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Background: Growing evidence indicates that restrictive criteria for determining eligibility of breast cancer patients for germline genetic testing (e.g. NCCN, etc.) can missa significant number who may benefit from testing. However, the clinical utility and outcomes of patients with germline pathogenic variants (“positive patients”) who fall outside of current criteria has not been studied,and there is limited data on the clinical impact of nonBRCA pathogenic variantsin patients who fall inside testing criteria. We present longitudinal data from a previous cohort of patients, who are being followed in a new genetics registry that correlates germlinetest results with impact on clinical decision making, disease status, treatmentcourse, clinical trial enrollment and overall survival. Methods: A large multi-center IRB approved prospective Registry initiated in 2017 collected andanalyzed data on 959 breast cancer patients, newly or previously diagnosed, atthe time of genetic test result return (Beitsch et al. JCO 2018)1.This abstract presents clinical data over the intervening 18-24 months on patients with positive variants (83) both in-criteria (IC) and out-of-criteria (OOC),collected via medical record review as part of the iGAP Registry(igapregistry.org), sponsored by Medneon (Cupertino, Ca). Results: Of the 44 positive patients for whom longitudinalclinical outcomes data have been analyzed to date, 24 met guidelines fortesting and 20 did not. 6 had a history of additional primary cancers at thetime of testing. 40/44 patients are disease free; of these 20 were IC,20 were OOC. 1/44 has stable disease and was OCC. 3/44 have progressive orrecurrent breast cancer and 2 were OCC and 1 was IC. 13/44received chemotherapy; 6 IC and 7 OOC. 5 patients (with mutations in BRCA1,BRCA2, PALB2, MUTYH) received carboplatin consistent with the sensitivity toplatinum agents conferred by deficiencies in homologous recombination (HR) andbase-excision repair (BER). Longitudinal outcomes stratified by gene result arein Table 1. Conclusions:This studyprovides initial evidence for the impact of germline genetic test results onlongitudinal patient outcomes, stratified by gene. It also begins to correlategermline results and chemotherapy, as 3/5 OOC patients receiving carboplatinhad mutations in HR or BER genes. This raises the possibility that certain treatment advantages and other beneficial changes in management could bewithheld from OOC patients if restrictive criteria persist, as well as limiting the opportunities for possible preventive interventions for their at-risk family members 1. BeitschPD, Whitworth PW, Hughes K, et al. Underdiagnosis of Hereditary Breast Cancer:Are Genetic Testing Guidelines a Tool or an Obstacle?. J Clin Oncol.2019;37(6):453-460. doi:10.1200/JCO.18.01631 Table 1Positive Gene Variant# reported mutations-by geneSubject Health Status Disease FreeSubject Health Status Stable or Progressive DiseaseNCCN # ICNCCN # OOCATM22002BLM11001BRCA122020BRCA255041CHEK266033DIS3L211001FH11010MITF11010MSH611001MUTYH98127NBN22011NF110101NTLH111001PALB232121RAD5011010RAD51C22011RAD51D32112RECQL422011VHL11010 Citation Format: Peter Beitsch, Rakesh Patel, Pat Whitworth, Barry Rosen, Rick Brown, Gia Compagnoni, Linsey Gold, Ian Grady, Edward Esplin, Sarah Nielsen, Max Brown, Melissa Trudrung, Chloe Wernecke, Mary Kay Hardwick, Robert Nussbaum. Longitudinal clinical outcomes of a multi-center universal genetic testing registry [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 PS8-30.

INTRODUCTION AND OBJECTIVE:Pathogenic/likely pathogenic (P/LP) germline genetic variants occur in ∼10-15% of all prostate cancer (PCa) patients. However, complicated and restrictive testing guideli...

ImportanceNational Comprehensive Cancer Network guidelines currently recommend germline testing for high-risk genes in selected patients with breast cancer. The clinical utility of recommending testing all patients with breast cancer with multigene panels is currently under consideration.ObjectiveTo examine the implications of universal testing of patients with breast cancer with respect to clinical decision-making.Design, Setting, and ParticipantsPatients from a previously reported cohort were assessed as in-criteria or out-of-criteria according to the 2017 guidelines and underwent testing with a multigene germline panel between 2017 to 2018. Patients were women and men aged 18 to 90 years, with a new and/or previous diagnosis of breast cancer who had not undergone either single or multigene testing. Clinicians from 20 community and academic sites documented patient clinical information and changes to clinical recommendations made according to test findings. Association between prevalence of pathogenic or likely pathogenic germline variants and previously unreported clinical features, including scores generated by the BRCAPRO statistical model, was determined. Data were analyzed from April 2020 to May 2022.ExposureNew and/or previous diagnosis of breast cancer.Main Outcomes and MeasuresDisease management recommendations that were changed as a result of genetic testing results are reported.ResultsClinicians were asked to assess changes to clinical management as a result of germline genetic testing for 952 patients. Informative clinician-reported recommendations were provided for 939 (467 in-criteria and 472 out-of-criteria) of the patients with breast cancer (936 [99.7%] female; 702 [74.8%] White; mean [SD] age at initial diagnosis, 57.6 [11.5] years). One or more changes were reported for 31 of 37 (83.8%) in-criteria patients and 23 of 34 (67.6%) out-of-criteria patients with a pathogenic or likely pathogenic variant. Recommendations were changed as a result of testing results for 14 of 22 (63.6%) out-of-criteria patients who had a variant in a breast cancer predisposition gene. Clinicians considered testing beneficial for two-thirds of patients with pathogenic or likely pathogenic variants and for one-third of patients with either negative results or variants of uncertain significance. There was no difference in variant rate between patients meeting the BRCAPRO threshold (≥10%) and those who did not (P = .86, Fisher exact test). No changes to clinical recommendations were made for most patients with negative results (345 of 349 patients [98.9%]) or variants of uncertain significance (492 of 509 patients [96.7%]).Conclusions and RelevanceIn this cohort study, germline genetic testing was used by clinicians to direct treatment for most out-of-criteria patients with breast cancer with pathogenic or likely pathogenic germline variants, including those with moderate-risk variants. Universal germline testing informs clinical decision-making and provides access to targeted treatments and clinical trials for all patients with breast cancer.

Purpose An estimated 10% of breast and ovarian cancers result from hereditary causes. Current testing guidelines for germ line susceptibility genes in patients with breast carcinoma were developed to identify carriers of BRCA1/ 2 variants and have evolved in the panel-testing era. We evaluated the capability of the National Comprehensive Cancer Network (NCCN) guidelines to identify patients with breast cancer with pathogenic variants in expanded panel testing. Methods An institutional review board–approved multicenter prospective registry was initiated with 20 community and academic sites experienced in cancer genetic testing and counseling. Eligibility criteria included patients with a previously or newly diagnosed breast cancer who had not undergone either single- or multigene testing. Consecutive patients 18 to 90 years of age were consented and underwent an 80-gene panel test. Health Insurance Portability and Accountability Act–compliant electronic case report forms collected information on patient demographics, diagnoses, phenotypes, and test results. Results More than 1,000 patients were enrolled, and data records for 959 patients were analyzed; 49.95% met NCCN criteria, and 50.05% did not. Overall, 8.65% of patients had a pathogenic/likely pathogenic (P/LP) variant. Of patients who met NCCN guidelines with test results, 9.39% had a P/LP variant. Of patients who did not meet guidelines, 7.9% had a P/LP variant. The difference in positive results between these groups was not statistically significant (Fisher’s exact test P = .4241). Conclusion Our results indicate that nearly half of patients with breast cancer with a P/LP variant with clinically actionable and/or management guidelines in development are missed by current testing guidelines. We recommend that all patients with a diagnosis of breast cancer undergo expanded panel testing.

Background: HBOC testing guidelines were established to identify patients with clinically actionable variants and limit economic burden. We report the impact of germline results on health outcome based on clinical decision making and treatment interventions, regardless of guidelines, in a multi-center registry. Methods: 20 community-based and academic sites participated in an IRB approved registry. Patients with breast cancer were tested with an 80-gene panel and clinical information was collected. Results: Data on 912 patients has been analyzed to date. 68% were recently diagnosed and the remaining were diagnosed in the past. 50.5% met NCCN criteria; 49.5% did not. Pathogenic/likely pathogenic (P/LP) germline mutations were found in 8.65% of patients. Of all patients with P/LP findings, 85% had variants in cancer-risk genes with established management recommendations and 80% had germline variants conferring eligibility for clinical trials and precision medicine-based cancer treatments, such as PARP inhibitors. When results were evaluated based on an 11 gene panel of genes most commonly associated with breast cancer, 4.9% (or X) were found to have variants and X percent of these had variants conferring eligibility for clinical trials and precision medicine. X Patients with variants outside of the 11 gene panel had eligibility for clinical trials and precision medicine. There was no significant association between BRCAPRO scores and patients having a P/LP finding, whether in BRCA1/2 alone (p=0.42) or for any cancer gene (p=0.57). For 62% of patients with P/LP germline mutations, clinicians reported results impacted patients’ health outcome; and for 69%, results impacted the health outcome of patients’ relatives. Physician reported impact on patient outcome associated significantly with the presence of P/LP germline findings (p Conclusions: Comprehensive panel testing of breast cancer patients impacts physician assessed patient outcomes and informs changes in surgical treatment strategy, medical therapies and proactive screening. The data suggest that BRCAPRO calculators are poor predictors of germline presence of P/LP findings. Physicians in this study demonstrate the ability to discern the clinically actionable value of P/LP mutations from non-actionable VUS. Multigene panels impact breast cancer patient care by identifying precision medicine treatment interventions and guiding long-term medical management and preventive surveillance for patients and family members. More patients are provided opportunities for precision medicine when a larger panel is used. Table 1. Comprehensive panel clinical management and treatment implications. Germline variants with implications for patient management and treatment. *P/LP variants in these genes confer potential clinical trial eligibility, e.g. NCT02401347.Table 1PatientsVariantsWith breast cancer management guidelines45 (56%)46 (55%)(ATM*, BRCA1*, BRCA2*, CHEK2*, NBN*, NF1, PALB2*, TP53*)With cancer management implications31 (38%)33 (39%)(BARD1*, FH, MITF, MSH6*, MUTYH*, PTCH1, RAD50*, RAD51C*, RAD51D*, RB1, RET, VHL)Evidence of actionability accruing5 (6%)5 (6%)(BLM, DIS3L2, RECQL4)Total8184 Citation Format: Peter Beitsch, Pat Whitworth, Kevin Hughes, Ian Grady, Karen Barbosa, Rakesh Patel, Michael Kinney, Paul Baron, Barry Rosen, Gia Compagnoni, Linda ann Smith, Rache Simmons, Cynara Coomer, Dennis Holmes, Eric Brown, Linsey Gold, Lisa Curcio, Patricia Clark, Tony Ruiz, Heather MacDonald, Sadia Khan, Lee Riley, Sam Lyons, Shan Yang, Mary K Hardwick, Edward D Esplin, Robert L Nussbaum. Comprehensive germline multigene panel testing changes clinical care for patients with breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-28.

10504 Background: Pathogenic/likely pathogenic (P/LP) germline genetic variants are estimated to occur in 10-15% of all prostate cancer (PCa) patients. However, genetic testing for PCa patients is underutilized, partially due to complicated and restrictive testing guidelines developed at a time when the cost of testing was high. We conducted a study based in community urology clinics to determine the incidence of P/LP variants in PCa patients who met and did not meet the NCCN 2019 PCa germline genetic testing criteria. Methods: An IRB-approved, multicenter, prospective registry was initiated with 15 community and academic urologists nationwide. Eligibility criteria included patients with a PCa diagnosis unselected for personal or family history, stage or histology who had not been previously tested. Consecutive patients ages 18-90 were consented and underwent an 84-gene germline panel test. HIPAA-compliant electronic case report forms distributed to clinician collected information on patient diagnoses, NCCN testing criteria, and results-based recommendations. Results: To date, 640 enrolled patients have genetic testing results available. Overall, 69 (10.8%) patients had 72 P/LP variants detected, 15% of which were in BRCA1/2. Of the 532 patients for whom we have clinician-reported data, 293 (55%) met NCCN criteria and 239 (45%) did not. Median age was 70 (range 44-90). Overall, 11.1% (59/532) of patients with clinician-reported data had a P/LP variant. 36 (12.3%) of patients who met NCCN criteria and 23 (9.6%) of patients who did not meet criteria had a P/LP variant. The difference in P/LP rate between the two groups was not statistically significant (p=0.33). If only a conservative 12-gene PCa panel was considered, P/LP yield was 5.5% (29/532), with 8 (28%) of these patients missed by guidelines. Stratification by self-reported ethnicity was: 76% White/Caucasian (52 patients w/ P/LP), 18% Black/African American (2 patients w/ P/LP), and

Background Interest and knowledge about the genetics and biology of inherited risk of and progression of disease is growing. Physicians are increasingly using tests and technology, including germline genetic, genomic, and biomarker testing, to provide insight into a healthy individual's risk and an affected individual's disease characteristics, in order to provide personalized clinical management. However, many barriers to adoption of precision medicine still exist in the clinical setting, including rapid advances in technology and research, complex guidelines for eligibility, variable quality and cost, and adequate understanding of appropriate implementation by medical professionals. Methods The iGAP Registry uses an innovative digital platform to collect genetic, genomic, biomarker data and correlates it with clinical, pathologic and outcome data to inform providers of an individual’s risk of developing cancer, guide them to appropriate clinical grade testing and provide clinical decision support to providers for prevention and management strategies over time. The iGAP Registry’s digital platform minimizes technological barriers to longitudinal research participation and is available in mobile and desktop formats, allowing for easy implementation in a wide variety of clinic and hospital settings. The risk tool uses predictive analytics to identify and curate patients at risk who are eligible for initial and further testing. The tool additionally can generate letters of medical necessity, each individualized by personal and family history, for eligibility for genetic testing (based on national guidelines) and additional imaging (based on validated cancer risk calculators). The insights tool provides physicians with decision support on how to interpret and manage abnormal genetic testing results on an individual level and supports improved understanding across lab terminology through variant classification. The insights tool also supplies letters of medical necessity and supporting evidence across many specialties. The platform connects the information stored in the risk and insights tools to a unique participant record and automatically feeds the data into a digital case report form for the research registry. Additional clinical data is entered for patients who consent to be a part of the Registry. This allows for seamless longitudinal data collection over time without disrupting typical clinical workflows, and is further enriched by emailed patient-reported outcomes and physician decision impact questionnaires. Follow-up occurs over 5 years after initial data entry for the 10,000 expected subjects in the Registry (Table 1). Conclusion The iGAP Registry is a multi-center longitudinal, observational research database with an integrated platform of clinically-useful tools designed to address gaps for providers specifically for identifying individuals at elevated risk based on clinical and pathologic factors, guiding them to appropriate genetic, genomic, and biomarker testing and providing clinical insights on actionable results for personalized management and prevention for the individual and their family members over time. The iGAP Registry is currently enrolling and accepting new sites at www.igapregistry.org or https://clinicaltrials.gov/ct2/show/NCT04419896. Table 1: Eligibility CriteriaRetrospective18 years or older;Is/was a patient at participating practice previously tested with germline, genomic, or biomarker tests;For germline patients, have a diagnosis of cancer or P/LP result.Prospective18 years or older;§Presents consecutively to a participating practice and who has previously been screened and tested;Receives/has received germline, genomic, or other biomarker testing, either through a prior provider or a participating practice;Consents to be a part of the registry. Citation Format: Rakesh Patel, Peter Beitsch, Pat Whitworth, Chloe Wernecke, Mary Kay Hardwick. The informed genetics annotated patient registry: The iGAP registry [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 OT-11-01.