Uncovering germline genetic variants responsible for cancer predisposition allows providers to implement personalized medical care for patients. The NCCN Guidelines were designed to help identify individuals who qualify for genetic testing, yet multiple studies have shown that approximately half of patients with pathogenic or likely pathogenic variants are missed using these guidelines. While guidelines have continued to evolve as more robust data have become available, patients who do not meet these guidelines at the time of assessment may not be identified as having a cancer predisposition syndrome. This can have significant implications for personal risk and cancer management and the ability to capture unaffected relatives to potentially prevent cancer altogether. It is increasingly evident that we are approaching pathogenic variant carrier frequencies that argue for a more aggressive expansion of guidelines. This has been a catalyst for societies recommending germline genetic testing for all patients with history of certain cancer types. Aside from NCCN, one such society is the American Society of Breast Surgeons (ASBrS). Here, we evaluate how updated version guidelines, which expand patient eligibility, capture patients that were previously missed using the prior guidelines. Furthermore, we evaluate subjects with personal history of breast cancer who meet ASBrS criteria but do not meet NCCN criteria for genetic testing.
Patient data was obtained from the Informed Genetics Annotated Patient (iGAP) Registry, an IRB-approved, patient-consented, multi-center longitudinal, observational study designed to capture genetic and genomic test results and their utilization and impact on treatment practices and outcomes. One thousand four hundred thirty-nine subjects were assessed using the most up to date guidelines at the time of assessment (NCCN 2.2021 (1207), 2.2020 (127), and 2.2019 (96) Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (BOP) Guidelines) and underwent germline genetic testing. Of these 1439 subjects, 704 met criteria for genetic testing while 735 did not meet criteria. These subjects were then reassessed using the recently updated 1.2022 BOP guidelines. Five hundred twenty-eight subjects with personal history of breast cancer who did not meet NCCN BOP criteria at the time of assessment (2019-2022) were also evaluated. Descriptive statistics were used to assess and compare data of these populations.
Of the 704 subjects who met 2.2021 BOP criteria, the average age was 55.62 years. 81.53% had a personal diagnosis of any cancer, while 85.94% had a family history of cancer. Of the 735 subjects who did not meet criteria, the average age was 62.09 years. 84.90% had a personal diagnosis of any cancer, while 58.78% had a family history of cancer. These 1439 subjects were reassessed using the updated 1.2022 BOP guidelines. For most subjects, this reflects a period of 7 months and 20 days between guideline versions (December 22, 2020, to August 11, 2021). An additional 71 subjects were identified as meeting criteria for genetic testing, of which 19.71% had at least one pathogenic or likely pathogenic variant in the germline. Variants were identified in the following genes: ATM, BAP1, BRCA2, CHEK2, MSH3, MUTYH, NBN, PALB2 and 2 others. All genes have implications for medical management and/or reproduction. Of this cohort, 85.92% had a personal history of cancer and 91.55% had a family history of cancer. The average age was 64.54 years. Of the 528 subjects with personal history of breast cancer who did not meet NCCN BOP criteria at the time of assessment (2019-2022), 13.8% had a pathogenic/likely pathogenic test result. All these patients meet ASBrS criteria for genetic testing. These subjects did meet other guidelines, including United States Preventive Services Task Force (USPSTF) (20.8%), and NCCN Colorectal (3.41%).
This study demonstrates that expanded NCCN qualifying criteria allows for the identification of more patients with clinically actionable germline genetic variants. In this cohort alone, nearly 20% of subjects had a clinically actionable variant that would have been missed due to a failure to offer germline testing using the prior guideline version. For breast cancer subjects specifically, nearly 14% had a clinically significant variant that would have been missed using NCCN guidelines. Providers and payors who use these guidelines as gold standard to offer and cover germline testing, rather than other available guidelines or clinical intuition, miss an opportunity for personalized cancer risk management. This may affect both treatment and prevention strategies. As NCCN qualifies all patients with ovarian cancer, pancreatic cancer, and certain neuroendocrine/adrenal tumors, this study begs the question, how long will we wait before genetic testing is offered to all patients with cancer?
© 2022 Published by Elsevier Inc.