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

Universal Genetic Counseling for Breast Cancer Patients Mitigates Social Determinants of Health and Improves Genetic Testing Rates Across All Races

INTRODUCTION: While available since 1996, genetic testing for breast cancer patients has been limited by stigma, cost, and poor access. Many patients were not captured by traditional NCCN criteria, particularly those with healthcare barriers. Previously, genetic testing was used in high-risk screening and determining prophylactic utility, but with recent targeted therapies, has allowed personalized therapeutic benefit for patients. We expanded genetic testing counseling at a three-hospital Midwestern community hospital system from only NCCN high-risk patients to all patients diagnosed with breast cancer. METHOD(S): The implementation of universal genetic counseling to all newly diagnosed breast cancer patients began at our system in 2020. Under IRB approval, all new breast cancer patients were retrospectively reviewed from January 2019 through December 2019 (genetics based on NCCN guidelines group) and January 2021 through December 2021 (genetics offered to all group). Patient data regarding completion of genetic testing, pathologic mutations identified, stage, race/ethnicity, insurance type, primary language, and age was included in the analysis. Categorical variables were compared using Pearson's chi-square or Fisher's exact test;age was analyzed using ANOVA. RESULT(S): We reviewed a total of 973 patients, 439 diagnosed in 2019 and 534 in 2021. Demographic differences between 2019 and 2021 were similar including age, race/ethnicity, insurance, primary language. Despite the SARS CoV-2 pandemic, the stage of diagnosis between 2019 and 2021 was also similar (p=0.194). Completion of genetic testing increased significantly from 204 (48.6%) in 2019 to 338 (63.3%) (p=0.000) in 2021 with the universal access group. Across all demographic groups, genetic testing increased with significant findings in Medicare patients (p=0.005) and older patients (p=0.041) and near significant findings in non-white populations (0.059).[Table] Overall number of pathological mutations increased, 32 (7.29% of all patients) in 2019 to 39 (7.30%) in 2021, with the most common being BRCA2 (n=11), CFTR (n=9), CHEK2 (n=8), and BRCA1 (n=6). CONCLUSION(S): Implementation of universal access to breast cancer genetic counseling allowed for a significant expansion in genetic testing completion and overall increase in pathological mutations found. We saw an increase within sub-populations that may have not been targeted by NCCN guidelines previously including older patients, minority groups, and varying insurance types. (Table Presented).

SARS-CoV-2 Kerala Isolate Spike Protein Induces Cancer Proliferating Markers for Lung and Breast Cancer: An In Silico Approach

Background: Coronavirus disease (COVID 19) has been emerging as a major threat to humans all over the world. Severe Acute Respiratory Syndrome CoronaVirus 2 (nSARS-CoV-2) is the causative agent for the disease resulting in severe acute respiratory illness. Earlier, it took several years to come up with a vaccine or other sorts of treatments for viral diseases. But now with the advent of biotechnology and development of bio-informatic tools, the process has been accelerated. The WHO reports 39,806,488 affected cases and 1,112,208 deaths till today all over the world (17 Oct 2020). nSARS-CoV-2 has a greater influence on people with comorbidities mainly cancer. Objective(s): The study herein attempts to understand the binding affinity of the spike protein of the novel coronavirus with the lung and breast cancer marker proteins by docking and ClusPro analysis. Method(s): The analysis was conducted in reference to hACE2 (human Angiotensin Converting Enzyme 2), the receptor of nSARS-CoV-2. Total 22 different marker proteins were analyzed using ClusPro. Result(s): BRCA1 (Breast Cancer type 1 susceptibility protein) and CXCR4 (a chemokine receptor belong-ing to the G protein coupled receptor family) were found to exhibit higher binding affinities.-73.82 kcal/mol and-66.45 kcal/mol were the global energies they showed upon binding to S protein respective-ly. Conclusion(s): Therefore, novel SARS-CoV-2 has a higher chance of inducing cancer in non-cancerous individuals and aids in cancer acceleration in cancer patients. This poses a threat to cancer patients and immunocompromised individuals. The study can be exploited to identify the optimal drug delivery system for novel SARS CoV2.Copyright © 2022 Bentham Science Publishers.

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.

Niraparib plus aromatase inhibitors (AI) for germinal mutated BRCA1/2 (gBRCAm) or homologous recombination-deficient (HRd), hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC): LUZERN interim analysis

Background: The poly(ADP-ribose) polymerase inhibitor niraparib showed clinical activity in advanced gBRCAm ovarian and breast cancers. LUZERN aims to assess the effectiveness of niraparib plus AI in HR+/HER2–, AI-resistant ABC with a pathogenic variant in homologous recombination-related genes. Here we report findings from the stage 1 interim analysis. Methods: This open-label, single-arm, Simon’s 2-stage, phase II trial is enrolling HR+/HER2– ABC patients (pts) with gBRCAm (cohort A;n=6 in stage 1, n=7 in stage 2) and gBRCA wild-type/HRd (cohort B;n=9 in stage 2). Pts had to have received ≤1 prior line of chemotherapy for ABC, 1–2 prior lines of endocrine therapy for early or ABC with secondary endocrine resistance to the last AI regimen. Pts receive niraparib (200/300mg daily orally) plus AI (same agent given with the prior regimen) on each 28-day cycle. Primary endpoint: clinical benefit rate (CBR) as per RECIST 1.1. Secondary endpoints: overall response rate, progression-free survival (PFS), and safety per CTCAE 5.0. If ≥1/6 pts experienced clinical benefit, the trial should proceed to stage 2. Results: Six pts were enrolled in stage 1. Median age was 46 years (range 32–76), 66.7% of pts had visceral disease, and 83.3% had received prior CDK4/6 inhibitor-containing regimen for ABC. At data cut-off, 50.0% of pts were ongoing and median duration of treatment was 4.6 months (range 2.4–5.7). One patient achieved complete response, meeting the criterion to proceed to stage 2. Median investigator-assessed PFS was 5.3 months (95%CI 3.9–NA). The most frequent adverse events (AEs) of any grade (G) were nausea (3 [50.0%]), neutropenia (2 [33.3%];16.7% G3), constipation (2 [33.3%]), and vomiting (1 [16.7%]). Serious AEs occurred in 3 pts (50.0%;G3 COVID-19 pneumonia;G3 pseudomonal bacteriemia;G2 sacral pain). No treatment-related discontinuations/deaths were reported. Conclusions: Niraparib plus AI showed preliminary activity with a tolerable safety profile in gBRCAm HR+/HER2– AI-resistant ABC pts. Based on the steering committee recommendation, enrolment in cohorts A and B is ongoing. Clinical trial identification: ClinicalTrials.gov identifier: NCT04240106. Legal entity responsible for the study: MEDSIR. Funding: GlaxoSmithKline. Disclosure: J.Á. García Saenz: Financial Interests, Personal, Advisory Board: Seagen, Gilead;Financial Interests, Personal, Invited Speaker: Novartis, Celgene, Eli Lilly, Eisai, AstraZeneca, Daiichi Sankyo, MSD, Exact Sciences;Financial Interests, Institutional, Funding: AstraZeneca. J. De la Haba Rodriguez: Financial Interests, Personal, Other, Consultant and Advisory Role, Research Funding and Speaking: Pfizer, Novartis, Roche, Lilly;Financial Interests, Personal, Other, grant support: Pfizer. J.E. Ales Martínez: Financial Interests, Personal, Other, travel grant: Pfizer;Financial Interests, Personal, Research Grant: MEDSIR. E. Alba Conejo: Financial Interests, Personal, Advisory Role: Roche, Novartis, Pfizer, Lilly, BMS, Astrazeneca, Pierre Fabre, Daiichi, Exact Sciences;Financial Interests, Personal, Research Grant: Pfizer. J. Balmaña: Financial Interests, Personal, Advisory Role: AstraZeneca, Pfizer;Financial Interests, Institutional, Other, Steering committee member: AstraZeneca;Financial Interests, Institutional, Principal Investigator: Medsir, Pfizer. J.M. Perez Garcia: Financial Interests, Personal, Advisory Role: Lilly,Roche, Eisai, Daichii Sankyo, AstraZeneca, Seattle Genetics, Medsir;Financial Interests, Personal, Other, travel expenses: Roche. M. Sampayo-Cordero: Financial Interests, Personal, Other, honoraria: Medsir, Syntax for Science, Optimapharm, and Ability pharma;Financial Interests, Personal, Research Grant: Medsir;Financial Interests, Personal, Other, travel expenses: Medsir, Syntax for Science, Optimapharm, and Roche;Financial Interests, Personal, Other, consultant: Medsir, Syntax for Science, and Optimapharm;Financial Interests, Personal, Speaker’s Bureau: Medsir;Financial Interests, Personal, Full or part-time Employment: Me sir. A. Malfettone: Non-Financial Interests, Personal, Full or part-time Employment: MEDSIR. J. Cortés: Financial Interests, Personal, Advisory Role: Roche, Celgene, Cellestia, Astrazeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp&Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks;Financial Interests, Personal, Other, honoraria: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp&Dohme, Daiichi Sankyo;Financial Interests, Institutional, Research Grant: Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London.;Financial Interests, Personal, Stocks/Shares: MEDSIR, Nektar Pharmaceuticals, Leuko (relative);Financial Interests, Personal, Other, travel, accomodation: Roche, Novartis, Eisai, pfizer, Daiichi Sankyo, Astrazeneca. A. Llombart Cussac: Financial Interests, Personal, Leadership Role: Eisai, Celgene, Lilly, Pfizer, Roche, Novartis, and MSD;Financial Interests, Personal, Stocks/Shares: MEDSIR and Initia-Research;Financial Interests, Personal, Advisory Role: Lilly, Roche, Pfizer, Novartis, Pierre-Fabre, GenomicHealth, GSK;Financial Interests, Personal, Speaker’s Bureau: Lilly, AstraZeneca, and MSD;Financial Interests, Personal, Research Grant: Roche, Foundation Medicine, Pierre-Fabre, and Agendia;Financial Interests, Personal, Other, travel compensation: Roche, Lilly, Novartis, Pfizer, and AstraZeneca. All other authors have declared no conflicts of interest.

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.

A qualitative analysis of coping with genetically exacerbated risk of breast and ovarian cancers among medically-underserved women with BRCA1/2 mutations

Individuals testing positive for BRCA1/2 genetic mutations, or hereditary breast and ovarian cancer mutations, are 33-55% more likely than women without these mutations to develop breast and/or ovarian cancers before the age of 70. While research involving these genetic mutations continues to emerge, there remains unanswered questions regarding prophylactic experiences and subsequent impacts on mental health within subgroups of BRCA1/2-positive women. The purpose of this analysis was to explore the impact of BRCA1/2 mutations, prophylactic surgeries, and surveillance regimens within the scope of everyday life within a sample of BRCA1/2 positive women from medically-underserved backgrounds living in the United States (US). A sample of 211 US adult women who have tested positive for BRCA1/2 mutations within the past 5 years and who identify with one or more medically-underserved populations (racial, ethnic, or sexual minority, person with a physical disability, chronically-ill, those in poverty, immigrant populations) elucidated compelling qualitative data. A total of 169 (80.1%) women completed open-ended questions at the end of the online survey. Thematic analysis was utilized to identify themes and subthemes concerning mental health, sources of stress, and methods of stress relief. The focus of the current analysis is on the sources of stress identified by the respondents. Fourteen subthemes were identified. The four most common stressors were concerns about post-treatment recovery (19% of respondents), recurrence of a new cancer (15%), medical unknown of having a genetic mutation that increases the risk of cancer (14%), and having to schedule and plan for continual surveillance (12%). The next five subthemes ranged from 7-9% and include waiting for medical results, personal finances and covering medical expenses, impact of the COVID-19 pandemic, pre-operative anxiety, and worrying about insurance coverage. Our findings support previous research on cancer stressors for women while adding important qualitative elements for a richer understanding. Furthermore, since much of the research on the lived experiences of BRCA1/2 has been on highly-educated, non-Hispanic white women, few studies have focused entirely on medically-underserved populations, which was the entirety of our sample. This work adds an important intersectional lens in which to better understand the experiences of living with a BRCA1/2 mutation.

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.

Especially in adversity, we need fresh thinking

While offering secondary care at home may suit some, and could reduce costs, it is clear that virtual wards need adequate staffing, and careful planning and evaluation, and cannot fully replace traditional hospital wards. A summary of research from NIHR tracks the uptake of mastectomy and bilateral salpingo-oophorectomy among healthy women who carry BRCA1 or BRCA2 genes and are at high risk of cancer (doi:10.1136/bmj.o258).3 Although most women opted to proceed with surgery, others did not, suggesting that more work is needed to understand their reasons and to examine alternative strategies. Claire Johnston and colleagues use available evidence on infectivity and covid-19 to help doctors share pragmatic and straightforward advice with patients and the public (doi:10.1136/bmj-2020-061402).4 Their work comes at a time when covid is re-exerting its pressure on health systems, with rising case numbers having an impact on hospital beds and staffing levels (doi:10.1136/bmj.o1638).5 In such a climate, complaints about clinical care, delays, overcrowding, staffing, and supply problems are likely to rise.

A randomized phase II trial of carboplatin with or without nivolumab in metastatic triple-negative breast cancer

Background: Platinum agents induce DNA crosslinking and cause accumulation of genotoxic stress, which leads to immune activation via IFN-γ signaling, making the combination with nivolumab (PD-1 antibody) an attractive strategy to enhance the benefit of either agent alone in metastatic triple-negative breast cancer (mTNBC). Methods: In this phase II open-label, investigator-initiated, multicenter trial, patients with unresectable locally advanced or mTNBC treated with 0-1 prior lines of chemotherapy in the metastatic setting were randomized 1:1 to carboplatin (AUC 6) with or without nivolumab (360 mg) IV every 3 weeks. Stratification factors included: germline BRCA (gBRCA) status, prior neo/adjuvant platinum, and number of prior lines of metastatic therapy. After approval of PD-L1 inhibition for mTNBC, the study was amended to include first-line mTNBC only and PD-L1 status was added as a stratification factor. Patients randomized to carboplatin alone were allowed to crossover at progression to receive nivolumab (+ nab-paclitaxel post-amendment). The primary objective was to compare progression-free survival (PFS) per RECIST 1.1 criteria of carboplatin with or without nivolumab in first-line mTNBC in the S intent-to-treat (ITT) population. Key secondary objectives were objective response rate (ORR), overall survival (OS), clinical benefit rate, and duration and time to objective response. PD-L1 status was confirmed centrally using the SP142 Ventana assay (positive, ≥1% IC). Paired researchbiopsies at baseline, on-treatment and at progression were performed, if safely accessible. The trial closed to accrual prior to reaching target accrual due to approval of PD-1 inhibition in combination with platinum-based chemotherapy for PD-L1+ mTNBC. Results: Between 1/30/2018 and 12/9/2020, 78 patients enrolled. Three patients did not receive protocol treatment, and the safety analysis was conducted among the 75 that received any treatment;37 received carboplatin + nivolumab (Arm A), 38 received carboplatin alone (Arm B). Median age was 59.1 yrs (range: 25.4-75.8). Four patients (5.3%) had a known gBRCA1/2 mutation. Sixty-two (82.7%) patients received 0 prior lines (ITT population) and 13 (17.3%) 1 prior line of metastatic therapy. Sixty-seven patients (89.3%) experienced any grade ≥2 treatment-related adverse event (AE). The most frequent AE were platelet count decrease (n=40;53.3%), anemia (n=36;48.0%), neutrophil count decrease (n=33;44.0%) and fatigue (n=24;32.0%). Grade 3/4 AE were observed in 46 (61.3%) patients, and there was one grade 5 AE (COVID19 pneumonia). Any grade ≥2 immune-related AE (irAE) were observed in 25 of the 37 (67.6%) patients treated with carboplatin + nivolumab. Grade 3/4 irAE were observed in 11 (29.7%) patients. In the ITT population (32 on Arm A;30 on Arm B), median PFS was 4.2 months with carboplatin + nivolumab, and 5.5 months with carboplatin (stratified HR 0.98, 95% CI [0.51-1.88];p=0.95). ORR was 25% vs. 23.3%, respectively. At a median follow-up of 23.5 months, median OS was 17.5 months vs. 10.7 months (stratified HR 0.63, 95% CI [0.32-1.24];p=0.18). In patients with PD-L1+ mTNBC (13 on Arm A;11 on Arm B), median PFS was 8.3 months and 4.7 months, respectively (stratified HR 0.63, 95% CI [0.21-1.89];p=0.41). ORR was 23.1% vs. 27.3%, respectively. Median OS was 17.5 months vs. 9.6 months (stratified HR 0.59, 95% CI [0.20-1.75];p=0.34). Conclusions: Addition of nivolumab to carboplatin in patients with previously untreated mTNBC, unselected by PD-L1 status, did not significantly improve PFS. A trend toward improved PFS and OS was observed in patients with PD-L1+ mTNBC. Tissue, blood and intestinal microbiome biomarker analyses are planned;bulk tumor and single-cell sequencing, and TCR sequencing in peripheral blood are ongoing.

Germline BRCA1/2 mutation testing in human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC): A real-world study in the Syapse Learning Health Network (LHN)

Background: Germline (g)BRCA1/2 mutations represent approximately 5% of metastatic breast cancer. Poly ADP-ribose polymerase inhibitors (PARPi) have shown improved clinical outcomes, a manageable toxicity profile, and favorable patient (pt)-reported outcomes versus chemotherapy in pts with gBRCA1/2 mutated HER2-locally advanced or metastatic breast cancer. With the advent of PARPi, clinical guidelines have broadened eligibility criteria for gBRCA1/2 testing. However, limited information is available on the impact of the COVID-19 pandemic on gBRCA1/2 testing rates. We assessed trends and factors associated with gBRCA1/2 testing in pts with HER2-ABC before and during the COVID-19 pandemic. Methods: This retrospective study included pts from the Syapse LHN, a longitudinal database of pts with cancer cared for in community-based, integrated care delivery networks in 25 states in the United States. Pts were eligible for gBRCA1/2 testing from initial ABC diagnosis until death or date of last contact with the participating health system. Information on gBRCA1/2 testing was obtained from scaled sources and further curated by Certified Tumor Registrars. Logistic regression evaluated the associations between age at diagnosis, family Shistory of relevant cancer, race/ethnicity, median household income, health system, and diagnosis year with gBRCA1/2 testing among HER2-ABCs;models included hormone receptor status. Results: The study population included 1769 pts with HER2-ABC, including 577 pts with triple negative ABC initially diagnosed from 2010: 96% were women, 69% were non-Hispanic White, and 94% had an estimated median household income >$30, 000 USD;median age at initial diagnosis was 61 years. The percentage of pts ever gBRCA1/2-tested among those eligible increased over time: 26%, 28%, and 31% by end of 2018, 2019, and 2020, respectively. Similarly, the percentages of new testing among eligible but not previously tested pts increased from 2018-March 2020, decreased from April-September 2020, and trended upwards thereafter (Table 1). In logistic regression models combining data from pre-and post-COVID-19 periods, family history of relevant cancer (odds ratio [OR]=1.9;95% CI, 1.5-2.4), younger age at diagnosis (>65 reference;<45: OR=12.8, 95% CI, 8.9-18.3;45-54: OR=6.7, 95% CI, 4.9-9.3;55-64: OR=2.0, 95% CI, 1.5-2.8), and diagnosis year of 2013 or later (OR=1.9, 95% CI, 1.4-2.6) were significantly associated with increased odds of gBRCA1/2 testing. Positive hormone receptor status (OR=0.5;95% CI, 0.4-0.6) and Hispanic ethnicity (OR=0.5;95% CI, 0.3-0.9) were significantly associated with reduced odds;associations with non-Hispanic Black ethnicity did not reach statistical significance (OR=0.8;95% CI, 0.6-1.1). Conclusion: Following the expanded eligibility criteria for gBRCA1/2 testing, testing rates increased from 2018 to 2019 and decreased only slightly during the national COVID-19 lockdown. Age at diagnosis, family history, diagnosis year, ethnicity, and hormone receptor status impacted the odds of testing. Given that gBRCA1/2 mutations are actionable, focused efforts should be developed to resume the pre-pandemic trajectory of gBRCA1/2 mutation testing.

eP520: Screening results in 186 any-health-status adults in primary care clinics receiving clinical NGS for 431 health risk and recessive genes

Introduction: The ACMG has recommended returning clinically relevant results for certain genes when identified in research or as secondary findings in diagnostic testing. Research studies have shown that genomic population screening detects patients with previously unrecognized and often actionable health risks or genetic conditions, with acceptably low levels of harm. Cascade testing of relatives at risk is enabled. Screening for recessive disorder carrier status with gene sequencing panels is common in clinical practice. Preventative screenings routinely occur in primary care settings. The cost of reliably sequencing of many genes in a clinically reliable fashion is approaching levels where offering genomic screening tests may be contemplated for entire populations, and the results used for preventative health purposes, including clinical correlation, early screening, and education. In anticipation of universal genome sequence-based screening, integrated with existing health risk screenings, we piloted a novel implementation of clinical genomic population screening in primary care, mostly family medicine clinics. Screening involved clinical sequencing and reporting of 431 genes where variants are associated with personal health risks or recessive disease carrier status. Methods: Interested primary care providers (PCPs) in two Family Medicine practice systems were invited to participate and given onboarding education. Adult patients with any health status were introduced to The Genomic DNA Test and provided test information by their PCPs in the context of preventative health assessment. Patient education materials included paper, online, and video information, a ‘hotline,’ and optional free genetic counseling. Patients completing a bespoke, health system-approved, written clinical consent provided blood or occasionally saliva samples that were NGS sequenced according to validated procedures in a commercial CLIA-certified genetic testing laboratory. Laboratory reports were returned to the PCP and patient after a local genetics professional added a 1-to-3-page messaging document, the Genomic Medicine Action Plan (GMAP). The PDF-format reports and GMAP were placed in the patient’s electronic health record. Only pathogenic (P) and likely pathogenic (LP) variants were reported. Variant classification was according to Sherloc, the performing laboratory’s system. Patients or providers could request free post-test genetic counseling locally, and the performing lab offered free family member testing and limited-cost partner testing for health risk panel genes and recessive disorder panel genes, respectively. Patients with health risk results were defined as being heterozygous for a P/LP variant for a dominant condition or for a recessive condition where some heterozygotes are symptomatic or co-dominant, hemizygous for a P/LP variant for an X-linked recessive condition, or bi-allelic and plausibly in trans for an autosomal (or X-linked in a female) recessive condition. Many such conditions that are common have reduced or low penetrance, and were characterized as increased risk compared to those not having those variants. When increased risk was identified, the GMAP recommended appropriate medical responses and/or patient education. As part of quality assessment of the pilot, the frequencies of reported results and certain events are monitored. Results: Between November 2019 and October 2021, 186 patients with a median age of 58 years were tested by 20 PCPs at no cost to patients or insurance. Testing volumes declined during the COVID-19 pandemic and when other health system events made high demands on PCPs and their staff. Only 13.3% of patients had no reportable variants in any of the 431 genes. Eighty point nine percent were carriers for at least one recessive disease. The most common recessive genes showing carrier status were HFE, SERPINA1, GALT, CFTR, BTD, F5, DHCR7, PC, GAA, GJB2, PMM2, PAH, and PKHD1. Twenty-six percent had at least one potential health risk result identified, 20% if the common thrombophilias are excluded. The most common category was hereditary cancer risk (7.5%), followed by F5, F2, and SERPINC1 thrombophilia variants (6.5%), hereditary hemochromatosis 1 (HFE) (4.3%), cardiovascular disorders, mostly cardiomyopathies (3.8%), alpha-1-antitrypsin deficiency or other pulmonary disorder (3.8%), familial Mediterranean fever heterozygotes (1.6%), G6PD deficiency (1.1%), and lipid disorder (0.5%). Two patients had health risks in two areas, and two in three areas. Interestingly, BRCA1 and BRCA2 variants were only identified in males. Thirteen patients, about 7%, had an amended report issued during the period. This happened when an unreported variant of uncertain significance was reclassified as LP or P, or when LP became P, and the performing laboratory issued an amended report. Surprisingly few patients took advantage of the free genetic counseling. No patient adverse events were reported by the participating PCPs despite ongoing outreach, nor by patients. Conclusion: Genomic population health screening can be successfully implemented in primary care settings with use of limited but essential genetic professional assistance, after careful planning and input from other medical specialties. A significant proportion of adults not selected for health status harbors germline genetic variants associated with increased health risk. In the absence of a culture where routine genomic screening is expected and where patient genomic competency is high, PCP capacity limits are a barrier to universality. Inclusion of genes for both health risk results with variable degrees of penetrance and for recessive carrier status, and multiple simultaneous results, dictates careful messaging of the implications, while doing so in a primary care setting begs a concise and efficient process. Rates of carrier detection were in-line with predictions based on general population frequencies. Rates of health risk detections were higher than earlier research programs because a larger number of genes with a much broader scope of health risk was included, including disorders with low penetrance yet meaningful clinical relevance and carefully-designed care pathways meant to optimize care while avoiding unnecessary additional testing. We conclude that genomic population health screening of primary care patients where large numbers of genes are clinically sequenced is feasible in a real-world health system, and that value exists for some tested patients now. Research to overcome certain technical limitations of current clinical genomic testing methods and to better stratify risk level in the context of incomplete penetrance should enhance the value of universally-offered genomic population health screening in the future.

The natural history of covid-19 in vaccinated inflammatory bowel disease patients

Background: Patients with Inflammatory Bowel Disease (IBD), especially those on immunosuppressive (IMS) treatment should be vaccinated against SARS-CoV-2 to prevent hospitalization, mechanical ventilation, and death. However, IMS may adversely affect vaccination, raising concerns as to how vulnerable these patients are to break through COVID-19 infections. Thus, we aimed to assess the proportion of IBD patients who despite complete vaccination developed COVID-19, as well as the course of the infection. Methods: This study was an initiative of the Hellenic Group for the study of IBD which involved seven IBD referral Centers. Patients attending these Centers who reported a COVID-19 infection at least 3 weeks after vaccination completion were asked to complete an on-line anonymous questionnaire which included patient demographics and IBD clinical and therapeutic data, a detailed vaccination history, and the course and outcome of COVID-19, especially the need for hospitalization, oxygen supply, and admission to ICU. In patients with grave outcome information was sought by family members Results: On estimate, 2940 patients reported full vaccination (Pfizer vaccine) in the 7 centers. Between 1st May 2021 and 30th October 2021, 46 (1.5%) fully vaccinated IBD patients reported COVID-19 infection [25 male, 32 CD, 14 UC, mean (SD) age 40.8 (13.7) years, mean (SD) IBD duration mean, 11.2 (10.8) years]. Five patients were receiving 5-ASAs, 2 corticosteroids, 5 azathioprine/methotrexate, 23 anti-TNFs as monotherapy and 3 in combination with azathioprine/methotrexate, and 1 with corticosteroids, 3 vedolizumab and 1 each ustekinumab, tofacitinib and rizakinzumab at the time of COVID-19 diagnosis;one patient was receiving no treatment. IBD was in remission in 37/46 patients (80.4%). Comorbidities were seen in 21 patients (thyroid disease 11;diabetes mellitus 2;hypertension 2;psoriasis 1;prior breast cancer 1;spondyoartropathy 2;dyslipidemia 1;and PSC 1 patient). The mean (SD) time between last vaccination dose and infection was 3.2 (1.4) months. Overall, 40 (86.9%) patients reported mild constitutional and respiratory symptoms, 4 (8.7%) were asymptomatic and only 2 patients (4.3%) required hospitalization which was uneventful in both. None needed high flow oxygen supply or ICU admission, and none reported symptoms of long COVID. No deaths were reported by patient relatives. IBD medications were stopped in 21 patients (45.6%) during the COVID-19 infection. Conclusion: A minority of fully vaccinated IBD vaccinated patients developed COVID-19 which was relatively mild and uneventful. These results reinforce the importance of vaccination especially in vulnerable populations.