RE: Polygenic risk of any, metastatic, and fatal prostate cancer in the Million Veteran Program

Prostate cancer (PCa) has a strong genetic component. After years of analytically rigorous research, 269 risk variants have been identified and validated through large, transancestry genome-wide association studies (1). Polygenic risk scores (PRS) comprised of these variants have been shown to be effective at stratifying PCa risk across diverse populations, although the clinical utility of such a genetic tool has been questioned given its limited ability to differentiate risk of indolent vs lethal disease (1-3). In this issue of the Journal, Pagadala and colleagues (4) evaluated a genetic risk score for PCa, described as a polygenic hazard score (PHS290), in the Millions Veteran Program, with their overall findings largely consistent with a previous publication by Chen et al. (2) that validated in the Millions Veteran Program and several other large biobanks the previously developed multiancestry PRS of 269 variants (1). Although the PHS290 is presented as a unique tool, it is a slight modification of the validated PRS, with 97.2% of variants being either the same variant or in linkage disequilibrium with an r value of more than 0.80 with highly correlated weights (r = 79%). This previous work is not described in the present publication, nor is a comparison of markers or weights provided, giving the impression that this risk score was independently developed.

Pagadala et al. (4) emphasized the association of the PHS290 with metastatic and fatal disease as though it were preferentially associated with these outcomes. However, their results confirm those of Chen et al. (2), demonstrating that PHS290 is not a stronger predictor of metastatic or lethal PCa than overall PCa. Results from Pagadala et al. (4) actually suggest that PHS290 would be slightly protective for fatal vs indolent PCa; a hazard ratio of 5.20 (95% confidence interval [CI] = 5.09 to 5.31) was observed for overall PCa across all populations combined, whereas attenuated hazard ratios of 4.89 (95% CI = 4.57 to 5.21) for metastatic disease and 4.42 (95% CI = 3.91 to 5.02) for fatal PCa were observed. Although results for less aggressive phenotypes were not provided, one can infer that the magnitude of the association with indolent PCa would be similar or larger than 5.2, contradicting the emphasis placed on PHS290 being overly important for lethal disease.

There is no question that genetic risk scores are effective predictors of PCa risk and are highly informative at predicting a man’s risk of developing PCa of any phenotype. Although subgroup analyses of highly clinically relevant endpoints such as metastatic and lethal disease are of keen scientific interest and draw public attention, highlighting such findings without presenting a balanced discussion of how the genetic risk score performs for less clinically significant phenotypes leads to a skewed interpretation of findings. A transparent presentation of the data is warranted to avoid misinterpreting the potential of the PHS290 by researchers working to improve PCa screening, physicians tasked with determining how to best evaluate their patient’s PCa risk, and patients who depend on the media to accurately interpret research findings and whose health and well-being are ultimately impacted by the research we conduct.

Funding

Not applicable.

Notes

Role of the funder: Not applicable.

Disclosures: The authors have no conflicts of interest to disclose.

Author contributions: CAH, ZK-J, BFD, and DVC: writing—original draft; writing—review & editing.

Data availability

No new data were generated or analyzed for this correspondence.