麻豆传媒

A new 18-gene urine test demonstrated higher diagnostic accuracy for high-grade prostate cancer compared with existing biomarker tests, a study showed.

In applying a testing approach with 95% sensitivity for high-grade prostate cancer (grade group [GG] 2 or greater), the test -- called MyProstateScore 2.0, or MPS2 -- would have safely avoided unnecessary additional testing with imaging or biopsy in 35% to 51% of men, with a negative predictive value (NPV) of 95% to 99%, reported Arul M. Chinnaiyan, MD, PhD, of the University of Michigan in Ann Arbor, and colleagues.

"For individual patients, NPVs approaching 100% provide clear guidance for confident decision-making," they wrote in . "For clinicians, uniform use of MPS2 could avoid unnecessary biopsies while preserving immediate detection of 95% of cancers of GG 2 or greater diagnosed using the biopsy all approach."

"Critically, MPS2 had 99% sensitivity and 99% NPV for cancers of GG 3 or greater, meaning the rare false-negative MPS2 results were almost uniformly more favorable cancers of GG 2 least likely to metastasize," they added. "These findings suggest that use of the test in patients with elevated PSA [prostate-specific antigen] levels can reduce the potential harms of prostate cancer screening while preserving its long-term benefits."

In explaining the rationale behind the development of the urine test, the researchers said that existing biomarker tests have not evolved to reflect current understanding of prostate cancer biology.

"We know that prostate cancer is very complicated, and every year we are discovering new markers and biologic aspects of prostate cancer," co-author John T. Wei, MD, also of the University of Michigan, told 麻豆传媒. "Tests get outdated and they're not incorporating new findings."

Wei said the MPS2 test builds upon the original urine-based test MyProstateScore, which incorporated PCA3 and TMPRSS2:ERG gene fusion expression with serum PSA level to estimate risk of high-grade cancers. The researchers hypothesized that supplementing this test with novel molecules selectively expressed by high-grade, aggressive cancers would improve testing accuracy.

They performed an RNA sequencing analysis of more than 58,000 genes to identify 54 markers of prostate cancer, including 17 "uniquely overexpressed" by high-grade cancers. From these candidate markers, the team derived the 18-gene assay.

The final MPS2 model included clinical variables and those 17 markers -- four high-grade cancer-specific genes (APOC1, B3GNT6, NKAIN1, and SCHLAP1), nine cancer-specific genes (PCGEM1, SPON2, TRGV9, PCA3, OR51E2, CAMKK2, TFF3, PCAT14, and TMSB15A), four curated markers (HOXC6, ERG, TMPRSS2:ERG, and KLK4), and the reference gene KLK3.

"What is powerful about this is unlike other tests that are static, we have shown that looking for prostate cancer is progressive -- in other words, you can incorporate new findings as they come out," Wei said. "And the findings in this validation study show that pretty clearly. We were able to find high-grade cancer with quite some fidelity. And, importantly, if this test does not show cancer, the chances of having lethal prostate cancer are incredibly low."

In their validation study, the researchers assessed MPS2, as well as another version of the model (with prostate volume [MPS2+]), the original MPS test, and multiple other biomarker tests, including serum PSA alone, the , the , and derived multiplex 2-gene and 3-gene models, in a cohort of 743 men (median age 62 years, median PSA level 5.6 ng/mL).

About one-third of men had a previous negative biopsy, and on study biopsy, 151 men (20.3%) had high-grade prostate cancer.

The analysis showed that the area under the receiver operating characteristic curve values for each of these tests were 0.60 using PSA alone, 0.66 using the risk calculator, 0.77 using PHI, 0.76 using the derived multiplex 2-gene model, 0.72 using the derived multiplex 3-gene model, and 0.74 using the original MPS model compared with 0.81 using the MPS2 model and 0.82 using the MPS2+ model.

Compared with other assays, MPS2 was more effective at helping patients avoid unnecessary biopsies.

The proportions of unnecessary biopsies that would have been avoided using each test were 11% for PSA alone, 20% for the risk calculator, 26% for PHI, 27% for the derived multiplex 2-gene model, 17% for the derived multiplex 3-gene model, and 23% for MPS compared with 37% for MPS2 and 41% for MPS2+.

Among men who had an initial biopsy, the proportions of unnecessary biopsies avoided were 35% for MPS2 and 42% for MPS2+, and 46% and 51%, respectively, among men who had repeat biopsies.

Chinnaiyan and colleagues acknowledged several limitations to their study, including the fact that their study population was not suitable for comparing biomarkers with multiparametric MRI (mpMRI), which they noted "remains a critical knowledge gap," and is currently being assessed in a prospective trial.

"Regardless, the externally validated performance of MPS2 supports its effectiveness in accurately ruling out the need for mpMRI and biopsy altogether," they added. "Additional studies are needed to corroborate these data and confirm the observed positive impact of MPS2 testing on longer-term outcomes."

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