Nussbaum, Robert L.

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 Hereditary factors play a role in the development of several cancers. Identification of germline predisposition can have implications for treatment and cancer prevention. While previous studies have found that universal multigene panel testing in patients with cancer yields increased detection of actionable heritable variants compared to targeted testing, patients belonging to racial and ethnic minority groups have been underrepresented in these studies. We undertook a prospective multi-site study of germline alternations among solid tumor cancer patients from under-represented minority (URM) populations receiving care at Mayo Clinic Comprehensive Cancer Centers between January 2020 and November 2022. Patients with a new or active cancer diagnosis (all stages) not selected for family history of cancer were tested with a >80-gene next generation sequencing panel. Of 532 patients (mean [SD] age, 57.2 [12.7] years; 320 (60.2%) female), 247 (46.4%) were Hispanic/Latino, 130 (24.4%) Black/African American, 80 (15.0%) Asian, 66 (12.4%) American Indian/Alaskan Native, 2 (0.4%) Native Hawaiian/Pacific Islander, and 7 (1.3%) other. PGV were found in 43 patients (8.1%), including 29 moderate- or high- penetrance cancer susceptibility genes. Variants of uncertain significance (VUS) were found in 272 patients (51.1%). Of those with a PGV, 29 (67.4%) had incremental clinically actionable findings that would not have been detected by established testing criteria, of which 16 were moderate- or high-penetrance variants. Younger age of diagnosis, gender, race, ethnicity, and stage of disease were not predictive of PGV. In this study of under-represented minority cancer patients, universal genetic testing found that 1 in 12 patients harbor a PGV, more than two-thirds of whom would remain undetected using current guidelines. The paucity of genomic data in URM populations also results in a large proportion of VUS which may lead to under-estimation of disease associated variants. Table 1. Clinical and Demographic Characteristics of Included Patients Positive Negative VUS Total N (%) 43 217 272 532 (8.1%) (40.8%) (51.1%) Age - mean (SD) 53.7 57.0 57.8 57.2 (12.7) (12.6) (12.8) (12.7) Gender - Female 26 132 162 320 (60.5%) (60.8%) (59.6%) (60.2%) Race/Ethnicity Hispanic/Latino 24 110 113 247 (55.8%) (50.7%) (41.5%) (46.4%) Black/African 5 56 69 130 American (11.6%) (25.8%) (25.4%) (24.4%) Asian 10 (23.3%) 23 (10.6%) 47 (17.3%) 80 (15.0%) American Indian/Alaskan Native 4 (9.3%) 26 (12.0%) 36 (13.2%) 66 (12.4%) Native Hawaiian/Pacific Islander 0 (0.0%) 0 (0.0%) 2 (0.7%) 2 (0.4%) Other 0 (0.0%) 2 (0.9%) 5 (1.8%) 7 (1.3%) Tumor Types Breast 19 (44.2%) 80 (36.9%) 110 (40.4%) 209 (39.3%) CNS 1 (2.3%) 2 (0.9%) 1 (0.4%) 4 (0.8%) GI 7 (16.3%) 46 (21.2%) 58 (21.3%) 111 (20.9%) GU 8 (18.6%) 57 (26.3%) 62 (22.8%) 127 (23.9%) GYN 0 (0.0%) 8 (3.7%) 10 (3.7%) 18 (3.4%) Head/Neck 5 (11.6%) 8 (3.7%) 6 (2.2%) 19 (3.6%) Lung 0 (0.0%) 6 (2.8%) 11 (4.0%) 17 (3.2%) Melanoma 0 (0.0%) 2 (0.9%) 1 (0.4%) 3 (0.6%) Sarcoma 2 (4.7%) 4 (1.8%) 4 (1.5%) 10 (1.9%) Other 1 (2.3%) 4 (1.8%) 9 (3.3%) 14 (2.6%) Citation Format: Kevork A. Khadarian, Sailaja Pisipati, Jeremy C. Jones, Gerardo Colon-Otero, Donald W. Northfelt, Lindsey Gary, Idara U. Ekpoh, Giovanna G. Moreno, Edward D. Esplin, Robert Nussbaum, Brandie Heald, Margaret A. Klint, Kathleen A. Barrus, Tanios S. Bekaii-Saab, Aleksandar Sekulic, Michael A. Golafshar, Katie L. Kunze, Cheryl L. Willman, Konstantinos N. Lazaridis, Niloy Jewel Samadder. Universal genetic testing for hereditary cancer syndromes in an under-represented minority population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1921.

10588 Background: Detection of pathogenic germline variants (PGVs) has implications for cancer screening, prognostication, treatment selection, clinical trial enrollment and family testing. Published guidelines provide indications for PGV testing, determined by clinical and demographic factors, but these leave a significant number of cases missed by guideline-directed testing (incremental PGV). We have previously shown that 50% of patients with PVGs would not have been detected with guideline-based testing alone. In this project, we aimed to determine the feasibility and generalizability of this approach within a more racially/ethnically diverse cohort from a community cancer practice. Methods: We completed a prospective study of proactive germline genetic sequencing among patients with solid tumor malignancies at a community-based oncology practice in downtown Jacksonville, FL between June 2020, and September 2021. The patients were unselected for cancer type, stage, family history, race/ethnicity, and age. PGVs identified using an 84-gene NGS platform were stratified by penetrance. National Comprehensive Cancer Networks (NCCN) guidelines were used to determine incremental PGV rates. Results: 221 patients were enrolled, median age 63.0 years, 21.7% male. 56.6% of patients were white (non-Hispanic), 32.6% were black/African American, 5.4% were Hispanic. 39.8% of patients were commercially insured, 52.4% insured by Medicare/Medicaid and 2.7% uninsured. The cohort was comprised predominantly of breast cancer (61.5%), lung cancer (10.4%) and colon cancer (7.2%) patients. A total of 27 PGVs were identified in 23 patients. We found no significant difference in the rate of PGVs based on race/ethnicity. The overall rate of variants of uncertain significance (VUS) was numerically higher in black/African American patients (61.1%) compared with other ancestry (45%). 13 of 23 (56.5%) patients with detected PGVs did not meet NCCN guidelines for germline genetic screening (incremental PGVs). Conclusions: This prospective study found that universal multi-gene panel testing among patients from a racially/ethnically diverse cohort from a community cancer practice was associated with an increased detection of heritable variants with treatment implications over the predicted yield of targeted testing based on guidelines. This study is the first to evaluate this approach in an exclusively community-based practice. Clinical trial information: NCT04456140.

INTRODUCTION: To report the prevalence and outcomes of unselected pancreatic cancer (PC) patients with pathogenic/likely pathogenic germline variants (PGVs) detected using a universal testing approach. METHODS: We undertook a prospective, multisite study of germline sequencing using a >80 gene next-generation sequencing platform among 250 patients with PC (not selected for age or family history of cancer) between April 1, 2018, and March 31, 2020. Demographic, tumor characteristics, and clinical outcomes were compared between PGV carriers and noncarriers. RESULTS: Of 250 patients, the mean age was 65 years (SD 8.7), 56% was male, 83.6% was White, and 65.6% had advanced disease (stages III and IV). PGVs were found in 15.2% (N = 38) of patients, and 2 patients had more than 1 PGV. Variants of uncertain significance were found in 44.4% (N = 111). Family history of cancer (odds ratio: 2.36, 95% confidence interval: 1.14–5.19, P = 0.025) was associated with a higher risk of PGV. In a median follow-up of 16.5 months, the median overall survival was 16.8 months in PGV carriers compared with 16.5 months in noncarriers (hazard ratio: 0.51, 95% confidence interval: 0.25–1.01, P = 0.05). Higher levels of carbohydrate antigen 19-9 and advanced disease stages (III and IV) were associated with worse outcomes in both groups. Overall, 68% of PGV carriers had mutations in homologous recombination repair genes, including BRCA1 , BRCA2 , PALB2 , ATM , CHEK2 , NBN , and RAD51C . DISCUSSION: Universal multigene panel testing in PC reveals that 1 in 6 patients are carriers of PGV. Multigene germline testing should be used to aid in treatment selection, prognostication, and familial cancer counseling.

4118 Background: Germline variations in cancer susceptibility genes have important implications on treatment and family counseling in pancreatic cancer (PC). We report the prevalence and clinical outcomes of unselected PC patients with pathogenic germline variants (PGV) detected using a universal testing approach. Methods: We undertook a prospective multi-site study of germline sequencing using an >80 gene next-generation sequencing platform among 250 PC patients (not selected for age or family cancer history) between April 1, 2018 and March 31, 2020. Demographic, tumor characteristics and clinical outcomes were compared between PGV carriers and non-carriers. Results: Of 250 patients, the mean age was 65 years (SD 8.7), 56% were male, 83.6% were white and 65.6% had advanced disease (Stage III and IV). PGV were found in 15.2% (N=38) of patients, two patients had more than one PGV. Variants of uncertain significance were found in 44.4% (N=111). Family history of cancer (OR 2.36, 95% CI: 1.14-5.19, p=0.025) was associated with a higher risk of PGV. In a median follow up of 16.5 months, median overall survival was 16.8 months in PGV carriers compared with 16.5 months in non-carriers (HR 0.51, 95 %CI, 0.25-1.01, p=0.05). Higher levels of CA 19-9 and advanced stages (III and IV) were associated with worse outcomes in both groups. Overall, 68% of PGV carriers had mutations in homologous recombination repair (HRR) genes, including BRCA1, BRCA2, PALB2, ATM, CHEK2, NBN, RAD51C. In 65% of HRR gene carrier’s systemic therapy with platinum was used. Conclusions: Universal multi-gene panel testing in pancreatic cancer reveals that 1 in 6 patients are carriers of PGV and is associated with improved survival. Multi-gene germline testing should be used to aid in treatment selection, prognostication, and familial cancer counseling. Distribution of the 40 PGV by penetrance status.[Table: see text]

Abstract Background: Hereditary factors play a key role in the risk of developing breast cancers. Identification of a germline predisposition can have important implications for treatment decisions, risk-reducing interventions, cancer screening, and testing for family members. Aim: To determine the prevalence of pathogenic or likely pathogenic germline mutations (P/LP) using a “universal” testing approach and uptake of no-cost cascade family testing in patients with breast cancer. Methods: We undertook a prospective multi-site study of germline genetic alterations among breast cancer patients receiving care at Mayo Clinic cancer centers in Rochester, MN; Eau Claire, WI; Jacksonville, FL and Phoenix, AZ between April 1, 2018 and March 31, 2020. Patients with a new or active breast cancer diagnosis (all stages) irrespective of cancer family history were tested with a >80-gene next generation sequencing panel.Results: Of 390 patients, the median age was 58 years (SD 12.3), 1% were male, 85% were white and 28% had advanced (stage 3-4) disease. P/LP were found in 12.1% (n=47) of patients, including 29 in moderate and high penetrance cancer susceptibility genes. 13 (3.3%) patients had mutations in BRCA1 or 2, while 33 (8.4%) had mutations in BRCAness (ATM, BAP1, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK2, NBN, PALB2, RAD50, RAD51C, RAD51D, WRN) associated genes. Of the P/LP findings the most frequent aberrations were in BRCA2 (13.5%), BRCA1 (11.5%), CHEK2 (11.5%), MUTYH (11.5%), and WRN (9.6%). Variants of uncertain significance were found in 209 (53.6%) including 26 (6.6%) with concurrent P/LP and VUS. 37 (9.4%) patients had mutations associated with published management recommendations, precision therapies and/or clinical trial eligibility. 10 (2.6%) patients had P/LP that would not have met current screening guidelines, including 4 with moderate or high penetrance mutations. Patients with younger age of diagnosis were less likely than patients with older age of diagnosis to have a P/LP mutation (OR= 0.47, 95%CI: 0.25-0.90 p = 0.020). Only 10 (21%) patients with P/LP had family members undergo familial site- specific testing at no cost.Conclusions: In this prospective multi-center study of unselected breast cancer patients, universal multi-gene panel testing found that 1 in 8 patients harbor P/LP germline variants. Current guidelines were able to identify the majority of patients with P/LP mutations. Familial site specific testing is greatly under-utilized even when cost is not a barrier. Multigene panels impact cancer patient care by identifying precision medicine treatment interventions, and guiding long-term medical management and preventive surveillance. Citation Format: Brenda Ernst, Natalie Ertz-Archambault, Deborah J Rhodes, Donald W Northfelt, Myra Wick, Douglas L Riegert-Johnson, Scott Okuno, Katie Kunze, Michael Golafshar, Cindy M Azevedo, PLS Uson Junior, ED Esplin, Robert Nussbaum, Margaret Klint, Sarah Mantia, Megan Hager, Keith Stewart, Niloy Jewel Samadder. Universal genetic testing in breast cancer patients: A multi-center prospective study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-05.

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is a rare autosomal recessive disorder of β-oxidation caused by pathogenic variants in the ACADS gene. Analyte testing for SCADD in blood and urine, including newborn screening (NBS) using tandem mass spectrometry (MS/MS) on dried blood spots (DBSs), is complicated by the presence of two relatively common ACADS variants (c.625G>A and c.511C>T). Individuals homozygous for these variants or compound heterozygous do not have clinical disease but do have reduced short-chain acyl-CoA dehydrogenase (SCAD) activity, resulting in elevated blood and urine metabolites. As part of a larger study of the potential role of exome sequencing in NBS in California, we reviewed ACADS sequence and MS/MS data from DBSs from a cohort of 74 patients identified to have SCADD. Of this cohort, approximately 60% had one or more of the common variants and did not have the two rare variants, and thus would need no further testing. Retrospective analysis of ethylmalonic acid, glutaric acid, 2-hydroxyglutaric acid, 3-hydroxyglutaric acid, and methylsuccinic acid demonstrated that second-tier testing applied before the release of the newborn screening result could reduce referrals by over 50% and improve the positive predictive value for SCADD to above 75%.