Predictive Value of Genomic Classifier Scores and Transcriptomic Data for Prostate Cancer Distant Metastasis Risk: A Multicenter Retrospective Study.

Abstract

Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) has a greater specificity and sensitivity for detection of extraprostatic prostate cancer than conventional imaging. The Decipher genomic classifier is an established prognostic biomarker being evaluated for its ability to predict systemic treatment intensification. The relationship between Decipher scores and PSMA-based spread remains unknown, as do differences in transcriptomic patterns of PSMA PET-based spread in the de novo vs. recurrent setting. We retrospectively identified patients who (a) had undergone staging with a PSMA PET prior to treatment or for evaluation of recurrence post-radical prostatectomy (RP) at two institutions and (b) had transcriptomic data available from the Genomics Resource for Intelligent Discovery (GRID) database from either biopsy or RP specimens. We classified the PSMA PET pattern of spread using molecular imaging (mi) staging as localized (miT+N0M0), node-positive (miN1M0), distant metastasis (miM1a-c), or negative/non-diagnostic. We used logistic regression to calculate the odds ratios (OR) with 95% confidence intervals (CI) for distant metastasis risk based on Decipher score both pre-treatment and post-RP. As an exploratory analysis, we compared each of the staging groups for differences in important transcriptomic signatures. Kruskal-Wallis and Pearson chi-squared tests were used for continuous and categorical variables, respectively. A total of 315 patients were included in this analysis (n = 164 pre-treatment, n = 151 post-RP). Eighty PSMA PET scans were negative, while 147 were miT+N0M0, 45 were miN1M0, and 43 were miM1a-c. A higher Decipher score was associated with distant metastasis (miM1a-c) on PSMA PET both pre-treatment (OR 1.3 [95% CI: 1.0-1.7] per 0.1 increase in Decipher score, P = 0.05) and post-RP (OR 1.2 [1.0-1.4] per 0.1 increase in Decipher score, P = 0.04). There were higher TP53 mutation (P = 0.01) and cell cycle progression (P = 0.04) signature scores in miM1a-c patients compared to miN1M0 or miT+N0M0 patients. Basal subtype was more prevalent per PAM50 in miM1a-c or miN1M0 patients (36%) than miT+N0M0 patients (19%, P=0.01). Patients with de novo miN1M0 or miM1a disease (n = 19) had higher Decipher scores (0.85 vs 0.57, P = 0.10) and IFNa response (P = 0.08) than patients with recurrent miN1M0 or miM1a disease (n = 35). Higher Decipher scores were associated with distant metastasis on PSMA PET in both the de novo and recurrent setting. Transcriptomic differences in pathways related to proliferation, p53 status, and PAM50 classification were seen when comparing localized, node-positive, and distant metastatic disease. Patients with de novo miN1M0 or miM1a disease may harbor more aggressive disease than those with miN1M0 or miM1a disease at recurrence.