Pathogenic mutations in ethnic Lebanese Arab patients with high risk for hereditary breast cancer

Background: Breast cancer accounts for 35-40% of cancer in women in Lebanese and Arab countries with 50% of patients (pts) diagnosed before age 50. Prevalence of pathogenic BRCA variants in high-risk pts is 5.6-20% (Abulkhair and El Saghir 2021). 7 BRCA1 and 7 BRCA2 pathogenic variants were found in 5.6% of 250 pts with high hereditary risk breast cancer using amplicon sequencing and MLPA (El Saghir 2015;Poulet 2016). We report results of Next Generation Sequencing (NGS) on selected cases based on Manchester Score. First report in ethnic Lebanese Arab pts. Method(s): Pts prospectively enrolled in 2009-2012. IRB approval secured. Pts signed informed consent. Data collected from medical records. Amplicon and MLPA was done on 250 patients. NGS was done on 100 cases with Manchester Score 14-56. DNAs of the 14 pts previously found to have a pathogenic variant (Manchester Score 10-59) were not re-sequenced. NGS on remaining 150 pts was not done due to Covid-19 pandemic and lack of additional funding. Result(s): NGS showed 7 pathogenic variants, 4 in PALB2 and 3 in ATM. No new BRCA variants were found. Two BRCA2 mutations noted by Amplicon/MLPA reported as VUS in 2015 are reclassified as pathogenic. Total BRCA2 pathogenic variants becomes 9. Total pathogenic variants 23. Risk of having hereditary breast cancer in pts with MS 10-59 is 20% (23/ 114), and at least 9.2% in the entire cohort (23/250). Age <=40 with family history (FH) carries 18.9% risk of harboring a pathogenic mutation while no FH, 1.4% (Table 1). All BRCA1 pts had triple negative and 7/9 BRCA2 pts had hormone receptor positive breast cancer. 4 unrelated pts shared the same c.1056_1057delGA PALB2 pathogenic variant thus we suggest this is a founder mutation in Lebanese Ethnic Arab population. Conclusion(s): Mutation rates in high hereditary risk pts with Manchester Score range 10-59 is 20%. Age <=40 with positive FH can be used to select pts for testing when resources are limited. Our data suggests that c.1056_1057delGA is a PALB2 founder mutation. No conflict of interest.Copyright © 2022 Elsevier Ltd. All rights reserved

Racial, ethnic, and sex-based disparities among high-risk individuals undergoing pancreatic cancer surveillance

Background: The international, multi-center Pancreatic Cancer Early Detection (PRECEDE) Consortium enrolls high-risk individuals (HRIs) undergoing pancreatic ductal adenocarcinoma (PDAC) surveillance. Enrollment began in 2020, and despite challenges related to the COVID-19 pandemic, the PRECEDE Consortium rapidly accrued a large cohort of HRIs. The purpose of this study is to describe the characteristics of this cohort and assess racial, ethnic, and sex-based disparities. Method(s): The PRECEDE Consortium (NCT04970056) is a prospective, multicenter study focused on improving survival from PDAC through early detection. Data from all HRIs who met criteria for PDAC surveillance and enrolled between May 2020 - March 2022 were collected and included in the analysis. Result(s): During the study period, 1299 HRIs enrolled in PRECEDE at 32 centers. HRIs were excluded if enrollment data was incomplete or criteria for PDAC surveillance were not met. Of 1113 who were included, 47.2% met criteria for familial pancreatic cancer (FPC) and 45.4% had a family history of PDAC along with a PV in a PDAC-risk gene (BRCA1, BRCA2, PALB2, ATM, MLH1, MSH2, MSH6, PMS2, or EPCAM). The remainder had familial atypical mole melanoma syndrome (5.7%), Peutz- Jeghers syndrome (1.6%), or hereditary pancreatitis (0.2%). More females than males enrolled (65.9% vs. 33.5%). The distribution of HRIs by race and ethnicity is depicted;the majority identified as white (87.7%). Study participants were primarily from the US (82.7%), the median age was 61 (27-85) and 18.5% had Ashkenazi Jewish ancestry. Nearly all HRIs consented to allow access to imaging data (99.6%), collection of germline DNA (97.7%), and biosample collection (99.5%). There were no race, ethnicity, or sex-based differences in rates of consent for collection of imaging, DNA, or biosamples. Conclusion(s): Enrollment of HRIs in prospective studies of PDAC surveillance is essential for advancing early detection research in PDAC. A distinct advantage of the PRECEDE Consortium for examining enrollment disparities is that recruitment began in 2020, providing a unique and current snapshot of the international PDAC surveillance landscape. Despite the recent attention on addressing disparities in healthcare delivery, significant racial, ethnic, and sex-based disparities persisted in the cohort of HRIs enrolled in the PRECEDE Consortium. Ensuring that the diversity of participants in the PRECEDE Consortium mirrors the communities served by participating centers is crucial. Further examining and addressing the reasons for these disparities is a major focus of the PRECEDE Consortium moving forward.

Frequency of germline testing after tumor sequencing by cancer type

Background: Tumor next generation sequencing (NGS) is used to identify somatic mutations. It can also identify potential germline mutations associated with cancer susceptibility. We aimed to describe the frequency of actionable tumor NGS results that met ESMO 2019 guidelines for germline genetic testing (GT), germline GT receipt and positive GT results in a large cancer cohort. Methods: Patients with tumor NGS from Sept 2019-Feb 2022 in a large health system in New York City were retrospectively identified. ESMO guidelines were used to identify potentially actionable germline mutations on NGS (Mandelker et al. 2019). Results: Of 3796 patients who underwent tumor NGS, 454 (12.0%) had at least one potential actionable germline mutation per ESMO guidelines. Cancer types with over 20% of patients whose tumor NGS results met ESMO criteria for germline GT included ampullary, ovarian, uterine, liver, skin, mesothelioma, and thyroid. The most common tumor mutations identified were BRCA2 [26.7%, 95% confidence interval (CI) 22.6-31.0], BRCA1 [14.1%, CI 11.0-17.6], MUTYH [9.9%, CI 7.3-13.0], MSH6 [7.9%, CI 5.6-10.8], and TSC2 [6.8%, CI 4.7-9.6]. Overall, 162 (35.7%) eligible patients per ESMO guidelines received germline GT, of which the most likely cancer types were ovarian (91.1%), pancreatic (66.7%), breast (58.3%), thyroid (50.0%), and uterine (46.9%) (Table). Of 162 patients who underwent germline GT, 98 (60.5%) had positive GT results with the most common cancer types being bone marrow (100%), esophageal (100%), ovarian (80.5%), pancreatic (66.7%) and lung (64.3%). Distribution of positive GT results was: 39 BRCA2;24 BRCA1;12 MUTYH;6 BRIP1;4 RAD51C;4 PALB2;3 MSH6;2 CHEK2;2 MSH2;2 RAD51D;and one each of SDHA, MLH1, NF1, PMS2. [Formula presented] Conclusions: Of 12% of patients who met ESMO criteria for germline GT, only 35% received GT and among those tested, 60% had a germline mutation. Mutations were prevalent across cancer types, highlighting the need for clinicians to know and implement society guidelines. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: B. Pothuri: Non-Financial Interests, Personal, Leadership Role, Clinical Practice Committee Chair, Board of Directors, COVID-19 Taskforce Co-chair: Society of Gynecologic Oncology;Non-Financial Interests, Personal, Leadership Role: Gynecologic Oncology Group;Non-Financial Interests, Personal, Leadership Role, Society Secretary: New York Obstetrical Society;Financial Interests, Personal and Institutional, Advisory Board, Advisory board consulting fee + clinical trial support at NYU: Clovis Oncology, AstraZeneca, Eisai, Sutro, Tesaro/GSK, Merck, Mersana, Seattle Genetics, Toray;Financial Interests, Personal, Advisory Board, Advisory board consulting fee, support for attending meetings: Gynecologic Oncology Group;Financial Interests, Personal, Advisory Board, Advisory board consulting fee: Lilly, Atossa, Elevar, Deciphera, Imab, Arquer Diagnostics;Financial Interests, Personal, Speaker’s Bureau: Bioascend, PERS, Vanium, OncLive;Financial Interests, Institutional, Funding, clinical trial support at NYU: Karyopharm, Immunogen, VBL Therapeutics, Roche/Genentech, Celsion, Takeda, Incyte. All other authors have declared no conflicts of interest.

Video-based germline testing for individuals with pancreatic ductal adenocarcinoma: Influence of COVID-19 pandemic

Purpose: National guidelines recommend universal germline genetic testing (GT) for patients with Pancreatic Ductal Adenocarcinoma (PDAC), but rates of testing remain low. Given the aggressiveness of PDAC, the window of opportunity for GT is short and often overshadowed by treatment initiation and other clinical milestones. Thus, there is an unmet need for a model that streamlines GT and makes it available to a wider audience in a rapid fashion. Moreover, in pandemic times, video-based alternatives for medical care are increasingly relevant. Methods: We implemented a novel care delivery model in which a seven-minute educational video describing the benefits, risks, and implications of GT was shown to PDAC patients. The video was shown in lieu of an initial consult with a genetic counselor. Only patients who had not undergone GT or previously met with a genetic counselor were included. After watching the video, patients could elect to pursue GT and get tested on-side or remotely (at home). Genetic counselors disclosed results and provided post-test counseling by phone. Clinical and germline data were collected through medical records on a cohort of PDAC patients seen at the Gastrointestinal Center-MD Anderson during a 2-year enrollment period (May 2019-July 2021), which included the COVID-19 pandemic period. Results: A total of 286 PDAC patients watched the educational video. From 175 patients that watched the video pre-pandemic, 12 declined testing, whereas in the post-pandemic period, none of the 111 patients declined testing (6.9% vs 0%;p<0.004). We excluded data from 29 patients who elected to undergo GT but declined to participate in the registry. From the 241 patients with successfully collected samples, 21 patients (8.7%) had a pathogenic variant (PV), 38 patients (15.8%) had a Variant of Uncertain Significance (VUS), and 182 patients (75.5%) tested negative. The pathogenic variants detected included: BRCA2 (most frequent), ATM, BRCA1, CDKN2A, PALB2 and APC. Conclusions: GT can have tremendously beneficial effects, such as qualifying for targeted treatment options and facilitating cancer prevention in probands' at-risk family members. Comparing uptake of GT pre- versus post-pandemic suggests that patients were more willing to trust information from a video platform, likely due to the global effect of living in a virtual society as a result of the pandemic. We suggest an approach in which every PDAC patient is shown a genetics educational video and given the choice to undergo GT and post-result counseling, greatly reducing the burden on genetic counselors. We report here the feasibility of implementing video-based germline testing in PDAC patients which resulted in unexpectedly high uptake levels, particularly post-pandemic. Further investigations are needed to explore the feasibility of a fully remote GT model in diverse populations to assess additional barriers to universal GT.