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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.

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: Pathogenic genetic variants are estimated to occur in 10-15% of all breast cancer patients, with BRCA 1/2 accounting for 40-50% of pathogenic/likely pathogenic (P/LP) variants. However, it is estimated that Methods: An IRB-approved multicenter prospective registry was initiated with 20 community and academic sites experienced incancer genetic testing and counseling. Eligibility criteria included patients with a breast cancer diagnosis who had not been previously tested. Consecutive patients aged 18-90 were consented and underwent an 80 gene panel test (Invitae –Multi-Cancer Panel). The non-inferiority study was powered to detect a difference in P/LP variant rate of 4 percentage points with statistical significance (p HIPAA compliant electronic case report forms collected information on patient diagnosis, test results, and physician recommendations made after test results were received. Results: Over 1000 patients were enrolled and data from 910 subjects analyzed to date. 50.4% met NCCN criteria and 49.5% did not. Median age for the enrolled patients is 60.5 and ranged from 22-93. 56.0% of patients were recently diagnosed with breast cancer. 10.9% of patients had a history of a prior non breast cancer. Overall, 8.9% of patients had a pathogenicvariant. 9.6% of patients who met NCCN criteria with test results had a P/LP variant. 8.2% of patients who did not meet criteria had a P/LP variant. The difference of positive cases among the two groups is not statistically significant (P = 0.49) 4.9% of patients had pathogenic variants if only an 11 gene standard breast cancer panel was considered. The spectrum of mutated genes varied between the two groups, with some overlap. Conclusions: There was no statistically significant difference in the number of pathogenic/likely pathogenic variants between those patients who met and those who did not meet NCCN guidelines. Expanded panel testing yields more medically actionable P/LP variants than testing BRCA 1/2 alone or breast cancer panels with 11 genes. This study demonstrates that there will be a significant number of patients with P/LP variants are missed if NCCN guidelines are required for genetic testing. Current NCCN guidelines for the genetic testing of breast cancer patients are an obstacle to identifying patients with P/LP variants and should be removed. Universal BC Genetic Testing RegistryNCCN Criteria (910 patients analyzed)#/% who have P/LP variants#/% who do not have P/LP variantsPatients who meet guidelines44/459 (9.6%)415/459 (90.4%)Patients who do not meet guidelines37/451 (8.2%)414/451 (91.8%) Citation Format: Beitsch P, Whitworth P, Baron P, Rosen B, Compagnoni G, Simmons R, Smith LA, Holmes D, Brown E, Gold L, Clark P, Coomer C, Grady I, Barbosa K, Riley L, Kinney M, Lyons S, MacDonald H, Kahn S, Ruiz A, Patel R, Curcio L, Esplin E, Yang S. Underdiagnosis of HBOC in breast cancer patients: Are genetic testing guidelines a tool or an obstacle? [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-09-06.

Background: The testing of hereditary breast and ovarian cancer (HBOC) patients for BRCA1/2 only was established years ago to identify patients with clinically actionable variants and limit the economic burden. However, the cost of genetic testing has plummeted, and the number of breast cancer-risk genes with management guidelines has expanded. We created a community-based registry to test all breast cancer patients. A primary objective of this registry included accruing and comparing patients who did and did not meet NCCN guidelines and determining if providing all breast cancer patients with comprehensive multi-gene panel testing yields additional clinical value than testing BRCA1/2 alone. Methods: An IRB-approved multicenter prospective registry was initiated with 20 community-based and academic breast sites, selected to insure geographic and ethnic diversity. Consecutive patients ages 18-90 with current or prior breast cancer were offered testing with an 80-gene panel (Invitae, San Francisco, CA). HIPAA-compliant case report forms collected patient diagnosis, test results, and physician recommendations made after test results. Results: Over 1,000 patients were enrolled and data on 911 have been analyzed to date. Median age of patients is 60.5 (range 22 to 93). 56.0% were recently diagnosed with breast cancer. Of these patients, 50.54% met NCCN criteria, and 49.5% did not. 10.9% had history of a prior non-breast cancer. The pathogenic/likely pathogenic (P/LP) variant rate for patients on a comprehensive 80-gene panel was 8.9%. When restricted to a guidelines-based 11-gene breast cancer panel (BRCA1/2, ATM, CDH1, CHEK2, NBN, NF1, PTEN, STK11, TP53, PALB2), 4.9% had P/LP variants; when limited to BRCA1/2, 1.6% had P/LP variants. Of all patients with P/LP findings, 93% had variants in cancer-risk genes with established management recommendations (Table 1) and 80% had germline variants conferring eligibility for precision medicine-based cancer treatments, such as PARP inhibitors, through actively enrolling clinical trials. Conclusions: This study demonstrates that comprehensive panel testing of breast cancer patients provides a higher yield of clinically actionable P/LP variants than BRCA1/2 testing alone. Limited panels may miss clinically relevant P/LP variants, leaving risk for preventable cancers undiscovered and unnecessarily restricting patients' treatment options. These results also suggest that variants in tumor suppressor genes, not previously thought related to breast cancer, may contribute to its etiology. A comprehensive panel strategy reveals untapped clinical utility and can impact breast cancer patient care by informing implementation of precision medicine treatment interventions and guiding long-term medical management and surveillance for patients and their family members. PatientsVariantsWith breast cancer management guidelines (including variants ATM*, BRCA1*, BRCA2*, CHEK2*, NBN*, NF1, PALB2*, TP53*)45 (56%)46 (55%)With cancer guidelines and clinical management implications (including variants BARD1*, FH, MITF, MSH6*, MUTYH*, PTCH1, RAD50*, RAD51C*, RAD51D*, RB1, RET, VHL)31 (38%)33 (39%)Evidence of actionability accruing (including variants BLM, DIS3L2, RECQL4)5 (6%)5 (6%)Totals8184*P/LP variants in these genes confer potential clinical trial eligibility, e.g. NCT02401347. Citation Format: Beitsch P, Whitworth P, Baron P, Rosen B, Compagnoni G, Simmons R, Smith LA, Holmes D, Brown E, Gold L, Clark P, Coomer C, Grady I, Barbosa K, Riley L, Kinney M, Lyons S, MacDonald H, Kahn S, Ruiz A, Patel R, Curcio L, Esplin E, Yang S, Michalski S. Expanded panel testing superior to BRCA1/2 and breast cancer panel in patients with breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-09-03.

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.

1583 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 participated in an IRB approved registry. Patients with breast cancer were tested with an 80-gene panel; clinical information was collected. Results: Data on 912 patients has been analyzed to date. 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. 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. 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). Physician reported impact on patient outcome associated significantly with the presence of P/LP germline findings (p < 0.00001). There was no significant difference in the clinician reported clinical utility of variants of uncertain significance (VUS) compared to negative results (p = 0.467). 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.