Assessment of BRCA1 and BRCA2 Germline Variant Data From Patients With Breast Cancer in a Real-World Data Registry.

PURPOSE: The emergence of large real-world clinical databases and tools to mine electronic medical records has allowed for an unprecedented look at large data sets with clinical and epidemiologic correlates. In clinical cancer genetics, real-world databases allow for the investigation of prevalence and effectiveness of prevention strategies and targeted treatments and for the identification of barriers to better outcomes. However, real-world data sets have inherent biases and problems (eg, selection bias, incomplete data, measurement error) that may hamper adequate analysis and affect statistical power. METHODS: Here, we leverage a real-world clinical data set from a large health network for patients with breast cancer tested for variants in BRCA1 and BRCA2 (N = 12,423). We conducted data cleaning and harmonization, cross-referenced with publicly available databases, performed variant reassessment and functional assays, and used functional data to inform a variant's clinical significance applying American College of Medical Geneticists and the Association of Molecular Pathology guidelines. RESULTS: In the cohort, White and Black patients were over-represented, whereas non-White Hispanic and Asian patients were under-represented. Incorrect or missing variant designations were the most significant contributor to data loss. While manual curation corrected many incorrect designations, a sizable fraction of patient carriers remained with incorrect or missing variant designations. Despite the large number of patients with clinical significance not reported, original reported clinical significance assessments were accurate. Reassessment of variants in which clinical significance was not reported led to a marked improvement in data quality. CONCLUSION: We identify the most common issues with BRCA1 and BRCA2 testing data entry and suggest approaches to minimize data loss and keep interpretation of clinical significance of variants up to date.

Olaparib not cost-effective as maintenance therapy for platinum-sensitive, BRCA1/2 germline-mutated metastatic pancreatic cancer.

OBJECTIVE: To assess the cost-effectiveness and budget impact of olaparib as a maintenance therapy in platinum-responsive, metastatic pancreatic cancer patients harboring a germline BRCA1/2 mutation, using the Swiss context as a model. METHODS: Based on data from the POLO trial, published literature and local cost data, we developed a partitioned survival model of olaparib maintenance including full costs for BRCA1/2 germline testing compared to FOLFIRI maintenance chemotherapy and watch-and-wait. We calculated the incremental cost-effectiveness ratio (ICER) for the base case and several scenario analyses and estimated 5-year budget impact. RESULTS: Comparing olaparib with watch-and wait and maintenance chemotherapy resulted in incremental cost-effectiveness ratios of CHF 2,711,716 and CHF 2,217,083 per QALY gained, respectively. The 5-year costs for the olaparib strategy in Switzerland would be CHF 22.4 million, of which CHF 11.4 million would be accounted for by germline BRCA1/2 screening of the potentially eligible population. This would amount to a budget impact of CHF 15.4 million (USD 16.9 million) versus watch-and-wait. CONCLUSIONS: Olaparib is not a cost-effective maintenance treatment option. Companion diagnostics are an equally important cost driver as the drug itself.

Bilateral Oophorectomy and All-Cause Mortality in Women With BRCA1 and BRCA2 Sequence Variations.

Importance: Preventive bilateral salpingo-oophorectomy is offered to women at high risk of ovarian cancer who carry a pathogenic variant in BRCA1 or BRCA2; however, the association of oophorectomy with all-cause mortality has not been clearly defined. Objective: To evaluate the association between bilateral oophorectomy and all-cause mortality among women with a BRCA1 or BRCA2 sequence variation. Design, Setting, and Participants: In this international, longitudinal cohort study of women with BRCA sequence variations, information on bilateral oophorectomy was obtained via biennial questionnaire. Participants were women with a BRCA1 or BRCA2 sequence variation, no prior history of cancer, and at least 1 follow-up questionnaire completed. Women were followed up from age 35 to 75 years for incident cancers and deaths. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) and 95% CIs for all-cause mortality associated with a bilateral oophorectomy (time dependent). Data analysis was performed from January 1 to June 1, 2023. Exposures: Self-reported bilateral oophorectomy (with or without salpingectomy). Main Outcomes and Measures: All-cause mortality, breast cancer-specific mortality, and ovarian cancer-specific mortality. Results: There were 4332 women (mean age, 42.6 years) enrolled in the cohort, of whom 2932 (67.8%) chose to undergo a preventive oophorectomy at a mean (range) age of 45.4 (23.0-77.0) years. After a mean follow-up of 9.0 years, 851 women had developed cancer and 228 had died; 57 died of ovarian or fallopian tube cancer, 58 died of breast cancer, 16 died of peritoneal cancer, and 97 died of other causes. The age-adjusted HR for all-cause mortality associated with oophorectomy was 0.32 (95% CI, 0.24-0.42; P < .001). The age-adjusted HR was 0.28 (95% CI, 0.20-0.38; P < .001) and 0.43 (95% CI, 0.22-0.90; P = .03) for women with BRCA1 and BRCA2 sequence variations, respectively. For women with BRCA1 sequence variations, the estimated cumulative all-cause mortality to age 75 years for women who had an oophorectomy at age 35 years was 25%, compared to 62% for women who did not have an oophorectomy. For women with BRCA2 sequence variations, the estimated cumulative all-cause mortality to age 75 years was 14% for women who had an oophorectomy at age 35 years compared to 28% for women who did not have an oophorectomy. Conclusions and Relevance: In this cohort study among women with a BRCA1 or BRCA2 sequence variation, oophorectomy was associated with a significant reduction in all-cause mortality.

MRI Surveillance and Breast Cancer Mortality in Women With BRCA1 and BRCA2 Sequence Variations.

Importance: Magnetic resonance imaging (MRI) surveillance is offered to women with a pathogenic variant in the BRCA1 or BRCA2 gene who face a high lifetime risk of breast cancer. Surveillance with MRI is effective in downstaging breast cancers, but the association of MRI surveillance with mortality risk has not been well defined. Objective: To compare breast cancer mortality rates in women with a BRCA1 or BRCA2 sequence variation who entered an MRI surveillance program with those who did not. Design, Setting, and Participants: Women with a BRCA1 or BRCA2 sequence variation were identified from 59 participating centers in 11 countries. Participants completed a baseline questionnaire between 1995 and 2015 and a follow-up questionnaire every 2 years to document screening histories, incident cancers, and vital status. Women who had breast cancer, a screening MRI examination, or bilateral mastectomy prior to enrollment were excluded. Participants were followed up from age 30 years (or the date of the baseline questionnaire, whichever was later) until age 75 years, the last follow-up, or death from breast cancer. Data were analyzed from January 1 to July 31, 2023. Exposures: Entrance into an MRI surveillance program. Main Outcomes and Measures: Cox proportional hazards modeling was used to estimate the hazard ratios (HRs) and 95% CIs for breast cancer mortality associated with MRI surveillance compared with no MRI surveillance using a time-dependent analysis. Results: A total of 2488 women (mean [range] age at study entry 41.2 [30-69] years), with a sequence variation in the BRCA1 (n = 2004) or BRCA2 (n = 484) genes were included in the analysis. Of these participants, 1756 (70.6%) had at least 1 screening MRI examination and 732 women (29.4%) did not. After a mean follow-up of 9.2 years, 344 women (13.8%) developed breast cancer and 35 women (1.4%) died of breast cancer. The age-adjusted HRs for breast cancer mortality associated with entering an MRI surveillance program were 0.20 (95% CI, 0.10-0.43; P < .001) for women with BRCA1 sequence variations and 0.87 (95% CI, 0.10-17.25; P = .93) for women with BRCA2 sequence variations. Conclusion and Relevance: Results of this cohort study suggest that among women with a BRCA1 sequence variation, MRI surveillance was associated with a significant reduction in breast cancer mortality compared with no MRI surveillance. Further studies of women with BRCA2 sequence variations are needed to ascertain these women obtain the same benefits associated with MRI surveillance.

Cost-Effectiveness of Adjuvant Olaparib for Patients With Breast Cancer and Germline BRCA1/2 Mutations.

Importance: The OlympiA trial found that 1 year of adjuvant olaparib therapy can improve distant disease-free survival and overall survival from early-stage breast cancer in patients with a germline BRCA1/2 mutation. However, olaparib, an oral poly-adenosine diphosphate ribose polymerase inhibitor, is estimated to cost approximately $14 000 per month in the US. Objective: To estimate the incremental cost-effectiveness of adjuvant olaparib compared with no olaparib in eligible patients. Design, Setting, and Participants: In an economic evaluation from a health care system perspective, the cost-effectiveness of adjuvant olaparib was analyzed using a Markov state-transition model. The model simulated costs and lifetime health outcomes of 42-year-old women with high-risk early-stage breast cancer and a known BRCA1/2 mutation who completed definitive primary therapy and neoadjuvant or adjuvant systemic therapy. The study was conducted from August 2021 to July 2023. The effectiveness of olaparib was based on the findings of the OlympiA randomized clinical trial, and other model parameters were identified from the literature. The model was calibrated to the 1-, 2-, 3-, and 4-year distant disease-free and overall survival observed in the OlympiA trial, and olaparib was assumed to reduce the risk of distant recurrence only in the first 4 years. Exposure: One year of adjuvant olaparib or no adjuvant olaparib. Main Outcome and Measure: Incremental cost-effectiveness ratio (ICER) in 2021 US dollars per quality-adjusted life-year (QALY) gained. All outcomes were discounted by 3% annually. Results: In the base case, adjuvant olaparib was associated with a 1.25-year increase in life expectancy and a 1.20-QALY increase at an incremental cost of $133 133 compared with no olaparib. The resulting ICER was approximately $111 000 per QALY gained. At a willingness-to-pay threshold of $150 000 per QALY, olaparib was cost-effective at its 2021 price and in more than 92% of simulations in probabilistic sensitivity analysis. The results were sensitive to assumptions about the effectiveness of olaparib and quality of life for patients with no disease recurrence. Conclusions and Relevance: In this study, from a US health care system perspective, adjuvant olaparib was a cost-effective option for patients with high-risk, early-stage breast cancer and a germline BRCA1/2 mutation.

Breast cancer surveillance in BRCA positive Sri Lankan women: health equity for a high-risk group at a limited resource setting.

BACKGROUND: BRCA1 and BRCA2 pathogenic variants account for 90% of hereditary breast malignancies, incurring a lifetime breast cancer risk of 85% and 40-45% respectively, in affected individuals. Well-resourced health care settings offer genetic counselling and genetic screening for susceptible individuals, followed by intense breast cancer surveillance programmes for those identified at high risk of breast cancer. Such high standards of care are not available in countries with limited resources. This study assessed breast cancer surveillance behaviors among a cohort of BRCA positive Sri Lankan women. METHODS: A retrospective case review of all patients diagnosed with pathogenic variants in BRCA1 and BRCA2 genes from 2015 to 2022 at the Human Genetics Unit, Faculty of Medicine, University of Colombo was carried out followed by telephone interviews of the respondents. Patients who were not contactable, deceased, undergone bilateral mastectomy and males were excluded from the interview component of the study. Standard descriptive statistics were used to analyze the data using SPSS statistics version 25. RESULTS: Only 25 patients were diagnosed during the study period:14/25 women responded (6/25 deceased, 3/25 non-contactable; 2/25 excluded). 71.4% (10/14) had performed breast self-examination during the preceding month; 35.7% (5/14) had a clinical breast examination (CBE), and 50% (7/14) had undergone a screening/diagnostic mammogram during the last one year. 28.5% (4/14) had undergone both mammography and CBE; 21.45% (3/14) mammogram only, 7.1% (1/14) had CBE only. 42.8%(6/14) had not undergone any surveillance(mammography, CBE or MRI). None had dual screening with mammogram and MRI. 85.71% (12/14) women expressed willingness to participate in a regular screening programme if made available. CONCLUSION: Fifty percent of BRCA1/2 positive women in our study had not undergone annual imaging-based surveillance by mammography or MRI, and none had undergone annual dual screening with mammography and MRI, indicating inadequate breast cancer surveillance in this high-risk group.

Clinical risk management of breast, ovarian, pancreatic, and prostatic cancers for BRCA1/2 variant carriers in Japan.

Opportunities for genetic counseling and germline BRCA1/2 (BRCA) testing are increasing in Japan owing to cancer genomic profiling testing and companion diagnostics being covered by national health insurance for patients with BRCA-related cancers. These tests are useful not only to judge whether platinum agents and PARP inhibitors are indicated but also to reveal an autosomal-dominant inherited cancer syndrome: hereditary breast and ovarian cancer. In individuals with germline BRCA variants, risk of cancers of the breast, ovary, pancreas, and prostate is significantly increased at various ages of onset, but the stomach, uterus, biliary tract, and skin might also be at risk. For women with pathogenic BRCA variants, breast awareness and image analyses should be initiated in their 20s, and risk-reducing procedures such as mastectomy are recommended starting in their 30s, with salpingo-oophorectomy in their late 30s. For male BRCA pathogenic variant carriers, prostatic surveillance should be applied using serum prostate-specific antigen starting in their 40s. For both sexes, image examinations ideally using endoscopic ultrasound and magnetic resonance cholangiopancreatography and blood testing should begin in their 50s for pancreatic surveillance. Homologous recombination pathway-associated genes are also causative candidates. Variant pathogenicity needs to be evaluated every 6-12 months when results are uncertain for clinical significance. Genetic counseling needs to be offered to the blood relatives of the pathogenic variant carriers with suitable timing. We review the recommended cross-organ BRCA risk management in Japan.

Nationwide Trends and Determinants of Germline BRCA1/2 Testing in Patients With Breast and Ovarian Cancer.

BACKGROUND: Germline genetic testing (GT) for BRCA1/2 is instrumental in identifying patients with breast and ovarian cancers who are eligible for PARP inhibitors (PARPi). Little is known about recent trends and determinants of GT since PARPi were approved for these patients. PATIENTS AND METHODS: We performed a retrospective cohort study of patients in a nationwide electronic health record (EHR)-derived oncology-specific database with the following GT eligibility criteria: breast cancer diagnosed at age ≤45 years, triple-negative breast cancer diagnosed at age ≤60 years, male breast cancer, or ovarian cancer. GT within 1 year of diagnosis was assessed and stratified by tumor type. Multivariable log-binomial regressions estimated adjusted relative risks (RRs) of GT by patient and tumor characteristics. RESULTS: Among 2,982 eligible patients with breast cancer, 56.4% underwent GT between January 2011 and March 2020, with a significant increase in GT over time (RR, 1.08; 95% CI, 1.05-1.11, for each year), independent of when PARPi were approved for BRCA1/2-mutated metastatic breast cancer in January 2018. In multivariable analyses, older age (RR, 0.93; 95% CI, 0.90-0.96, for every 5 years) and Medicare coverage (RR, 0.69; 95% CI, 0.49-0.96 vs commercial insurance) were associated with less GT. Among 5,563 eligible patients with ovarian cancer, 35.4% underwent GT between January 2011 and March 2020, with a significant increase in GT over time (RR, 1.11; 95% CI, 1.07-1.14, for each year) that accelerated after approval of PARPi for BRCA1/2-mutated, chemotherapy-refractory ovarian cancer in December 2014 (RR, 1.42; 95% CI, 1.19-1.70). Older age (RR, 0.95; 95% CI, 0.93-0.97, for every 5 years) and Black or African American race (RR, 0.80; 95% CI, 0.65-0.98 vs White race) were associated with less GT. CONCLUSIONS: GT remains underutilized nationwide among patients with breast and ovarian cancers. Although GT has increased over time, significant disparities by age, race, and insurance status persist. Additional work is needed to design, implement, and evaluate strategies to ensure that all eligible patients receive GT.

The economic value of knowing BRCA status: universal BRCA testing for breast cancer prevention.

BACKGROUND: This study aimed to estimate the incremental lifetime effects, costs, and net monetary benefit (NMB) of knowing BRCA information by universal genetic testing of all US women without breast cancer turning 40 in a given year, and the cumulative savings or losses of yearly cohort testing over 16 years. We compared two strategies: (1) 'with BRCA information' and (2) 'without BRCA information.' METHODS: Incremental NMB (INMB) was calculated as the monetized benefit per person of knowing BRCA status. The net monetized value (cumulated INMB) of knowing BRCA information was estimated by multiplying the INMB with the eligible population or the year 2020 cohort of US women age 40 and extended for a total of 16 yearly cohorts. RESULTS: Universal testing of the female population at the age of 40 in a given year provided aan INMB of $663/person (payer) and $1,006/person (society).Escalated to the U.S. population of women age 40 , knowing BRCA status resulted in lifetime cumulated INMB of $1.3 billion (payer) and $2.0 billion (society) for the 2020 cohort; and yielded accumulated monetized value of $18.3 billion (payer) and $27.6 billion (society) over 16 yearly cohorts of 40-year-old women. CONCLUSIONS: The universal testing for BRCA status of all US women at age 40 provides compelling short-term and long-term economic value.

Genetic testing in privately insured women with surgically treated breast cancer.

PURPOSE: Rates of BRCA1 and BRCA2 prevalence among women with breast cancer vary by age, hormone receptor status, and family history. Recommendations for genetic testing have varied between overlapping guidelines, payor coverage policies, and have evolved over time, resulting in unclear implications for adoption into routine breast cancer care. METHODS: Using a large, private insurer database, we examined rates of BRCA1/BRCA2 genetic testing in women with newly diagnosed invasive breast cancer undergoing surgery from 2015 through 2019. RESULTS: Testing increased among women 50 years or older from 26 to 38%, remained stable at 66% in both 2015 and 2019 in the under 50 population, and was slightly decreased in women under age 45 years. CONCLUSION: Among privately insured patients with breast cancer, rates are increasing in older women, but appear persistently underused in younger women.

Systematic mapping review of guidelines for BRCA1/2 genetic testing globally: investigating geographic and regional disparities in health equity for women and families at risk for hereditary ovarian cancer.

OBJECTIVE: Identification of persons at risk for hereditary syndromes through genetic testing prior to cancer diagnosis may proactively reduce the cancer burden morbidity and mortality. Using a framework of health equity, this study characterizes the global landscape of publication and reference to BRCA1/2 genetic testing guidelines (GTG). METHODS: This study used a systematic literature search supplemented by an International Gynecologic Cancer Society (IGCS) informal survey and cross referenced with Myriad Genetics records, to identify published GTG, their country of origin, and countries referencing them. RESULTS: Of 1011 identified publications, 166 met the inclusion criteria, from which 46 unique guidelines were identified, published by 18 countries and two regions (Europe and the UK). Authorship from the USA accounted for 63% of publications on GTG. Systematic mapping reviews revealed 34 countries with published and/or referenced guidelines, the IGCS survey revealed 22 additional countries, and coordination with Myriad Genetics revealed additional information for two countries and primary information for one country. Of the 57 countries evaluated, 33% published their own guidelines and reference guidelines from another country/region, 5% published their own guidelines without referencing another country/region, and 61% only referenced a guideline from another country/region. No data were available for 138 of 195 countries, disproportionately from Africa, the Middle East, Eastern Europe, and Southeast Asia. CONCLUSIONS: Global geographic disparities in the publication and referencing of GTG exist, with a large emphasis on North American and European guidelines in the published literature. These disparities highlight a need for uniform BRCA GTG to improve global health equity.

Promoters of BRCA testing under insurance coverage for non-metastatic breast cancer patients in Japan: a retrospective cohort study.

BACKGROUND: We investigated the barriers to and promoters of taking BRCA testing, after the start of national healthcare insurance coverage for non-metastatic breast cancer patients in Japan. PATIENTS AND METHODS: This was a multi-center, retrospective, cohort study. We included stage 0 to III breast cancer patients who were diagnosed and met the criteria for insurance coverage of BRCA testing between April 2020 and December 2021. We examined the association between BRCA testing and possible exposures: breast cancer diagnosis at 45 years or younger, triple-negative breast cancer (TNBC) diagnosis at the age of 60 or younger, two or more primary breast cancers, family history of breast cancer or ovarian cancer in the third degree of relatives, male breast cancer, medical expense limits, and parity. We used logistic regression analysis. RESULTS: We included 222 patients and 123 (55.4%) of them underwent the test. In univariate analysis, a family history of ovarian cancer (odds ratio (OR) 10.59; 95% CI 1.35-82.96, p = 0.025), diagnosis of breast cancer at the age of 45 or younger (OR 2.78; 95% CI 1.52-5.14, p = 0.0009), and diagnosis of TNBC at the age of 60 or younger (OR 3.95; 95% CI 1.55-10.07, p = 0.004) were associated with taking the test. After multivariate logistic regression analysis, a family history of ovarian cancer (adjusted OR 12.80; 95% CI 1.51-108.80, p = 0.0195), diagnosis of breast cancer at the age of 45 or younger (adjusted OR 4.43; 95% CI 1.98-9.90, p = 0.0003), and TNBC at the age of 60 or younger (adjusted OR 5.28; 95% CI 1.90-14.66, p = 0.0014) were consistently associated. CONCLUSION: For non-metastatic breast cancer patients whose BRCA testing is covered by insurance, costs would no longer be a definite barrier. Physicians should keep in mind that a family history of ovarian cancer, breast cancer diagnosis at 45 years of age or younger and TNBC diagnosis at 60 years of age or younger are strong promoters.

In silico and structure-based assessment to classify VUS identified in the α-helical domain of BRCA2.

Breast cancer type 2 susceptibility (BRCA2) protein plays a crucial role in DNA double-strand breaks repair mechanism by homologous recombination. Pathogenic mutations in the BRCA2 gene confer an increased risk of hereditary breast and ovarian cancer (HBOC). Different missense mutations are identified from a larger cohort of patient populations in the BRCA2. However, most missense mutations are classified as 'Variants of Uncertain Significance' (VUS) due to a lack of data from structural, functional, and clinical assessments. Therefore, this study focused on assessing VUS identified in the α-helical domain of h-BRCA2 using different in silico tools and structure-based molecular dynamics simulation. A total of 286 identified VUS were evaluated using Align-GVGD, PROVEAN and PANTHER servers and 18 variants were predicted to be pathogenic. Further, out of 18 variants analyzed using the ConSurf server, 16 variants were found to be evolutionary conserved. These 16 conserved variants were submitted to PremPS and Dynamut server to assess the effect of the mutation at the protein structure level; 12 mutations were predicted to have a destabilizing effect on the native protein structure. Finally, molecular dynamics simulations revealed 5 variants BRCA2 Cys2646Tyr, Asp2665Val, Trp2619Arg, Trp2619Ser and Tyr2660Cys can alter the folding pattern and need further validation using in vitro, structural and in vivo studies to classify as pathogenic.Communicated by Ramaswamy H. Sarma.

The avoiding late diagnosis of ovarian cancer (ALDO) project; a pilot national surveillance programme for women with pathogenic germline variants in BRCA1 and BRCA2.

BACKGROUND: Our study aimed to establish 'real-world' performance and cost-effectiveness of ovarian cancer (OC) surveillance in women with pathogenic germline BRCA1/2 variants who defer risk-reducing bilateral salpingo-oophorectomy (RRSO). METHODS: Our study recruited 875 female BRCA1/2-heterozygotes at 13 UK centres and via an online media campaign, with 767 undergoing at least one 4-monthly surveillance test with the Risk of Ovarian Cancer Algorithm (ROCA) test. Surveillance performance was calculated with modelling of occult cancers detected at RRSO. The incremental cost-effectiveness ratio (ICER) was calculated using Markov population cohort simulation. RESULTS: Our study identified 8 OCs during 1277 women screen years: 2 occult OCs at RRSO (both stage 1a), and 6 screen-detected; 3 of 6 (50%) were ≤stage 3a and 5 of 6 (83%) were completely surgically cytoreduced. Modelled sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) for OC were 87.5% (95% CI, 47.3 to 99.7), 99.9% (99.9-100), 75% (34.9-96.8) and 99.9% (99.9-100), respectively. The predicted number of quality-adjusted life years (QALY) gained by surveillance was 0.179 with an ICER cost-saving of -£102,496/QALY. CONCLUSION: OC surveillance for women deferring RRSO in a 'real-world' setting is feasible and demonstrates similar performance to research trials; it down-stages OC, leading to a high complete cytoreduction rate and is cost-saving in the UK National Health Service (NHS) setting. While RRSO remains recommended management, ROCA-based surveillance may be considered for female BRCA-heterozygotes who are deferring such surgery.

A cost-utility analysis of BRCA1 and BRCA2 testing in high-risk breast cancer patients and family members in Thailand: a cost-effective policy in resource-limited settings.

Background: Screening for germline pathogenic BRCA1 or BRCA2 variants (gBRCA) in high-risk breast cancer patients is known to be cost-effective in high-income countries. Nationwide adoption of genetics testing in high-risk breast cancer population remains poor. Our study aimed to assess gBRCA health economics data in the middle-income country setting of Thailand. Methods: Decision tree and Markov model were utilized to assess cost-utility between the testing vs. no-testing groups from a societal and lifetime perspective and lifetime. We interviewed 264 patients with breast/ovarian cancer and their family members to assess relevant costs and quality of life using EQ-5D-5L. One-way sensitivity, probabilistic sensitivity (Monte Carlo simulation), and budget impact analyses were done to estimate the outcome under Thailand's Universal Health Coverage scheme. Results: The predicted lifetime cost and Quality-adjusted Life Years (QALY) for those with breast cancer were $13,788 and 10.22 in the testing group and $13,702 and 10.07 in the no-testing group. The incremental cost-effectiveness ratio for gBRCA testing in high-risk breast cancer patients was $573/QALY. The lifetime cost for the family members of those with gBRCA was $14,035 (QALY 9.99), while the no-testing family members group was $14,077 (QALY 9.98). Performing gBRCA testing in family members was cost-saving. Conclusion: Cost-utility analysis demonstrated a cost-effective result of gBRCA testing in high-risk breast cancer patients and cost-saving in familial cascade testing. The result was endorsed in the national health benefits package in 2022. Other middle-income countries may observe the cost-effective/cost-saving aspects in common genetic diseases under their national health schemes.

Germline Testing and Somatic Tumor Testing for BRCA1/2 Pathogenic Variants in Ovarian Cancer: What Is the Optimal Sequence of Testing?

PURPOSE: In 2020, ASCO recommended that all women with epithelial ovarian cancer have germline testing for BRCA1/2 mutations, and those without a germline pathogenic variant (PV) should have somatic tumor testing to determine eligibility for a poly (ADP-ribose) polymerase inhibitor. Consequently, the majority of patients with ovarian cancer will have both germline testing and somatic testing. An alternate strategy is tumor testing first and then germline testing if there is a PV in the tumor and/or significant family history. The objective was to conduct a cost-effectiveness analysis comparing the two testing strategies. METHODS: The Markov model compared the costs (US dollars) and benefits of two testing strategies for newly diagnosed ovarian cancer: (1) ASCO strategy and (2) tumor testing triage for germline testing. Data were applied from SOLO-1, and costs were from wholesale acquisition prices, Medicare, and published sources. Sensitivity analyses accounted for uncertainty around various parameters. Monte Carlo simulation estimated the number tested and identified with germline and somatic BRCA PV for olaparib maintenance treatment annually in the US population. RESULTS: The ASCO strategy was more effective but more costly than tumor testing triage in identifying patients for olaparib, with an incremental cost-effectiveness ratio of $281,296 US dollars per progression-free life year gained. Assuming 10,000 eligible patients with ovarian cancer annually, Monte Carlo simulation yielded comparable numbers of patients with BRCA PV in the germline and tumor with the ASCO and tumor testing triage strategies (2,080 v 2,062, respectively), but substantially higher number of patients tested using the ASCO strategy (8,052 v 3,076). CONCLUSION: The ASCO strategy may identify more BRCA PVs but is not cost-effective. Tumor testing in epithelial ovarian cancer as triage for germline testing is the favored strategy in this health care system.

Computational structural assessment of BReast CAncer type 1 susceptibility protein (BRCA1) and BRCA1-Associated Ring Domain protein 1 (BARD1) mutations on the protein-protein interface.

Breast cancer type 1 susceptibility protein (BRCA1) is closely related to the BRCA2 (breast cancer type 2 susceptibility protein) and BARD1 (BRCA1-associated RING domain-1) proteins. The homodimers were formed through their RING fingers; however they form more compact heterodimers preferentially, influencing BRCA1 residues 1-109 and BARD1 residues 26-119. We implemented an integrative computational pipeline to screen all the mutations in BRCA1 and identify the most significant mutations influencing the Protein-Protein Interactions (PPI) in the BRCA1-BARD1 protein complex. The amino acids involved in the PPI regions were identified from the PDBsum database with the PDB ID: 1JM7. We screened 2118 missense mutations in BRCA1 and none in BARD1 for pathogenicity and stability and analyzed the amino acid sequences for conserved residues. We identified the most significant mutations from these screenings as V11G, M18K, L22S, and T97R positioned in the PPI regions of the BRCA1-BARD1 protein complex. We further performed protein-protein docking using the ZDOCK server. The native protein-protein complex showed the highest binding score of 2118.613, and the V11G mutant protein complex showed the least binding score of 1992.949. The other three mutation protein complexes had binding scores between the native and V11G protein complexes. Finally, a molecular dynamics simulation study using GROMACS was performed to comprehend changes in the BRCA1-BARD1 complex's binding pattern due to the mutation. From the analysis, we observed the highest deviation with lowest compactness and a decrease in the intramolecular h-bonds in the BRCA1-BARD1 protein complex with the V11G mutation compared to the native complex or the complexes with other mutations.

Identification of the most common BRCA alterations through analysis of germline mutation databases: Is droplet digital PCR an additional strategy for the assessment of such alterations in breast and ovarian cancer families?

Breast and ovarian cancer represent two of the most common tumor types in females worldwide. Over the years, several non­modifiable and modifiable risk factors have been associated with the onset and progression of these tumors, including age, reproductive factors, ethnicity, socioeconomic status and lifestyle factors, as well as family history and genetic factors. Of note, BRCA1 and BRCA2 are two tumor suppressor genes with a key role in DNA repair processes, whose mutations may induce genomic instability and increase the risk of cancer development. Specifically, females with a family history of breast or ovarian cancer harboring BRCA1/2 germline mutations have a 60­70% increased risk of developing breast cancer and a 15­40% increased risk for ovarian cancer. Different databases have collected the most frequent germline mutations affecting BRCA1/2. Through the analysis of such databases, it is possible to identify frequent hotspot mutations that may be analyzed with next­generation sequencing (NGS) and novel innovative strategies. In this context, NGS remains the gold standard method for the assessment of BRCA1/2 mutations, while novel techniques, including droplet digital PCR (ddPCR), may improve the sensitivity to identify such mutations in the hereditary forms of breast and ovarian cancer. On these bases, the present study aimed to provide an update of the current knowledge on the frequency of BRCA1/2 mutations and cancer susceptibility, focusing on the diagnostic potential of the most recent methods, such as ddPCR.