Introduction:

Prostate cancer (PCa) screening may be improved by focusing screening efforts on men that are at high risk. We investigated the sensitivity of a germ-line marker of PCa risk (Prompt - PGS) alone and in combination with family history (FH) to identify men at risk for metastatic PCa.

Methods:

After IRB approval, 100 men presenting to the University of California San Diego oncology clinic with metastatic PCa were prospectively enrolled. Baseline clinical characteristics and saliva were collected on all patients. DNA was harvested from saliva and the Prompt - PGS calculated based on genotype at 33 single nucleotide polymorphisms and weighted by odds ratio (OR) and allele frequency. Based on previous studies, a Prompt score < 0.6 indicated low, 0.6 to 1.3 intermediate and >1.3 high risk of PCa.  Men with a FH were considered at least intermediate risk. Sensitivity calculations were based on a hypothetical screening algorithm whereby low risk patients would not be screened, and intermediate/high risk men underwent screening.

Results:

100 men were enrolled at a median age of 63.3 years old (IQR 60.1-71.1) and followed for a median of 100.8 months (IQR 57-166.4). 21% of men in this cohort had a FH, 6%, 50% and 44% of men had low, intermediate and high Prompt scores respectively. When FH is added, this climbs to 95%. The high-risk cohort was older at the time of metastasis, and for most of the analysis comparative statistics could not be reliable employed given the very low number of false negatives. 59 men died during the study period at a median time of 100.8 month (IQR 52.3-171.4). Of those, 4 (6.8%), 27(45.7%), and 28(47.5%) were in the low, intermediate, and high-risk groups respectively. Within the high-risk group, Prompt - PGS without FH accounted for 71.4% of the patients. Sensitivity for death during study period was 93.2% for the hypothetical PCa screening paradigm. A majority of men that presented with metastatic PCa did not undergo routine PSA based screening (68% vs 32%). Of the 68 men that did not undergo not-for-cause PSA screening, 64 (94.1%) would be included in our hypothetical PCa screening paradigm. Of the 59 men that died during our study period, a majority 40 (67.8%) did not undergo routine not-for-cause PSA screening. Of the 40 men that did not undergo PSA screening and passed away, 37 (92.5%) would be included and 3 (7.5%) would be excluded from our hypothetical PCa screening paradigm.

Conclusion:

We present, to our knowledge, the only analysis of the performance of a low penetrance germline genetic risk score stratification of a cohort of men with known metastatic PCa. In a cohort of men with metastatic PCa at presentation, only 5% were identified as low risk by our criteria, and the majority (55%) fell within the high-risk group. Of the men with a high Prompt - PGS, 77.3% had a negative family history. 68% of the men in this analysis did not undergo regular PSA screening; based on Prompt alone, 94.1% of these men would have been flagged for screening. We demonstrate that a screening strategy based on our proposed risk grouping would have missed 5% and captured 95% of a metastatic PCa cohort. Of the men that died in our study period, only 6.8% would have remained unscreened under our hypothetical paradigm. Prompt-PGS alone and together with FH is a sensitive means of identifying men who should consider PCa screening. 

Funding: N/A