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.

Financial toxicity in BRCA1 and BRCA2 carriers.

OBJECTIVE: Financial toxicity (FT), the cumulative financial burden experienced due to medical care, is a well-established adverse effect of healthcare. Patients with BRCA mutations have significantly increased cancer risks compared to non-affected individuals, requiring more frequent screenings and, at times, prophylactic surgery, increasing their risk for FT. Our primary aim in this study was to describe rates of FT among BRCA carriers. METHODS: We performed a novel, cross-sectional study of FT in BRCA1/2 carriers. Participants were recruited via phone and/or email to complete consents and surveys on REDCap. The FACIT-COST tool, a validated tool for measuring FT, was used to assess FT; scores were divided into tertiles, with high FT defined as COST score < 24. RESULTS: 265 BRCA positive female participants met enrollment criteria; 76 (28.7%) consented to participate and completed the survey. Participants were primarily non-Hispanic White (97.4%), privately insured (82.9%), and employed full time (67.1%). A significant proportion (22.7%) of participants reported delaying or avoiding care secondary to finances. No statistically significant association was seen between financial toxicity groups and analyzed demographics. Participants with high FT were more likely to engage in all surveyed cost-saving measures, with 41.7% of participants reporting delays/avoidance of care due to cost (p = 0.02). CONCLUSIONS: This study of FT in BRCA carriers shows that financial toxicity exists as an issue in this high-risk patient population. This work serves as the first description of FT in BRCA mutation carriers and highlights the importance of incorporating routine counseling on cost when discussing recommendations for screening and clinical care with this patient population.

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.

Hereditary Ovarian Cancer: Towards a Cost-Effective Prevention Strategy.

Ovarian cancer (OC) is the most lethal gynaecological malignancy. The search for a widely affordable and accessible screening strategy to reduce mortality from OC is still ongoing. This coupled with the late-stage presentation and poor prognosis harbours significant health-economic implications. OC is also the most heritable of all cancers, with an estimated 25% of cases having a hereditary predisposition. Advancements in technology have detected multiple mutations, with the majority affecting the BRCA1 and/or BRCA2 genes. Women with BRCA mutations are at a significantly increased lifetime risk of developing OC, often presenting with a high-grade serous pathology, which is associated with higher mortality due to its aggressive characteristic. Therefore, a targeted, cost-effective approach to prevention is paramount to improve clinical outcomes and mortality. Current guidelines offer multiple preventive strategies for individuals with hereditary OC (HOC), including genetic counselling to identify the high-risk women and risk-reducing interventions (RRI), such as surgical management or chemoprophylaxis through contraceptive medications. Evidence for sporadic OC is abundant as compared to the existing dearth in the hereditary subgroup. Hence, our review article narrates an overview of HOC and explores the RRI developed over the years. It attempts to compare the cost effectiveness of these strategies with women of the general population in order to answer the crucial question: what is the most prudent clinically and economically effective strategy for prevention amongst high-risk women?

Germline Variant Spectrum Among African American Men Undergoing Prostate Cancer Germline Testing: Need for Equity in Genetic Testing.

PURPOSE: Guidelines for prostate cancer (PCA) germline testing (GT) have expanded, with impact on clinical management and hereditary cancer assessment. African American (AA) men have lower engagement in GT, with concern for widening disparities in genetically informed care. We evaluated the germline spectrum in a cohort of men with PCA enriched for AA men who underwent GT to inform tailored genetic evaluation strategies. METHODS: Participants included AA and White men with PCA tested with a 14-gene PCA panel: ATM, BRCA1, BRCA2, CHEK2, EPCAM, HOXB13, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, RAD51D, and TP53. Germline analysis was performed per standard clinical testing and variant classification protocols. Data were compared with Fisher's exact, chi-squared, or two sample t-tests, as appropriate. Multivariable analysis was conducted using Akaike's Information Criterion. The significance level was set a priori at .05. RESULTS: The data set included 427 men all tested using the 14-gene PCA panel: AA (n = 237, 56%) and White (n = 190, 44%). Overall, the pathogenic/likely pathogenic (P/LP) variant rate was 8.2%, with AA men having lower rates of P/LP variants then White men (5.91% v 11.05%, respectively; P = .05). Borderline associations with P/LP variant status were observed by race (AA v White; odds ratio = 0.51; P = .07) and age (> 50 v ≤ 50 years; odds ratio = 0.48; P = .06). The P/LP spectrum was narrower in AA men (BRCA2, PALB2, ATM, and BRCA1) than White men (BRCA2, ATM, HOXB13, CHEK2, TP53, and NBN). A significant difference was noted in rates of variants of uncertain significance (VUSs) between AA men and White men overall (25.32% v 16.32%; P = .02) and for carrying multiple VUSs (5.1% v 0.53%, P = .008). CONCLUSION: Germline evaluation in a cohort enriched for AA men highlights the narrower spectrum of germline contribution to PCA with significantly higher rates of multiple VUSs in DNA repair genes. These results underscore the imperative to engage AA men in GT, the need for larger panel testing in AA men, and the necessity to incorporate novel genomic technologies to clarify VUS to discern the germline contribution to PCA. Furthermore, tailored genetic counseling for AA men is important to ensure understanding of VUS and promote equitable genetics care delivery.

Evaluation of a Four-Gene Panel for Hereditary Cancer Risk Assessment.

BRCA1/2 are tumor suppressor genes involved in DNA double-strand break repair. They are the most penetrant genes for hereditary breast and ovarian cancers, but pathogenic variants in these two genes can be identified only in a fraction of hereditary cases. Following the diffusion of BRCA molecular testing and the availability of specific therapeutic strategies for the management of pathogenic variant carriers, the demand for the analysis of additional predisposing genetic factors has increased. Indeed, there is accumulating evidence regarding the role of other genes, including CHEK2 and PALB2. Both of them are involved in the same molecular pathway as BRCA genes, with CHEK2 being responsible for cell cycle stopping to allow the repair of DNA double-strand breaks and PALB2 being able to interact with BRCA1 and activate BRCA2. Thus, their role as additional hereditary cancer predisposing factors is intriguing. Accordingly, guidelines for hereditary cancer risk assessment have been updated to include the criteria for additional genes testing. In this context, we validated a commercially available kit allowing for the simultaneous analysis of BRCA1, BRCA2, CHEK2 and PALB2. Forty-eight patients, already tested for BRCA mutational status, were re-analyzed in the present study. Results comparison showed that the tested method was able to correctly identify all the variants previously detected in the same patients. In particular, all single-nucleotide variants and small indels were correctly identified. Moreover, two copy number variants, included to assess the software's performance in detecting this kind of gene alteration, were also detected. Even if copy number variant estimation still requires confirmation by a molecular technique to avoid false positive results, it is able to reduce the number of patients requiring multiplex ligation probe amplification analysis, positively impacting the test's turnaround time. Finally, since the time and costs of the analysis are similar to those required just for BRCA genes, this strategy may be affordable for providing a more comprehensive test for hereditary cancer risk assessment.

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.

Attitude towards hereditary cancer risk management among women with cancer in Taiwan.

BACKGROUND: Risk management intentions prior to genetic counseling predict risk management uptake following genetic testing. Limited studies examined the attitude and understanding towards genetic counseling/testing in underserved countries. The purposes of this study were to explore knowledge and attitude towards genetic counseling, testing, and risk management for breast and ovarian cancer, and to understand the factors influencing risk management intentions in women with cancer in Taiwan. METHODS: Cross-sectional with correlational design was used in this study. Participants were enrolled for genetic testing based on clinical criteria suspected of having hereditary cancer. Survey was conducted using a standardized questionnaire including (1) demographics and personal/family history of cancer; (2) prior experience or consideration of genetic testing and reasons for not considering; (3) perception and attitude towards genetic counseling; and (4) intentions for risk management with a hypothetical BRCA1 mutation status. Multinomial logistic regression was used to analyze the predictors of participants' intentions for cancer risk management strategies. RESULTS: A total of 430 women with cancer were analyzed in which 51.6% had family history of cancer in first-degree relatives. Only 30.7% had considered genetic testing and 28.4% had known about genetic counseling prior to the study. When prompted with the services of genetic counseling, the attitude towards genetic counseling was fairly positive (score of 19.8 ± 2.9 out of 25). Given hypothetical BRCA1 mutation status, enhanced breast cancer screening with annual breast MRI was much more accepted than cancer risk reducing interventions. More positive attitude towards genetic counseling (each score point increase) was associated with higher odds of intention for breast MRI (OR 1.20, 95% CI 1.09-1.32) and preventive tamoxifen (OR 1.11, 95% CI 1.02-1.22). Having considered genetic testing prior to the study was associated with higher odds of intention for all four risk management strategies: breast MRI (OR 2.99, 95% CI 1.46-6.11), preventive tamoxifen (OR 1.79, 95% CI 1.00-3.17), risk-reducing mastectomy (OR 2.24, 95% CI 1.13-4.42), and risk-reducing salpingo-oophorectomy (OR 2.69, 95% CI 1.27-6.93). CONCLUSION: Knowledge of genetic testing and positive attitude towards genetic counseling were associated with increased willingness to consider cancer risk management strategies for hereditary breast and ovarian cancer syndrome. Given the limited knowledge on genetic testing and counseling in the studied population, increasing public awareness of these services may increase adoption of the risk management strategies.

Cost-utility analysis of risk-reducing strategies to prevent breast and ovarian cancer in BRCA-mutation carriers in Switzerland.

OBJECTIVE: We aimed to identify the most cost-effective of all prophylactic measures available in Switzerland for women not yet affected by breast and ovarian cancer who tested positive for a BRCA1/2 mutation. METHODS: Prophylactic bilateral mastectomy (PBM), salpingo-oophorectomy (PBSO), combined PBM&PBSO and chemoprevention (CP) initiated at age 40 years were compared with intensified surveillance (IS). A Markov model with a life-long time horizon was developed from the perspective of the Swiss healthcare system using mainly literature-derived data to evaluate costs, quality-adjusted life years (QALYs) and survival. Costs and QALYs were discounted by 3% per year. Robustness of the results was tested with deterministic and probabilistic sensitivity analyses. RESULTS: All prophylactic measures were found to be cost-saving with an increase in QALYs and life years (LYs) compared to IS. PBM&PBSO were found to be most cost-effective and dominated all other strategies in women with a BRCA1 or BRCA2 mutation. Lifetime costs averaged to 141,293 EUR and 14.5 QALYs per woman with a BRCA1 mutation under IS, versus 76,639 EUR and 19.2 QALYs for PBM&PBSO. Corresponding results for IS per woman with a BRCA2 mutation were 102,245 EUR and 15.5 QALYs, versus 60,770 EUR and 19.9 QALYs for PBM&PBSO. The results were found to be robust in sensitivity analysis; no change in the dominant strategy for either BRCA-mutation was observed. CONCLUSION: All more invasive strategies were found to increase life expectancy and quality of life of women with a BRCA1 or BRCA2 mutation and were cost-saving for the Swiss healthcare system compared to IS.

Olaparib as first line in BRCA-mutated advanced ovarian carcinoma: Is it cost-effective in Spain?

OBJECTIVE: To estimate the cost-effectiveness of olaparib after being funded by the Spanish National Health Service (SNHS) as first-line monotherapy maintenance treatment in patients with advanced high-grade serous ovarian carcinoma (HGSOC) and BRCA mutations in Spain. METHODS: A semi-Markov model with one-month cycles was adapted to the Spanish healthcare setting, using the perspective of the SNHS, and a time horizon of 50 years. Two scenarios were compared: receiving olaparib vs. no maintenance treatment. The model comprised four health states and included the clinical results of the SOLO1 study, along with the direct healthcare costs associated with the use of first-line and subsequent treatment resources (2020 €). A discount rate of 3% was applied for future cost and quality-of-life outcomes. A probabilistic sensitivity analysis (PSA) was also carried out and a cost-effectiveness threshold of €25,000 per quality adjusted life year (QALY) was considered. RESULTS: The introduction of olaparib as a first-line maintenance treatment for advanced HGSOC patients with BRCA mutations implied a cost of €131,614.98 compared to €102,369.54 without olaparib (difference: €29,245.44), with an improvement of 2.00 QALYs (5.56 and 3.57, respectively). Therefore, olaparib is cost-effective for advanced HGSOC patients with BRCA mutations, with an incremental cost-effectiveness ratio of €14,653.2/QALY. The results from the PSA showed that 92.1% of the simulations fell below the €25,000/QALY threshold. The model showed that olaparib could improve the overall survival by 2 years, vs. no maintenance treatment. CONCLUSIONS: Olaparib as first-line maintenance treatment is cost-effective in advanced HGSOC patients with BRCA mutations in Spain.

Assessment of the Risk of Breast Cancer Development Applying NCI Tool among Iraqi Women.

OBJECTIVE: As part of the bioinformatics studies, we utilized National Cancer Institute (NCI)'s Breast Cancer Risk Assessment Tool to estimate the five-year period and lifetime risk of breast cancer development among Iraqi risky women. METHODS: Totally, 110 risky women aged 21-67 (mean=36±7.4) years were interviewed by a series of questions regarding the risk of breast cancer development. Moreover, 100 cases with mutation in the BRCA1 or BRCA2 genes were included. RESULTS: Our results demonstrated that the patient's estimated risk of breast cancer development during the next five years and lifetime (until the age 90 years) included 0.96% (p=0.211) and 9.97% (p=0.002), respectively being relatively low. Accordingly, the lifetime risk for the breast cancer development was significantly higher (10.38%) than that of 5-year. However, the age of patients was not significantly associated to the breast cancer development as there was no significant difference among various age groups. CONCLUSION: It was concluded that long-term or lifetime period plays as a significant risk factor for developing breast cancer among female patients who had had a screening episode in Iraq.

Multigene assessment of genetic risk for women for two or more breast cancers.

PURPOSE: The prevalence, penetrance, and spectrum of pathogenic variants that predispose women to two or more breast cancers is largely unknown. METHODS: We queried clinical and genetic data from women with one or more breast cancer diagnosis who received multigene panel testing between 2013 and 2018. Clinical data were obtained from provider-completed test request forms. For each gene on the panel, a multivariable logistic regression model was constructed to test for association with risk of multiple breast cancer diagnoses. Models accounted for age of diagnosis, personal and family cancer history, and ancestry. Results are reported as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: This study included 98,979 patients: 88,759 (89.7%) with a single breast cancer and 10,220 (10.3%) with ≥ 2 breast cancers. Of women with two or more breast cancers, 13.2% had a pathogenic variant in a cancer predisposition gene compared to 9.4% with a single breast cancer. BRCA1, BRCA2, CDH1, CHEK2, MSH6, PALB2, PTEN, and TP53 were significantly associated with two or more breast cancers, with ORs ranging from 1.35 for CHEK2 to 3.80 for PTEN. Overall, pathogenic variants in all breast cancer risk genes combined were associated with both metachronous (OR 1.65, 95% CI 1.53-1.79, p = 7.2 × 10-33) and synchronous (OR 1.33, 95% CI 1.19-1.50, p = 2.4 × 10-6) breast cancers. CONCLUSIONS: This study demonstrated that several high and moderate penetrance breast cancer susceptibility genes are associated with ≥ 2 breast cancers, affirming the association of two or more breast cancers with diverse genetic etiologies.

Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.

Can population BRCA screening be applied in non-Ashkenazi Jewish populations? Experience in Macau population.

BACKGROUND: Pathogenic mutation in BRCA genes causes high cancer risk. Identifying the mutation carriers plays key roles in preventing BRCA mutation-related cancer. Population screening has demonstrated its power for comprehensive identification of the mutation carriers. However, it is only recommended for the Ashkenazi Jewish population with high prevalence of three founder mutations, but not for non-Ashkenazi Jewish populations as the cost-effectiveness could be too low due to their lower mutation prevalence and lack of founder mutation. Population screening would not benefit the majority of the human population for BRCA mutation-related cancer prevention. METHODS: We used population BRCA screening in 6000 residents, 1% of the Macau population, an ethnic Chinese population with unique genetic, linguistic and cultural features, and its BRCA mutation has not been analysed before. RESULTS: We called BRCA variants, identified 18 carriers with 14 pathogenic mutations and determined the prevalence of 0.29% in the population (95% CI 0.15% to 0.42%). We compared the testing cost between the Ashkenazi Jewish population, the Sephardi Jewish population and the Macau population, and observed only a few fold differences. CONCLUSION: Our study shows that testing cost is not the most important factor in considering population BRCA screening, at least for the populations in the developed countries/regions, regardless of the status of mutation prevalence and founder mutation.

Health Care Disparities and Demand for Expanding Hereditary Breast Cancer Screening Guidelines in African Americans.

BACKGROUND: Genomic medicine has led to significant advancements in the prevention and treatment of cancer. The National Comprehensive Cancer Network (NCCN) guidelines recommend BRCA1/2 screening in high-risk individuals; however, the guidelines have not incorporated differences within ethnic cohorts beyond Ashkenazi Jewish ethnicity. We analyzed the prevalence of BRCA1/2 mutations in various ethnicities and identified high-risk personal characteristics and family history incorporating differences within ethnic cohorts beyond Ashkenazi Jewish ethnicity. PATIENTS AND METHODS: We reviewed data collected by a Michigan medical genetic clinic in a community-based hospital from 2008 to 2018. A retrospective chart analysis was conducted of 1090 patients who received genetic counseling regarding hereditary cancer syndromes. RESULTS: We found a statistically significant higher rate of pathogenic BRCA1/2 mutation prevalence in African American patients, at 8.1%, compared to non-Ashkenazi Jewish white patients, at 3.6% (P = .02). African Americans have a mutational prevalence nearing that of the Ashkenazi Jewish population. CONCLUSION: Revision of the NCCN guidelines regarding hereditary cancer syndrome testing in various ethnic groups is imperative and overdue. Future studies are needed to identify health care disparities in and socioeconomic barriers to genetic testing.

Cost-effectiveness of Maintenance Therapy Based on Molecular Classification Following Treatment of Primary Epithelial Ovarian Cancer in the United States.

Importance: There are large randomized clinical trials-SOLO-1 (Olaparib Maintenance Monotherapy in Patients With BRCA Mutated Ovarian Cancer Following First Line Platinum Based Chemotherapy [December 2018]), PRIMA (A Study of Niraparib Maintenance Treatment in Patients With Advanced Ovarian Cancer Following Response on Front-Line Platinum-Based Chemotherapy [September 2019]), and PAOLA-1 (Platine, Avastin and Olaparib in 1st Line [December 2019])-reporting positive efficacy results for maintenance regimens for women with primary, advanced epithelial ovarian cancer. The findings resulted in approval by the US Food and Drug Administration of the treatments studied as of May 2020. However, there are pressing economic considerations given the many eligible patients and substantial associated costs. Objective: To evaluate the cost-effectiveness of maintenance strategies for patients with (1) a BRCA variant, (2) homologous recombination deficiency without a BRCA variant, or (3) homologous recombination proficiency. Design, Setting, and Participants: In this economic evaluation of the US health care sector using simulated patients with primary epithelial ovarian cancer, 3 decision trees were developed, one for each molecular signature. The maintenance strategies evaluated were olaparib (SOLO-1), olaparib-bevacizumab (PAOLA-1), bevacizumab (PAOLA-1), and niraparib (PRIMA). Base case 1 assessed olaparib, olaparib-bevacizumab, bevacizumab, and niraparib vs observation of a patient with a BRCA variant. Base case 2 assessed olaparib-bevacizumab, bevacizumab, and niraparib vs observation in a patient with homologous recombination deficiency without a BRCA variant. Base case 3 assessed olaparib-bevacizumab, bevacizumab, and niraparib vs observation in a patient with homologous recombination proficiency. The time horizon was 24 months. Costs were estimated from Medicare claims, wholesale acquisition prices, and published sources. Probabilistic sensitivity analyses with microsimulation were then conducted to account for uncertainty and assess model stability. One-way sensitivity analyses were also performed. The study was performed from January through June 2020. Main Outcomes and Measures: Incremental cost-effectiveness ratios (ICERs) in US dollars per progression-free life-year saved (PF-LYS). Results: Assuming a willingness-to-pay threshold of $100 000/PF-LYS, none of the drugs could be considered cost-effective compared with observation. In the case of a patient with a BRCA variant, olaparib was the most cost-effective (ICER, $186 777/PF-LYS). The third-party payer price per month of olaparib would need to be reduced from approximately $17 000 to $9000 to be considered cost-effective. Olaparib-bevacizumab was the most cost-effective in the case of a patient with homologous recombination deficiency without a BRCA variant (ICER, $629 347/PF-LYS), and bevacizumab was the most cost-effective in the case of patient with homologous recombination proficiency (ICER, $557 865/PF-LYS). Even at a price of $0 per month, niraparib could not be considered cost-effective as a maintenance strategy for patients with homologous recombination proficiency. Conclusions and Relevance: The findings of this study suggest that, at current costs, maintenance therapy for primary ovarian cancer is not cost-effective, regardless of molecular signature. For certain therapies, lowering the drug price alone may not make them cost-effective.

Cost-Effectiveness of Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer.

BACKGROUND: Maintenance therapy with the PARP inhibitor olaparib for metastatic pancreatic cancer (MPC) with a germline BRCA1 or BRCA2 mutation has been shown to be effective. We aimed to evaluate the cost-effectiveness of maintenance olaparib for MPC from the US payer perspective. MATERIALS AND METHODS: A partitioned survival model was adopted to project the disease course of MPC. Efficacy and toxicity data were gathered from the Pancreas Cancer Olaparib Ongoing (POLO) trial. Transition probabilities were estimated from the reported survival probabilities in each POLO group. Cost and health preference data were derived from the literature. The incremental cost-utility ratio, incremental net-health benefit, and incremental monetary benefit were measured. Subgroup analysis, one-way analysis, and probabilistic sensitivity analysis were performed to explore the model uncertainties. RESULTS: Maintenance olaparib had an incremental cost-utility ratio of $191,596 per additional progression-free survival (PFS) quality-adjusted life-year (QALY) gained, with a high cost of $132,287 and 0.691 PFS QALY gained, compared with results for a placebo. Subgroup analysis indicated that maintenance olaparib achieved at least a 16.8% probability of cost-effectiveness at the threshold of $200,000/QALY. One-way sensitivity analyses revealed that the results were sensitive to the hazard ratio of PFS and the cost of olaparib. When overall survival was considered, maintenance olaparib had an incremental cost-utility ratio of $265,290 per additional QALY gained, with a high cost of $128,266 and 0.483 QALY gained, compared with results for a placebo. CONCLUSIONS: Maintenance olaparib is potentially cost-effective compared with placebo for patients with a germline BRCA mutation and MPC. Economic outcomes could be improved by tailoring treatment based on individual patient factors.

Management of early breast cancer during the COVID-19 pandemic in Brazil.

PURPOSE: The COVID-19 pandemic has impacted early breast cancer (EBC) treatment worldwide. This study analyzed how Brazilian breast specialists are managing EBC. METHODS: An electronic survey was conducted with members of the Brazilian Society of Breast Cancer Specialists (SBM) between April 30 and May 11, 2020. Bivariate analysis was used to describe changes in how specialists managed EBC at the beginning and during the pandemic, according to breast cancer subtype and oncoplastic surgery. RESULTS: The response rate was 34.4% (503/1462 specialists). Most of the respondents (324; 64.4%) lived in a state capital city, were board-certified as breast specialists (395; 78.5%) and either worked in an academic institute or one associated with breast cancer treatment (390; 77.5%). The best response rate was from the southeast of the country (240; 47.7%) followed by the northeast (128; 25.4%). At the beginning of the pandemic, 43% changed their management approach. As the outbreak progressed, this proportion increased to 69.8% (p < 0.001). The southeast of the country (p = 0.005) and the state capital cities (p < 0.001) were associated with changes at the beginning of the pandemic, while being female (p = 0.001) was associated with changes during the pandemic. For hormone receptor-positive tumors with the best prognosis (Ki-67 < 20%), 47.9% and 17.7% of specialists would recommend neoadjuvant endocrine therapy for postmenopausal and premenopausal women, respectively. For tumors with poorer prognosis (Ki-67 > 30%), 34% and 10.9% would recommend it for postmenopausal and premenopausal women, respectively. Menopausal status significantly affected whether the specialists changed their approach (p < 0.00001). For tumors ≥ 1.0 cm, 42.9% of respondents would recommend neoadjuvant systemic therapy for triple-negative tumors and 39.6% for HER2 + tumors. Overall, 63.4% would recommend immediate total breast reconstruction, while only 3.4% would recommend autologous reconstruction. In breast-conserving surgery, 75% would recommend partial breast reconstruction; however, 54.1% would contraindicate mammoplasty. Furthermore, 84.9% of respondents would not recommend prophylactic mastectomy in cases of BRCA mutation. CONCLUSIONS: Important changes occurred in EBC treatment, particularly for hormone receptor-positive tumors, as the outbreak progressed in each region. Systematic monitoring could assure appropriate breast cancer treatment, mitigating the impact of the pandemic.