Young, Sarah

ObjectiveThis study describes the prevalence of pathogenic germline variants (PGVs) in head and neck cancer patients, the incremental yield compared to a guideline‐based approach to genetic evaluation, and the uptake of family variant testing.Study DesignProspective cohort study.SettingThree tertiary academic medical centers.MethodsGermline sequencing using an 84‐gene screening platform among unselected head and neck cancer patients who received care at Mayo Clinic Cancer Centers between April 2018 and March 2020.ResultsAmongst 200 patients, the median age was 62.0 years (Q1, Q3: 55, 71), 23.0% were female, 89.0% white/non‐Hispanic, 5.0% Hispanic/Latinx, 6% of another race, and 42.0% had prognostic stage IV disease. The most common subsites were the oropharyngeal (45.0%) and salivary glands (12.0%). The most common histology was squamous cell carcinoma (74.5%). Twenty‐one patients (10.5%) had a total of 22 PGVs; 20 of the 21 patients (95.2%) did not meet criteria for testing by current guidelines. Regarding penetrance of the 22 PGVs, 11 were high or moderate (most commonPMS2orHOXB13), and 11 were low or recessive (most commonMUTYH,WNR, orRECQL4). One patient had a change in care based on an identified PGV. Family variant testing was completed at a rate of 4.8%.ConclusionsUniversal gene panel testing identified a PGV in 10.5% of head and neck cancer patients; almost all would have been missed by current guideline‐based testing. One of 21 patients had a treatment change due to their PGV, indicating that head and neck cancer treatment decisions are not yet widely informed by germline alterations.Level of Evidence3Laryngoscope, 133:3378–3388, 2023

Abstract Sarcomas are rare heterogenous mesenchymal tumors with over 75 different subtypes, with varying biology and outcomes, with no clear inciting factor in the vast majority. The germline genetic susceptibility to sarcoma is not very well characterized. Identification of any underlying germline predisposition can have important implications for treatment of patients and screening recommendations for family members. To determine the prevalence of pathogenic germline variants (PGV) in patients with sarcomas, we undertook the Interrogating Cancer Etiology Using Proactive Genetic Testing (INTERCEPT) study, a prospective multi-site study of germline sequencing using a >80-gene next-generation sequencing platform. The study was done at the three Mayo Clinic Cancer Centers between April 1, 2018, and March 31, 2020. Patients were not selected based on stage, family cancer history, ethnicity, or age. Family cascade testing was offered at no charge. Results: 115 adult patients with soft tissue sarcoma were included in the study. The median age was 60 years, 58.5% were male, 81% were White. The anatomical location of the primary tumor included extremities (33.0%), retroperitoneum (18.2%), trunk (12.2%), head and neck (7.8%). Family history of cancer was present in 63% of the study population. Ten patients (8.7%) had a PGV. Thirty percent of the patients with PGV had stage IV sarcoma (3/10), and 70% (7/10) had earlier stage sarcoma (stages I-III). Among patients who were found to have a variant of uncertain significance (VUS), 40% (22/55) had stage IV sarcoma and 60% (33/55) had earlier stage disease. Of the 10 patients with PGV, high to medium penetrance gene abnormalities were identified in 8 patients (80%) involving TP53 (3), BRCA1 (1), SDHA (1), ATM (2) and heterozygous deletion of NBN (1) genes. Of these PGV, gene deletions were observed in 6/10 while missense variants comprised the remaining 4. The vast majority of the PGV (70%) would not have been identified using the current guidelines utilizing the 2018 or 2020 National Comprehensive Cancer Network (NCCN), National Society of Genetic Counselors (NSGC) or American College of Medical Genetics and Genomics. Conclusion: In this prospective, multi-site study comprising over 100 patients with diverse sarcomas, unselected germline testing identified a PGV in 1 in 11 patients (8.7%) with the majority of these not being detected using current standard of care guidelines for genetic testing. Because of the rarity of sarcomas, in addition to limited effective treatment options for advanced disease, large scale germline testing in sarcomas represents a potentially impactful strategy to assess therapeutic options and for assessment of familial risk. Citation Format: Isaak Ailts, Michael A. Golafshar, Katie L. Kunze, Margaret Klint, Kathleen Barrus, Samuel Nussbaum, Edward Esplin, Brandie Leach, Sarah Young, Niloy Jewel Samadder, Mahesh Seetharam. Germline cancer susceptibility gene testing in unselected patients with soft tissue sarcoma: a multi-center prospective study. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P056.