Leach, Brandie

376 Background: Germline genetic testing (GGT) is becoming increasingly important in the management of genitourinary (GU) malignancies as novel targeted drug therapies emerge. Selection for genetic studies and testing has historically been highly selective and based on pathologic characteristics, family history, and age of diagnosis. The aim of our study was to investigate the prevalence of pathogenic variants (PGVs) in inherited cancer susceptibility genes utilizing a universal testing approach and to characterize the rate of PGVs that would have been missed based on current NCCN guidelines. Methods: A multisite single-institutional prospective study (INTERCEPT) offered GGT to all patients with new or active diagnoses of GU malignancies (bladder, prostate, and renal cancers) from April 1, 2018 to March 31, 2020 at Mayo Clinic Arizona, Mayo Clinic Florida and Mayo Clinic Rochester. Participants were offered GGT with a panel of >80 genes through Invitae Corp. Demographic, tumor characteristics and genetic results were evaluated. PGVs were classified as high-, intermediate-, or low- penetrance variants based on published literature. Respective NCCN GU GGT guidelines were used to determine if the PGVs discovered using our universal testing approach would have been missed with guideline-directed GGT. Results: A total of 3095 pan-cancer patients were enrolled in the study; 601 of which had a GU malignancy including: prostate cancer (358 patients), renal cancer (137), and bladder cancer (106). The mean age of enrollment was 66.8 years (SD 9.1), 89% were male, and 85.9% of patients were Non-Hispanic white. PGVs were identified in 82 of all GU patients (13.6%) and variants of undetermined significance (VUS) in 289 (48.1%) patients. PGV prevalence breakdown by cancer type was: 13.7% of prostate, 13.1% renal, and 14.2% bladder cancer patients. The proportion of high penetrance PGVs varied by malignancy type. Of all patients, 326 (54.2%) had advanced (stage III/IV) disease and 377 (64.4%) of these were metastatic upon initial evaluation. The majority of all PGVs identified were incremental, defined as PGVs that would not have been identified based on guideline-concordant GGT: 100% (15/15 patients) with bladder, 77.8% (14/18) with renal, and 57.1% (28/49) with prostate cancer. Conclusions: Universal GGT for prostate, renal and bladder cancer revealed that over 1 in 10 patients harbored potentially actionable PGVs, most of which would not have been identified with guidelines-based GGT. Utilization of GGT can impact our understanding of GU cancer pathogenesis, aid in familial cascade testing, and influence treatment decisions.

e22537 Background: Germline and tumor next-generation sequencing (NGS) are complementary tests whose benefit in capturing patients (pts) potentially eligible for precision therapies is maximized when the tests are paired, as qualifying pathogenic variants (PVs) are missed if either test was done in isolation (Lincoln et al. 2020). Germline NGS has the additional benefit of informing prevention through surveillance and cascade testing. We highlight the benefits of a universal approach to concurrent testing in a subset of the previously reported cohort of pan-cancer pts who underwent universal germline NGS (Samadder et al. 2020). Methods: Unselected pts with solid tumors underwent an 80+ gene germline panel and 315+ gene tumor panel. Variants in genes unique to the germline or tumor panels, including microsatellite instability (MSI) and tumor mutation burden (TMB), were also evaluated. Results: 104 pts [81.7% White, non-Hispanic, 71.2% male] with 23 cancer types [28% colorectal, 13% lung, 11% prostate, 49% other] were included. Five (5%) pts had no actionable tumor alterations or germline variants identified (Table). 18 pts (17%) had 19 pathogenic germline variants (PGVs) identified, 11 (58%) of which were detected on tumor NGS (Table). 92 pts had >1 tumor alteration identified, of which 12% were confirmed as PGVs (Table). Notably, tumor NGS revealed 81 pts (78%) pts with biomarkers that would could not have been identified with germline testing alone, such as variants in genes not on germline panel (80) or MSI-high (4), or TMB-high (21) status of the tumor. Conclusions: Germline and tumor NGS are complementary tests that often detect different actionable alterations. There is value in confirming both the presence and absence of somatic variants in the germline in order to make appropriate clinical recommendations for the patient and their family members. [Table: see text]

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.

PURPOSE Diagnosis of Mismatch Repair Deficiency (MMRD) is crucial for tumor management and early detection in patients with the cancer predisposition syndrome constitutional mismatch repair deficiency (CMMRD). Current diagnostic tools are cumbersome and inconsistent both in childhood cancers and in determining germline MMRD. PATIENTS AND METHODS We developed and analyzed a functional Low-pass Genomic Instability Characterization (LOGIC) assay to detect MMRD. The diagnostic performance of LOGIC was compared with that of current established assays including tumor mutational burden, immunohistochemistry, and the microsatellite instability panel. LOGIC was then applied to various normal tissues of patients with CMMRD with comprehensive clinical data including age of cancer presentation. RESULTS Overall, LOGIC was 100% sensitive and specific in detecting MMRD in childhood cancers (N = 376). It was more sensitive than the microsatellite instability panel (14%, P = 4.3 × 10 −12 ), immunohistochemistry (86%, P = 4.6 × 10 −3 ), or tumor mutational burden (80%, P = 9.1 × 10 −4 ). LOGIC was able to distinguish CMMRD from other cancer predisposition syndromes using blood and saliva DNA ( P < .0001, n = 277). In normal cells, MMRDness scores differed between tissues (GI > blood > brain), increased over time in the same individual, and revealed genotype-phenotype associations within the mismatch repair genes. Importantly, increased MMRDness score was associated with younger age of first cancer presentation in individuals with CMMRD ( P = 2.2 × 10 −5 ). CONCLUSION LOGIC was a robust tool for the diagnosis of MMRD in multiple cancer types and in normal tissues. LOGIC may inform therapeutic cancer decisions, provide rapid diagnosis of germline MMRD, and support tailored surveillance for individuals with CMMRD.

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.