Importance Moving to multigene testing for all women with breast cancer (BC) could identify many more mutation carriers who can benefit from precision prevention. However, the cost-effectiveness of this approach remains unaddressed. Objective To estimate incremental lifetime effects, costs, and cost-effectiveness of multigene testing of all patients with BC compared with the current practice of genetic testing (BRCA) based on family history (FH) or clinical criteria. Design, Setting, and Participants This cost-effectiveness microsimulation modeling study compared lifetime costs and effects of high-riskBRCA1/BRCA2/PALB2(multigene) testing of all unselected patients with BC (strategy A) withBRCA1/BRCA2testing based on FH or clinical criteria (strategy B) in United Kingdom (UK) and US populations. Data were obtained from 11 836 patients in population-based BC cohorts (regardless of FH) recruited to 4 large research studies. Data were collected and analyzed from January 1, 2018, through June 8, 2019. The time horizon is lifetime. Payer and societal perspectives are presented. Probabilistic and 1-way sensitivity analyses evaluate model uncertainty. Interventions In strategy A, all women with BC underwentBRCA1/BRCA2/PALB2testing. In strategy B, only women with BC fulfilling FH or clinical criteria underwentBRCAtesting. AffectedBRCA/PALB2carriers could undertake contralateral preventive mastectomy;BRCAcarriers could choose risk-reducing salpingo-oophorectomy (RRSO). Relatives of mutation carriers underwent cascade testing. Unaffected relative carriers could undergo magnetic resonance imaging or mammography screening, chemoprevention, or risk-reducing mastectomy for BC risk and RRSO for ovarian cancer (OC) risk. Main Outcomes and Measures Incremental cost-effectiveness ratio (ICER) was calculated as incremental cost per quality-adjusted life-year (QALY) gained and compared with standard £30 000/QALY and $100 000/QALY UK and US thresholds, respectively. Incidence of OC, BC, excess deaths due to heart disease, and the overall population effects were estimated. Results BRCA1/BRCA2/PALB2multigene testing for all patients detected with BC annually would cost £10 464/QALY (payer perspective) or £7216/QALY (societal perspective) in the United Kingdom or $65 661/QALY (payer perspective) or $61 618/QALY (societal perspective) in the United States compared with currentBRCAtesting based on clinical criteria or FH. This is well below UK and US cost-effectiveness thresholds. In probabilistic sensitivity analysis, unselected multigene testing remained cost-effective for 98% to 99% of UK and 64% to 68% of US health system simulations. One year’s unselected multigene testing could prevent 2101 cases of BC and OC and 633 deaths in the United Kingdom and 9733 cases of BC and OC and 2406 deaths in the United States. Correspondingly, 8 excess deaths due to heart disease occurred in the United Kingdom and 35 in the United States annually. Conclusions and Relevance This study found unselected, high-risk multigene testing for all patients with BC to be extremely cost-effective compared with testing based on FH or clinical criteria for UK and US health systems. These findings support changing current policy to expand genetic testing to all women with BC.

A Cost-effectiveness Analysis of Multigene Testing for All Patients With Breast Cancer.

Background Ovarian cancer is the fifth most common cause of cancer death for women in the UK. Up to 18% of cases can be attributed to germline mutations in BRCA1 and BRCA2 genes. Identifying patients who carry a BRCA mutation provides important information about potential response to treatment and eligibility for therapies such as poly ADP ribose polymerase (PARP) inhibitors. Implementation of systematic genetic testing of patients with ovarian cancer via oncology clinics (mainstreamed genetic testing, MGT) is increasing. Methods and results This service evaluation reports on the first year of MGT at a tertiary oncology centre in London, UK. In total, 122 patients with high-grade non-mucinous ovarian cancer underwent BRCA germline testing via MGT. Eighteen patients (14.8%) were found to carry a deleterious BRCA1 / BRCA2 mutation. Four BRCA carriers did not meet previous criteria for genetic testing and would have been missed. Six BRCA carriers accessed PARP inhibitors post-MGT. Only 22% of patients with a variant of unknown significance (VUS) were referred to clinical genetics services. Conclusions MGT appears to be a feasible way of providing BRCA testing to patients with ovarian cancer. Greater clarity of how oncologists use VUS results is needed, as well as further research on psychosocial implications of MGT for patients with ovarian cancer, which may include somatic testing in the future.

/pdf/mainstreamed-genetic-testing-for-women-with-ovarian-cancer-npr12zsmip.pdf

Mainstreamed genetic testing for women with ovarian cancer: first-year experience

Background While the requirement for thresholds for testing for mutations in BRCA1/2 is being questioned, they are likely to remain for individuals unaffected by a relevant cancer. It is still useful to provide pretesting likelihoods, but models need to take into account tumour pathology. Methods The Manchester Scoring System (MSS) is a well-used, simple, paper-based model for assessing carrier probability that already incorporates pathology data. We have used mutation testing data from 4115 unrelated samples from affected non-Jewish individuals alongside tumour pathology to further refine the scoring system. Results Adding additional points for high-grade serous ovarian cancer BRCA1/2 pathogenic variant. Validation in a population series of ovarian cancer from Cambridge showed high sensitivity at the 10% threshold 15/17 (88.2%). Conclusions The new pathology-adjusted Manchester score MSS3 appears to provide an effective and simple-to-use estimate of the 10% and 20% thresholds for BRCA1/2 likelihood. For unaffected individuals, the 20-point (20%) threshold in their affected first-degree relative can be used to determine eligibility at the 10% threshold.

https://jmg.bmj.com/content/jmedgenet/54/10/674.full.pdf

Pathology update to the Manchester Scoring System based on testing in over 4000 families.

BACKGROUND: Newer approaches to genetic counselling are required for population-based testing. We compare traditional face-to-face genetic counselling with a DVD-assisted approach for population-based BRCA1/2 testing. METHODS: A cluster-randomised non-inferiority trial in the London Ashkenazi Jewish population. INCLUSION CRITERIA: Ashkenazi Jewish men/women >18 years; exclusion criteria: (a) known BRCA1/2 mutation, (b) previous BRCA1/2 testing and (c) first-degree relative of BRCA1/2 carrier. Ashkenazi Jewish men/women underwent pre-test genetic counselling prior to BRCA1/2 testing in the Genetic Cancer Prediction through Population Screening trial (ISRCTN73338115). Genetic counselling clinics (clusters) were randomised to traditional counselling (TC) and DVD-based counselling (DVD-C) approaches. DVD-C involved a DVD presentation followed by shorter face-to-face genetic counselling. Outcome measures included genetic testing uptake, cancer risk perception, increase in knowledge, counselling time and satisfaction (Genetic Counselling Satisfaction Scale). Random-effects models adjusted for covariates compared outcomes between TC and DVD-C groups. One-sided 97.5% CI was used to determine non-inferiority. SECONDARY OUTCOMES: relevance, satisfaction, adequacy, emotional impact and improved understanding with the DVD; cost-minimisation analysis for TC and DVD-C approaches. RESULTS: 936 individuals (clusters=256, mean-size=3.6) were randomised to TC (n=527, clusters=134) and DVD-C (n=409, clusters=122) approaches. Groups were similar at baseline, mean age=53.9 (SD=15) years, women=66.8%, men=33.2%. DVD-C was non-inferior to TC for increase in knowledge (d=-0.07; lower 97.5% CI=-0.41), counselling satisfaction (d=-0.38, 97.5% CI=1.2) and risk perception (d=0.08; upper 97.5% CI=3.1). Group differences and CIs did not cross non-inferiority margins. DVD-C was equivalent to TC for uptake of genetic testing (d=-3%; lower/upper 97.5% CI -7.9%/1.7%) and superior for counselling time (20.4 (CI 18.7 to 22.2) min reduction (p<0.005)). 98% people found the DVD length and information satisfactory. 85-89% felt it improved their understanding of risks/benefits/implications/purpose of genetic testing. 95% would recommend it to others. The cost of genetic counselling for DVD-C=£7787 and TC=£17 307. DVD-C resulted in cost savings=£9520 (£14/volunteer). CONCLUSIONS: DVD-C is an effective, acceptable, non-inferior, time-saving and cost-efficient alternative to TC. TRIAL REGISTRATION NUMBER: ISRCTN 73338115.

/pdf/cluster-randomised-non-inferiority-trial-comparing-dvd-18gam4p47s.pdf

Cluster-randomised non-inferiority trial comparing DVD-assisted and traditional genetic counselling in systematic population testing for BRCA1/2 mutations

Ovarian cancer is a common and complex malignancy with poor prognostic outcome. Most women with ovarian cancer are diagnosed with advanced stage disease due to a lack of effective detection strategies in the early stage. Traditional treatment with cytoreductive surgery and platinum-based combination chemotherapy has not significantly improved prognosis and 5-year survival rates are still extremely poor. Therefore, novel treatment strategies are needed to improve the treatment of ovarian cancer patients. Recent advances of next generation sequencing technologies have both confirmed previous known mutated genes and discovered novel candidate genes in ovarian cancer. In this review, we illustrate recent advances in identifying ovarian cancer gene mutations, including those of TP53, BRCA1/2, PIK3CA, and KRAS genes. In addition, we discuss advances in targeting therapies for ovarian cancer based on these mutated genes in ovarian cancer. Further, we associate between detection of mutation genes by liquid biopsy and the potential early diagnostic value in ovarian cancer.

/pdf/cellular-mechanism-of-gene-mutations-and-potential-16tsxaq805.pdf

Cellular Mechanism of Gene Mutations and Potential Therapeutic Targets in Ovarian Cancer

Background Over recent years genetic testing for germline mutations in BRCA1/BRCA2 has become more readily available because of technological advances and reducing costs.

Objective To explore the feasibility and acceptability of offering genetic testing to all women recently diagnosed with epithelial ovarian cancer (EOC).

Methods Between 1 July 2013 and 30 June 2015 women newly diagnosed with EOC were recruited through six sites in East Anglia, UK into the Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study. Eligibility was irrespective of patient age and family history of cancer. The psychosocial arm of the study used self-report, psychometrically validated questionnaires (Depression Anxiety and Stress Scale (DASS-21); Impact of Event Scale (IES)) and cost analysis was performed.

Results 232 women were recruited and 18 mutations were detected (12 in BRCA1 , 6 in BRCA2 ), giving a mutation yield of 8%, which increased to 12% in unselected women aged <70 years (17/146) but was only 1% in unselected women aged ≥70 years (1/86). IES and DASS-21 scores in response to genetic testing were significantly lower than equivalent scores in response to cancer diagnosis (p<0.001). Correlation tests indicated that although older age is a protective factor against any traumatic impacts of genetic testing, no significant correlation exists between age and distress outcomes.

Conclusions The mutation yield in unselected women diagnosed with EOC from a heterogeneous population with no founder mutations was 8% in all ages and 12% in women under 70. Unselected genetic testing in women with EOC was acceptable to patients and is potentially less resource-intensive than current standard practice.

https://jmg.bmj.com/content/jmedgenet/53/10/655.full.pdf

New paradigms for BRCA1/BRCA2 testing in women with ovarian cancer: results of the Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study

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New paradigms for BRCA1/BRCA2 testing in women with ovarian cancer: results of the Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study