BRCA Testing In Patients Research Articles

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.

Temporal Patterns and Adoption of Germline and Somatic BRCA Testing in Ovarian Cancer.

To describe the testing rate, patient characteristics, temporal trends, timing, and results of germline and somatic BRCA testing in patients with ovarian cancer using real-world data. We included a cross-sectional subset of adult patients diagnosed with ovarian cancer between January 1, 2011, and November 30, 2018, who received frontline treatment and were followed for at least 1 year in a real-world database. The primary outcome was receipt of BRCA testing, classified by biosample source as germline (blood or saliva) or somatic (tissue). Lines of therapy (frontline, second line, third line) were derived based on dates of surgery and chemotherapy. Descriptive statistics were analyzed. Among 2,557 patients, 72.2% (n=1,846) had at least one documented BRCA test. Among tested patients, 62.5% (n=1,154) had only germline testing, 10.6% (n=197) had only somatic testing, and 19.9% (n=368) had both. Most patients had testing before (9.7%, n=276) or during (48.6%, n=1,521) frontline therapy, with 17.6% (n=273) tested during second-line and 12.7% (n=129) tested during third-line therapy. Patients who received BRCA testing, compared with patients without testing, were younger (mean age 63 years vs 66 years, P <.001) and were more likely to be treated at an academic practice (10.4% vs 7.0%, P =.01), with differences by Eastern Cooperative Oncology Group performance score ( P <.001), stage of disease ( P <.001), histology ( P <.001), geography ( P <.001), and type of frontline therapy ( P <.001), but no differences based on race or ethnicity. The proportion of patients who received BRCA testing within 1 year of diagnosis increased from 24.6% of patients in 2011 to 75.6% of patients in 2018. In a large cohort of patients with ovarian cancer, significant practice disparities existed in testing for actionable BRCA mutations. Despite increased testing over time, many patients did not receive testing, suggesting missed opportunities to identify patients appropriate for targeted therapy and genetic counseling.

Cost-Effectiveness Analysis of Germline and Somatic BRCA Testing in Patients With Advanced Ovarian Cancer.

BRCA testing is necessary for establishing a management strategy for ovarian cancer. Several BRCA testing strategies, including germline and somatic testing, are implemented in clinical practice in Korea. We aimed to comparatively evaluate their cost-effectiveness from patients' perspective. We developed a decision model comprising five BRCA testing strategies implemented in Korea: (1) germline testing first, followed by somatic tumor testing for patients without a germline variant; (2) somatic testing first, followed by germline testing for patients with a variant detected by somatic testing; (3) both germline and somatic testing; (4) germline testing alone; and (5) somatic testing alone, with no testing as the comparator. One-way sensitivity analysis was conducted to test the uncertainty of key parameters. Assuming a willingness-to-pay of $20,000 per progression-free life-year gain (PF-LYG), all five strategies were considered cost-effective. Strategy 4 was the most cost-effective option, with an incremental cost-effectiveness ratio (ICER) of $2,547.7 per PF-LYG, followed by strategy 1, with an ICER of $3,978.4 per PF-LYG. Even when the parameter values were varied within the possible range, the ICERs of all strategies did not exceed the willingness-to-pay threshold. Considering the importance of knowing a patient's BRCA gene status, germline testing first, followed by somatic testing, may be a reasonable option.

Abstract P3-14-17: Exploring racial disparities in BRCA testing for triple negative breast cancer patients: A real-world data analysis

Abstract Background and Objective: BRCA testing for patients (pts) with triple negative breast cancer (TNBC) is important because it has secondary prevention implications for patients and multigenerational implications allowing for earlier detection of BRCA gene carriers in the family and enabling primary prevention. And with the advent of PARP inhibitors it also has treatment implications. The NCCN guidelines recommended in January 2015 that BRCA testing be performed for all pts with TNBC diagnosed at age 60 or younger regardless of race, ethnicity or family history. To understand disparities in BRCA testing among TNBC pts we analyzed the proportion tested, explored barriers to testing, and made comparisons by race, ethnicity, and socioeconomic status (SES). Methods: Adult pts with TNBC diagnosed at or under age 60 between January 1, 2015 and December 31, 2020 were identified in the Syapse Learning Health Network, a real-world database with clinical and genomic data from community health systems. Study end was June 1, 2021, allowing for a minimum follow up of 5 months. Electronic health records were reviewed to calculate proportion tested and barriers to testing. SES was estimated using zip code level median household income from the 2010 census and stratified based on the national poverty level (low <150%, middle 150-299%, high 300%+). χ;2 statistics were used to assess differences between groups. Results: 577 pts with a median age at TNBC of 50 and median follow up of 18 months were included. 65.2% self-identified as white, 27.9% as Black or African American (AA), 1.4% Asian, 1.4% American Indian or Alaska Native, and 4.2% other. 8% identified as Hispanic/Latino. Due to relative size of racial/ethnic groups, the stratified analyses focused on comparisons between white and AA pts. Overall, 459 (79.5%) pts received a test, but with 83% of white pts receiving tests as compared to 72.7% of AA pts (p=0.009). 71.4% of pts with low SES received a test vs. 81.8% for middle and 79.4% with high SES (p=0.068). Among the 118 pts with no test, 48 (40.7%) did not have documentation of a test referral or evidence of testing offered in clinician notes. This differed by race with white pts less likely to have test offer documented vs. AA pts (53.1% vs. 72.7%, p=0.064). Among the 48 pts with no evidence of test offer, additional details were often not documented. However some clinician notes cited a perceived ineligibility due to lack of family history, transferring out or move to hospice, and pt refusal. Among the 70 (59.3%) pts who were offered a test but did not receive it, reasons included 37.1% choosing not to be tested, 11.4% due to early death, loss to follow up or transferring away, and 7.1% lacked adequate health insurance. These reasons varied by race, with 59.4% of AA pts choosing not to be tested vs. 20.6% of white pts (p=0.003) (Table 1). Conclusions: Real-world data provides insight into BRCA testing patterns in routine clinical practice where racial disparities are well documented and persistent. While the overall proportion of pts who received BRCA testing was high, AA pts experienced more barriers. Despite AA pts having greater evidence of a test offer vs. white pts, there was a significant gap in testing favoring white pts, with the most notable reason for lack of testing being pt choice. The clinical significance of BRCA testing in TNBC indicates a need to create targeted strategies to close gaps in education, confidence and access among patients and providers to improve testing levels. Table 1.BRCA testing barriers among patients who were offered a test but did not receive it (N=70)Total (n=70)White (n=34)Black or African American (n=32)Low SES (n=19)Middle SES (n=43)High SES (n=8)Lack of adequate health insurance, n (%)5 (7.1)3 (8.8)1 (3.1)3 (15.8)1 (2.3)1 (12.5)Patient chose not to be tested, n (%)26 (37.1)7 (20.6)19 (59.4)8 (42.1)14 (32.6)4 (50.0)Deceased before testing occurred, n (%)5 (7.1)3 (8.8)2 (6.3)1 (5.3)4 (9.3)0 (0)LTFU/Transferred, n (%)3 (4.3)2 (5.9)1 (3.1)1 (5.3)1 (2.3)1 (12.5)Other, n (%)7 (10.0)6 (17.6)1 (3.1)1 (5.3)6 (14.0)0 (0)Unknown, n (%)24 (34.3)13 (38.2)8 (25.0)5(26.3)17 (39.5)2 (25.0) Citation Format: Jeanna Wallenta Law, Hanadi BuAli, Sherri Costa, Michael P. Mullane, Mohamed Hendawi, Michael McPhee, Bryanne Collini, Mahder Teka, Francesca Coutinho, Ronda Broome, Frank M. Wolf, Liz Toland, Trista Weber, Anna Berry, Thomas D. Brown, Haythem Ali. Exploring racial disparities in BRCA testing for triple negative breast cancer patients: A real-world data analysis [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 P3-14-17.

Use of Germline BRCA Testing in Patients With Ovarian Cancer and Commercial Insurance

Use of Germline BRCA Testing in Patients With Ovarian Cancer and Commercial Insurance

BRCA screening, treatment patterns and response among patients with ovarian cancer in the second line treatment setting: results from a real world survey

Objective: Although BRCA gene testing of patients diagnosed with ovarian cancer (OC) is now recommended, the level of testing undertaken in various countries is largely unknown. This study describes BRCA mutation screening patterns and results, demographics, clinical characteristics and the use of poly (ADP-ribose) polymerase inhibitors (PARPi) as maintenance treatment within a real-world sample of patients with advanced OC in the second-line (2L) treatment setting. Methods: Data were collected using the Adelphi Real World OC Disease Specific Programme (DSP)™, a point-in-time survey of physicians and their consulting patients with OC in clinical practice, undertaken across Europe (EU5: France, Germany, Italy, Spain and United Kingdom) and the United States (US) between December 2017–March 2018. Physicians completed a detailed patient record form for their next eight consecutively consulting patients, capturing data on their clinical history and treatment. All analysis was descriptive. Results: Of 1315 patients identified, 1096 (83%) were receiving 2L treatment and 219 (17%) were receiving 2L maintenance treatment; either PARPi (olaparib, rucaparib or niraparib, n = 103) or a non-PARPi (n = 116). BRCA screening rates varied between countries, increased with each line of therapy and were higher in the EU5 (55%) than the US (44%). 28% of patients receiving 2L treatment had a BRCA1/2 mutation. Patients receiving PARPi maintenance treatment had better Eastern Cooperative Oncology Group (ECOG) performance status, higher BRCA screening rates and higher proportions of serous epithelial OC than those receiving 2L treatment or non-PARPi maintenance. Common reasons for choosing 2L treatments were progression-free/overall survival benefit and improvement of quality of life. Conclusions: Despite guidelines recommending BRCA testing in patients with OC, many OC patients undergoing 2L treatment were not screened for BRCA mutations. Decisions related to PARPi use in 2L maintenance appeared to be driven by BRCA status, histology and response to first-line treatment.

Association of electronic-health record (EHR)-derived race with BRCA testing in patients (pts) with breast cancer (BC) with similar genetic ancestry (GA) in a clinicogenomic database (CGDB).

6524 Background: Disparities in health outcomes can be affected by biological factors associated with GA and social determinants of health. These factors can be teased apart using GA data from comprehensive genomic profiling (CGP) in pts with cancer. CGDBs that link EHR data with CGP enable the selection of pts with similar GA. Holding GA constant provides an opportunity to directly study the effects of reported race in health disparities. This study evaluated a published racial disparity (BRCA testing rates in African American [AA] vs White pts with BC) in a population with fixed, similar GA. Methods: The nationwide (US-based) deidentified Flatiron Health and Foundation Medicine (FMI) BC CGDB (Q3 2020) was used. For each pt, GA fractions from 5 geographic ancestry groups (African [AFR]; Admixed American; East Asian; European [EUR]; South Asian) were derived by FMI using an admixture analysis workflow using genes captured in the CGP assay. To focus on BRCA testing in AA vs White pts and find a sufficient population with similar GA but AA or White race, pts with admixture of both EUR and AFR ancestry were selected. The chosen fractions were: Cohort 1=35%-65% AFR and EUR each; Cohort 2=25%-60% AFR and EUR each; Cohort 3=30%-60% AFR. Cohorts overlap but were chosen to increase sample size. In each cohort, documented BRCA testing prevalence, time from diagnosis to BRCA test date, age at BRCA test and overall survival (OS) were compared between races. Other race (OR) and missing race (MR) were also reported. Results: Most pts (4130/6903) in the BC CGDB had ≥75% EUR ancestry; 129 pts had AFR ancestry fractions ≥25% with EUR ancestry >0%. AA pts had the lowest BRCA testing rates (39%, 43%, 44% for Cohorts 1-3, respectively), which were 18%, 10% and 17% lower compared with White pts, respectively (Table). In Cohorts 1-3, AA pts experienced a longer median time between diagnosis and testing (399, 668, 900 days) compared with White pts (93, 667, 106 days). The median age at BRCA test was 16, 9 and 8 years younger in AA pts (49, 47 and 50 years) compared with White pts. Although pts with MR data had the lowest OS compared with the other races within each cohort, the sample size of each arm for all cohorts was too small to make conclusions. Conclusions: This study demonstrated that when holding GA constant, racial disparities persist in BRCA testing patterns and outcome in pts with BC from a CGDB. With increasing availability of linked clinical and genomic data, further exploration of disparities in genetically similar cohorts can provide deeper insight for cancer outcomes and health disparities research.[Table: see text]

Tumor BRCA Testing in High Grade Serous Carcinoma: Mutation Rates and Optimal Tissue Requirements

Simple SummaryApproximately 25% of women diagnosed with tubo-ovarian high-grade serous carcinoma have germline deleterious mutations in BRCA1 or BRCA2, characteristic of hereditary breast and ovarian cancer syndrome, while somatic mutations have been detected in 3–7%. We set out to determine the mutation rates and optimal tissue requirements for tumor BRCA testing in 291 tissue samples. Initial testing was successful in 78% and deemed indeterminate in 13%. Repeat testing was successful in 67% of retested samples, with an overall success rate of 86%. Clinically significant BRCA variants were identified in 17% of patients. Successful sequencing was dependent on sample type, tumor cellularity and size (p ≤ 0.001) but not on neoadjuvant chemotherapy or age of blocks. In summary, our study shows a 17% tumor BRCA mutation rate, with an overall success rate of 86%. Biopsy and cytology samples and post-chemotherapy specimens can be used, and optimal tumors measure ≥5 mm in size with at least 20% cellularity.Background: Approximately 25% of women diagnosed with tubo-ovarian high-grade serous carcinoma have germline deleterious mutations in BRCA1 or BRCA2, characteristic of hereditary breast and ovarian cancer syndrome, while somatic mutations have been detected in 3–7%. We set out to determine the BRCA mutation rates and optimal tissue requirements for tumor BRCA testing in patients diagnosed with tubo-ovarian high-grade serous carcinoma. Methods: Sequencing was performed using a multiplexed polymerase chain reaction-based approach on 291 tissue samples, with a minimum sequencing depth of 500X and an allele frequency of >5%. Results: There were 253 surgical samples (87%), 35 biopsies (12%) and 3 cytology cell blocks (1%). The initial failure rate was 9% (25/291), including 9 cases (3%) with insufficient tumor, and 16 (6%) with non-amplifiable DNA. Sequencing was successful in 78% (228/291) and deemed indeterminate due to failed exons or variants below the limit of detection in 13% (38/291). Repeat testing was successful in 67% (28/42) of retested samples, with an overall success rate of 86% (251/291). Clinically significant (pathogenic, likely pathogenic) variants were identified in 17% (48/276) of complete and indeterminate cases. Successful sequencing was dependent on sample type, tumor cellularity and size (p ≤ 0.001) but not on neoadjuvant chemotherapy or age of blocks (p > 0.05). Conclusions: Our study shows a 17% tumor BRCA mutation rate, with an overall success rate of 86%. Biopsy and cytology samples and post-chemotherapy specimens can be used for tumor BRCA testing, and optimal tumors measure ≥5 mm in size with at least 20% cellularity.

Discrepancies in Genetic Testing Procedures of BRCA1/2 Mutations: A National Survey Across China.

International guidelines recommend BRCA testing for patients with breast and ovarian cancer. Little is known about the genetic testing practices of BRCA1/2 mutations in laboratories across China. This study was designed to assess the discrepancies in genetic testing procedures of BRCA1/2 mutations across China. An online survey was developed for depicting the BRCA1/2 testing landscape in China. Our results show that there were several variations among the laboratories in technologies adopted, large genomic rearrangement detection, probe design, quality control, variant of uncertain significance interpretation, and disposition of variants in public databases. The discrepancies observed in our study would affect the authenticity of results, thus necessitating the formulation of proper national and international guidelines for optimal BRCA1/2 testing clinical practice for efficient management and patient care of this population.

Genetic Counseling in the Follow-up of Breast Cancer patients; Conversion of a Luminal Tumor to TNBC

Background: Triple-negative subtype does not have any of the receptors that are commonly found in breast cancer. Patients suffering from Triple-negative breast cancer are at risk of early metastasis and BRCA mutation. The conversion of the receptors during the metastatic progression or local recurrence of breast cancer is a well-known topic that affects the therapeutic measures and outcome. Confirmation of immunohistochemistry is essential in these conditions, but genetic evaluation is controversial. Case presentation: A woman suffering from primary luminal breast cancer presented with femoral bone metastasis in the follow-up after two years. Bone metastasis was compatible with the triple-negative subtype. This case was discussed at the weekly breast multidisciplinary team session of the Department of Breast Surgery, Tehran University of Medical Sciences.Question: Does the patient need genetics counseling in a conversion setting? And does the new specimen need CISH/FISH techniques to confirm TNBC tumors?Conclusion: There are no strong guidelines to recommend genetic counseling and BRCA testing for patients with breast cancer biomarkers conversion. Re-assessing the specimen for ER, PR, and HER-2 is necessary for this setting.

The first Japanese nationwide multicenter study of BRCA mutation testing in ovarian cancer: CHARacterizing the cross-sectionaL approach to Ovarian cancer geneTic TEsting of BRCA (CHARLOTTE)

IntroductionBRCA gene mutations are associated with hereditary ovarian cancer. BRCA plays a key role in genome integrity, and mutations result in an increased risk for ovarian cancer. Although various guidelines...