PROSTest, a Multigene Liquid Biopsy Signature, Effectively Stratifies Patients With High PSA for Prostate Biopsy.

BACKGROUND

Prostate-specific antigen (PSA) remains the standard biomarker for prostate cancer (PCa) detection, but its limited specificity-particularly in the 3-10 ng/mL range-leads to overdiagnosis and unnecessary biopsies. Including multiparameteric MRI (mpMRI) helps to reduce the number of PSA-false-positive biopsies, but there is still a need for noninvasive diagnostics that improve risk stratification and reduce unnecessary interventions.

METHODS

PROSTest is a peripheral blood-based assay that quantifies a 27-gene signature in the androgen receptor (AR) signaling pathway in addition to 3 housekeeping genes (HKGs). PCR results are fed into a proprietary machine learning (ML) algorithm to produce a numerical score on a scale of 0-100 with a clinically validated cutoff of 50 for a final binary readout; positive or negative for likelihood of cancer on biopsy. In this report, the diagnostic performance of PROSTest was evaluated in 1,894 male subjects including 970 individuals with actionable results (PSA ≥ 3.0 ng/mL). We focused on two PSA-graded intended-use populations: subjects aged ≥ 45 years with PSA 3-10 ng/mL (n = 467), and those with PSA > 10 ng/mL (n = 503). PSA and PROSTest were conducted on all subjects.

RESULTS

In the 970 cohort, adding the PROSTest achieved an AUC of 0.96 and was significantly more accurate than PSA alone for differentiating PCa from benign prostatic disease (Chi = 134.1, p < 0.0001). In the 467 subjects with PSA 3-10 ng/mL, the PROSTest achieved an AUC of 0.94, with 94% sensitivity and 91% specificity. The PPV for PROSTest was 91.6% (95%CI: 88.3-94.1%) and NPV was 95.6% (95%CI: 91.6-97.7%). The blood-based gene expression profiling correctly identified 435 of 467 subjects (93.1%) and was significantly more accurate than PSA alone where only 271 of 467 (58.0%) with high PSA had PCa (Chi = 155.9, p < 0.0001). The sensitivity of the assay for detecting PCa was 97.0% (263/271). In the 503 subjects with PSA > 10 ng/mL, PROSTest yielded an AUC of 0.93 versus 0.76 for PSA (z = 5.3, p < 0.0001). Despite the very high levels of PSA ( > 10 g/mL), 63 (20 BPH and 43 non-BPH controls) out of the 503 (12.5%) subjects were negative for PCa. PROSTest sensitivity was 93.6% (412/440) and the accuracy was 92.8% (467/503). The PPV for PROSTest was 98.1% (95%CI: 96.4-99.0%) and NPV was 66.3% (95%CI: 57.6-74.0%). If PROSTest was used, it would have precluded 55 of the 63 (87.5%) PSA-falsely driven biopsies.

CONCLUSIONS

PROSTest demonstrates improved stratification value relative to PSA and could significantly reduce PSA-driven false positive biopsies. Out of 259 non-PCa subjects biopsied based on high PSA levels, applying PROSTest could potentially eliminate 227 biopsies (87.6%). PROSTest superior NPV was not confounded as a tradeoff for the PPV as PROSTest exhibited a sensitivity of ~95% (675/711 PCa detected).