A family history of breast cancer will not predict female early onset breast cancer in a population-based setting

ABSTRACT: BACKGROUND: An increased risk of breast cancer for relatives of breast cancer patients has been demonstrated in many studies, and having a relative diagnosed with breast cancer at an early age is an indication for breast cancer screening. This indication has been derived from estimates based on data from cancer-prone families or from BRCA1/2 mutation families, and might be biased because BRCA1/2 mutations explain only a small proportion of the familial clustering of breast cancer. The aim of the current study was to determine the predictive value of a family history of cancer with regard to early onset of female breast cancer in a population based setting. METHODS: An unselected sample of 1,987 women with and without breast cancer was studied with regard to the age of diagnosis of breast cancer. RESULTS: The risk of early-onset breast cancer was increased when there were: (1) at least 2 cases of female breast cancer in first-degree relatives (yes/no; HR at age 30: 3.09; 95% CI: 128-7.44), (2) at least 2 cases of female breast cancer in first or second-degree relatives under the age of 50 (yes/no; HR at age 30: 3.36; 95% CI: 1.12-10.08), (3) at least 1 case of female breast cancer under the age of 40 in a first- or second-degree relative (yes/no; HR at age 30: 2.06; 95% CI: 0.83-5.12) and (4) any case of bilateral breast cancer (yes/no; HR at age 30: 3.47; 95%: 1.33-9.05). The positive predictive value of having 2 or more of these characteristics was 13% for breast cancer before the age of 70, 11% for breast cancer before the age of 50, and 1% for breast cancer before the age of 30. CONCLUSION: Applying family history related criteria in an unselected population could result in the screening of many women who will not develop breast cancer at an early age

Association between a 46-SNP Polygenic Risk Score and melanoma risk in Dutch patients with familial melanoma

Background Familial clustering of melanoma suggests a shared genetic predisposition among family members, but only 10%–40% of familial cases carry a pathogenic variant in a known high-risk melanoma susceptibility gene. We investigated whether a melanoma-specific Polygenic Risk Score (PRS) is associated with melanoma risk in patients with genetically unexplained familial melanoma. Methods Dutch familial melanoma cases (n=418) were genotyped for 46 SNPs previously identified as independently associated with melanoma risk. The 46-SNP PRS was calculated and standardised to 3423 healthy controls (sPRS) and the association between PRS and melanoma risk was modelled using logistic regression. Within the case series, possible differences were further explored by investigating the PRS in relation to (1) the number of primary melanomas in a patient and (2) the extent of familial clustering of melanoma. Results The PRS was significantly associated with melanoma risk, with a per-SD OR of 2.12 (95% CI 1.90 to 2.35, p<0.001), corresponding to a 5.70-fold increased risk (95% CI 3.93 to 8.28) when comparing the top 90th to the middle 40–60th PRS percentiles. The mean PRS was significantly higher in cases with multiple primary melanomas than in cases with a single melanoma (sPRS 1.17 vs 0.71, p=0.001). Conversely, cases from high-density melanoma families had a lower (but non-significant) mean PRS than cases from low-density families (sPRS 0.60 vs 0.94, p=0.204). Conclusion Our work underlines the significance of a PRS in determining melanoma susceptibility and encourages further exploration of the diagnostic value of a PRS in genetically unexplained melanoma families

Design of the BRISC study: a multicentre controlled clinical trial to optimize the communication of breast cancer risks in genetic counselling

Background: Understanding risks is considered to be crucial for informed decision-making. Inaccurate risk perception is a common finding in women with a family history of breast cancer attending genetic counseling. As yet, it is unclear how risks should best be communicated in clinical practice. This study protocol describes the design and methods of the BRISC (Breast cancer RISk Communication) study evaluating the effect of different formats of risk communication on the counsellee's risk perception, psychological well-being and decision-making regarding preventive options for breast cancer. Methods and design: The BRISC study is designed as a pre-post-test controlled group intervention trial with repeated measurements using questionnaires. The intervention-an additional risk consultation-consists of one of 5 conditions that differ in the way counsellee's breast cancer risk is communicated: 1) lifetime risk in numerical format (natural frequencies, i.e. X out of 100), 2) lifetime risk in both numerical format and graphical format (population figures), 3) lifetime risk and age-related risk in numerical format, 4) lifetime risk and age-related risk in both numerical format and graphical format, and 5) lifetime risk in percentages. Condition 6 is the control condition in which no intervention is given (usual care). Participants are unaffected women with a family history of breast cancer attending one of three participating clinical genetic centres in the Netherlands. Discussion: The BRISC study allows for an evaluation of the effects of different formats of communicating breast cancer risks to counsellees. The results can be used to optimize risk communication in order to improve informed decision-making among women with a family history of breast cancer. They may also be useful for risk communication in other health-related services. Trial registration: Current Controlled Trials ISRCTNI4566836

Optimal selection for BRCA1 and BRCA2 mutation testing using a combination of ' easy to apply ' probability models

To establish an efficient, reliable and easy to apply risk assessment tool to select families with breast and/or ovarian cancer patients for BRCA mutation testing, using available probability models. In a retrospective study of 263 families with breast and/or ovarian cancer patients, the utility of the Frank (Myriad), Gilpin (family history assessment tool) and Evans (Manchester) model was analysed, to select 49 BRCA mutation-positive families. For various cutoff levels and combinations, the sensitivity and specificity were calculated and compared. The best combinations were subsequently validated in additional sets of families. Comparable sensitivity and specificity were obtained with the Gilpin and Evans models. They appeared to be complementary to the Frank model. To obtain an optimal sensitivity, five ‘additional criteria' were introduced that are specific for the selection of small or uninformative families. The optimal selection is made by the combination ‘Frank ⩾16% or Evans2 ⩾12 or one of five additional criteria'. The efficiency of the selection of families for mutation testing of BRCA1 and BRCA2 can be optimised by using a combination of available easy to apply risk assessment models

Cost-effectiveness of MRI compared to mammography for breast cancer screening in a high risk population

<p>Abstract</p> <p>Background</p> <p>Breast magnetic resonance imaging (MRI) is a sensitive method of breast imaging virtually uninfluenced by breast density. Because of the improved sensitivity, breast MRI is increasingly being used for detection of breast cancer among high risk young women. However, the specificity of breast MRI is variable and costs are high. The purpose of this study was to determine if breast MRI is a cost-effective approach for the detection of breast cancer among young women at high risk.</p> <p>Methods</p> <p>A Markov model was created to compare annual breast cancer screening over 25 years with either breast MRI or mammography among young women at high risk. Data from published studies provided probabilities for the model including sensitivity and specificity of each screening strategy. Costs were based on Medicare reimbursement rates for hospital and physician services while medication costs were obtained from the Federal Supply Scale. Utilities from the literature were applied to each health outcome in the model including a disutility for the temporary health state following breast biopsy for a false positive test result. All costs and benefits were discounted at 5% per year. The analysis was performed from the payer perspective with results reported in 2006 U.S. dollars. Univariate and probabilistic sensitivity analyses addressed uncertainty in all model parameters.</p> <p>Results</p> <p>Breast MRI provided 14.1 discounted quality-adjusted life-years (QALYs) at a discounted cost of $18,167 while mammography provided 14.0 QALYs at a cost of$4,760 over 25 years of screening. The incremental cost-effectiveness ratio of breast MRI compared to mammography was $179,599/QALY. In univariate analysis, breast MRI screening became <$50,000/QALY when the cost of the MRI was < $315. In the probabilistic sensitivity analysis, MRI screening produced a net health benefit of -0.202 QALYs (95$50,000/QALY. Breast MRI screening was superior in 0%, < $50,000/QALY in 22$50,000/QALY in 34%, and inferior in 44% of trials.</p> <p>Conclusion</p> <p>Although breast MRI may provide health benefits when compared to mammographic screening for some high risk women, it does not appear to be cost-effective even at willingness to pay thresholds above $120,000/QALY.</p

Определение скорости перемещения деформаций растяжений в массиве при подземной выемке угля

Приведена швидкість переміщення деформацій в непорушеному масиві. Встановлено, що швидкість в породах середнього ступеня метаморфізму складає 15 м/добу. Середня швидкість переміщення деформацій в сланцях – 10 м/добу, в піщаниках – 15 м/добу. При повторній підробці швидкість переміщення деформацій складає 17 м/добу.Deformation’s speed travel in the virgin rock massif is given in this article. It has been determined that deformation’s speed in the rocks of medium-scale metamorphism was 15 meters over the entire circadian period. The average speed of deformation’s travel in the shale rocks is 10 meters over the entire circadian period and in the sandstone is 15 meters over the entire circadian period. During the recurring undermining the speed travel of deformations is 17 meters over the entire circadian period

Cancer risks among BRCA1 and BRCA2 mutation carriers

BRCA1 and BRCA2 mutations increase breast and ovarian cancer risks substantially enough to warrant risk reduction surgery, despite variable risk estimates. Underlying this variability are methodological issues, and also complex genetic and nongenetic effects. Although many modifying factors are unidentified, known factors can already be incorporated in individualised risk prediction

Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers

Ovarian carcinomas with mutations in the tumour suppressor BRCA2 are particularly sensitive to platinum compounds. However, such carcinomas ultimately develop cisplatin resistance. The mechanism of that resistance is largely unknown. Here we show that acquired resistance to cisplatin can be mediated by secondary intragenic mutations in BRCA2 that restore the wild-type BRCA2 reading frame. First, in a cisplatin-resistant BRCA2-mutated breast-cancer cell line, HCC1428, a secondary genetic change in BRCA2 rescued BRCA2 function. Second, cisplatin selection of a BRCA2-mutated pancreatic cancer cell line, Capan-1 (refs 3, 4), led to five different secondary mutations that restored the wild-type BRCA2 reading frame. All clones with secondary mutations were resistant both to cisplatin and to a poly(ADP-ribose) polymerase (PARP) inhibitor (AG14361). Finally, we evaluated recurrent cancers from patients whose primary BRCA2-mutated ovarian carcinomas were treated with cisplatin. The recurrent tumour that acquired cisplatin resistance had undergone reversion of its BRCA2 mutation. Our results suggest that secondary mutations that restore the wild-type BRCA2 reading frame may be a major clinical mediator of acquired resistance to platinum-based chemotherapy