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Implementation of Universal Germline Genetic Testing Into Standard of Care for Patients With Prostate Cancer: The Time Is Now - Beyond the Abstract

Results from a recent prostate cancer germline genetic testing (GGT) study provide strong evidence to support GGT for all patients with prostate cancer. The PROstate Cancer registry in Large patient population AIMed to assess efficacy in germline testing (PROCLAIM) trial investigated the impact of universal GGT in a prospective, unselected US population of patients from primarily community urology practices, where the majority of prostate cancer patient care occurs.

Of the 958 patients with evaluable outcomes, approximately 50% met 2019 National Comprehensive Cancer Network (NCCN) prostate cancer GGT guidelines and approximately 50% did not meet guidelines. The majority (65%) of patients had localized, low-risk, or intermediate-risk disease. Overall, the prevalence of pathogenic/likely pathogenic germline variants (PGVs) in the meeting NCCN criteria cohort was 7.7%. As predicted, the prevalence of PGVs did not differ significantly between patients meeting testing criteria and those not meeting criteria (8.8% vs. 6.6%, respectively). Most importantly, 42% of patients with PGVs would have been missed by guideline-restricted testing. Extrapolating these findings to the estimated incidence of 288,300 new patients diagnosed with prostate cancer in 2023, restriction of GGT to only patients meeting NCCN test criteria may annually miss approximately 9,000 men with hereditary forms of prostate and other cancers.

Furthermore, in the PROCLAIM trial, PGVs were significantly more frequent in White compared with non-White patients (9.0 v 2.9%, respectively). Strikingly, among non-White patients, the PGV prevalence was nominally higher among patients who did not meet GGT criteria (4.0%) compared with those who did meet the criteria (1.8%), suggesting that guidelines may be unintentionally creating barriers to genetics-informed care in underrepresented and underserved populations. Allowing for broader GGT testing criteria should mitigate these disparities by increasing the number of (diverse) individuals tested, resulting in a better representation of potential genetic variation prevalence.

Certain PGVs in patients with prostate cancer confer significant prognostic and predictive information. PGV status is critical for determining eligibility for targeted therapies such as poly (ADP-ribose) polymerase inhibitors, which are now US Food and Drug Administration approved for both first and second-line therapy for metastatic castrate-resistant prostate cancer and are being studied in the hormone-sensitive, localized high-risk, and maintenance therapy settings. Furthermore, identification of a PGV in a mismatch repair (MMR) gene (EPCAM, MLH1, MSH2, MHS6, PMS2) is often an indication that the tumor may be MMR deficient and thus confers eligibility for treatment with the immune checkpoint inhibitor pembrolizumab. Clinical trials are an added benefit of undergoing GGT, as eligibility criteria are often dependent on DDR gene status.

Patients with PGVs in certain cancer predisposition genes are also at risk of other cancers, such as male breast cancer, colorectal cancer, pancreatic cancer, and melanoma. Individuals at risk of these cancers are recommended to undergo increased surveillance (eg, mammograms/breast magnetic resonance imaging, colonoscopies, pancreatic cancer screening by using magnetic resonance cholangiopancreatography and endoscopic ultrasound) to detect cancers at an earlier and potentially, curable stage. One study found that among patients with cancer, 11% had PGVs identified only after presenting with a second primary cancer that possibly could have been detected earlier or prevented given current gene-specific surveillance and risk-reduction recommendations, hence representing a missed opportunity for individual patient disease detection or prevention and informing family members.

In addition to improving patient management, universal GGT may benefit family members, enabling cascade family variant testing. Identifying unaffected family members with PGVs in both high-risk and moderate-risk genes is critically important for both cancer prevention and earlier diagnosis and the likely reduction in health care costs, as well as lives saved through early cancer detection.

Recent research has measured the real-world clinical utility of universal GGT for patients with prostate cancer. Clinician-reported recommendations and outcomes for 982 patients from the PROCLAIM trial showed that GGT results influenced care for patients with prostate cancer, including those who did not meet NCCN testing criteria, and those with low-risk localized disease.

GGT is an important tool that enables personalized management of patients with prostate cancer, including access to approved prostate cancer therapeutics, opportunities for clinical trials, and testing of family members at risk of prostate cancer and other cancers. Prostate cancer is one of the most common hereditary cancers, along with breast, ovarian, pancreatic, and colorectal cancers, and guidelines for these cancers have all transitioned to either recommendation or consideration of universal testing; prostate cancer should not be the exception.

Thus, we recommend that all patients with prostate cancer should be offered comprehensive, multigene panel GGT for assessment of PGVs in genes that are associated with hereditary cancer and have implications for evaluation and management.

Written by: Neal Shore,1 Sarah M Nielsen,2 Edward D Esplin,2 Emmanuel S Antonarakis,3 Pedro C Barata,4 Tomasz M Beer,5,6 Himisha Beltran,7 Alan Bryce,8 Michael S Cookson,9 E David Crawford,10 Tanya B Dorff,8 Daniel J George,11 Elisabeth I Heath,12 Brian T Helfand,13 Maha Hussain,14 Rana R Mckay,10 Alicia K Morgans,7 Michael J Morris,15 Channing J Paller,16 Ashley E Ross,14 Oliver Sartor,17 John Shen,18 Paul Sieber,19 Matthew R Smith,20 David R Wise,21 Andrew J Armstrong11

  1. Carolina Urologic Research Center, Myrtle Beach, SC.
  2. Labcorp Genetics Inc (formerly Invitae Corp), San Francisco, CA.
  3. University of Minnesota, Masonic Cancer Center, Minneapolis, MN.
  4. Case Western Reserve University, Cleveland, OH.
  5. The Knight Cancer Institute, Oregon Health & Science University, Portland, OR.
  6. Exact Sciences Corporation, Madison, WI.
  7. Dana Faber Cancer Institute, Boston, MA.
  8. City of Hope Cancer Center, Goodyear, AZ.
  9. Stephenson Cancer Center, OU Health, The University of Oklahoma, Oklahoma City, OK.
  10. University California, San Diego, La Jolla, CA.
  11. Duke Cancer Institute, Duke University, Durham, NC.
  12. Karmanos Cancer Institute, Detroit, MI.
  13. NorthShore University HealthSystem/Endeavor Health, Evanston, IL.
  14. Northwestern Feinberg School of Medicine, Chicago, IL.
  15. Memorial Sloan Kettering Cancer Center, New York, NY.
  16. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD.
  17. Mayo Clinic, Rochester, MN.
  18. UCLA David Geffen School of Medicine, Los Angeles, CA.
  19. Keystone Urology Specialists, Lancaster, PA.
  20. Massachusetts General Hospital, Boston, MA.
  21. Perlmutter Cancer Center, NYU Langone Health, New York, NY.
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