One of the major findings they highlight is that HOXB13, BRCA2, ATM, and CHEK2 are the 4 rare pathogenic mutations that seem to have the most robust and consistent data indicating that they are associated with increased risk of developing prostate cancer. Their association with prostate cancer aggressiveness still needs to be determined as some of these mutations have not consistently been shown to be associated with disease aggressiveness. Xu et al also highlight the several studies that evaluated polygenic risk scores in large databases, all of which found that these scores correlate with increased prostate cancer risk at an earlier age. Noticeably, they do so independently of family history and rare pathogenic mutations and could allow for the identification of many additional patients at high risk for prostate cancer – patients that would have otherwise been missed with family history and pathogenic mutation testing alone.
Yet, if germline genetic testing is so powerful at predicting prostate cancer risk, then why is not widely used? In their review, Xu et al also discuss current barriers to the widespread use of germline genetic testing in the screening population. For instance, in order to bring polygenic risks scores to the clinic, they will need to be done in CLIA-certified labs, easy to interpret for the clinician and patient, and applicable to the general population. In addition, prospective trials are still very much needed to further validate these tests. Xu, Pavlovich, and Ross are in fact currently leading a multicenter prospective observational trial (GenBx) aiming to evaluate the genetic risk score’s (combined with rare pathogenic mutation data) ability to predict prostate biopsy findings in men of various genetic ancestries with elevated PSA.2 This trial is likely to be instrumental in obtaining recognition of the GRS’s value by clinical guidelines.
Pending validation with the GenBx trial, additional questions on how best to implement germline genetic testing in screening protocols will need to be addressed. For example, earlier and more aggressive screening could be proposed in men at higher inherited risk. The BARCODE1 trial is also actively enrolling patients to address this question, and the GenBx trial is likely to be informative on the clinical utility of such screening protocols.3 If implemented along with a decreased recommendation for biopsying men at low risk levels, such protocols may help reduce overdiagnosis of indolent prostate cancers while identifying at an early stage those with lethal potential and ultimately reduce healthcare costs.
Written by: Claire M. de la Calle, MD, The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
References:
- Xu J, Resurreccion WK, Shi Z, et al. Inherited risk assessment and its clinical utility for predicting prostate cancer from diagnostic prostate biopsies. Prostate Cancer Prostatic Dis. 2022
- Xu J. Performance of Inherited Risk Assessment for Predicting Prostate Cancer From Prostate Biopsy (GenBx). ClinicalTrials.gov2022.
- Benafif S, Ni Raghallaigh H, McGrowder E, et al. The BARCODE1 Pilot: a feasibility study of using germline single nucleotide polymorphisms to target prostate cancer screening. BJU Int. 2021