Germline Genetic Test Results Research Articles

Evaluating genetic features and clinical characteristics of young women diagnosed with breast cancer by the age of 35.

10580 Background: Breast cancer in young women tends to be more aggressive with a unique distribution of molecular phenotypes compared to the general population. We evaluated the clinical characteristics and germline genetic test results in this cohort. Methods: We performed a single center retrospective review of 167 women diagnosed with breast cancer by 35, treated at our institution between the years 2013 to 2023. We reviewed medical records under Institutional Review Board approval for demographics, family history, tumor characteristics, surgical interventions performed, germline genetic test results, and number of pathogenic mutations identified. We used both descriptive and comparative quantitative statistics (student’s t test, Mann Whitney U Test and Chi Square tests) to compare data between patients with a pathogenic mutation and those without a pathogenic mutation. Results: Germline genetic testing was performed in 92.2% of individuals. The majority (81.4%) had no pathogenic mutation, whereas 15.6% had a pathogenic mutation implicated in hereditary breast cancer, and 3.0% had a pathogenic mutation not implicated in hereditary breast cancer. Our population was diverse - 60.4% white, 25.1% black, 7.8% Hispanic, and 6.5% Asian. Most patients had tumors that were high grade (56.3%), had a bilateral mastectomy performed (57.4%), did not have recurrence (87.4%), had exposure to oral contraceptives prior to diagnosis (59.9%), and had a family history of breast cancer (52.1%). 3.5% of patients were pregnant at the time of diagnosis. 26 patients were found to have pathogenic mutations implicated in hereditary breast cancer including BRCA1 (10), BRCA2 (10), CHEK2 (2), TP53 (2) and 88.5% of these patients underwent bilateral mastectomy. A higher proportion of patients with a pathogenic mutation were found to be progesterone receptor (PR) negative (56.8% vs 34.9; p = 0.029), undergo bilateral mastectomy (80.8% vs 53.2%; p = 0.009), be stage 1 at diagnosis (50.0% vs 19.1%; p < 0.001), have invasive ductal carcinoma (80.8% vs 59.6%; p = 0.040), and have a family history of breast cancer (73.1% vs 48.9%; p = 0.024) compared to those with no pathogenic mutation. While not statistically significant, a higher proportion of patients with pathogenic mutations experienced recurrence (19.2% vs 11.3%; p = 0.330). Conclusions: Our study showed that breast cancer diagnosed in young women has a more aggressive disease biology with 56.3% of the cohort found to have grade 3 disease. A higher proportion of those who had a pathogenic mutation implicated in hereditary breast cancer were found to be PR negative, underwent bilateral mastectomy, and had a family history of breast cancer. As our study was an exploratory observational study, further prospective multi-center studies are needed to help corroborate our findings and to better elucidate the potential clinical significance.

Population-Level Identification of Patients With Lynch Syndrome for Clinical Care, Quality Improvement, and Research.

Identification of those at risk of hereditary cancer syndromes using electronic health record (EHR) data sources is important for clinical care, quality improvement, and research. We describe diagnostic processes, previously seldom reported, for a common hereditary cancer syndrome, Lynch syndrome (LS), using EHR data within a community-based, multicenter, demographically diverse health system. Within a retrospective cohort enrolled between 2015 and 2020 at Kaiser Permanente Northern California, we assessed electronic diagnostic domains for LS including (1) family history of LS-associated cancer; (2) personal history of LS-associated cancer; (3) LS screening via mismatch repair deficiency (MMRD) testing of newly diagnosed malignancy; (4) germline genetic test results; and (5) clinician-entered diagnostic codes for LS. We calculated proportions and overlap for each diagnostic domain descriptively. Among 5.8 million individuals, (1) 28,492 (0.49%) had a family history of LS-associated cancer of whom 3,635 (13%) underwent genetic testing; (2) 100,046 (1.7%) had a personal history of a LS-associated cancer; and (3) 8,711 (0.1%) were diagnosed with colorectal cancer of whom 7,533 (86%) underwent MMRD screening and of the positive screens (486), 130 (27%) underwent germline testing. One thousand seven hundred and fifty-seven (0.03%) were diagnosed with endometrial cancer of whom 1,613 (92%) underwent MMRD screening and of the 195 who screened positive, 55 (28%) underwent genetic testing. (4) 30,790 (0.05%) had LS germline genetic testing with 707 (0.01%) testing positive; and (5) 1,273 (0.02%) had a clinician-entered diagnosis of LS. It is feasible to electronically characterize the diagnostic processes of LS. No single data source comprehensively identifies all LS carriers. There is underutilization of LS genetic testing for those eligible and underdiagnosis of LS. Our work informs similar efforts in other settings for hereditary cancer syndromes.

Abstract PO2-08-09: Prevalence of germline genetic variants in breast cancer susceptibility genes among patients with metaplastic breast cancer

Abstract Background: Pathogenic or likely pathogenic variants (PV) in breast cancer (BC) susceptibility genes are present in approximately 5-10% of individuals with breast cancer and approximately 13-15% of those with triple-negative breast cancer (TNBC). Identifying patients with PV in BRCA1 and BRCA2 can inform selection of appropriate candidates for poly(ADP-ribose) polymerase inhibitors (PARPi), which have improved progression-free and overall survival in the metastatic and adjuvant settings, respectively. Metaplastic breast cancer (MpBC) is a rare, aggressive subtype of breast cancer that is often triple-negative and refractory to chemotherapy. To date, limited data describe germline genetic findings in patients with MpBC. Methods: We conducted a retrospective chart review including patients with pathology results at the Hospital of the University of Pennsylvania from 2021 through May 2023 demonstrating MpBC. Germline genetic test results and tumor histopathologic characteristics including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status were evaluated. Descriptive statistics as well as two-tailed t tests were used for data analysis. Results: Of 89 patients identified with MpBC, 51 had germline genetic testing results available for review. Nine patients (17.6%) had MpBC with PV in BC predisposition genes (PV-MpBC) and 42 (82.4%) had PV-negative MpBC (PVneg-MpBC). Seven patients (13.7%) had a PV in BRCA1, 1 (2.0%) in BRCA2, and 1 (2.0%) in CHEK2. Median age at diagnosis was 45 years for patients with PV-MpBC and 56.5 years for those with PVneg-MpBC (p=0.005). Among patients with PV-MpBC, 6 (66.7%) had ER and PR negative disease by ASCO-CAP guidelines and 3 (33.3%) had ER and/or PR positive disease. Among patients with PVneg-MpBC, 31 (73.8%) had ER and PR negative disease and 11 (26.2%) had ER and/or PR positive disease. All 9 patients with PV-MpBC had HER2-negative disease, one (11.1%) of whom had HER2-low disease. Among patients with PVneg-MpBC, 40 (95.2%) had HER2-negative disease, two (4.8%) of whom had HER2-low disease, and 2 (4.8%) had HER2-positive BC. Conclusions: The frequency of PV in breast cancer susceptibility genes among patients with MpBC is comparable to, and possibly higher than, the reported rates of such PV in patients with TNBC, for whom genetic testing is recommended. If confirmed in a larger dataset, germline testing should be considered for all patients with MpBC regardless of ER, PR, and HER2 status, as findings may help identify candidates for PARPi therapy and genetically-directed clinical trials. Citation Format: Kaitlin Demarest, Anupma Nayak, Payal Shah. Prevalence of germline genetic variants in breast cancer susceptibility genes among patients with metaplastic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-08-09.

Abstract 4806: The potential impact of a Von Hippel-Lindau clinical care center for patients at the University of Illinois Chicago

Abstract Introduction: Von Hippel-Lindau (VHL) is an inherited autosomal dominant cancer syndrome causing early-onset tumors in various organs. It poses high risks of renal cell carcinoma, hemangioblastomas, pheochromocytomas, and paragangliomas among others. VHL can be clinically diagnosed based on the Danish, international, or Dutch guidelines, or through molecular diagnosis by identifying a pathogenic variant in the VHL gene. There is now an FDA-approved HIF-2 alpha inhibitor that is effective for the treatment of VHL-related manifestations, and the identification of eligible patients is paramount to receive this benefit. In addition, the screening recommendations for VHL are extensive and result in significant burden on patients. We suspect that VHL is under-diagnosed in the clinical setting, and we further hypothesize that this burden may contribute to care gaps and disparities in access to VHL-related care. Methods: This is a single-institution, retrospective study conducted at the University of Illinois Health and Hospitals System (UIH). We assessed the prevalence of patients with VHL-related tumors by examining ICD diagnosis codes from 2010 to 2023. Additionally, we analyzed the subset of these patients who underwent germ-line genetic testing. Furthermore, we examined our cohort of VHL patients more closely to explore the burden of VHL-related care. We examined the time to germ-line genetic and cascade testing from first clinical touchpoint at UIH, as well as the total number of clinical departments accessed at UIH. Demographics, clinical characteristics, germ-line genetic testing results, and information on clinical visits were also collected from those with a molecular or clinical diagnosis of VHL. Results: We found 9,875 patients with at least one VHL-associated tumor. Among them, 1,379 had two or more VHL-associated tumors, with <2% undergoing germline genetic testing. We identified 10 individuals diagnosed with VHL. Of the ten patients, 30% were black, 30% were white, and 40% self-identified as other. Age of onset for VHL-related screening ranged from 10 to 37 years. All patients diagnosed with VHL underwent germ-line genetic testing, with 60% opting for cascade testing of at-risk family members. Patient care was fragmented, with on average, each VHL patient seeking care from five different UIC clinical departments (range 1-11) and receiving care from multiple separate institutions (range 1-4). Conclusion: Our data revealed that most patients with VHL-associated tumors did not receive genetic testing, demonstrating a potential missed opportunity for early diagnosis and interventions to improve outcomes for VHL-related disease. Furthermore, our data highlights the clinical burden of VHL, and supports the potential impact of a coordinated care program for these patients. Citation Format: Neha Hippalgaonkar, Kirsten Drabek, Aseem Aseem, Tara Maga, Lara Balay, Vivian Pan, Pamela Ganschow, Karine Tawagi, Neha Awati, Natalie Reizine. The potential impact of a Von Hippel-Lindau clinical care center for patients at the University of Illinois Chicago [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4806.

An Australian mainstream genetic testing program: Clinicians views about current and future practices.

Germline genetic testing results can guide treatment decisions for oncology patients and are now offered to many cancer patients. Mainstream testing refers to genetic testing arranged by a non-genetics specialist. This repeated cross-sectional study aimed: (1) to capture clinician views on the existing mainstreaming genetic testing program for ovarian, breast, prostate, and endometrial cancer patients, and (2) to ascertain the interest of clinicians to consider changing practice to adopt mainstream testing. Mainstreaming has occurred since 2015 for patients with ovarian and some breast cancer patients, expanding to include prostate cancer patients in 2019, and endometrial cancer patients in 2020. Two web-based surveys were administered within two health districts, covering seven hospitals in NSW. Fifty-four clinicians (70% response rate) participated. Clinicians who had arranged mainstream genetic testing (n=30) were overall satisfied (76%), viewed the process as time-efficient and accessible for patients, and desired continuation of the program. Of those clinicians yet to engage in the program (n=24), 88% expressed an interest in learning about mainstream testing. These clinicians identified time constraints, maintenance of current genetic knowledge, and completing the consenting and counseling process as barriers to mainstreaming. Future mainstreaming models are discussed. From the clinician's perspective, the mainstreaming program is considered a desirable pathway for germline testing of oncology patients. Access to ongoing education and resources is needed for the ongoing success of the program.

When Germline Genetic Testing Results Are Unclear: Highlighting Variants of Uncertain Significance.

With the advent of high-throughput next-generation sequencing (NGS) and multigene panel testing, genetic testing and interpretations have become increasingly complex. Specifically, reports demonstrating "variant of uncertain significance" (VUS) present interpretative challenges. Misinterpretation of a VUS may result in clinical harm, emotional distress for patients and family members, and potential health-care provider liability. The following article and deidentified case study illustrate how a lack of health-care provider and patient understanding of a germline VUS resulted in a negative patient outcome and unnecessary surgery.

Abstract P6-02-09: Racial/Ethnic Groups Have Different Rates of Pathogenic Variants in Common Cancer Genes

Abstract Background: Racial/ethnic disparities have been well-documented in access to cancer screening and treatment, as well as treatment outcomes. Less is known regarding the yield of genetic pathogenic variants (PVs) in non-white populations. Methods: Patient data was obtained from the Informed Genetics Annotated Patient Registry (iGAP), an IRB-approved multi-center longitudinal, observational study, in which 2148 patients self-declared race/ethnicity and underwent germline genetic testing at any lab. Analyses were limited to 24 cancer susceptibility genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, NBN, PALB2, PTEN, STK11, TP53, APC, BMPR1A, CDK4, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, RAD51C, RAD51D, SMAD4), 21 of which have clinical management guidelines from the NCCN (excluding NBN, BARD1, CDK4).1 Descriptive statistics were used to assess and compare data from these populations and germline genetic testing results. Results: The Registry included 2148 patients, 1662 (77.37%) with a personal history and 1536 (71.51%) with a family history of cancer. The patients were 74.39% White, 6.33% Hispanic, 5.59% African/Black, 5.03% Asian, 1.63% Other, 1.35% Ashkenazi, and 5.68% Unknown. The overall germline PV rate in the cohort was 0.1089 PVs/patient tested, with 234 PVs detected in 227 patients. The PV rate among racial/ethnic groups were as follows: White 170/1598 (0.1064), Asian 8/108 (0.0741), Hispanic 27/136 (0.1985), African/Black 11/120 (0.0917), Ashkenazi 6/29 (0.2069). In patients self-reporting as Hispanic, the PV rate was similar to PV rate in those self-reporting as Ashkenazi, and significantly higher (p=0.00027) than PV rate in those of other self-reported race/ethnicity. Gene level PV rates are shown in Table 1. Conclusions: Those who reported being Hispanic had an increased overall PV rate. This could be due to the greater representation of Hispanics from New Mexico who may have Ashkenazi ethnicity. Further studies are needed to understand whether these differences are a result of disparate access to testing, true population differences, lack of data in non-White populations skewing variant classification or other factors. Table 1. Gene PV Rates by Racial/Ethnic Category. Citation Format: Peter Beitsch, Chloe Wernecke, Rakesh Patel, Barry Rosen, Gia Compagnoni, Ian Grady, Eric Brown, Lindsay Gold, Pat Whitworth, Linda Ann Smith, Mariusz Wirga, Richard Reitherman, Steven Cai, Toan Nguyen, Valerie Traina, Dennis Holmes, Paul Baron, Brittany Krautheim, Anne Peled, Walt Taylor, Kelly Bontempo, Brenna Bentley, Krista Ortega, Pouyan Ahmadi. Racial/Ethnic Groups Have Different Rates of Pathogenic Variants in Common Cancer Genes [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-02-09.

Comparison of Germline Genetic Testing Before and After a Medical Policy Covering Universal Testing Among Patients With Colorectal Cancer

In 2020, some health insurance plans updated their medical policy to cover germline genetic testing for all patients diagnosed with colorectal cancer (CRC). Guidelines for universal tumor screening via microsatellite instability and/or immunohistochemistry (MSI/IHC) for mismatch repair protein expression for patients with CRC have been in place since 2009. To examine whether uptake of MSI/IHC screening and germline genetic testing in patients with CRC has improved under these policies and to identify actionable findings and management implications for patients referred for germline genetic testing. The multicenter, retrospective cohort study comprised 2 analyses of patients 18 years or older who were diagnosed with CRC between January 1, 2017, and December 31, 2020. The first analysis used an insurance claims data set to examine use of MSI/IHC screening and germline genetic testing for patients diagnosed with CRC between 2017 and 2020 and treated with systemic therapy. The second comprised patients with CRC who had germline genetic testing performed in 2020 that was billed under a universal testing policy. Patient demographic characteristics, clinical information, and use of MSI/IHC screening and germline genetic testing were analyzed. For 9066 patients with newly diagnosed CRC (mean [SD] age, 64.2 [12.7] years; 4964 [54.8%] male), administrative claims data indicated that MSI/IHC was performed in 6645 eligible patients (73.3%) during the study period, with 2288 (25.2%) not receiving MSI/IHC despite being eligible for coverage. Analysis of a second cohort of 55 595 patients with CRC diagnosed in 2020 and covered by insurance found that only 1675 (3.0%) received germline genetic testing. In a subset of patients for whom germline genetic testing results were available, 1 in 6 patients had pathogenic or likely pathogenic variants, with most of these patients having variants with established clinical actionability. This nationwide cohort study found suboptimal rates of MSI/IHC screening and germline genetic testing uptake, resulting in clinically actionable genetic data being unavailable to patients diagnosed with CRC, despite universal eligibility. Effective strategies are required to address barriers to implementation of evidence-based universal testing policies that support precision treatment and optimal care management for patients with CRC.

Lynch Syndrome Identification in Endometrial Cancer Patients: Should Universal Screening be Used for all Histologies?

Background: There is an increased proportion of non-endometrioid histologies in Lynch syndrome-associated compared to sporadic endometrial cancer; however, screening recommendations do not differ between type I and type II cancers. Objective: Our objective was to examine the frequency of Lynch syndrome identified in type I and type II endometrial cancers and their associated characteristics. Methods: We reviewed patients with type I and type II endometrial cancer who were screened for Lynch Syndrome or referred for genetic testing according to an age and family history-based screening protocol. All patients were seen and treated at a large academic institution affiliated with a county safety-net hospital. Clinical, pathologic, immunohistochemistry, and germline genetic testing results were obtained as well as the choice of genetic screening approach, personal and family history, and compliance with testing were assessed. Results: 234 women with type I and 29 patients with type II endometrial cancer were identified. Lynch syndrome was diagnosed in a total of eight (3.4%) type I endometrial cancer patients, all identified after age-based tumor screening. In type II endometrial cancer group, three (10.3%) patients had Lynch syndrome. One was referred for testing after abnormal immunohistochemistry screening under age 60. The other two were >60 years old and identified after abnormal immunohistochemistry screening performed on physician’s request. Conclusion: Age-based screening may not diagnose Lynch Syndrome in women with type II endometrial cancers. Our findings underscore the need for a universal screening approach in patients with type II endometrial cancers, even in a low-resource population.

Abstract P3-09-11: Clinical characteristics associated withBRCA1/2mutations identified on routine tumor tissue genotyping in metastatic breast cancer

Abstract Background: Tumor tissue genotyping (TG) can identify actionable mutations for potential therapeutic intervention. PARP inhibitors are approved for the treatment of metastatic breast cancer (MBC) in germline BRCA1/2 carriers, and may have efficacy in somatic BRCA1/2-mutant MBC. We studied the clinical features of BRCA1/2 mutations detected on routine TG of tumors in patients with MBC. Methods: Consecutive patients with MBC at an academic medical center who underwent TG (institutional next generation sequencing (NGS), 91 gene assay; coverage includes BRCA1 exons 2-23 and BRCA2 exons 2-27) as part of routine clinical care from June 2016 to September 2020 were identified. The subset with BRCA1/2 mutations underwent further chart review to determine demographics, coexisting genomic landscape, germline genetic testing results, cell-free DNA (cfDNA) results, and treatment with a PARP inhibitor. Variant classification and presumed germline/somatic status was determined by pathologists, using a combination of automated bioinformatics tools and manual review of NGS read pile-ups, allele frequency, variant annotation, and by querying publically-available genomic databases including ClinVar, COSMIC, and gnomAD. Pathogenic status of mutations was determined via manual review by a molecular genetic pathologist using online genomic resources (ClinVar, mycancergenome, ARUP, and pubmed). Concordance between cfDNA and TG was assessed. Results: Of 372 patients with MBC who underwent TG, 46 (12.4%) had BRCA1/2 mutations identified on TG (85% on metastatic specimens), 15 (33%) BRCA1 and 31 (67%) BRCA2, with 1 patient having both BRCA1 and BRCA2 mutations. Of these, 26 (57%) were hormone receptor (HR)+/HER2-, 14 (30%) were triple negative (TNBC), 3 (6.5%) were HR-/HER2+, and 3 (6.5%) had HR+/HER2+ MBC. Thirty-four mutations (74%) were pathogenic. Median age at MBC diagnosis was 61 years (range 31-82). Common co-existing mutations found in TG included TP53 (37%), PI3KCA (22%), NF1 (8.6%), ESR1 (8.6%), MAP3K1 (6.5%), ATM (6.5%), and PTEN (6.5%). Of 22 patients with BRCA1/2 mutations on TG who had cfDNA testing results available, 10 (45%) had concordant BRCA1/2 mutations seen in TG and cfDNA. On expert review, 29 (63%) BRCA1/2 mutations were presumed germline mutations, and 17 (37%) were presumed somatic mutations. Eighteen patients with germline genetic testing results available had confirmed germline BRCA1/2 mutations. Fourteen patients with presumed germline BRCA1/2 mutations received a PARP inhibitor with a median duration of response (DOR) of 6 months (range 2-28). Two patients with presumed somatic BRCA1/2 mutations received a PARP inhibitor with median DOR of 13 months (range 10-16). Conclusions: TG can identify both germline and somatic BRCA1/2 mutations in a proportion of patients with MBC, especially HR+/HER2- and TNBC, and in conjunction with TP53 mutations. Some of these mutations in TG are concordant with cfDNA. The identification of BRCA1/2 mutations on TG may lead to consideration of genotype-directed therapy with a PARP inhibitor in germline and somatic BRCA1/2-mutant cancers. Citation Format: Neelima Vidula, Erica Blouch, Alexander Farahani, Hetal Marble, Andrzej Niemierko, Kathleen Hesler, Elyssa Denault, Dejan Juric, Leif W. Ellisen, Beverly Moy, Steven Isakoff, Jochen Lennerz, Aditya Bardia. Clinical characteristics associated withBRCA1/2mutations identified on routine tumor tissue genotyping in metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-09-11.

Abstract P3-07-03: Real-world evidence database reveals 17.74% of individuals with breast cancer harbor a germline pathogenic or likely-pathogenic variant with implications for medical management and/or reproduction

Abstract Background:Uncovering germline genetic variants responsible for cancer predisposition allows providers to implement personalized medical care for patients. Guidelines were designed to help identify individuals who qualify for genetic testing, yet multiple studies have shown that approximately half of patients with P/LP variants are missed using these guidelines. While guidelines have continued to evolve as more robust data have become available, patients who do not meet these guidelines may not be identified as having a cancer predisposition syndrome. In studies focusing on patients with multiple cancer subtypes, comparisons of universal genetic testing versus guideline-directed for patients revealed a 12.5% likelihood of a pathogenic germline variant. This has also been studied specifically in patients with colorectal cancer, revealing that 15.5% of affected individuals have an identifiable pathogenic variant. As research continues to evaluate universal testing in oncology, it is increasingly evident that we are approaching pathogenic variant carrier frequencies that argue for a more aggressive expansion of guidelines. This has been the catalyst for recommending germline genetic testing for all patients with breast cancer. However, as insurance companies and national guidelines do not yet support this recommendation, here we set out to examine the mutation rate in all patients with breast cancer versus patients with breast cancer diagnosed at or before age 65 years. Methods:Patient data was obtained from the Informed Genetics Annotated Patient Registry (iGAP), an IRB-approved multi-center longitudinal, observational study designed to capture genetic and genomic test results and their utilization and impact on treatment practices and outcomes. Descriptive statistics were used to assess and compare data of these populations and germline genetic testing results. Results:Of the 1,302 subjects currently enrolled in the registry, 1,132 have been diagnosed with any cancer type (86.89%), of which 868 have specifically been diagnosed with breast cancer (76.657%). Results indicate that 19.04% of individuals (1 in 4.56) with any cancer type have a germline pathogenic or likely-pathogenic variant associated with cancer predisposition and/or implications for reproduction. Specific to breast cancer, results indicate that 17.74% of individuals (1 in 5.6) harbor a germline pathogenic or likely-pathogenic variant with these same implications. Of the patients with breast cancer, 71.54% were diagnosed prior to age 65 years, while 28.45% were diagnosed at or above age 65 years. 108 patients diagnosed before age 65 years had a P/LP (70.12%) while 46 diagnosed at or above age 65 years had a P/LP variant (29.87%). Conclusion:The iGAP real-world evidence database reveals 17.74% (1 in 5.6) of individuals with breast cancer harbor a pathogenic or likely-pathogenic variant in the germline with implications for medical management and/or reproduction. Given the implications these results can have on patients’ and family members’ health, testing guidelines for breast cancer should be expanded so those with hereditary predispositions can be identified and make informed decisions about preventative measures to reduce risks for a second cancer and overall mortality. Identifying those pathogenic/likely-pathogenic variants also allows for cascade testing of at-risk, likely unaffected relatives, helping reduce overall cancer incidence in the general population. Additionally, since cancer predisposition genes can also confer reproductive implications related to autosomal recessive disorders, expanding testing guidelines can arm patients with additional information that can aid in reproductive decision making. Citation Format: Kelly Bontempo, Chloe Wernecke, Caitlin Mauer, Brenna Bentley, Maureen Graham, Pat Whitworth, Rakesh Patel, Peter Beitsch. Real-world evidence database reveals 17.74% of individuals with breast cancer harbor a germline pathogenic or likely-pathogenic variant with implications for medical management and/or reproduction [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-07-03.

Investigating the role of somatic sequencing platforms for phaeochromocytoma and paraganglioma in a large UK cohort.

ObjectivesPhaeochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumours with malignant potential and a hereditary basis in almost 40% of patients. Germline genetic testing has transformed the management of PPGL enabling stratification of surveillance approaches, earlier diagnosis and predictive testing of at‐risk family members. Recent studies have identified somatic mutations in a further subset of patients, indicating that molecular drivers at either a germline or tumour level can be identified in up to 80% of PPGL cases. The aim of this study was to investigate the clinical utility of somatic sequencing in a large cohort of patients with PPGL in the United Kingdom.Design and PatientsProspectively collected matched germline and tumour samples (development cohort) and retrospectively collected tumour samples (validation cohort) of patients with PPGL were investigated.MeasurementsClinical characteristics of patients were assessed and tumour and germline DNA was analysed using a next‐generation sequencing strategy. A screen for variants within ‘mutation hotspots’ in 68 human cancer genes was performed.ResultsOf 141 included patients, 45 (32%) had a germline mutation. In 37 (26%) patients one or more driver somatic variants were identified including 26 likely pathogenic or pathogenic variants and 19 variants of uncertain significance. Pathogenic somatic variants, observed in 25 (18%) patients, were most commonly identified in the VHL, NF1, HRAS and RET genes. Pathogenic somatic variants were almost exclusively identified in patients without a germline mutation (all but one), suggesting that somatic sequencing is likely to be most informative for those patients with negative germline genetic test results.ConclusionsSomatic sequencing may further stratify surveillance approaches for patients without a germline genetic driver and may also inform targeted therapeutic strategies for patients with metastatic disease.

Pilot experience using tumor-based next generation sequencing increases compliance and reduces barriers for ovarian cancer genetic testing

<h3>Objectives:</h3> Although hereditary risk assessment is advised for all ovarian/tubal/peritoneal (OTP) cancer patients, a variety of barriers limit universal compliance. A workflow using tumor-based next generation sequencing (NGS) germline testing implemented by the pathologist at the time of primary or interval debulking surgery. The objective of this study is to report compliance and turnaround time of a pilot workflow of germline testing via tumor-based NGS in OTP cancer. may reduce some of these barriers. <h3>Methods:</h3> We identified all patients with a new diagnosis of epithelial OTP carcinoma who underwent primary or interval debulking surgery from January to August 2020. All patients were recommended to undergo tumor and germline sequencing, either through our institutional NGS platform or through commercial sequencing. We compared time to results as well as influence of results on maintenance/second-line therapy. <h3>Results:</h3> We identified 35 patients with a median age of 61 (range 29-78) and a median follow-up time of 5 months (range 0-13). Our stage breakdown included 8 Stage I, 4 Stage II, 20 Stage III, and 3 Stage IV patients. A total of 24 patients had high grade serous carcinoma, with 5 endometrioid, 3 clear cell, 2 mucinous, and one high grade NOS tumor. A total of 11 patients underwent interval debulking surgery after neoadjuvant chemotherapy. All but 2 (94.2%) of patients received a genetic counseling referral. A total of 2 patients did not have sequencing performed, while 1 patient did not have enough tumor for sequencing at the time of interval debulking surgery. A total of 10 patients had both tumor and germline sequencing performed at the time of tumor testing, while 20 others had tumor only sequencing. For those patients who did not have a known hereditary germline mutation prior to surgery, the mean turnaround time for germline genetic testing results was 26.5 days (range 19-51) in the NGS + germline group whereas the median turnaround time after commercial testing was 75 days (regardless of primary or interval debulking, range 19-202), p=0.006. A total of 5 patients were identified as germline carriers of the <i>BRCA1</i> or <i>BRCA2</i> mutation, with 1 addition germline finding of a pathogenic variant in ATM. An additional 5 patients had somatic pathogenic mutations in homologous recombination repair pathway genes, all of whom are receiving or being considered for PARP inhibitor maintenance after primary treatment. <h3>Conclusions:</h3> Combining somatic and germline tumor testing at the time of staging/debulking surgery requires upfront coordination with pathology and patient consent, but streamlines the genetic testing process to improve testing rates allow timely results for treatment planning. This approach may also identify additional patients with homologous recombination deficient tumors through simultaneous somatic mutation assessment.

Abstract 803: Molecular diagnosis and immunotherapy of a rare lung carcinoma patient associated with PMS2 c.1144+1G&amp;gt;A mutation-driven Lynch syndrome

Abstract Background: Lynch syndrome (LS) is an autosomal dominant genetic disease caused by mutations in DNA mismatch repair (MMR) genes, leading to an increased risk of colorectal cancer and other malignancies. Tumors with MMR-deficiency often have microsatellite instability (MSI) and high mutational burden (TMB) which predict high response rate to immunotherapy. Therefore, accurate diagnosis of LS can create valuable opportunities for the clinical management of a broad spectrum of cancers. Methods: We conducted next-generation sequencing to assess both somatic and germline mutations of the proband. LS diagnosis was confirmed by mismatch repair protein immunochemistry and germline genetic testing results. Furthermore, we applied Sanger sequencing to screen the candidate variant in his family members. Results: Our proband is a 62-year-old Chinese diagnosed with invasive lung adenocarcinoma (pT1aN2M0, stage IIIA) in the right inferior lobe. Based on the near completely loss of PMS2 in cancer cells by MMR IHC, as well as instability of three MSI markers (NR21, BAT-26 and MONO-27), we suspected LS and performed a germline NGS panel analysis which revealed a G&amp;gt;A nucleotide substitution (c.1144+1G&amp;gt;A) located at the +1 position of intron 10 of the PMS2 gene. We also found that the proband has an oncogenic KRAS p.G13D somatic mutation and his young daughter with the same PMS2 variant has no cancer yet. To characterize the pathogenicity of this PMS2 germline variant, we conducted a comprehensive genetic analysis according to the ACMG/Sherloc guidelines. In silico analysis with three splice prediction programs suggested that the PMS2 c.1144+1G&amp;gt;A variant will generate aberrant splicing transcripts. The population data in the gnomAD web portal showed that the allele frequency of PMS2 c.1144+1G&amp;gt;A variant is 2/282496 without homozygotes, falling into the pathogenic range defined by the Sherloc guideline. Importantly, in a family with germline PMS2 c.1144+2T&amp;gt;A variant, which disrupts the same splice donor site as c.1144+1G&amp;gt;A, the cosegregation between this variant and LS-related cancers was clearly seen. Based on all these results, we classified the PMS2 c.1144+1G&amp;gt;A variant as likely pathogenic, and disruption of this specific PMS2 splicing site results in LS. Combination chemotherapy with cisplatin (75 mg/m2), pemetrexed (500 mg/m2), and nivolumab (200 mg) was administered after surgery every 3 weeks for a total of 4 cycles to the patient. He achieved 16 months DFS. We then provided an up-to-date genetic counseling to the patient's daughter with the same PMS2 variant. Conclusion: Our findings suggest that accurate LS diagnosis with modern pathology approaches including MSI/MMR-d testing and NGS sequencing offers extracolonic cancer patients the opportunity to reduce cancer-related morbidity and mortality through innovative treatments such as immunotherapy. Citation Format: Quanli Han, Xiaomo Li, Tonghui Ma, Qi Wang, Zhi Cui. Molecular diagnosis and immunotherapy of a rare lung carcinoma patient associated with PMS2 c.1144+1G&amp;gt;A mutation-driven Lynch syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 803.

Cancer-specific mortality associated with germline genetic testing results among women with breast cancer or ovarian cancer treated with chemotherapy.

10517 Background: Breast and ovarian cancer patients increasingly undergo germline genetic testing. While studies suggest a greater chemotherapy benefit for carriers of BRCA1/2 pathogenic variants, little is known about whether pathogenic variants in other genes are associated with cancer mortality. Methods: Georgia and California Surveillance, Epidemiology and End Results (SEER) registry records of women diagnosed with breast cancer or ovarian cancer from 2013-2017 were linked to results of clinical germline genetic testing from four participating laboratories. Patients were included if they linked to a genetic result, had stages I-III breast cancer or I-IV epithelial ovarian cancer and received chemotherapy. Multivariable Cox proportional hazard models were used to examine the association of genetic results, demographic and clinical factors with cancer-specific mortality. Results: 21,348 breast and 4,320 ovarian cancer patients were analyzed with median follow-up of 41 months. Pathogenic variants were present in 12% of patients with estrogen and progesterone receptor-positive, HER2-negative breast cancer, 9% with HER2-positive breast cancer, 17% with triple-negative breast cancer and 18% with ovarian cancer. Pathogenic variants were most common in BRCA1/2, CHEK2, PALB2, ATM and BRIP1. Among triple-negative breast cancer patients, mortality was lower with pathogenic variants in BRCA1 (hazard ratio (HR) 0.27, 95% confidence interval (CI) 0.17-0.45) and genes other than BRCA1/2 (HR 0.33, CI 0.13-0.81) versus no pathogenic variant. Genetic results were not associated with mortality in other breast cancer subtypes. Among ovarian cancer patients, mortality was lower with pathogenic variants in BRCA2 (HR 0.36, CI 0.26-0.49) and in genes other than BRCA1/2 (HR 0.48, CI 0.33-0.70). Conclusions: Among breast and ovarian cancer patients treated with chemotherapy, those with germline pathogenic variants in several cancer-associated genes had equivalent or lower short-term mortality than those testing negative. These results may guide patient counseling and clinical trial design.

Improved universal tumor screening program with paired testing: Experience at a large community-based teaching hospital.

e22505 Background: Lynch syndrome (LS) is the most common cause of hereditary predisposition to colon, endometrial, and other cancers. The universal tumor screening program for LS at Beaumont Health (BH) utilizes immunohistochemistry (IHC) of the mismatch repair (MMR) proteins to identify patients for genetics evaluation. We present the 8-year experience of the program at a large community-based teaching hospital. Methods: The MMR IHC results for all colorectal cancer (CRC) resection specimens screened from August 2012 to September 2020 were reviewed. Specimens with absent MLH1 and PMS2 were evaluated for MLH1 promoter hypermethylation with reflex to BRAF V600E mutation analysis. All abnormal results were referred for cancer genetics evaluation. The distribution of abnormal MMR and germline genetic testing results was analyzed. Results: Specimens from 2361 CRC resections were screened, and 511 specimens had abnormal MMR IHC (22%). Most cases of absent MLH1 and PMS2 were explained by hypermethylation or BRAF analysis (n = 338, 66% of all abnormal, 89% of MLH1 and PMS2). Of the remaining cases showing MMR deficiency (n = 173), the most common result was absence of MSH2 and MSH6 (n = 67), followed by absence of MLH1 and PMS2 (n=41, see table). Germline genetic testing of 83 individuals with abnormal MMR IHC revealed 49 cases of Lynch syndrome [MLH1 (n=9), MSH2 (n= 25), MSH6 (n=7), PMS2 (n=7), EPCAM (n=1)]. A significant proportion of cases (n=34, 40%) had negative germline testing, and had unexplained MMR deficiency. Paired germline/tumor testing was implemented in 2017, and 14 patients had this analysis. Using this approach, 5 individuals were identified to have somatic mutations explaining their result, and the proportion of unexplained cases was reduced to 29% (n = 4). Conclusions: Recent advances in cancer screening and therapeutics have underscored the importance of analyzing tumors for mismatch repair deficiency (dMMR), with known challenges to implementation and interpretation of results. The BH cancer genetics program has demonstrated successful growth of a universal tumor screening program over 8 years. This has led to the identification of a large number of dMMR tumors (22% of all CRC resections) and LS cases (2% of all CRC resections), which impacts management for patients and their families. Recent implementation of paired germline/tumor testing has improved the testing algorithm, and resulted in more accurate interpretation of a greater proportion of abnormal IHC results. This combined approach allows for focused high-risk screening for LS patients, access to novel therapeutic interventions including immune therapies for patients with dMMR tumors, and future precision oncology approaches.[Table: see text]

Does Transfusion of Red Blood Cells Impact Germline Genetic Test Results?

Purpose: molecular testing is often indicated for recently transfused patients. However, there are no guidelines regarding the potential interference from donor DNA or whether it is necessary to wait for a period of time post-transfusion prior to genetic testing. While the majority of patients are transfused in the non-trauma setting using leukoreduced (LR) red blood cell products, the degree of leukoreduction varies among centers and is not universally practiced. Methods: whole blood units collected from anonymous donors were used in an in vitro transfusion model. One unit was split: half being leukoreduced simulating a leukopenic recipient and half left untreated. Donors were simulated by leukoreduced, partially leukoreduced (PLR), or non-leukoreduced units, transfused in 2, 5, or 16 unit equivalents. DNA from the combinations were subjected to short tandem repeat (STR) analysis for chimerism detection. Results: donor DNA was not detectable in any of the LR combinations, but detected in the PLR combinations, ranging from 0.1 to 1.5% donor DNA in the immunocompetent recipient and 6.3–27.8% in the leukopenic recipient. Non-LR donor DNA was also detected (13–95%). Conclusion: donor-derived DNA from leukoreduced blood products is unlikely to interfere with the interpretation of germline genetic testing in immunocompetent recipients but may interfere in immunocompromised recipients.

Disparities in precision medicine—Examining germline genetic counseling and testing patterns among men with prostate cancer

IntroductionThis study sought to examine whether germline genetic counseling and testing were employed differentially among men with prostate cancer by race and/or ethnicity and other social factors. MethodsIn this retrospective analysis, all patients with prostate cancer listed as a visit diagnosis during the study period (April 2011 to August 2020) were identified from electronic health records. Patient characteristics were collected along with genetic counselor visits and germline genetic testing results in electronic health records. Multivariable analyses were performed with the primary outcome defined as the receipt of a genetic counseling visit and receipt of genetic testing. ResultsA total of 14,610 patients with a prostate cancer diagnosis code were identified. The majority of patients were White (72%), aged >=65 years (62.7%), English-speaking (95%), married (71.4%), and publicly insured (58.7%). A total of 667 patients completed an appointment with a genetic counselor. A total of 439 patients received germline genetic test result, of whom 403 (91.8%) had also completed an appointment with a genetic counselor. Patients that were 65 years or older (adjusted odds ratio 0.53, 95%CI 0.44–0.65) and non-English proficient (adjusted odds ratio 0.71, 95%CI 0.42–1.21) were less likely to receive genetic counseling. Receiving genetic counseling was the strongest independent predictor of receipt of genetic testing. ConclusionsThe results of the current study highlight that the role of social factors in contributing to disparities in genetic counseling and testing among men with prostate cancer. These results underscore the importance of developing novel strategies to tackle contributors of observed disparities including language, age, and insurance status.

Investigation of triple negative breast cancer rates in women diagnosed with breast cancer in Trinidad and Tobago.

e19005 Background: According to the WHO/PAHO, Trinidad and Tobago (T&amp;T) has the 2nd highest breast cancer mortality rate in the Caribbean region. In T&amp;T, citizens of African descent make up about 36.8% of the T&amp;T population, with 24.8% being of East Indian ancestry, and 32.4% identifying as having mixed heritage. In the United States, it has been showed that African American women, despite being diagnosed less often, have an earlier onset of breast cancer with less favorable clinical outcomes. One of the factors studied has been the higher frequency of triple negative breast cancer (TNBC) in African American women particularly when these patients are diagnosed at a younger age. Notably, a large proportion of breast cancer cases in T&amp;T appear to occur at a young age, with nearly 36% of them being diagnosed under the age of 50. However, breast cancer tumor phenotypes have not been well studied. Therefore, we sought to investigate the distribution of tumor hormone receptor markers in the T&amp;T breast cancer population. Methods: At the National Radiotherapy Center, T&amp;T’s main oncology unit, we investigated breast cancer patients born in T&amp;T using paper chart reviews. We collected information about their demographics, personal breast cancer diagnosis, tumor hormone receptor status and germline genetic testing results. Results: So far, we reviewed 90 patient charts, and in our sample, 33.3% (30/90) had TNBC. This is higher than the rates in the US where TNBC accounts for 10-20% of breast cancer patients, and of those TNBC cases, 10.6% have BRCA 1 or BRCA 2 mutations. In our T&amp;T sample, of those with TNBC, 23.3% (7/30) had a HBOC mutation (5 BRCA, 1 TP53 and 1 PTEN). Average diagnosis age of TNBC cases reported in our sample was 45.7 years. In our sample, 52.2% (47/90) identified as having African ancestry, 37.8% (34/90) identified as having East Indian ancestry and 10% (9/90) identified as Mixed. Of the patients with TNBC, 63.3% (19/30) were of African ancestry, 30.0% (9/30) were of East Indian ancestry and 6.7% (2/30) identified as Mixed. Conclusions: Therefore, our sample results suggest that there is a significant portion of the breast cancer cases being TNBC in the T&amp;T population, particularly in citizens with African ancestry. As we continue to finalize the incoming data, we hope to draw associations between tumor pathology, clinical presentation and genetic profiles. However, these initial results demonstrate the need to study tumor pathology within the T&amp;T population, as this could lead to improved clinical and screening guidelines specific to T&amp;T citizens.

Association of Germline Genetic Testing Results With Locoregional and Systemic Therapy in Patients With Breast Cancer

The increasing use of germline genetic testing may have unintended consequences on treatment. Little is known about how women with pathogenic variants in cancer susceptibility genes are treated for breast cancer. To determine the association of germline genetic testing results with locoregional and systemic therapy use in women diagnosed with breast cancer. For this population-based cohort study, data from women aged 20 years or older who were diagnosed with stages 0 to III breast cancer between 2014 and 2016 were accrued from the Surveillance, Epidemiology and End Results (SEER) registries of Georgia and California. The women underwent genetic testing within 3 months after diagnosis and were reported to the Georgia and California SEER registries by December 1, 2017. Pathogenic variant status based on linked results of clinical germline genetic testing by 4 laboratories that did most such testing in the studied regions. Potential deviation of treatment from practice guidelines was assessed in the following clinical scenarios: (1) surgery: receipt of bilateral mastectomy by women eligible for less extensive unilateral surgery (unilateral breast tumor); (2) radiotherapy: omission in women indicated for postlumpectomy radiotherapy (all lumpectomy recipients except age ≥70 with stage I, estrogen and/or progesterone receptor [ER/PR] positive, ERBB2 [formerly HER2]-negative disease); and (3) chemotherapy: receipt by women eligible to consider chemotherapy omission (stages I-II, ER/PR-positive, ERBB2-negative, and 21-gene recurrence score of 0-30, which was the upper limit of the intermediate risk range during the study years). The adjusted percentage treated and adjusted odds ratio (OR) are reported based on multivariable modeling for each treatment-eligible group. A total of 20 568 women (17.3%) of 119 198 were eligible (mean [SD] age, 51.4 [12.2]). Compared with women whose test results were negative, those with BRCA1/2 pathogenic variants were more likely to receive bilateral mastectomy for a unilateral tumor (61.7% vs 24.3%; OR, 5.52, 95% CI, 4.73-6.44), less likely to receive postlumpectomy radiotherapy (50.2% vs 81.5%; OR, 0.22, 95% CI, 0.15-0.32), and more likely to receive chemotherapy for early-stage, ER/PR-positive disease (38.0% vs 30.3%; OR, 1.76, 95% CI, 1.31-2.34). Similar patterns were seen with pathogenic variants in other breast cancer-associated genes (ATM, CDH1, CHEK2, NBN, NF1, PALB2, PTEN, and TP53) but not with variants of uncertain significance. Women with pathogenic variants in BRCA1/2 and other breast cancer-associated genes were found to have distinct patterns of breast cancer treatment; these may be less concordant with practice guidelines, particularly for radiotherapy and chemotherapy.