Rationale for Requested Change: Indications for and implications of germline genetic testing (GGT) in patients with prostate cancer (PCa) have expanded over the past decade, particularly related to precision therapies and management. Germline genetic testing (GGT) has become the standard of care for many cancers such as breast, ovarian, colorectal, pancreatic, and metastatic PCa, and it is imperative that patients be offered timely and equitable access to testing as it can inform patient-physician shared decision making for management of the current cancer as well as anticipatory guidance for disease progression. Testing can enhance shared decision making by informing diagnosis, prognosis, risk stratification and therapeutic treatment selection for active PCa as well as follow-up cancer screening and long-term cancer risk management for unaffected individuals or those in remission. Additionally, GGT guides screening for and prevention of secondary malignancies for the patient and cascade testing for at-risk family members. Therefore, clinicians should offer all patients with PCa the opportunity to undergo comprehensive GGT for pathogenic germline variants known to be associated with familial cancer and/or known to have implications for treatment and management.
Based on recently published data from the PROstate Cancer registry in Large patient population AIMed to assess efficacy in germline testing (PROCLAIM) trial, there was no significant difference in the prevalence of pathogenic germline variants (PGVs) among patients who met National Comprehensive Cancer Network (NCCN) GGT criteria versus those who did not (8.8% vs. 6.6%, odds ratio 1.38, 95% CI 0.85-2.23).1 NCCN criteria missed nearly half of all patients with PGVs. Therefore, consistent with this and other published evidence and calls for expanded GGT in prostate and other cancer types, it is appropriate that comprehensive GGT should be offered to all patients with PCa, as it enables personalized management, including access to approved therapeutics, eligibility for clinical trials, screening for prevention of second primary cancers and testing of family members for risk of prostate and other cancers.2 Furthermore, the PROCLAIM trial demonstrated that GGT can be effectively implemented into routine practice among community urology practices, where the vast majority of cancer care for patients with PCa occurs.1
This proposed guideline change would help to reconcile and reduce current variations in practice patterns related to the complexity of current GGT criteria, by reducing the GGT indication for patients to a single criterion, namely the diagnosis of prostate cancer. Currently, there are multiple, and sometimes conflicting, guidelines for PCa GGT published by various professional societies and consensus committees.3–5 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 patients6, and only 13% in those with metastatic castration-resistant disease.7 We hypothesize that the uptake of GGT will increase with a universal testing recommendation as the clinician barrier of identifying which patients qualify for testing will be removed. Accordingly, we hypothesize that access to approved therapeutics and enrollment in clinical trials will also increase.
The benefit to patients of expanding GGT eligibility criteria is that it increases access to genetics-informed care for all patients, particularly those from historically underrepresented and underserved populations. This was highlighted by the PROCLAIM trial, which found that among non-White patients, the PGV prevalence was actually higher in patients not meeting NCCN criteria compared to those who met criteria1, suggesting that NCCN guidelines disproportionately disadvantage individuals from these underrepresented populations and perpetuate existing healthcare disparities. Allowing for broader GGT testing criteria may help to mitigate this disparity. Restrictive GGT guidelines that rely heavily on family history information are also a barrier for patients in whom this information may be incomplete or unavailable. Additionally, the histopathological features, namely Grade Group or intraductal/cribriform histology, that determine GGT eligibility are subject to interpretative differences amongst pathologists.8
The identification of PGVs has important implications for patients with PCa and their families, including prognosis, risk stratification for early-stage disease, treatment, screening for other non-prostate cancers and cascade testing for at-risk family members.9,10 Certain PGVs in PCa confer significant prognostic and predictive information. For example, PGVs in BRCA2, and possibly BRCA1, HOXB13 and ATM, are associated with more aggressive tumors, higher likelihood of progression to metastasis, and have poorer outcomes,11–13 as well as higher risk of grade reclassification during active surveillance.14,15 Accordingly, identification of a PGV in one of these genes, or potentially other DDR genes pending further research, is relevant for the management of localized, low or intermediate risk PCa, as it can inform discussions or strategies for active surveillance, including closer clinical follow-up, consideration of additional surveillance such as MRI, or earlier definitive treatment approach.9,10,14
A recommendation of universal testing for PCa will emphasize the importance of GGT throughout the PC disease continuum, especially as DDR status is expected to be increasingly incorporated into future treatment guidelines as data matures. While FDA-approved therapeutics and clinical trials often include germline or somatic pathogenic variant status in their eligibility, it is notable that somatic testing alone is insufficient in the assessment of an individual with cancer, because it will negate the benefits of GGT, such as, tailored screening, early cancer detection, and risk assessment of the proband, and at-risk relatives.16 Therefore, to derive the most benefit for patients and their family members, germline and somatic testing can be used in a complementary fashion. Indeed, somatic testing alone will miss up to 8% of PGVs 17 and GGT alone could miss up to 50% of actionable somatic alterations.18 Furthermore, GGT may be a more accessible and cost-effective pathway to actionable genetic information compared to tumor profiling due to ease of sample collection and lower cost of testing.
While the hypothetical impacts to cancer care or prevention are compelling, recent research has measured the real-world clinical utility of universal PCa GGT in clinical practice. Clinician-reported recommendations and outcomes have been reported from the PROCLAIM trial. Evaluable clinician responses were available for 982 patients from PROCLAIM trial, which showed that patients with pathogenic variants, including those who did not meet testing criteria, were significantly more likely to receive recommendations regarding treatment changes (18% vs 1.4%, p<0.001), follow-up changes (64% vs. 11.2%, p<0.001), and cascade testing (71% vs 5.4%, p<0.001) than those with non-pathogenic results.19,20 Additionally, clinicians noted that GGT was beneficial for two-thirds of PGV-positive patients, one-third of patients with variant of uncertain significance (VUS) results and one-quarter of patients with negative results. This study demonstrates that GGT influenced clinician recommendations for patients with PCa, with altered treatment and follow-up strategies recommended for those with pathogenic variants, including those who did not meet criteria for testing.19,20 Additionally, negative results aid in shared decision-making by reassuring clinicians and patients and excluding patients from the highest risk groups (and the attendant intensive treatments).
Germline genetic testing is a powerful 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 for prostate cancer and other cancers. We believe that the body of evidence presented makes a strong case for consideration of comprehensive germline genetic testing for all patients diagnosed with prostate cancer. In particular, the PROCLAIM trial demonstrated that pathogenic germline variant prevalence is similar between patients meeting and not meeting NCCN criteria, it impacts shared decision making between physicians and patients, and it is able to be routinely implemented among community urology practices.1 Prostate cancer 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; prostate cancer should not be the exception.
We greatly appreciate the invaluable clinical resource the NCCN guidelines are for the management of patients with prostate cancer and thank you for considering our proposal in the context of the evidence reviewed.
Sincerely,
Neal Shore, MD, FACS
Medical Director, Carolina Urologic Research Center
Chief Medical Officer, Surgery/Urology, GenesisCare
Atlantic Urology Clinics
W. Michael Korn, MD
Chief Medical Officer, Invitae Corporation
Edward D. Esplin, MD, PhD
Clinical Geneticist, Invitae Corporation
Sarah Young, CGC
Oncology Clinical Program Manager, Invitae Corporation
Emmanuel S. Antonarakis, MD
Clark Endowed Professor of Medicine
Director of GU Oncology, Associate Director of Translation
Division of Hematology, Oncology and Transplantation
University of Minnesota, Masonic Cancer Center
Andrew J. Armstrong, MD ScM FACP
Professor of Medicine, Surgery, Pharmacology and Cancer Biology
Director of Research, the Duke Cancer Institute Center for Prostate and Urologic Cancers
Divisions of Medical Oncology and Urology, Duke University
Pedro C. Barata, MD, MSc
Co-Leader Genitourinary (GU) Disease Team
Director of GU Medical Oncology Research Program
University Hospitals Seidman Cancer Center
Associate Professor of Medicine, Case Western Reserve University
Case Comprehensive Cancer Center
Tomasz M. Beer, MD, FACP
Adjunct Professor of Medicine, Oregon Health & Science University Knight Cancer Institute
Chief Medical Officer for Multi-cancer Early Detection, Exact Sciences Corporation
Elisabeth I. Heath, MD FACP
Associate Center Director, Translational Sciences
Chair, Genitourinary Oncology Multidisciplinary Team
Professor of Oncology and Medicine
Hartmann Endowed Chair for Prostate Cancer Research
Director, Prostate Cancer Research
Karmanos Cancer Institute
Brian Helfand, MD
Chief, Division of Urology, NorthShore University HealthSystem
Clinical Professor, University of Chicago
Maha Hussain, MD, FACP, FASCO
Genevieve Teuton Professor of Medicine
Division of Hem/Onc
Deputy Director, Robert H. Lurie Comprehensive Cancer Center
Northwestern University Feinberg School of Medicine
Rana Mckay, MD
Associate Professor of Medicine, University of California San Diego
Alicia K. Morgans, MD, MPH
Associate Professor of Medicine, Harvard Medical School
Medical Director, Survivorship Program
Dana-Farber Cancer Institute
Ashley E Ross, MD, PhD
Associate Professor, Urology
Northwestern Feinberg School of Medicine
Matthew R. Smith, MD, PhD
Director, Genitourinary Malignancies Program
Massachusetts General Hospital Cancer Center
David Wise, MD, PhD
Director – Genitourinary Medical Oncology Program
NYU Langone’s Laura and Isaac Perlmutter Cancer Center
