training cohort of 499 men with PSA levels between 2 ng/mL and 20 ng/mL.

They validated the prognostic score in a cohort of 1,064 men derived from 22 U.S. academic and community medical centers. Eligible participants were aged 50 years or older, disease free, and scheduled for an initial or repeated prostate needle biopsy due to suspicious digital rectal examination findings or PSA levels.

The assay’s ability to discriminate high-grade disease from low-grade or benign disease on initial biopsy — using the area under receiver operating characteristic curve (AUC) — served as the primary outcome measure.

Two-hundred fifty-five patients (median age, 62 years; median PSA, 5 ng/mL) in the training cohort met the study criteria. Among these patients, the addition of the urine exosome gene expression assay to standard of care appeared associated with improved discrimination (AUC = 0.77; 95% CI, 0.71-0.83) compared with standard of care alone (AUC = 0.66; 95% CI, 0.58-0.72; P < .001). Using PSA alone had an AUC of 0.61 (95% CI, 0.54-0.69), and use of the gene assay alone had an AUC of 0.74 (95% CI, 0.68-0.8).

For high-grade disease, a binary urine exosome gene expression assay with a 15.6 cutoff demonstrated a negative predictive value of 0.96 and a positive predictive value of 0.37. When using an assay score greater than 15.6 to prompt biopsy, 20% of prostate biopsies could have been avoided while missing 2% of all high-grade disease and no cases of dominant GS pattern 4 high-risk disease.

Independent validation in eligible 519 patients showed that the assay plus standard of care better distinguished high- and low-grade disease from benign disease (AUC = 0.73; 95% CI, 0.68-0.77) compared with standard of care alone (AUC = 0.63; 95% CI, 0.58-0.68; P < .001).

Validation also showed that, with a cutoff greater than 15.6, the urine exosome gene expression assay demonstrated good clinical performance in predicted high-grade disease while avoiding 27% of biopsies. The negative predictive value was 91% and sensitivity 92%, which indicated the assay missed 12 of 148 (8%) high-grade cancers. Seventy-five percent of missed cancers had less than one-third of cores involved, and 5% had dominant GS pattern 4.

The researchers acknowledged study limitations, including their inability to include digital rectal examination and free PSA as standard-of-care variables. Further, the study did not include a central pathology review.

“Men with high PSA levels are typically advised to have a biopsy, even though most have no cancer at all, or have a type of disease that can be monitored without treatment,” McKiernan said. “In other words, a lot of men are undergoing unnecessary biopsies. Given the pain and risks associated with performing a prostate biopsy, that is not a trivial thing.”

The urine exosome gene expression assay may represent a needed noninvasive diagnostic tool for prostate cancer, Hiten D. Patel, MD, MPH, Heather J. Chalfin, MD, and H. Ballentine Carter, MD, all of James Buchanan Brady Urological Institute at Johns Hopkins Medicine, wrote in an accompanying editorial.

“Currently, we do not have a single population-based screening test to supplant PSA–based stewardship in screening for prostate cancer,” Patel and colleagues wrote. “However, McKiernan and colleagues have introduced a novel urinary gene expression signature that may be the least invasive of available options by not requiring a digital rectal examination or phlebotomy as a reflex test in men for whom PSA testing raises the suspicion of prostate cancer. In the near future, a panel of markers associated with the risk of high-grade prostate cancer may decrease the rate of overdiagnosis and overtreatment of prostate cancer that prompted the U.S. Preventive Services Task Force to issue a grade D recommendation for prostate cancer screening.” – by Cameron Kelsall

Disclosure: Exosome Diagnostics funded this study, and several study researchers report employment or consultant roles with Exosome Diagnostics. McKiernan reports no relevant financial disclosures. Patel, Chalfin and Carter report no relevant financial disclosures.