Evaluation of the BOADICEA risk assessment model in women with a family history of breast cancer

The ability of the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) model to predict BRCA1 and BRCA2 mutations and breast cancer incidence in women with a family history of breast cancer was evaluated. Observed mutations in 263 screened families were compared to retrospective predictions. Similarly, observed breast cancers in 640 women were compared to retrospective predictions of breast cancer incidence. The ratios of observed to expected number of BRCA1- , BRCA2- and BRCA(1 or 2) mutations were 1.43 (95% CI 1.05–1.90), 0.63 (95% CI 0.34–1.08), and 1.12 (95% CI 0.86–1.44), showing a significant underestimation of BRCA1 mutations. Discrimination between carriers and non-carriers as measured by area under the receiver operating characteristic (ROC) curve was 0.83 (95% CI 0.76–0.88). The ratio of observed to expected number of invasive breast cancers was 1.41 (0.91–2.08). The corresponding area under the ROC curve for prediction of invasive breast cancer at individual level was 0.62 (95% CI 0.52–0.73). In conclusion, the BOADICEA model can predict the total prevalence of BRCA(1 or 2) mutations and the incidence of invasive breast cancers. The mutation probability as generated by BOADICEA can be used clinically as a guideline for screening, and thus decrease the proportion of negative mutation analyses. Likewise, individual breast cancer risks can be used for selecting women whose risk of breast cancer indicates follow-up. Application of local mutation frequencies of BRCA1 and BRCA2 could improve the ability to distinguish between the two genes

More on Co-Occurrence of COMT and BRCA1/2 Variants in a Population

Movassagh et al. (May 25 issue) report an association between a synonymous variant (rs165631) in COMT and a reduced risk of cancer among female carriers of the mutation BRCA1 or BRCA2. The result was based on an analysis involving 25 patients with breast cancer who had germline BRCA1/2 alterations in the Cancer Genome Atlas and 15 presumably cancer-free women with BRCA1/2 nonsense and frameshift alterations in the Exome Sequencing Project of the National Heart, Lung, and Blood Institute (NHLBI). Given the potential for misinterpretation of the results, we feel obliged to correct the impression that rs165631 protects carriers of the BRCA1 or BRCA2 mutation from cancer

Specifying the ovarian cancer risk threshold of 'premenopausal risk-reducing salpingo-oophorectomy' for ovarian cancer prevention: a cost-effectiveness analysis

BACKGROUND: Risk-reducing salpingo-oophorectomy (RRSO) is the most effective intervention to prevent ovarian cancer (OC). It is only available to high-risk women with >10% lifetime OC risk. This threshold has not been formally tested for cost-effectiveness. OBJECTIVE: To specify the OC risk thresholds for RRSO being cost-effective for preventing OC in premenopausal women. METHODS: The costs as well as effects of surgical prevention ('RRSO') were compared over a lifetime with 'no RRSO' using a decision analysis model. RRSO was undertaken in premenopausal women >40 years. The model was evaluated at lifetime OC risk levels: 2%, 4%, 5%, 6%, 8% and 10%. Costs and outcomes are discounted at 3.5%. Uncertainty in the model was assessed using both deterministic sensitivity analysis and probabilistic sensitivity analysis (PSA). Outcomes included in the analyses were OC, breast cancer (BC) and additional deaths from coronary heart disease. Total costs and effects were estimated in terms of quality-adjusted life-years (QALYs); incidence of OC and BC; as well as incremental cost-effectiveness ratio (ICER). DATA SOURCES: Published literature, Nurses Health Study, British National Formulary, Cancer Research UK, National Institute for Health and Care Excellence guidelines and National Health Service reference costs. The time horizon is lifetime and perspective: payer. RESULTS: Premenopausal RRSO is cost-effective at 4% OC risk (life expectancy gained=42.7 days, ICER=£19 536/QALY) with benefits largely driven by reduction in BC risk. RRSO remains cost-effective at >8.2% OC risk without hormone replacement therapy (ICER=£29 071/QALY, life expectancy gained=21.8 days) or 6%if BC risk reduction=0 (ICER=£27 212/QALY, life expectancy gained=35.3 days). Sensitivity analysis indicated results are not impacted much by costs of surgical prevention or treatment of OC/ BC or cardiovascular disease. However, results were sensitive to RRSO utility scores. Additionally, 37%, 61%, 74%, 84%, 96% and 99.5% simulations on PSA are cost-effective for RRSO at the 2%, 4%, 5%, 6%, 8% and 10% levels of OC risk, respectively. CONCLUSIONS: Premenopausal RRSO appears to be extremely cost-effective at ≥4% lifetime OC risk, with ≥42.7 days gain in life expectancy if compliance with hormone replacement therapy is high. Current guidelines should be re-evaluated to reduce the RRSO OC risk threshold to benefit a number of at-risk women who presently cannot access risk-reducing surgery

Incorporating tumour pathology information into breast cancer risk prediction algorithms.

INTRODUCTION: Mutations in BRCA1 and BRCA2 confer high risks of breast cancer and ovarian cancer. The risk prediction algorithm BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) may be used to compute the probabilities of carrying mutations in BRCA1 and BRCA2 and help to target mutation screening. Tumours from BRCA1 and BRCA2 mutation carriers display distinctive pathological features that could be used to better discriminate between BRCA1 mutation carriers, BRCA2 mutation carriers and noncarriers. In particular, oestrogen receptor (ER)-negative status, triple-negative (TN) status, and expression of basal markers are predictive of BRCA1 mutation carrier status. METHODS: We extended BOADICEA by treating breast cancer subtypes as distinct disease end points. Age-specific expression of phenotypic markers in a series of tumours from 182 BRCA1 mutation carriers, 62 BRCA2 mutation carriers and 109 controls from the Breast Cancer Linkage Consortium, and over 300,000 tumours from the general population obtained from the Surveillance Epidemiology, and End Results database, were used to calculate age-specific and genotype-specific incidences of each disease end point. The probability that an individual carries a BRCA1 or BRCA2 mutation given their family history and tumour marker status of family members was computed in sample pedigrees. RESULTS: The cumulative risk of ER-negative breast cancer by age 70 for BRCA1 mutation carriers was estimated to be 55% and the risk of ER-positive disease was 18%. The corresponding risks for BRCA2 mutation carriers were 21% and 44% for ER-negative and ER-positive disease, respectively. The predicted BRCA1 carrier probabilities among ER-positive breast cancer cases were less than 1% at all ages. For women diagnosed with breast cancer below age 50 years, these probabilities rose to more than 5% in ER-negative breast cancer, 7% in TN disease and 24% in TN breast cancer expressing both CK5/6 and CK14 cytokeratins. Large differences in mutation probabilities were observed by combining ER status and other informative markers with family history. CONCLUSIONS: This approach combines both full pedigree and tumour subtype data to predict BRCA1/2 carrier probabilities. Prediction of BRCA1/2 carrier status, and hence selection of women for mutation screening, may be substantially improved by combining tumour pathology with family history of cancer.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Are the so-called low penetrance breast cancer genes, ATM, BRIP1, PALB2 and CHEK2, high risk for women with strong family histories?

A woman typically presents for genetic counselling because she has a strong family history and is interested in knowing the probability she will develop disease in the future; that is, her absolute risk. Relative risk for a given factor refers to risk compared with either population average risk (sense a), or risk when not having the factor, with all other factors held constant (sense b). Not understanding that these are three distinct concepts can result in failure to correctly appreciate the consequences of studies on clinical genetic testing. Several studies found that the frequencies of mutations in ATM, BRIP1, PALB2 and CHEK2 were many times greater for cases with a strong family history than for controls. To account for the selected case sampling (ascertainment), a statistical model that assumes that the effect of any measured variant multiplies the effect of unmeasured variants was applied. This multiplicative polygenic model in effect estimated the relative risk in the sense b, not sense a, and found it was in the range of 1.7 to 2.4. The authors concluded that the variants are "low penetrance". They failed to note that their model fits predicted that, for some women, absolute risk may be as high as for BRCA2 mutation carriers. This is because the relative risk multiplies polygenic risk, and the latter is predicted by family history. Therefore, mutation testing of these genes for women with a strong family history, especially if it is of early onset, may be as clinically relevant as it is for BRCA1 and BRCA2

Specifying the ovarian cancer risk threshold of "premenopausal risk-reducing salpingo-oophorectomy' for ovarian cancer prevention: a cost-effectiveness analysis

BACKGROUND: Risk-reducing salpingo-oophorectomy (RRSO) is the most effective intervention to prevent ovarian cancer (OC). It is only available to high-risk women with >10% lifetime OC risk. This threshold has not been formally tested for cost-effectiveness. OBJECTIVE: To specify the OC risk thresholds for RRSO being cost-effective for preventing OC in premenopausal women. METHODS: The costs as well as effects of surgical prevention ('RRSO') were compared over a lifetime with 'no RRSO' using a decision analysis model. RRSO was undertaken in premenopausal women >40 years. The model was evaluated at lifetime OC risk levels: 2%, 4%, 5%, 6%, 8% and 10%. Costs and outcomes are discounted at 3.5%. Uncertainty in the model was assessed using both deterministic sensitivity analysis and probabilistic sensitivity analysis (PSA). Outcomes included in the analyses were OC, breast cancer (BC) and additional deaths from coronary heart disease. Total costs and effects were estimated in terms of quality-adjusted life-years (QALYs); incidence of OC and BC; as well as incremental cost-effectiveness ratio (ICER). DATA SOURCES: Published literature, Nurses Health Study, British National Formulary, Cancer Research UK, National Institute for Health and Care Excellence guidelines and National Health Service reference costs. The time horizon is lifetime and perspective: payer. RESULTS: Premenopausal RRSO is cost-effective at 4% OC risk (life expectancy gained=42.7 days, ICER=£19 536/QALY) with benefits largely driven by reduction in BC risk. RRSO remains cost-effective at >8.2% OC risk without hormone replacement therapy (ICER=£29 071/QALY, life expectancy gained=21.8 days) or 6%if BC risk reduction=0 (ICER=£27 212/QALY, life expectancy gained=35.3 days). Sensitivity analysis indicated results are not impacted much by costs of surgical prevention or treatment of OC/ BC or cardiovascular disease. However, results were sensitive to RRSO utility scores. Additionally, 37%, 61%, 74%, 84%, 96% and 99.5% simulations on PSA are cost-effective for RRSO at the 2%, 4%, 5%, 6%, 8% and 10% levels of OC risk, respectively. CONCLUSIONS: Premenopausal RRSO appears to be extremely cost-effective at ≥4% lifetime OC risk, with ≥42.7 days gain in life expectancy if compliance with hormone replacement therapy is high. Current guidelines should be re-evaluated to reduce the RRSO OC risk threshold to benefit a number of at-risk women who presently cannot access risk-reducing surgery