BRCA Testing Research Articles

Disparities in Genetic Management of Breast and Ovarian Cancer Patients.

Hereditary breast and ovarian cancer syndrome (HBOC) is most often caused by pathogenic variants in the BRCA1 or BRCA2 genes. Guidelines exist for genetic testing in patients at high risk, yet significant disparities in genetic testing and management remain. These disparities result in missed opportunities for cancer prevention and treatment. This review details the multiple layers of disparities in genomic knowledge, testing referral, completion, and posttesting risk reduction for at-risk populations. A comprehensive search of the PubMed database was conducted in September 2023 for studies addressing disparities at all points of HBOC risk assessment and risk reduction. Disparities in genomic knowledge, referral and testing, and in cancer risk reduction exist by race, ethnicity, insurance status, socioeconomic status, age, and care setting in the United States. Many mitigation strategies have been explored with some success. Each component contributes to a "leaky pipe" in BRCA testing and management whereby patients eligible for intervention trickle out of the pipe due to inequities at each step. Implementation of proven strategies aimed at disparity reduction in this setting is essential, as well as additional strategy development. This review provides clinicians with a comprehensive understanding of disparities in the identification and management of individuals at risk for or diagnosed with HBOC and strategies to reduce disparities in their own practice.

BRCA and homologous recombination repair deficiency testing in advanced ovarian cancer: A real-world data analysis

BRCA and homologous recombination repair deficiency testing in advanced ovarian cancer: A real-world data analysis

BRCA awareness and testing experience in the UK Jewish population: A qualitative study

BRCA awareness and testing experience in the UK Jewish population: A qualitative study

Population-based BRCA1 and BRCA2 genetic testing is cost-effective in Canada

Population-based BRCA1 and BRCA2 genetic testing is cost-effective in Canada

P145 Exploring the clinical and economic value of different BRCA testing strategies and treatment pathways within prostate cancer

P145 Exploring the clinical and economic value of different BRCA testing strategies and treatment pathways within prostate cancer

PALB2 analysis in the diagnostic process of breast cancer: An Italian monocentric experience.

The clinical utility of germline BRCA1 and BRCA2 testing is well established in patients with family history suggestive for hereditary breast and ovarian cancer syndrome. Recently, germline PALB2 pathogenic variants were also associated with an increased risk of breast and other cancers and, in the Italian population, it has been described in few studies without a systematic germline analysis of BRCA1, BRCA2 and PALB2. In this study, we described ASST Sette Laghi cancer genetic counselling services' experience in the analysis of 402 patients with suspected breast and ovarian cancer syndrome, by using BRCA1, BRCA2 and PALB2 germline genetic test. The frequency of PALB2 pathogenic variants was 1.2% compared to 3.5% and 3.2% for BRCA1 and BRCA2, respectively, whereas class 3 variants were detected in 0.3% and 0.5% of the BRCA1 and BRCA2 investigated patients, respectively. PALB2 pathogenic variants were identified in patients with a strong family history for breast cancer. Moreover, PALB2 variants were significantly associated with a younger age of breast cancer onset (mean age, 40.25 years) compared to wild-type patients (mean age 51.2 years, p-value = 0.0331). Similar to BRCA-associated breast cancer, the majority of PALB2 breast cancers were identified at an advanced clinical stage. Pedigree analysis revealed a family history of breast and ovarian cancer syndrome in all PALB2 pathogenic variants carriers (early breast cancer onset, bilateral breast cancer and ovarian cancer). In conclusion, the germline analysis of BRCA1, BRCA2 and PALB2 should be included in breast cancer clinical practice as a not negligible number of PALB2 carriers could be identified and referred to specific surveillance protocols.

Effects of personal cancer history and genomic risk information on mothers' psychological adaptation to inherited breast/ovarian cancer syndrome.

This study aimed to understand long-term coping responses of mothers (N = 287) receiving genetic counseling and testing (GCT) for hereditary breast/ovarian cancer (HBOC) syndrome. Psychological characteristics, including cancer-specific distress (Impact of Events Scale-Revised, α = .85) and coping (Brief COPE, α = .93) were assessed via structured personal communication, along with epidemiologic items assessing personal and family history of cancer. Genetic risk was determined by BRCA1/2 carriage. A principal component analysis was conducted on the coping measure to reduce its summary score to active coping (α = .91) with nine approach-oriented strategies responsive to stress. A multivariable regression model examined the main and interacting effects of clinical and psychological characteristics on maternal coping. Personal cancer history (F = 4.99, df = 1, p = .026), BRCA test result (F = 22.20, df = 1, p < .001), and cancer-specific distress (F = 17.80, df = 1, p < .001) were associated with greater engagement in active coping strategies. When controlling for cancer-specific distress, the interaction between personal cancer history and genetic test results was significant, such that women previously unaffected by cancer who received positive BRCA results reported the greatest levels of active coping (F = 7.92, p < .001). These findings indicate that previous cancer history, genetic risk, and psychological distress independently and jointly impact how women adapt to the threat of cancer over time.

A quality initiative focused on BRCA and HRD testing and use of first line maintenance in advanced ovarian cancer.

286 Background: In May of 2020, the approval of two Poly (ADP-ribose) polymerase inhibitors (PARPi) changed the landscape for treatment among patients (pts) with advanced ovarian cancer (aOC). As such, National Comprehensive Cancer Network guidelines recommend BRCA testing for individuals with epithelial ovarian cancer and Homologous Recombination Repair Deficiency (HRD) testing for pts who are BRCA germline negative to guide the decision of maintenance therapy. Regional Cancer Care Associates (RCCA) conducted a quality initiative (QI) with Integra Connect PrecisionQ to assess the rates of BRCA testing, HRD testing, and use of first line maintenance (LOT 1M) therapy based on biomarker status. This QI focused on interventions to optimize testing and LOT 1M treatment in these pts. We aim to show the improvement in BRCA testing, HRD testing, and rates of LOT 1M therapy use after implementation of the QI, in pts with aOC at RCCA. Methods: Using the de-identified IC PrecisionQ database, 90 RCCA pts with aOC as defined by stage III and IV were selected for medical chart curation at baseline. Pts in the baseline group received first-line treatment between 1/1/2020 to 5/31/2022. The baseline data was reviewed with RCCA clinical leadership and findings were presented at a standing practice clinical meeting on 6/20/2024. Post-baseline, we evaluated 28 aOC pts who started a new first-line of therapy between 7/1/2023 to 4/30/2024 to assess BRCA and HRD testing rates and use of LOT 1M among maintenance eligible (ME) pts. ME was defined by a complete response, partial response, or for those where no response was known and had either received maintenance or had no subsequent treatment after 180 days of completing first line therapy. Maintenance therapies included PARPi(s) and bevacizumab. Descriptive analyses were performed and proportions were compared using a chi-squared test. Results: The baseline cohort had 90 pts of which 66% were stage III and 34% were stage IV. The post-baseline cohort had 28 pts of which 54% were stage III and 46% were stage IV. The rate of BRCA testing at baseline was 86% compared to 93% post-baseline. The rate of HRD testing at baseline was 41% compared to 71% post-baseline (p &lt;0.01). The rate of LOT 1M use among maintenance eligible pts at baseline was 57% (N=76) compared to 78% (N=23) post-baseline. PARPi maintenance at baseline was 67% (N=43) compared to 67% (N=14) post-baseline. While rates of maintenance therapy use remained the same from baseline to post-baseline for BRCA mutated pts at 80%, the use of maintenance increased in HRD positive pts from 71% (N = 7) to 77% (N=13). Conclusions: The QI at RCCA that focused on BRCA and HRD testing and treatment with LOT 1M among aOC pts led to improvements against clinical guidelines. QI programs are critical to transforming cancer care and can be useful tools to drive improvement in testing and treatment.

A quality initiative in BRCA testing and timing of BRCA test prior to surgery in HER2- early stage breast cancer.

287 Background: The University of Pittsburgh Medical Center (UPMC) collaborated with Integra Connect PrecisionQ (IC) on a quality initiative to improve BRCA 1/2 (BRCA) testing in patients (pts) with early-stage (I-III) human epidermal growth factor receptor negative (HER2-) breast cancer (BC). The project involved developing a baseline of BRCA testing, reviewing the results with leadership, conducting a focus group with physicians to identify improvements, and then monitoring the results of BRCA testing thereafter during a post-baseline period. The project sought to improve the identification of pts who may be eligible for olaparib given the updated approval on March 11, 2022, for early-stage high-risk germline BRCA mutated pts. We aim to show the improvement in BRCA testing and timing of test in relation to surgery among HER2- BC pts at UPMC. Methods: Using the de-identified IC PrecisionQ database, 202 UPMC pts with early-stage HER2- BC were selected for medical chart curation as baseline group. Pts in the baseline group received surgery between 7/1/2021 to 6/30/2022. The baseline data was reviewed with UPMC clinical leadership and findings were discussed among a focus group of 8 physicians on 7/17/2023. Following the meeting, UPMC practices performed genetic testing at the office as opposed to sending pts to directly to genetic counseling. Post-baseline, we evaluated 70 pts who underwent surgery between 8/1/2023 to 1/31/2024 to assess BRCA rates and timing of BRCA testing in relation to surgery. Descriptive analyses were performed and proportions were compared using a chi-squared test. Results: Among the baseline cohort of 202 pts, 72% were hormone receptor positive (HR+) and 28% were hormone receptor negative (HR-). Among the post-baseline cohort of 70 pts, 77% were HR+ and 23% were HR-. The rate of BRCA testing at baseline was 44% compared to 56% post-baseline (p 0.05). Among HR+ pts, BRCA testing increased from 38% to 50% and among HR- pts, BRCA testing increased from 67% to 81%. The rate of BRCA testing prior to surgery at baseline was 58% (N= 88) compared to 80% (N=40) post-baseline (p &lt;0.01). Among HR+ pts age &lt;65, BRCA testing at baseline was 46% (N=54) compared to 51% (N=35) post-baseline. Among HR- pts age &lt;65 BRCA testing at baseline was 84% (N=25) compared to 100% (N=9) post-baseline. Conclusions: The quality initiative at UPMC that focused on BRCA testing among HER2- BC pts led to an improvement from 44% to 56% of pts being tested. Among those who were tested, there was an increase from 58% to 80% tested prior to surgery. Given the recent updates on January 4 th , 2024 by ASCO and SSO recommending BRCA1/2 testing to all women younger than age 65 with breast cancer, such QIs can be a useful tool to align a practice’s approach to new standards of care.

Real World Evidence Study to Assess Incidence, Treatment Patterns, Clinical Outcomes, and Health Care Resource Utilization in Early-Stage, High-Risk HER2-Negative Breast Cancer in Alberta, Canada

BackgroundData are needed to improve the current understanding of the epidemiology of patients with high-risk, HER2-negative, early breast cancer (eBC) (hormone receptor positive [HR+]/HER2-negative BC and triple-negative BC [TNBC]). Patients and MethodsThis retrospective longitudinal cohort study used real-world, population-level data that included all individuals newly diagnosed with high-risk, HER2-negative eBC in Alberta, Canada, between 2010 and 2019. Data on treatment, laboratory results and pathology findings were collected through electronic health records and administrative databases. ResultsThe annual cumulative incidence of high-risk, HER2-negative eBC ranged from 6% to 9% of all incident BC cases. Individuals with TNBC were more likely to be younger, had stage II disease, grade 3 histology and received systemic therapy at a community centre (P < .05) compared to individuals with HR+/HER2-negative eBC. Only 14% of individuals diagnosed in 2010-2017 underwent germline BRCA testing postdiagnosis. Neoadjuvant systemic therapy was given to 37% of individuals. Adjuvant systemic therapy use increased from 77% (2012-2015) to 84% (2019). The 5-year overall survival (OS) from initiation of adjuvant systemic therapy or date of surgery (for individuals who did not receive adjuvant systemic therapy) was 77% (95% CI: 75-79). OS was significantly worse among individuals who were older, had grade 3 histology, had stage III disease, or had nodal involvement (P < .05). OS among individuals with TNBC between 2016 and 2019 who initiated adjuvant capecitabine was markedly worse compared to the overall cohort (2-year OS: 70% vs. 89%). ConclusionOutcomes analyses in this high-risk, HER2-negative eBC population suggest a continued unmet clinical need.

Mutational landscape of BRCA gene mutations in Indian breast cancer patients: retrospective insights from a diagnostic lab

BackgroundPresence of Germline mutations in the BRCA1 and BRCA2 genes is the most significant epidemiological factor for breast cancer (BC), where germline BRCA1 (gBRCA 1) mutation increases the risk for BC by 59–87% and gBRCA 2 mutation increases the risk by 38–80%. In this retrospective study, we have analyzed NGS-based genetic data for samples received at our laboratory for genetic testing over a three-year period to understand the prevalence and pattern if any of BRCA1 and BRCA2 mutations in Indian breast cancer patients.ResultsBRCA gene sequencing using NGS was performed in 395 consecutive cases of BC referred for testing to our lab between 2021 and 2023. Genetic analysis of mutations BRCA 1 and BRCA 2 genes resulted in 115 (29%) positive patients. Out of 115 patients, 79 reported BRCA1 mutations, whereas 36 had BRCA2 mutations. Exon 10 (57.3%) of BRCA1 and exon 11 (52%) of BRCA2 were the most mutated exons observed in this study. The c.1961delA (26.4%) variant, followed by the c.68_69delAG (22.7%) variant in BRCA1, and the c.6373delA (20.5%) variant in BRCA2, were the most common mutations found in our study. Our data shows positive correlation of younger age group (20–45 years) with BRCA positive status (Chi-square p value = 0.001).ConclusionBRCA mutation prevalence was 29.1% in our data which is higher than Western countries. Based on our findings BRCA screening looks imperative for women with BC especially younger women (< 50 years), as family history based BRCA testing would miss out many BRCA positive candidates which could benefit from PARP therapy options.

Economic Evaluation of Population-Based BRCA1 and BRCA2 Testing in Canada

Population-based BRCA testing can identify many more BRCA carriers who will be missed by the current practice of BRCA testing based on family history (FH) and clinical criteria. These carriers can benefit from screening and prevention, potentially preventing many more breast and ovarian cancers and deaths than the current practice. To estimate the incremental lifetime health outcomes, costs, and cost-effectiveness associated with population-based BRCA testing compared with FH-based testing in Canada. For this economic evaluation, a Markov model was developed to compare the lifetime costs and outcomes of BRCA1/BRCA2 testing for all general population women aged 30 years compared with FH-based testing. BRCA carriers are offered risk-reducing salpingo-oophorectomy to reduce their ovarian cancer risk and magnetic resonance imaging (MRI) and mammography screening, medical prevention, and risk-reducing mastectomy to reduce their breast cancer risk. The analyses were conducted from both payer and societal perspectives. This study was conducted from October 1, 2022, to February 20, 2024. Outcomes of interest were ovarian cancer, breast cancer, additional heart disease deaths, and incremental cost-effectiveness ratio ICER per quality-adjusted life-year (QALY). One-way and probabilistic-sensitivity-analyses (PSA) were undertaken to explore the uncertainty. In the simulated cohort of 1 000 000 women aged 30 years in Canada, the base case ICERs of population-based BRCA testing were CAD $32 276 (US $23 402.84) per QALY from the payer perspective or CAD $16 416 (US $11 903.00) per QALY from the societal perspective compared with FH-based testing, well below the established Canadian cost-effectiveness thresholds. Population testing remained cost-effective for ages 40 to 60 years but not at age 70 years. The results were robust for multiple scenarios, 1-way sensitivity, and PSA. More than 99% of simulations from payer and societal perspectives were cost-effective on PSA (5000 simulations) at the CAD $50 000 (US $36 254.25) per QALY willingness-to-pay threshold. Population-based BRCA testing could potentially prevent an additional 2555 breast cancers and 485 ovarian cancers in the Canadian population, corresponding to averting 196 breast cancer deaths and 163 ovarian cancer deaths per 1 000 000 population. In this economic evaluation, population-based BRCA testing was cost-effective compared with FH-based testing in Canada from payer and societal perspectives. These findings suggest that changing the genetic testing paradigm to population-based testing could prevent thousands of breast and ovarian cancers.

Genetic Testing Among Breast Cancer Patients in the Eastern Region of Saudi Arabia: Single-Center Experience

BackgroundGenetic testing for persons with a heightened likelihood of harboring a germline mutation permits early identification and appropriate management. This study aimed to identify the proportion of breast cancer (BC) patients who were offered genetic testing and the prevalence of BRCA mutations among them. Additionally, we assessed the demographic and clinical features of BC patients in the Eastern Region of Saudi Arabia.Materials and MethodsData from 2535 patients with BC were retrieved from the registry between 2017 and 2021. The data were analyzed and presented using univariate and bivariate statistics. Odds ratios and 95% confidence intervals using logistic regression analysis were computed to identify the predictors of BRCA testing.ResultsPatients with BC ranged in age from 18 to 103 years, and the mean age was 49.60 ± 12.14 years. BC was detected in men in 29 (1.1%) cases. Among diagnosed patients with BC, a total of 96 (3.7%) patients underwent testing for BRCA gene mutations. Of them, 36 (37.5%) patients had a BRCA gene mutation. The likelihood of undergoing BRCA testing was higher for those who were diagnosed with the condition before the age of 50, patients who were referred from private institutions, and patients with a history of previously diagnosed cancer. The likelihood of conducting BRCA testing was significantly lower among those with distant metastases.ConclusionThe proportion of BRCA testing among BC patients was found to be relatively low. The development of a cost-effective, locally developed risk assessment tool that incorporates genetic counseling and testing for those with a familial predisposition to BC is imperative.

LBA64 Outcomes of BRCA and in-house homologous recombination deficiency (HRD) testing in women with ovarian and breast cancer: A multicentre registry study

LBA64 Outcomes of BRCA and in-house homologous recombination deficiency (HRD) testing in women with ovarian and breast cancer: A multicentre registry study

Low testing rates and high BRCA prevalence: Poly (ADP-ribose) polymerase inhibitor use in Middle East BRCA/homologous recombination deficiency-positive cancer patients.

Poly (ADP-ribose) polymerase inhibitors (PARPis) are approved as first-line therapies for breast cancer gene (BRCA)-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer. They are also effective for new and recurrent ovarian cancers that are BRCA- or homologous recombination deficiency (HRD)-positive. However, data on these mutations and PARPi use in the Middle East are limited. To assess BRCA/HRD prevalence and PARPi use in patients in the Middle East with breast/ovarian cancer. This was a single-center retrospective study of 57 of 472 breast cancer patients tested for BRCA mutations, and 25 of 65 ovarian cancer patients tested for HRD. These adult patients participated in at least four visits to the oncology service at our center between August 2021 and May 2023. Data were summarized using descriptive statistics and compared using counts and percentages. Response to treatment was assessed using Response Evaluation Criteria in Solid Tumors criteria. Among the 472 breast cancer patients, 12.1% underwent BRCA testing, and 38.5% of 65 ovarian cancer patients received HRD testing. Pathogenic mutations were found in 25.6% of the tested patients: 26.3% breast cancers had germline BRCA (gBRCA) mutations and 24.0% ovarian cancers showed HRD. Notably, 40.0% of gBRCA-positive breast cancers and 66.0% of HRD-positive ovarian cancers were Middle Eastern and Asian patients, respectively. PARPi treatment was used in 5 (33.3%) gBRCA-positive breast cancer patients as first-line therapy (n = 1; 7-months progression-free), for maintenance (n = 2; > 15-months progression-free), or at later stages due to compliance issues (n = 2). Four patients (66.6%) with HRD-positive ovarian cancer received PARPi and all remained progression-free. Lower testing rates but higher BRCA mutations in breast cancer were found. Ethnicity reflected United Arab Emirates demographics, with breast cancer in Middle Eastern and ovarian cancer in Asian patients.

The Cost-Effectiveness of Germline BReast CAncer Gene Testing in Metastatic Prostate Cancer Followed by Cascade Testing of First-Degree Relatives of Mutation Carriers

ObjectivesPatients with metastatic prostate cancer (mPCa) with BReast CAncer gene (BRCA) mutations benefit from targeted treatments (eg, olaparib). In addition, family members of affected patients have increased risk of hereditary cancers and benefit from early detection and prevention. International guidelines recommend genetic testing in mPCa; however, the value for money of testing patients with mPCa and cascade testing of blood-related family members has not been assessed. In this context, we evaluated the cost-effectiveness of germline BRCA testing in patients with mPCa followed by cascade testing of first-degree relatives (FDRs) of mutation carriers. MethodsWe conducted a cost-utility analysis of germline BRCA testing using 2 scenarios: (1) testing patients with mPCa only and (2) testing patients with mPCa and FDRs of those who test positive. A semi-Markov multi–health-state transition model was constructed using a lifetime time horizon. The analyses were performed from an Australian payer perspective. Decision uncertainty was characterized using probabilistic analyses. ResultsCompared with no testing, BRCA testing in mPCa was associated with an incremental cost of AU$3731 and a gain of 0.014 quality-adjusted life-years (QALYs), resulting in an incremental cost-effectiveness ratio of AU$265 942/QALY. Extending testing to FDRs of variant-positive patients resulted in an incremental cost-effectiveness ratio of AU$16 392/QALY. Probability of cost-effectiveness at a willingness-to-pay of AU$75 000/QALY was 0% in the standalone mPCa analysis and 100% in the cascade testing analysis. ConclusionBRCA testing when performed as a standalone strategy in patients with mPCa may not be cost-effective but demonstrates significant value for money after the inclusion of cascade testing of FDRs of mutation carriers.

BRCA Testing for Patients Treated in Italy: A National Survey of Breast Centers Associated with Senonetwork.

Breast units (BUs) provide breast cancer (BC) care, including prevention, treatment, and genetic assessment. Genetic research has highlighted BRCA1/2 mutations as key hereditary BC risk factors. BRCA testing is crucial for personalized treatment and prevention strategies. However, the integration of BRCA testing in Italian BUs faces multiple challenges. This study, by Senonetwork Italia, aimed to evaluate genetic testing practices and identify obstacles within Italian BUs. Senonetwork Italia conducted a 16-question web-based survey involving 153 BUs. The survey assessed aspects of BRCA testing, including timing, urgency, counseling, patient selection, and multi-gene panels. Of the 153 BUs, 109 (71.2%) responded. Testing before surgery was performed by 70.6% of centers, with urgent cases acknowledged by 87.2%. Most centers (56.0%) arranged urgent pre-test counseling within a week. BRCA mutation status influenced treatment decisions in 99.1% of cases. Multi-gene panels were used by 33.0% of centers for all genetic counseling cases, while 56.0% followed standard referral criteria. The main challenges included cost, reimbursement, and reporting timelines. This survey highlights significant variations in BRCA testing practices across Italian BUs and identifies key logistical and financial challenges. There is a need for standardized practices of genetic testing to ensure personalized and effective BC management in Italy.

Online Provision of BRCA1 and BRCA2 Health Information: A Search Engine Driven Systematic Web-Based Analysis.

BRCA genetic testing is available for UK Jewish individuals but the provision of information online for BRCA is unknown. We aimed to evaluate online provision of BRCA information by UK organisations (UKO), UK Jewish community organisations (JCO), and genetic testing providers (GTP). Google searches for organisations offering BRCA information were performed using relevant sets of keywords. The first 100 website links were categorised into UKOs/JCOs/GTPs; additional JCOs were supplemented through community experts. Websites were reviewed using customised questionnaires for BRCA information. Information provision was assessed for five domains: accessibility, scope, depth, accuracy, and quality. These domains were combined to provide a composite score (maximum score = 5). Results were screened (n = 6856) and 45 UKOs, 16 JCOs, and 18 GTPs provided BRCA information. Accessibility was high (84%,66/79). Scope was lacking with 35% (28/79) addressing >50% items. Most (82%, 65/79) described BRCA-associated cancers: breast and/or ovarian cancer was mentioned by 78%(62/79), but only 34% (27/79) mentioned ≥1 pancreatic, prostate, melanoma. Few websites provided carrier frequencies in the general (24%,19/79) and Jewish populations (20%,16/79). Only 15% (12/79) had quality information with some/minimal shortcomings. Overall information provision was low-to-moderate: median scores UKO = 2.1 (IQR = 1), JCO = 1.6 (IQR = 0.9), and GTP = 2.3 (IQR = 1) (maximum-score = 5). There is a scarcity of high-quality BRCA information online. These findings have implications for UK Jewish BRCA programmes and those considering BRCA testing.

LGG-24. PEDIATRIC GANGLIOGLIOMA WITH GERMLINE BRCA2 MUTATION

Abstract BACKGROUND BRCA1 and BRCA2 are genes associated with breast and ovarian cancer development in adults. Their influence on brain tumor formation is less understood. METHODS Retrospective review RESULTS An 11 year-old girl was diagnosed with ganglioglioma after presenting with seizures. Tumor sequencing revealed three mutations: a PDAP1-BRAF fusion, a BRAF-HIP1 non-canonical fusion, and a pathogenic BRCA2 variant D252*fs. Upon further review, a family history of breast cancer in the grandmother and several great-aunts was identified, and genetic testing confirmed this mutation to be germline. We then conducted an institutional review and identified a second pediatric low-grade glioma (pilocytic astrocytoma) patient with a pathogenic mutation in BRCA2 (T3085Fs*26) in addition to a BRAF-KIAA1549 fusion; the family declined germline BRCA2 testing. BRCA1/2 knockout models have demonstrated that both genes play a role in brain development. Concurrent BRCA2 and TP53 loss triggers formation of early onset murine medulloblastoma, a finding not observed with TP53 loss alone. In human patients, heterozygous and biallelic mutations in BRCA2 were identified as risk factors for medulloblastoma development in a recent integrative genomic analysis. Retrospective review CONCLUSION We report two cases of BRCA2 mutation in pediatric low-grade gliomas, one of which was confirmed to be germline. While somatic variants of BRCA2 have been reported in both high- and low-grade glioma, their role in these tumors has not been established to date. The BRCA2 tumor predisposition syndrome increases the risk of some types of brain tumors such as medulloblastoma, although the risk remains low compared to the risk of developing breast or ovarian cancer later in life. More evidence is required to determine whether BRCA2 germline mutations can similarly increase the risk of glioma formation.

Real-world tumor BRCA testing patterns and PARP inhibitor use in HER2-negative metastatic breast cancer.

1113 Background: Testing for BRCA1/BRCA2 mutations (BRCAm) aids systemic treatment decisions for patients (pts) with metastatic breast cancer (mBC). This retrospective study explored real-world germline/tumor (g/t) BRCA testing patterns and PARP inhibitor (PARPi) use in US pts with mBC. Methods: Data from pts ≥18 years old diagnosed with HER2-negative mBC from 2014–2022 were captured in the nationwide Flatiron Health electronic health record-derived deidentified database. Patterns and timing of prospective or incidental BRCA testing were compared across mBC subtypes (hormone receptor-positive [HR+ mBC]/triple-negative mBC [mTNBC]) and disease stage (recurrent/ de novo). BRCAm prevalence was compared by testing modality and mBC subtype. PARPi initiation was assessed in pts with mBC diagnosed from 2018 onwards and a positive BRCAm test result. Clinical characteristics were compared by receipt of a BRCA test, testing modality, and PARPi initiation. Real-world overall survival (OS) by PARPi use was estimated using the Kaplan-Meier method. Results: Of 15,006 pts (including 12,349 with HR+ mBC; 1998 with mTNBC), 8178 (54.5%) did not receive any type of BRCA test, 4654 (31.0%) received a gBRCA test, 3075 (20.5%) received a tumor tissue DNA (ttDNA) test, and 1418 (9.4%) received a circulating tumor DNA (ctDNA) test. BRCA testing prevalence was numerically higher in pts with mTNBC (n=1164; 58.3%) than in pts with HR+ mBC (n=5323; 43.1%). As expected, testing prevalence was higher with ttDNA than with ctDNA (mTNBC: n=569 [28.5%] vs n=137 [6.9%]; HR+ mBC: n=2339 [18.9%] vs n=1224 [9.9%]). Over 93% of pts (recurrent and de novo) who received a tBRCA test were tested after an mBC diagnosis, and &gt;1/3 were tested after first-line therapy, with median times from diagnosis to a ttDNA and ctDNA test of 127 and 431 days, respectively. Both gBRCA and tBRCA testing rates increased from 2014–2022, and testing occurred earlier in pts with recurrent than de novo disease. Among pts with tBRCAm, 66.0% had HR+ mBC, and 25.6% had mTNBC. BRCA1 mutations were more common in mTNBC (59.0%) than in HR+ mBC (22.9%) tumors. Of 219 pts with tBRCAm tumors who were diagnosed with mBC from 2018 onwards, PARPi was initiated in 39/74 (52.7%) pts with gBRCAm, 15/71 (21.1%) pts who were gBRCAm-negative, and 19/74 (25.7%) pts with gBRCAm status unknown. Among pts with g or tBRCAm and available OS data, median OS was numerically longer in pts who received PARPi (32.3 months [95% CI: 24.2, 47.4], n=128) versus pts who did not (29.0 months [95% CI: 21.9, 31.9], n=204; median follow-up time 23.2 months). Conclusions: While NCCN guidelines recommend gBRCA testing for all pts with mBC, more than half of pts with HER2-negative mBC (56.9% of pts with HR+ mBC) did not receive any BRCA test. Among pts with tBRCAm, ~2/3 had HR+ disease. Despite the potential benefits of PARPi for pts with BRCAm mBC, utilization remained low from 2018–2022.