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1.
JAMA Netw Open ; 4(3): e2037657, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33704474

RESUMO

Importance: If magnetic resonance imaging (MRI) mitigates overdiagnosis of prostate cancer while improving the detection of clinically significant cases, including MRI in a screening program for prostate cancer could be considered. Objective: To evaluate the benefit-harm profiles and cost-effectiveness associated with MRI before biopsy compared with biopsy-first screening for prostate cancer using age-based and risk-stratified screening strategies. Design, Setting, and Participants: This decision analytical model used a life-table approach and was conducted between December 2019 and July 2020. A hypothetical cohort of 4.48 million men in England aged 55 to 69 years were analyzed and followed-up to 90 years of age. Exposures: No screening, age-based screening, and risk-stratified screening in the hypothetical cohort. Age-based screening consisted of screening every 4 years with prostate-specific antigen between the ages of 55 and 69 years. Risk-stratified screening used age and polygenic risk profiles. Main Outcomes and Measures: The benefit-harm profile (deaths from prostate cancer, quality-adjusted life-years, overdiagnosis, and biopsies) and cost-effectiveness (net monetary benefit, from a health care system perspective) were analyzed. Both age-based and risk-stratified screening were evaluated using a biopsy-first and an MRI-first diagnostic pathway. Results were derived from probabilistic analyses and were discounted at 3.5% per annum. Results: The hypothetical cohort included 4.48 million men in England, ranging in age from 55 to 69 years (median, 62 years). Compared with biopsy-first age-based screening, MRI-first age-based screening was associated with 0.9% (1368; 95% uncertainty interval [UI], 1370-1409) fewer deaths from prostate cancer, 14.9% (12 370; 95% UI, 11 100-13 670) fewer overdiagnoses, and 33.8% (650 500; 95% UI, 463 200-907 000) fewer biopsies. At 10-year absolute risk thresholds of 2% and 10%, MRI-first risk-stratified screening was associated with between 10.4% (7335; 95% UI, 6630-8098) and 72.6% (51 250; 95% UI, 46 070-56 890) fewer overdiagnosed cancers, respectively, and between 21.7% fewer MRIs (412 100; 95% UI, 411 400-412 900) and 53.5% fewer biopsies (1 016 000; 95% UI, 1 010 000-1 022 000), respectively, compared with MRI-first age-based screening. The most cost-effective strategies at willingness-to-pay thresholds of £20 000 (US $26 000) and £30 000 (US $39 000) per quality-adjusted life-year gained were MRI-first risk-stratified screening at 10-year absolute risk thresholds of 8.5% and 7.5%, respectively. Conclusions and Relevance: In this decision analytical model of a hypothetical cohort, an MRI-first diagnostic pathway was associated with an improvement in the benefit-harm profile and cost-effectiveness of screening for prostate cancer compared with biopsy-first screening. These improvements were greater when using risk-stratified screening based on age and polygenic risk profile and may warrant prospective evaluation.

2.
Nat Commun ; 12(1): 1236, 2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33623038

RESUMO

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10-180). Comparing the 80th/20th PHS2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.


Assuntos
Grupos Étnicos/genética , Herança Multifatorial/genética , Neoplasias da Próstata/genética , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Autorrelato
3.
Artigo em Inglês | MEDLINE | ID: mdl-33420416

RESUMO

BACKGROUND: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46). MATERIALS AND METHOD: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy. RESULTS: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer. CONCLUSIONS: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.

6.
J Med Ethics ; 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33208479

RESUMO

Epigenetic markers could potentially be used for risk assessment in risk-stratified population-based cancer screening programmes. Whereas current screening programmes generally aim to detect existing cancer, epigenetic markers could be used to provide risk estimates for not-yet-existing cancers. Epigenetic risk-predictive tests may thus allow for new opportunities for risk assessment for developing cancer in the future. Since epigenetic changes are presumed to be modifiable, preventive measures, such as lifestyle modification, could be used to reduce the risk of cancer. Moreover, epigenetic markers might be used to monitor the response to risk-reducing interventions. In this article, we address ethical concerns related to personal responsibility raised by epigenetic risk-predictive tests in cancer population screening. Will individuals increasingly be held responsible for their health, that is, will they be held accountable for bad health outcomes? Will they be blamed or subject to moral sanctions? We will illustrate these ethical concerns by means of a Europe-wide research programme that develops an epigenetic risk-predictive test for female cancers. Subsequently, we investigate when we can hold someone responsible for her actions. We argue that the standard conception of personal responsibility does not provide an appropriate framework to address these concerns. A different, prospective account of responsibility meets part of our concerns, that is, concerns about inequality of opportunities, but does not meet all our concerns about personal responsibility. We argue that even if someone is responsible on grounds of a negative and/or prospective account of responsibility, there may be moral and practical reasons to abstain from moral sanctions.

7.
Cancers (Basel) ; 12(11)2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33158149

RESUMO

The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.

8.
Public Health Nutr ; : 1-9, 2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32744211

RESUMO

OBJECTIVE: The aim of this cross-sectional study was to examine the association between childhood obesity and modifiable population-level risk factors, after accounting for deprivation. DESIGN: A review of the literature identified population-level risk factors including a healthy childcare setting, the local food environment, accessible open space, community safety and crime. Data for these risk factors were then identified and matched by each of the twenty-two local government areas in Wales to each child that had data on height and weight in the Wales Childhood Measurement Programme (CMP) (2012-2017). Multivariable logistic regression was used to identify associations with childhood obesity. SETTING: The current study was undertaken in Wales, UK, where approximately one in eight 4-5-year-olds are classified as obese. PARTICIPANTS: All participants were children aged 4 or 5 years who attend school, measured as part of the CMP, between 2012 and 2017 (n 129 893, mean age 5·0 (sd 0·4) years). RESULTS: After adjusting for deprivation, small but statistically significant associations were found between childhood obesity and percentage of land available as accessible open space OR 0·981 (95 % CI: 0·973, 0·989) P < 0·001) and density of fast food outlets OR 1·002 (95 % CI 1·001, 1·004, P = 0·001). No other population-level risk factors were associated with childhood obesity. CONCLUSIONS: The current study indicates that, even after accounting for deprivation, risk factors such as the density of fast food outlets and access to green space should be considered when tackling childhood obesity as a public health issue.

9.
Cancers (Basel) ; 12(7)2020 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-32664613

RESUMO

Endometrial cancer is the most common female genital tract cancer in developed countries. We systematically reviewed the current health-economic evidence on early detection and prevention strategies for endometrial cancer based on a search in relevant databases (Medline/Embase/Cochrane Library/CRD/EconLit). Study characteristics and results including life-years gained (LYG), quality-adjusted life-years (QALY) gained, and incremental cost-effectiveness ratios (ICERs) were summarized in standardized evidence tables. Economic results were transformed into 2019 euros using standard conversion methods (GDP-PPP, CPI). Seven studies were included, evaluating (1) screening for endometrial cancer in women with different risk profiles, (2) risk-reducing interventions for women at increased or high risk for endometrial cancer, and (3) genetic testing for germline mutations followed by risk-reducing interventions for diagnosed mutation carriers. Compared to no screening, screening with transvaginal sonography (TVS), biomarker CA-125, and endometrial biopsy yielded an ICER of 43,600 EUR/LYG (95,800 EUR/QALY) in women with Lynch syndrome at high endometrial cancer risk. For women considering prophylactic surgery, surgery was more effective and less costly than screening. In obese women, prevention using Levonorgestrel as of age 30 for five years had an ICER of 72,000 EUR/LYG; the ICER for using oral contraceptives for five years as of age 50 was 450,000 EUR/LYG. Genetic testing for mutations in women at increased risk for carrying a mutation followed by risk-reducing surgery yielded ICERs below 40,000 EUR/QALY. Based on study results, preventive surgery in mutation carriers and genetic testing in women at increased risk for mutations are cost-effective. Except for high-risk women, screening using TVS and endometrial biopsy is not cost-effective and may lead to overtreatment. Model-based analyses indicate that future biomarker screening in women at increased risk for cancer may be cost-effective, dependent on high test accuracy and moderate test costs. Future research should reveal risk-adapted early detection and prevention strategies for endometrial cancer.

11.
Cancer Epidemiol Biomarkers Prev ; 29(9): 1731-1738, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32581112

RESUMO

BACKGROUND: A polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening. METHODS: United Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups. RESULTS: The expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age. CONCLUSIONS: PHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS. IMPACT: Personalized genetic risk assessments could inform prostate cancer screening decisions.

12.
Nat Rev Clin Oncol ; 17(11): 687-705, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32555420

RESUMO

The European Collaborative on Personalized Early Detection and Prevention of Breast Cancer (ENVISION) brings together several international research consortia working on different aspects of the personalized early detection and prevention of breast cancer. In a consensus conference held in 2019, the members of this network identified research areas requiring development to enable evidence-based personalized interventions that might improve the benefits and reduce the harms of existing breast cancer screening and prevention programmes. The priority areas identified were: 1) breast cancer subtype-specific risk assessment tools applicable to women of all ancestries; 2) intermediate surrogate markers of response to preventive measures; 3) novel non-surgical preventive measures to reduce the incidence of breast cancer of poor prognosis; and 4) hybrid effectiveness-implementation research combined with modelling studies to evaluate the long-term population outcomes of risk-based early detection strategies. The implementation of such programmes would require health-care systems to be open to learning and adapting, the engagement of a diverse range of stakeholders and tailoring to societal norms and values, while also addressing the ethical and legal issues. In this Consensus Statement, we discuss the current state of breast cancer risk prediction, risk-stratified prevention and early detection strategies, and their implementation. Throughout, we highlight priorities for advancing each of these areas.

13.
Eur J Hum Genet ; 28(10): 1467-1475, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32514134

RESUMO

We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated for random sizes of the training set. The performance of a representative Established-SNP model was estimated for random sizes of the testing set. Mean HR98/50 (hazard ratio of top 2% to average in test set) of the Established-SNP model increased from 1.73 [95% CI: 1.69-1.77] to 2.41 [2.40-2.43] when the number of training samples was increased from 1 thousand to 30 thousand. Corresponding HR98/50 of the Discovery-SNP model increased from 1.05 [0.93-1.18] to 2.19 [2.16-2.23]. HR98/50 of a representative Established-SNP model using testing set sample sizes of 0.6 thousand and 6 thousand observations were 1.78 [1.70-1.85] and 1.73 [1.71-1.76], respectively. We estimate that a study population of 20 thousand men is required to develop Discovery-SNP PHS models while 10 thousand men should be sufficient for Established-SNP models.

16.
Cancer Prev Res (Phila) ; 13(5): 429-442, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32071120

RESUMO

Ovarian cancer imposes a substantial health and economic burden. We systematically reviewed current health-economic evidence for ovarian cancer early detection or prevention strategies. Accordingly, we searched relevant databases for cost-effectiveness studies evaluating ovarian cancer early detection or prevention strategies. Study characteristics and results including quality-adjusted life years (QALY), and incremental cost-effectiveness ratios (ICER) were summarized in standardized evidence tables. Economic results were transformed into 2017 Euros. The included studies (N = 33) evaluated ovarian cancer screening, risk-reducing interventions in women with heterogeneous cancer risks and genetic testing followed by risk-reducing interventions for mutation carriers. Multimodal screening with a risk-adjusted algorithm in postmenopausal women achieved ICERs of 9,800-81,400 Euros/QALY, depending on assumptions on mortality data extrapolation, costs, test performance, and screening frequency. Cost-effectiveness of risk-reducing surgery in mutation carriers ranged from cost-saving to 59,000 Euros/QALY. Genetic testing plus risk-reducing interventions for mutation carriers ranged from cost-saving to 54,000 Euros/QALY in women at increased mutation risk. Our findings suggest that preventive surgery and genetic testing plus preventive surgery in women at high risk for ovarian cancer can be considered effective and cost-effective. In postmenopausal women from the general population, multimodal screening using a risk-adjusted algorithm may be cost-effective.

17.
J Med Screen ; 27(3): 138-145, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31701797

RESUMO

OBJECTIVES: Risk stratification may improve the benefit/harm ratio of breast screening. Research on acceptability among potential invitees is necessary to guide implementation. We assessed women's attitudes towards and willingness to undergo risk assessment and stratified screening. METHODS: Women in England aged 40-70 received summary information about the topic, and completed face-to-face computer-assisted interviews. Questions assessed willingness to undergo multifactorial breast cancer risk assessment, more frequent breast screening (if at very high risk), or less frequent or no screening (if at very low risk), and preferences for delivery of assessment results. RESULTS: Among 933 women, 85% considered breast cancer risk assessment a good idea, and 74% were willing to have it. Among 125 women unwilling to have risk assessment, reasons commonly related to 'worry' (14%) and 'preferring not to know' (14%). Among those willing to have risk assessment (n = 689), letters/emails were generally preferred (42%) for results about very low-risk status. Face-to-face communication was most commonly preferred for results of very high-risk status (78%). General practitioners were most commonly preferred sources of assessment results (≈40%). Breast cancer specialists were often preferred for results of very high-risk status (38%). Risk-stratified breast screening was considered a good idea by 70% and 89% were willing to have more frequent screening. Fewer would accept less (51%) or no screening (37%) if at very low risk. CONCLUSIONS: Women were generally in favour of multifactorial breast cancer risk assessment and risk-stratified screening. Some were unwilling to accept less or no screening if at very low risk.

19.
PLoS Med ; 16(12): e1002998, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31860675

RESUMO

BACKGROUND: The United States Preventive Services Task Force supports individualised decision-making for prostate-specific antigen (PSA)-based screening in men aged 55-69. Knowing how the potential benefits and harms of screening vary by an individual's risk of developing prostate cancer could inform decision-making about screening at both an individual and population level. This modelling study examined the benefit-harm tradeoffs and the cost-effectiveness of a risk-tailored screening programme compared to age-based and no screening. METHODS AND FINDINGS: A life-table model, projecting age-specific prostate cancer incidence and mortality, was developed of a hypothetical cohort of 4.48 million men in England aged 55 to 69 years with follow-up to age 90. Risk thresholds were based on age and polygenic profile. We compared no screening, age-based screening (quadrennial PSA testing from 55 to 69), and risk-tailored screening (men aged 55 to 69 years with a 10-year absolute risk greater than a threshold receive quadrennial PSA testing from the age they reach the risk threshold). The analysis was undertaken from the health service perspective, including direct costs borne by the health system for risk assessment, screening, diagnosis, and treatment. We used probabilistic sensitivity analyses to account for parameter uncertainty and discounted future costs and benefits at 3.5% per year. Our analysis should be considered cautiously in light of limitations related to our model's cohort-based structure and the uncertainty of input parameters in mathematical models. Compared to no screening over 35 years follow-up, age-based screening prevented the most deaths from prostate cancer (39,272, 95% uncertainty interval [UI]: 16,792-59,685) at the expense of 94,831 (95% UI: 84,827-105,630) overdiagnosed cancers. Age-based screening was the least cost-effective strategy studied. The greatest number of quality-adjusted life-years (QALYs) was generated by risk-based screening at a 10-year absolute risk threshold of 4%. At this threshold, risk-based screening led to one-third fewer overdiagnosed cancers (64,384, 95% UI: 57,382-72,050) but averted 6.3% fewer (9,695, 95% UI: 2,853-15,851) deaths from prostate cancer by comparison with age-based screening. Relative to no screening, risk-based screening at a 4% 10-year absolute risk threshold was cost-effective in 48.4% and 57.4% of the simulations at willingness-to-pay thresholds of GBP£20,000 (US$26,000) and £30,000 ($39,386) per QALY, respectively. The cost-effectiveness of risk-tailored screening improved as the threshold rose. CONCLUSIONS: Based on the results of this modelling study, offering screening to men at higher risk could potentially reduce overdiagnosis and improve the benefit-harm tradeoff and the cost-effectiveness of a prostate cancer screening program. The optimal threshold will depend on societal judgements of the appropriate balance of benefits-harms and cost-effectiveness.


Assuntos
Detecção Precoce de Câncer , Antígeno Prostático Específico/análise , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia , Idoso , Análise Custo-Benefício , Detecção Precoce de Câncer/métodos , Inglaterra , Humanos , Incidência , Tábuas de Vida , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Anos de Vida Ajustados por Qualidade de Vida , Medição de Risco
20.
PLoS One ; 14(6): e0218188, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31188874

RESUMO

BACKGROUND: Personal cancer risk assessments enable stratified care, for example, offering preventive surgical measures such as risk-reducing mastectomy (RRM) to women at high risk for breast cancer. In scenario-based experiments, we investigated whether different benefit-harm ratios of RRM influence women's consideration of this, whether this consideration is influenced by women's perception of and desire to know their personal cancer risk, or by their intention to take a novel cancer risk-predictive test, and whether consideration varies across different countries. METHOD: In January 2017, 1,675 women 40 to 75 years of age from five European countries-Czech Republic, Germany, UK, Italy, and Sweden-took part in an online scenario-based experiment. Six different scenarios of hypothetical benefit-harm ratios of RRM were presented in accessible fact box formats: Baseline risk/risk reduction pairings were 20/16, 20/4, 10/8, 10/2, 5/4, and 5/1 out of 1,000 women dying from breast cancer. RESULTS: Varying the baseline risk of dying from breast cancer and the extent of risk reduction influenced the decision to consider RRM for 23% of women. Decisions varied by country, risk perception, and the intention to take a cancer risk-predictive test. Women who expressed a stronger intention to take such a test were more likely to consider having RRM. The desire to know one's risk of developing any female cancer in general moderated women's decisions, whereas the specific desire to know the risk of breast cancer did not. CONCLUSIONS: In this hypothetical scenario-based study, only for a minority of women did the change in benefit-harm ratio inform their consideration of RRM. Because this consideration is influenced by risk perception and the intention to learn one's cancer risks via a cancer risk-predictive test, careful disclosure of different potential preventive measures and their benefit-harm ratios is necessary before testing for individual risk. Furthermore, information on risk testing should acknowledge country-specific sensitivities for benefit-harm ratios.


Assuntos
Neoplasias da Mama/psicologia , Tomada de Decisões , Predisposição Genética para Doença , Intenção , Mastectomia/psicologia , Adulto , Idoso , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , República Tcheca , Feminino , Alemanha , Humanos , Itália , Pessoa de Meia-Idade , Prognóstico , Risco , Comportamento de Redução do Risco , Inquéritos e Questionários , Suécia , Reino Unido
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