Evaluation of PSA and PSA Density in a Multiparametric Magnetic Resonance Imaging-Directed Diagnostic Pathway for Suspected Prostate Cancer: The INNOVATE Trial

Abstract

Objectives: To assess the clinical outcomes of mpMRI before biopsy and evaluate the space remaining for novel biomarkers. Methods: The INNOVATE study was set up to evaluate the validity of novel fluidic biomarkers in men with suspected prostate cancer who undergo pre-biopsy mpMRI. We report the characteristics of this clinical cohort, the distribution of clinical serum biomarkers, PSA and PSA density (PSAD), and compare the mpMRI Likert scoring system to the Prostate Imaging–Reporting and Data System v2.1 (PI-RADS) in men undergoing biopsy. Results: 340 men underwent mpMRI to evaluate suspected prostate cancer. 193/340 (57%) men had subsequent MRI-targeted prostate biopsy. Clinically significant prostate cancer (csigPCa), i.e., overall Gleason ≥ 3 + 4 of any length OR maximum cancer core length (MCCL) ≥4 mm of any grade including any 3 + 3, was found in 96/195 (49%) of biopsied patients. Median PSA (and PSAD) was 4.7 (0.20), 8.0 (0.17), and 9.7 (0.31) ng/mL (ng/mL/mL) in mpMRI scored Likert 3,4,5 respectively for men with csigPCa on biopsy. The space for novel biomarkers was shown to be within the group of men with mpMRI scored Likert3 (178/340) and 4 (70/350), in whom an additional of 40% (70/178) men with mpMRI-scored Likert3, and 37% (26/70) Likert4 could have been spared biopsy. PSAD is already considered clinically in this cohort to risk stratify patients for biopsy, despite this 67% (55/82) of men with mpMRI-scored Likert3, and 55% (36/65) Likert4, who underwent prostate biopsy had a PSAD below a clinical threshold of 0.15 (or 0.12 for men aged <50 years). Different thresholds of PSA and PSAD were assessed in mpMRI-scored Likert4 to predict csigPCa on biopsy, to achieve false negative levels of ≤5% the proportion of patients whom who test as above the threshold were unsuitably high at 86 and 92% of patients for PSAD and PSA respectively. When PSA was re tested in a sub cohort of men repeated PSAD showed its poor reproducibility with 43% (41/95) of patients being reclassified. After PI-RADS rescoring of the biopsied lesions, 66% (54/82) of the Likert3 lesions received a different PI-RADS score. Conclusions: The addition of simple biochemical and radiological markers (Likert and PSAD) facilitate the streamlining of the mpMRI-diagnostic pathway for suspected prostate cancer but there remains scope for improvement, in the introduction of novel biomarkers for risk assessment in Likert3 and 4 patients, future application of novel biomarkers tested in a Likert cohort would also require re-optimization around Likert3/PI-RADS2, as well as reproducibility testing.

Histo-MRI map study protocol: a prospective cohort study mapping MRI to histology for biomarker validation and prediction of prostate cancer

“…Thresholds of index test parameters based on previous work from the INNOVATE trial will be applied to determine whether a lesion is positive or negative. 7 This will be compared with a histological reference standard allowing assessment of false positive rate, sensitivity and specificity.…”

“…The field of view (FOV) is 180×180 mm and acquired voxel size=0.9×0.9×3.5 mm with a scan duration of 5 min 50 s. LWF values for lesions identified on mpMRI will be calculated after data processing by a previously described method. 7 …”

“…We anticipate a biopsy rate of 57% in the cohort and of those biopsied, 75% to be scored Likert 3 or 4, based on results from the recent INNOVATE trial at our institution. 7 Therefore, a sample size of 300 will provide sufficient power, with an estimated 171 men predicted to have biopsy and of these men, 128 to have a Likert score of 3 or 4.…”

“…Results from a recent trial at our institution showed that men undergoing biopsy with mpMRI scores of Likert 3 (indeterminate for csPCa) and Likert 4 (likely to have csPCa) had false-positive rates of 85% and 40%, respectively. 7 However, when mpMRI is scored as highly likely to have csPCa (Likert 5/5), the percentage of false positives is low at 2%. 7 Therefore, there is a clinical need for biomarkers to better stratify men with Likert 3 or Likert 4 mpMRI scores to reduce false positives without missing men with csPCa.…”

“… 7 However, when mpMRI is scored as highly likely to have csPCa (Likert 5/5), the percentage of false positives is low at 2%. 7 Therefore, there is a clinical need for biomarkers to better stratify men with Likert 3 or Likert 4 mpMRI scores to reduce false positives without missing men with csPCa.…”