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Efficacy of National Comprehensive Cancer Network Guidelines in Identifying Pathogenic Germline Variants Among Unselected Patients with Prostate Cancer: The PROCLAIM Trial - Beyond the Abstract

The concept for this study came from previous work showing that germline genetic testing (GGT) guidelines are missing patients with prostate and other cancers that harbor potentially actionable pathogenic germline variants (PGVs).1–3 Hence the hypothesis that a “universal” approach to GGT may be the most effective way to identify patients who can benefit from genetics-informed, personalized management of their disease, including approved therapeutics, clinical trial enrollment, screening for prevention of second primary cancers, and cascade testing of at-risk family members.4,5

However, most of the previous studies of GGT in “unselected” populations of patients with prostate cancer (PCa) were retrospective cohorts of convenience from single laboratories or cancer risk clinics, and have not been sufficient to change testing guidelines.2,6–8 The PROCLAIM trial aimed to demonstrate the impact of universal GGT in an unselected population of PCa patients from primarily community (urology) practices, where the vast majority of cancer care takes place.

PROCLAIM was modeled after Beitsch et al.’s study in patients with breast cancer, showing that the yield of PGVs in patients who met National Comprehensive Cancer Network (NCCN) was not statistically different from the yield in patients who did not meet NCCN criteria.1 Ultimately, these findings led to the American Society of Breast Surgeons (ASBrS) amending their guidelines to recommend GGT for all breast cancer patients.9 The broadening of GGT criteria is particularly relevant for PCa, where there are multiple, and sometimes conflicting, guidelines for GGT put forth by various professional societies and consensus committees.10–12 The complexity of the current criteria may impede the routine implementation of GGT. Accordingly, the uptake of GGT for PCa has been documented to be as low as 1% across all PCa patients,13 and only 13% in those with metastatic castration-resistant disease.14 Cited barriers to implementation of GGT among genitourinary healthcare providers include lack of familiarity with genetics, lack of efficient clinical workflows, limited/delayed access to genetic specialists, clinical time allotment, processing constraints, insurance concerns, and medicolegal concerns.15,16

The PROCLAIM trial was designed to test the hypothesis that the frequency of potentially actionable PGVs is similar between PCa patients meeting NCCN criteria for GGT and those not meeting criteria. In just under two years, in the middle of the COVID-19 pandemic, the 15 participating sites enrolled a total of 958 patients with evaluable outcomes. By design, ~50% of enrolled patients met 2019 NCCN PCa GGT guidelines (“in criteria”) and ~50% did not meet guidelines (“out of criteria”). Notably, 22% of enrolled patients reported non-White, primarily Black/African-American, race/ethnicity. Additionally, the majority of patients had localized, low- or intermediate-risk disease, the most common PCa disease state, and an understudied population from the GGT perspective. As predicted, the prevalence of PGVs between in-criteria and out-of-criteria patients was not statistically different (8.8% vs. 6.6%, respectively), and nearly 50% of patients with PGVs would have been missed by guidelines-restricted testing.

One of the most striking findings from this study was the difference in PGV prevalence between White and non-White patients. PGVs were significantly more frequent in White compared to non-White patients, both overall (9.0 vs. 2.9%, respectively) and in patients meeting testing criteria (11.0% vs. 1.8%, respectively).


Figure 1. NCCN Criteria Status and Race or Ethnicity of PGV-positive Patients

The percent of patients with at least one PGV, where patients are stratified by clinician-reported race/ethnicity. Non-White patients were patients with clinician-reported races/ethnicities of Asian, Black/African American, Hispanic, or Pacific Islander and excluded patients of other, multiple, or unknown race/ethnicity.

Unfortunately, these findings are not unexpected given the over-representation of White participants in genetic studies that inform genetic testing criteria and variant interpretation databases, resulting in higher rates of uncertain findings and lower rates of definitive molecular diagnoses in individuals from historically underrepresented populations compared to their White counterparts.17,18 However, an enlightening finding was that among non-White patients, the PGV prevalence was actually higher among out of criteria patients (4.0%) compared to in criteria patients (1.8%), suggesting that guidelines may be unintentionally creating barriers to genetics-informed care in underrepresented and underserved populations.

We believe that the PROCLAIM trial presents strong evidence to consider comprehensive GGT for all patients diagnosed with PCa. Aside from the PGV data, it also demonstrated that GGT is able to be routinely implemented among community urology practices. PCa is one of the most common hereditary cancers, along with breast, ovarian, pancreatic, and colorectal cancer, and guidelines for the aforementioned cancers have all transitioned to either recommendation or consideration of universal testing;9,19,20 PCa should not be an exception. The identification of PGVs in PCa has important implications for prognosis, risk stratification for early-stage disease, treatment, screening for other non-prostate cancers, and cascade testing for family members at risk for PCa and other cancers. In particular, PGV status can indicate eligibility for targeted therapies, namely PARP inhibitors, which are now FDA-approved for both first and second-line therapy for metastatic castrate-resistant PCa,21–25, and may move into the hormone-sensitive setting pending ongoing clinical trials.26–28

Ultimately, successful implementation of GGT into routine care will take collaboration among healthcare providers, patients, testing laboratories, and guidelines committees. Advances in physician education and technology-driven novel genetics service delivery models will also be essential in order to scale GGT and ensure that all patients and families are receiving maximal benefit.29


Written by: Neal Shore,1 Mukaram Gazi,2 Christopher Pieczonka,3 Sean Heron,4 Rishi Modh,4 David Cahn,5 Laurence H Belkoff,6 Aaron Berger,7 Brian Mazzarella,8 Joseph Veys,9 Charles Idom,9 David Morris,10 Gautam Jayram,10 Alexander Engelman,11 Raviender Bukkapatnam,12 Paul Dato,13 Richard Bevan-Thomas,14 Robert Cornell,15 David R Wise,16 Mary Kay Hardwick,17 Ryan D Hernandez,18 Susan Rojahn,17 Paige Layman,17 Kathryn E Hatchell,17 Brandie Heald,17 Robert L Nussbaum,19 Sarah M Nielsen,17 Edward D Esplin17

  1. Carolina Urologic Research Center, Myrtle Beach, SC, USA. 
  2. University Urology Associates of New Jersey, Hamilton, NJ, USA.
  3. Associated Medical Professionals, Syracuse, NY, USA.
  4. Advanced Urology Institute, St. Petersburg, FL, USA.
  5. Colorado Urology, Lakewood, CO, USA.
  6. MidLantic Urology, Bala Cynwyd, PA, USA.
  7. Associated Urological Specialists, Chicago Ridge, IL, USA.
  8. Urology Austin, Austin, TX, USA.
  9. North Georgia Urology, Dalton, GA, USA.
  10. Urology Associates, P.C., Nashville, TN, USA.
  11. TGH Cancer Institute, Tampa, FL, USA.
  12. Florida Urology Partners, Tampa, FL, USA.
  13. Genesis Healthcare Partners, San Diego, CA, USA.
  14. Urology Partners, Arlington, TX, USA.
  15. Urosurgery Houston, Houston, TX, USA.
  16. Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
  17. Invitae Corporation, San Francisco, CA, USA.
  18. Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
  19. Invitae Corporation, San Francisco, CA, USA; Volunteer Faculty, University of California San Francisco, San Francisco, CA, USA.

References:

  1. Beitsch, P. D. et al. Underdiagnosis of Hereditary Breast Cancer: Are Genetic Testing Guidelines a Tool or an Obstacle? J. Clin. Oncol. 37, 453–460 (2019).
  2. Nicolosi, P. et al. Prevalence of Germline Variants in Prostate Cancer and Implications for Current Genetic Testing Guidelines. JAMA Oncol 5, 523–528 (2019).
  3. Esplin, E. D. et al. Universal Germline Genetic Testing for Hereditary Cancer Syndromes in Patients With Solid Tumor Cancer. JCO Precis Oncol 6, e2100516 (2022).
  4. Samadder, N. J. et al. Comparison of Universal Genetic Testing vs Guideline-Directed Targeted Testing for Patients With Hereditary Cancer Syndrome. JAMA Oncol (2020)
  5. Subbiah, V. & Kurzrock, R. Universal Germline and Tumor Genomic Testing Needed to Win the War Against Cancer: Genomics Is the Diagnosis. J. Clin. Oncol. JCO2202833 (2023).
  6. Giri, V. N. et al. Germline genetic testing for inherited prostate cancer in practice: Implications for genetic testing, precision therapy, and cascade testing. The Prostate 79, 333–339 (2019).
  7. Pritzlaff, M. et al. Diagnosing hereditary cancer predisposition in men with prostate cancer. Genet. Med. 22, 1517–1523 (2020).
  8. Greenberg, S. E. et al. Clinical Germline Testing Results of Men With Prostate Cancer: Patient-Level Factors and Implications of NCCN Guideline Expansion. JCO Precis Oncol 5, (2021).
  9. Manahan, E. R. et al. Consensus Guidelines on Genetic Testing for Hereditary Breast Cancer from the American Society of Breast Surgeons. Ann. Surg. Oncol. 26, 3025–3031 (2019).
  10. Schaeffer, E. M. et al. NCCN Guidelines® Insights: Prostate Cancer, Version 1.2023: Featured Updates to the NCCN Guidelines. J. Natl. Compr. Canc. Netw. 20, 1288–1298 (2022).
  11. Giri, V. N. et al. Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019. J. Clin. Oncol. 38, JCO2000046 (2020).
  12. Eastham, J. A. et al. Clinically Localized Prostate Cancer: AUA/ASTRO Guideline, Part I: Introduction, Risk Assessment, Staging, and Risk-Based Management. J. Urol. 208, 10–18 (2022).
  13. Kurian, A. W. et al. Germline Genetic Testing After Cancer Diagnosis. JAMA (2023) doi:10.1001/jama.2023.9526.
  14. Shore, N. et al. Real-world genetic testing patterns in metastatic castration-resistant prostate cancer. Future Oncol. 17, 2907–2921 (2021).
  15. Concepcion, R. S. Germline testing for prostate cancer: community urology perspective. Can. J. Urol. 26, 50–51 (2019).
  16. Paller, C. J. et al. Germline Genetic Testing in Advanced Prostate Cancer; Practices and Barriers: Survey Results from the Germline Genetics Working Group of the Prostate Cancer Clinical Trials Consortium. Clinical Genitourinary Cancer vol. 17 275–282.e1 (2019).
  17. Bree, K. K., Henley, P. J. & Pettaway, C. A. Germline Predisposition to Prostate Cancer in Diverse Populations. Urol. Clin. North Am. 48, 411–423 (2021).
  18. Wyatt, R. et al. Disparities in germline genetic testing results from a cohort of 493,515 black and white patients. J. Clin. Oncol. 41, 10550–10550 (2023).
  19. Daly MB, Pal T, Arun B, et al. National Comprehensive Cancer Network. NCCN guidelines: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (version 3.2023).NCCN
  20. Gupta S, Weiss JM, Axell L, et al. National Comprehensive Cancer Network. NCCN guidelines: Genetic/Familial High-Risk Assessment: Colorectal (version 1.2023). (n.d.). NCCN
  21. de Bono, J. et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N. Engl. J. Med. 382, 2091–2102 (2020).
  22. Abida, W. et al. Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration. J. Clin. Oncol. 38, 3763–3772 (2020).
  23. Clarke, N. W. et al. Abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evid. 1, (2022).
  24. Agarwal, N. et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet (2023) doi:10.1016/S0140-6736(23)01055-3.
  25. Chi, K. N. et al. Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer. J. Clin. Oncol. 41, 3339–3351 (2023).
  26. Rathkopf, D. E. et al. AMPLITUDE: A study of niraparib in combination with abiraterone acetate plus prednisone (AAP) versus AAP for the treatment of patients with deleterious germline or somatic homologous recombination repair (HRR) gene-altered metastatic castration-sensitive prostate cancer (mCSPC). J. Clin. Oncol. 39, TPS176–TPS176 (2021).
  27. Agarwal, N. et al. TALAPRO-3: A phase 3, double-blind, randomized study of enzalutamide (ENZA) plus talazoparib (TALA) vs placebo plus ENZA in patients with DDR gene-mutated, metastatic castration-sensitive prostate cancer (mCSPC). J. Clin. Oncol. 41, TPS279–TPS279 (2023).
  28. Markowski, M. C. et al. TRIUMPH: Phase II trial of rucaparib monotherapy in patients with metastatic hormone-sensitive prostate cancer harboring germline DNA repair gene mutations. J. Clin. Oncol. 41, 190–190 (2023).
  29. Shore, N., Wise, D. & Young, S. N. Understanding the Underutilization of Germline Genetic Testing in Prostate Cancer. ASCO Daily News (2023).
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