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1.
Eur Urol ; 78(4): 494-497, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32532514

RESUMO

A BRCA2 prostate cancer cluster region (PCCR) was recently proposed (c.7914 to 3') wherein pathogenic variants (PVs) are associated with higher prostate cancer (PCa) risk than PVs elsewhere in the BRCA2 gene. Using a prospective cohort study of 447 male BRCA2 PV carriers recruited in the UK and Ireland from 1998 to 2016, we estimated standardised incidence ratios (SIRs) compared with population incidences and assessed variation in risk by PV location. Carriers of PVs in the PCCR had a PCa SIR of 8.33 (95% confidence interval [CI] 4.46-15.6) and were at a higher risk of PCa than carriers of other BRCA2 PVs (SIR = 3.31, 95% CI 1.97-5.57; hazard ratio = 2.34, 95% CI 1.09-5.03). PCCR PV carriers had an estimated cumulative PCa risk of 44% (95% CI 23-72%) by the age of 75 yr and 78% (95% CI 54-94%) by the age of 85 yr. Our results corroborate the existence of a PCCR in BRCA2 in a prospective cohort. PATIENT SUMMARY: In this report, we investigated whether the risk of prostate cancer for men with a harmful mutation in the BRCA2 gene differs based on where in the gene the mutation is located. We found that men with mutations in one region of BRCA2 had a higher risk of prostate cancer than men with mutations elsewhere in the gene.

2.
Cancers (Basel) ; 12(5)2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32429029

RESUMO

Unselected population-based personalised ovarian cancer (OC) risk assessment combining genetic/epidemiology/hormonal data has not previously been undertaken. We aimed to perform a feasibility study of OC risk stratification of general population women using a personalised OC risk tool followed by risk management. Volunteers were recruited through London primary care networks. INCLUSION CRITERIA: women ≥18 years. EXCLUSION CRITERIA: prior ovarian/tubal/peritoneal cancer, previous genetic testing for OC genes. Participants accessed an online/web-based decision aid along with optional telephone helpline use. Consenting individuals completed risk assessment and underwent genetic testing (BRCA1/BRCA2/RAD51C/RAD51D/BRIP1, OC susceptibility single-nucleotide polymorphisms). A validated OC risk prediction algorithm provided a personalised OC risk estimate using genetic/lifestyle/hormonal OC risk factors. Population genetic testing (PGT)/OC risk stratification uptake/acceptability, satisfaction, decision aid/telephone helpline use, psychological health and quality of life were assessed using validated/customised questionnaires over six months. Linear-mixed models/contrast tests analysed impact on study outcomes. MAIN OUTCOMES: feasibility/acceptability, uptake, decision aid/telephone helpline use, satisfaction/regret, and impact on psychological health/quality of life. In total, 123 volunteers (mean age = 48.5 (SD = 15.4) years) used the decision aid, 105 (85%) consented. None fulfilled NHS genetic testing clinical criteria. OC risk stratification revealed 1/103 at ≥10% (high), 0/103 at ≥5%-<10% (intermediate), and 100/103 at <5% (low) lifetime OC risk. Decision aid satisfaction was 92.2%. The telephone helpline use rate was 13% and the questionnaire response rate at six months was 75%. Contrast tests indicated that overall depression (p = 0.30), anxiety (p = 0.10), quality-of-life (p = 0.99), and distress (p = 0.25) levels did not jointly change, while OC worry (p = 0.021) and general cancer risk perception (p = 0.015) decreased over six months. In total, 85.5-98.7% were satisfied with their decision. Findings suggest population-based personalised OC risk stratification is feasible and acceptable, has high satisfaction, reduces cancer worry/risk perception, and does not negatively impact psychological health/quality of life.

3.
J Med Genet ; 57(12): 829-834, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32170000

RESUMO

Advances in technology have led to a massive expansion in the capacity for genomic analysis, with a commensurate fall in costs. The clinical indications for genomic testing have evolved markedly; the volume of clinical sequencing has increased dramatically; and the range of clinical professionals involved in the process has broadened. There is general acceptance that our early dichotomous paradigms of variants being pathogenic-high risk and benign-no risk are overly simplistic. There is increasing recognition that the clinical interpretation of genomic data requires significant expertise in disease-gene-variant associations specific to each disease area. Inaccurate interpretation can lead to clinical mismanagement, inconsistent information within families and misdirection of resources. It is for this reason that 'national subspecialist multidisciplinary meetings' (MDMs) for genomic interpretation have been articulated as key for the new NHS Genomic Medicine Service, of which Cancer Variant Interpretation Group UK (CanVIG-UK) is an early exemplar. CanVIG-UK was established in 2017 and now has >100 UK members, including at least one clinical diagnostic scientist and one clinical cancer geneticist from each of the 25 regional molecular genetics laboratories of the UK and Ireland. Through CanVIG-UK, we have established national consensus around variant interpretation for cancer susceptibility genes via monthly national teleconferenced MDMs and collaborative data sharing using a secure online portal. We describe here the activities of CanVIG-UK, including exemplar outputs and feedback from the membership.

4.
Cancer Prev Res (Phila) ; 13(4): 411-422, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31988145

RESUMO

Tamoxifen reduces breast cancer incidence in women at increased risk, but may cause side effects. We examined women's knowledge of tamoxifen's potential harms and benefits, and the extent to which knowledge reflects subjective judgments of awareness and decision quality. After a hospital appointment, 408 (55.7%) women at increased risk of breast cancer completed a survey assessing objective knowledge about the potential benefit (risk reduction) and harms (endometrial cancer, thromboembolic events, and menopausal side effects) of tamoxifen, and subjective tamoxifen knowledge and decisional quality. Two hundred fifty-eight (63.2%) completed a 3-month follow-up survey. Sixteen percent (15.7%) of participants recognized the potential benefit and three major harms of using tamoxifen. These women were more likely to have degree-level education [vs. below degree level; OR, 2.24; 95% confidence interval (CI), 1.11-4.55] and good numeracy (vs. poor numeracy; OR, 5.91; 95% CI, 1.33-26.19). Tamoxifen uptake was higher in women who recognized all harms and benefits (vs. not recognizing; OR, 2.47; 95% CI, 0.94-6.54). Sixty-six percent (65.8%) of tamoxifen users were unaware of its potential benefit and harms. Most (87.1%) women reported feeling informed about tamoxifen, and subjective decisional quality was high [Mean (SD), 17.03 (1.87), out of 18]. Knowledge regarding the potential harms and benefit of tamoxifen is low in women considering prevention therapy, and they may need additional support to make informed decisions about tamoxifen preventive therapy.

5.
Eur Urol ; 77(1): 24-35, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31495749

RESUMO

BACKGROUND: BRCA1 and BRCA2 mutations have been associated with prostate cancer (PCa) risk but a wide range of risk estimates have been reported that are based on retrospective studies. OBJECTIVE: To estimate relative and absolute PCa risks associated with BRCA1/2 mutations and to assess risk modification by age, family history, and mutation location. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective cohort study of male BRCA1 (n = 376) and BRCA2 carriers (n = 447) identified in clinical genetics centres in the UK and Ireland (median follow-up 5.9 and 5.3 yr, respectively). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Standardised incidence/mortality ratios (SIRs/SMRs) relative to population incidences or mortality rates, absolute risks, and hazard ratios (HRs) were estimated using cohort and survival analysis methods. RESULTS AND LIMITATIONS: Sixteen BRCA1 and 26 BRCA2 carriers were diagnosed with PCa during follow-up. BRCA2 carriers had an SIR of 4.45 (95% confidence interval [CI] 2.99-6.61) and absolute PCa risk of 27% (95% CI 17-41%) and 60% (95% CI 43-78%) by ages 75 and 85 yr, respectively. For BRCA1 carriers, the overall SIR was 2.35 (95% CI 1.43-3.88); the corresponding SIR at age <65 yr was 3.57 (95% CI 1.68-7.58). However, the BRCA1 SIR varied between 0.74 and 2.83 in sensitivity analyses to assess potential screening effects. PCa risk for BRCA2 carriers increased with family history (HR per affected relative 1.68, 95% CI 0.99-2.85). BRCA2 mutations in the region bounded by positions c.2831 and c.6401 were associated with an SIR of 2.46 (95% CI 1.07-5.64) compared to population incidences, corresponding to lower PCa risk (HR 0.37, 95% CI 0.14-0.96) than for mutations outside the region. BRCA2 carriers had a stronger association with Gleason score ≥7 (SIR 5.07, 95% CI 3.20-8.02) than Gleason score ≤6 PCa (SIR 3.03, 95% CI 1.24-7.44), and a higher risk of death from PCa (SMR 3.85, 95% CI 1.44-10.3). Limitations include potential screening effects for these known mutation carriers; however, the BRCA2 results were robust to multiple sensitivity analyses. CONCLUSIONS: The results substantiate PCa risk patterns indicated by retrospective analyses for BRCA2 carriers, including further evidence of association with aggressive PCa, and give some support for a weaker association in BRCA1 carriers. PATIENT SUMMARY: In this study we followed unaffected men known to carry mutations in the BRCA1 and BRCA2 genes to investigate whether they are at higher risk of developing prostate cancer compared to the general population. We found that carriers of BRCA2 mutations have a high risk of developing prostate cancer, particularly more aggressive prostate cancer, and that this risk varies by family history of prostate cancer and the location of the mutation within the gene.

6.
J Med Genet ; 57(4): 226-236, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31719169

RESUMO

BACKGROUND: Germline TP53 gene pathogenic variants (pv) cause a very high lifetime risk of developing cancer, almost 100% for women and 75% for men. In the UK, annual MRI breast screening is recommended for female TP53 pv carriers. The SIGNIFY study (Magnetic Resonance Imaging screening in Li Fraumeni syndrome: An exploratory whole body MRI) study reported outcomes of whole-body MRI (WB-MRI) in a cohort of 44 TP53 pv carriers and 44 matched population controls. The results supported the use of a baseline WB-MRI screen in all adult TP53 pv carriers. Here we report the acceptability of WB-MRI screening and effects on psychosocial functioning and health-related quality of life in the short and medium terms. METHODS: Psychosocial and other assessments were carried out at study enrolment, immediately before MRI, before and after MRI results, and at 12, 26 and 52 weeks' follow-up. RESULTS: WB-MRI was found to be acceptable with high levels of satisfaction and low levels of psychological morbidity throughout. Although their mean levels of cancer worry were not high, carriers had significantly more cancer worry at most time-points than controls. They also reported significantly more clinically significant intrusive and avoidant thoughts about cancer than controls at all time-points. There were no clinically significant adverse psychosocial outcomes in either carriers with a history of cancer or in those requiring further investigations. CONCLUSION: WB-MRI screening can be implemented in TP53 pv carriers without adverse psychosocial outcomes in the short and medium terms. A previous cancer diagnosis may predict a better psychosocial outcome. Some carriers seriously underestimate their risk of cancer. Carriers of pv should have access to a clinician to help them develop adaptive strategies to cope with cancer-related concerns and respond to clinically significant depression and/or anxiety.

7.
Int J Gynecol Cancer ; 30(2): 221-226, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31744886

RESUMO

OBJECTIVE: Pathogenic BRCA variants account for 5.8-24.8% of ovarian cancers. The identification of such a variant can have a significant impact on the affected individual and their relatives, determining eligibility for targeted therapies, predicting treatment response, and granting access to disease prevention strategies. Cancer services are responding to the increased demand for genetic testing with the introduction of mainstreamed genetic testing via oncology clinics. This study aimed to evaluate patient experience of the mainstreamed genetic testing pathway at a tertiary referral center in London, UK. METHODS: Study participants were patients diagnosed with high-grade non-mucinous ovarian cancer, tested via a mainstreamed genetic testing pathway at the tertiary referral center between February 2015 and June 2017. Eligible participants were invited to complete the retrospective study questionnaire. Five quantitative measures with additional free-text items were used to evaluate the patient experience of mainstreamed genetic testing. RESULTS: The tertiary referral center tested 170 ovarian cancer patients. Twenty-three pathogenic BRCA mutations were identified (23/170, 13.5%). One-hundred and six patients (106/170, 62.4%) met the study inclusion criteria. Twenty-nine of those invited to participate (29/106, 27.4%) returned the retrospective study questionnaire. Pathogenic BRCA1/2 variants were identified within four respondents (4/29, 13.8%). Motivations for genetic testing related to improved medical management, and the ability to provide relatives with genetic information. Participants did not appear to be adversely affected by result disclosure post-mainstreamed genetic testing. Two individuals with a pathogenic variant reported that the support provided by the tertiary referral center post-result disclosure could have been improved. CONCLUSION: Results of the current study support further psychosocial research into the expansion of the mainstreamed genetic testing pathway. The results, although promising, have also highlighted the importance of genetic awareness within the multi-disciplinary team and the provision of timely psychological support from genetic specialists.


Assuntos
Testes Genéticos/métodos , Neoplasias Ovarianas/genética , Adulto , Idoso , Proteína BRCA1/genética , Proteína BRCA2/genética , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/psicologia , Aceitação pelo Paciente de Cuidados de Saúde , Inquéritos e Questionários
8.
Cancer Epidemiol Biomarkers Prev ; 29(2): 368-378, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792088

RESUMO

BACKGROUND: Tobacco smoking and alcohol consumption have been intensively studied in the general population to assess their effects on the risk of breast cancer, but very few studies have examined these effects in BRCA1 and BRCA2 mutation carriers. Given the high breast cancer risk for mutation carriers and the importance of BRCA1 and BRCA2 in DNA repair, better evidence on the associations of these lifestyle factors with breast cancer risk is essential. METHODS: Using a large international pooled cohort of BRCA1 and BRCA2 mutation carriers, we conducted retrospective (5,707 BRCA1 mutation carriers and 3,525 BRCA2 mutation carriers) and prospective (2,276 BRCA1 mutation carriers and 1,610 BRCA2 mutation carriers) analyses of alcohol and tobacco consumption using Cox proportional hazards models. RESULTS: For both BRCA1 and BRCA2 mutation carriers, none of the smoking-related variables was associated with breast cancer risk, except smoking for more than 5 years before a first full-term pregnancy (FFTP) when compared with parous women who never smoked. For BRCA1 mutation carriers, the HR from retrospective analysis (HRR) was 1.19 [95% confidence interval (CI), 1.02-1.39] and the HR from prospective analysis (HRP) was 1.36 (95% CI, 0.99-1.87). For BRCA2 mutation carriers, smoking for more than 5 years before an FFTP showed an association of a similar magnitude, but the confidence limits were wider (HRR = 1.25; 95% CI, 1.01-1.55 and HRP = 1.30; 95% CI, 0.83-2.01). For both carrier groups, alcohol consumption was not associated with breast cancer risk. CONCLUSIONS: The finding that smoking during the prereproductive years increases breast cancer risk for mutation carriers warrants further investigation. IMPACT: This is the largest prospective study of BRCA mutation carriers to assess these important risk factors.

9.
Eur Urol ; 76(6): 831-842, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31537406

RESUMO

BACKGROUND: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations. OBJECTIVE: To report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3 yr of screening, by BRCA status. DESIGN, SETTING, AND PARTICIPANTS: Men aged 40-69 yr with a germline pathogenic BRCA1/2 mutation and male controls testing negative for a familial BRCA1/2 mutation were recruited. Participants underwent PSA screening for 3 yr, and if PSA > 3.0 ng/ml, men were offered prostate biopsy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PSA levels, PrCa incidence, and tumour characteristics were evaluated. Statistical analyses included Poisson regression offset by person-year follow-up, chi-square tests for proportion t tests for means, and Kruskal-Wallis for medians. RESULTS AND LIMITATIONS: A total of 3027 patients (2932 unique individuals) were recruited (919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, and 497 BRCA2 noncarriers). After 3 yr of screening, 527 men had PSA > 3.0 ng/ml, 357 biopsies were performed, and 112 PrCa cases were diagnosed (31 BRCA1 carriers, 19 BRCA1 noncarriers, 47 BRCA2 carriers, and 15 BRCA2 noncarriers). Higher compliance with biopsy was observed in BRCA2 carriers compared with noncarriers (73% vs 60%). Cancer incidence rate per 1000 person years was higher in BRCA2 carriers than in noncarriers (19.4 vs 12.0; p = 0.03); BRCA2 carriers were diagnosed at a younger age (61 vs 64 yr; p = 0.04) and were more likely to have clinically significant disease than BRCA2 noncarriers (77% vs 40%; p = 0.01). No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 noncarriers. The 4 kallikrein marker model discriminated better (area under the curve [AUC] = 0.73) for clinically significant cancer at biopsy than PSA alone (AUC = 0.65). CONCLUSIONS: After 3 yr of screening, compared with noncarriers, BRCA2 mutation carriers were associated with a higher incidence of PrCa, younger age of diagnosis, and clinically significant tumours. Therefore, systematic PSA screening is indicated for men with a BRCA2 mutation. Further follow-up is required to assess the role of screening in BRCA1 mutation carriers. PATIENT SUMMARY: We demonstrate that after 3 yr of prostate-specific antigen (PSA) testing, we detect more serious prostate cancers in men with BRCA2 mutations than in those without these mutations. We recommend that male BRCA2 carriers are offered systematic PSA screening.

10.
Histopathology ; 75(6): 813-824, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31310679

RESUMO

AIMS: Lynch syndrome (LS) is associated with an increased risk of developing endometrial carcinoma (EC) and ovarian carcinoma (OC). There is considerable variability in current practices and opinions related to screening of newly diagnosed patients with EC/OC for LS. An online survey was undertaken to explore the extent of these differences. METHODS AND RESULTS: An online questionnaire was developed by a panel of experts and sent to all members of the British Association of Gynaecological Pathologists (BAGP) and the International Society of Gynecological Pathologists (ISGyP). Anonymised results were received and analysed. Thirty-six BAGP and 44 ISGyP members completed the survey. More than 90% of respondents were aware of the association of LS with both EC and OC, but 34% were not aware of specific guidelines for LS screening. Seventy-one per cent of respondents agreed that universal screening for LS should be carried out in all newly diagnosed EC cases, with immunohistochemistry (IHC) alone as the preferred approach. Only 36% of respondents currently performed IHC or microsatellite instability testing on all newly diagnosed EC cases, with most of the remaining respondents practising selective screening, based on clinical or pathological features or both. A significant minority of respondents (35%) believed that patient consent was required before performance of mismatch repair (MMR) protein IHC. Almost all respondents favoured the use of standardised terminology for reporting MMR protein staining results, and this is proposed herein. CONCLUSION: There is wide support for universal LS screening in patients with EC, but this survey highlights areas of considerable variation in practice.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/patologia , Reparo de Erro de Pareamento de DNA , Neoplasias do Endométrio/patologia , Neoplasias Ovarianas/patologia , Idoso , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias do Endométrio/diagnóstico , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Neoplasias Ovarianas/diagnóstico , Inquéritos e Questionários
12.
Clin Breast Cancer ; 19(1): e116-e126, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30518498

RESUMO

INTRODUCTION: Uptake of preventive therapies for breast cancer is low. We examined whether women at increased risk of breast cancer can be categorized into groups with similar medication beliefs, and whether belief group membership was prospectively associated with uptake of preventive therapy. PATIENTS AND METHODS: Women (n = 732) attending an appointment to discuss breast cancer risk were approached; 408 (55.7%) completed the Beliefs About Medicines and the Perceived Sensitivity to Medicines questionnaires. Uptake of tamoxifen at 3 months was reported in 258 (63.2%). The optimal number of belief groups were identified using latent profile analysis. RESULTS: Uptake of tamoxifen was 14.7% (38/258). One in 5 women (19.4%; 78/402) reported a strong need for tamoxifen. The model fit statistics supported a 2-group model. Both groups held weak beliefs about their need for tamoxifen for current and future health. Group 2 (38%; 154/406 of the sample) reported stronger concerns about tamoxifen and medicines in general, and stronger perceived sensitivity to the negative effects of medicines compared with group 1 (62%; 252/406). Women with low necessity and lower concerns (group 1) were more likely to initiate tamoxifen (18.3%; 33/180) than those with low necessity and higher concerns (group 2) (6.4%; 5/78). After adjusting for demographic and clinical factors, the odds ratio was 3.37 (95% confidence interval, 1.08-10.51; P = .036). CONCLUSION: Uptake of breast cancer preventive therapy was low. A subgroup of women reported low need for preventive therapy and strong medication concerns. These women were less likely to initiate tamoxifen. Medication beliefs are targets for supporting informed decision-making.


Assuntos
Neoplasias da Mama/prevenção & controle , Neoplasias da Mama/psicologia , Cultura , Conhecimentos, Atitudes e Prática em Saúde , Adesão à Medicação/estatística & dados numéricos , Medicina Preventiva/métodos , Tamoxifeno/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Tomada de Decisões , Feminino , Seguimentos , Humanos , Adesão à Medicação/psicologia , Pessoa de Meia-Idade , Pré-Medicação/métodos , Prognóstico , Estudos Prospectivos , Fatores de Risco , Inquéritos e Questionários
13.
J Med Genet ; 56(3): 195-198, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29535157

RESUMO

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 BRCA2genes. 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.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Gerenciamento Clínico , Feminino , Genes BRCA1 , Genes BRCA2 , Estudos de Associação Genética/métodos , Testes Genéticos/métodos , Mutação em Linhagem Germinativa , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Ovarianas/epidemiologia , Reino Unido
14.
BMJ Open ; 8(7): e021782, 2018 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-30021754

RESUMO

OBJECTIVE: Population-based risk assessment, using genetic testing and the provision of appropriate risk management, could lead to prevention, early detection and improved clinical management of ovarian cancer (OC). Previous research with mostly white British participants found positive attitudes towards such a programme. The current study aimed to explore the attitudes of South Asian (SA) women and men in the UK with the aim of identifying how best to implement such a programme to minimise distress and maximise uptake. DESIGN: Semistructured qualitative focus group discussions. SETTING: Community centres across North London and Luton. PARTICIPANTS: 49 women and 13 men who identified as SA (Indian, Pakistani or Bangladeshi), which constitutes the largest non-European ethnic minority group in the UK. METHODS: Seven community-based focus groups were held. Group discussions were transcribed verbatim, coded and analysed thematically. RESULTS: Awareness and knowledge of OC symptoms and specific risk factors was low. The programme was acceptable to most participants and attitudes to it were generally positive. Participants' main concerns related to receiving a high-risk result following the genetic test. Younger women may be more cautious of genetic testing, screening or risk-reducing surgery due to the importance of marriage and childbearing in their SA cultures. CONCLUSIONS: A crucial first step to enable implementation of population-based genetic risk assessment and management in OC is to raise awareness of OC within SA communities. It will be important to engage with the SA community early on in programme implementation to address their specific concerns and to ensure culturally tailored decision support.


Assuntos
Conhecimentos, Atitudes e Prática em Saúde/etnologia , Promoção da Saúde/métodos , Neoplasias Ovarianas/psicologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Bangladesh/etnologia , Detecção Precoce de Câncer , Feminino , Grupos Focais , Testes Genéticos , Humanos , Índia/etnologia , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Paquistão/etnologia , Pesquisa Qualitativa , Medição de Risco/métodos , Reino Unido , Adulto Jovem
15.
Am J Hum Genet ; 103(1): 3-18, 2018 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-29909963

RESUMO

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.


Assuntos
Predisposição Genética para Doença/genética , Variação Genética/genética , Neoplasias Primárias Múltiplas/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Feminino , Testes Genéticos/métodos , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo
16.
J Med Genet ; 55(6): 372-377, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29661970

RESUMO

Genetic testing for hereditary cancer predisposition has evolved rapidly in recent years with the discovery of new genes, but there is much debate over the clinical utility of testing genes for which there are currently limited data regarding the degree of associated cancer risk. To address the discrepancies that have arisen in the provision of these tests across the UK, the UK Cancer Genetics Group facilitated a 1-day workshop with representation from the majority of National Health Service (NHS) clinical genetics services. Using a preworkshop survey followed by focused discussion of genes without prior majority agreement for inclusion, we achieved consensus for panels of cancer genes with sufficient evidence for clinical utility, to be adopted by all NHS genetics services. To support consistency in the delivery of these tests and advice given to families across the country, we also developed management proposals for individuals who are found to have pathogenic mutations in these genes. However, we fully acknowledge that the decision regarding what test is most appropriate for an individual family rests with the clinician, and will depend on factors including specific phenotypic features and the family structure.


Assuntos
Predisposição Genética para Doença , Guias como Assunto , Neoplasias/diagnóstico , Aconselhamento Genético , Testes Genéticos/métodos , Humanos , Mutação , Neoplasias/genética , Neoplasias/patologia , Reino Unido
17.
Breast Cancer Res Treat ; 170(3): 633-640, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29687178

RESUMO

PURPOSE: Uptake of preventive therapy for women at increased breast cancer risk in England is unknown following the introduction of UK clinical guidelines in 2013. Preventive therapy could create socioeconomic inequalities in cancer incidence if it is more readily accepted by particular socio-demographic groups. In this multicentre study, we investigated uptake of tamoxifen and evaluated socio-demographic and clinical factors associated with initiation. We explored women's experiences of treatment decision-making using qualitative interview data. METHODS: Between September 2015 and December 2016, women (n = 732) attending an appointment at one of 20 centres in England to discuss breast cancer risk were approached to complete a survey containing socio-demographic details and nulliparity. Of the baseline survey respondents (n = 408/732, 55.7% response rate), self-reported uptake of tamoxifen at 3-month follow-up was reported in 258 (63.2%). Sixteen women participated in semi-structured interviews. RESULTS: One in seven (38/258 = 14.7%) women initiated tamoxifen. Women who had children were more likely to report use of tamoxifen than those without children (OR = 5.26; 95%CI: 1.13-24.49, p = 0.035). Interview data suggested that women weigh up risks and benefits of tamoxifen within the context of familial commitments, with exposure to significant other's beliefs and experiences of cancer and medication a basis for their decision. CONCLUSIONS: Uptake of tamoxifen is low in clinical practice. There were no socio-demographic differences in uptake, suggesting that the introduction of breast cancer preventive therapy is unlikely to create socioeconomic inequalities in cancer incidence. Women's decision-making was influenced by familial priorities, particularly having children.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/prevenção & controle , Pré-Medicação , Medicina Preventiva , Adulto , Neoplasias da Mama/terapia , Quimioprevenção , Tomada de Decisões , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Pessoa de Meia-Idade , Razão de Chances , Pré-Medicação/métodos , Medicina Preventiva/métodos , Estudos Prospectivos , Vigilância em Saúde Pública , Pesquisa Qualitativa , Fatores de Risco , Fatores Socioeconômicos , Reino Unido/epidemiologia
18.
Genet Med ; 20(12): 1575-1582, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29565421

RESUMO

PURPOSE: BRCA1/BRCA2 predictive test negatives are proven noncarriers of a BRCA1/BRCA2 mutation that is carried by their relatives. The risk of developing breast cancer (BC) or epithelial ovarian cancer (EOC) in these women is uncertain. The study aimed to estimate risks of invasive BC and EOC in a large cohort of BRCA1/BRCA2 predictive test negatives. METHODS: We used cohort analysis to estimate incidences, cumulative risks, and standardized incidence ratios (SIRs). RESULTS: A total of 1,895 unaffected women were eligible for inclusion in the BC risk analysis and 1,736 in the EOC risk analysis. There were 23 incident invasive BCs and 2 EOCs. The cumulative risk of invasive BC was 9.4% (95% confidence interval (CI) 5.9-15%) by age 85 years and the corresponding risk of EOC was 0.6% (95% CI 0.2-2.6%). The SIR for invasive BC was 0.93 (95% CI 0.62-1.40) in the overall cohort, 0.85 (95% CI 0.48-1.50) in noncarriers from BRCA1 families, and 1.03 (95% CI 0.57-1.87) in noncarriers from BRCA2 families. The SIR for EOC was 0.79 (95% CI 0.20-3.17) in the overall cohort. CONCLUSION: Our results did not provide evidence for elevated risks of invasive BC or EOC in BRCA1/BRCA2 predictive test negatives.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias Ovarianas/genética , Adulto , Idoso , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/epidemiologia , Medição de Risco , Fatores de Risco
19.
JNCI Cancer Spectr ; 2(2): pky023, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31360853

RESUMO

Background: For BRCA1 and BRCA2 mutation carriers, the association between oral contraceptive preparation (OCP) use and breast cancer (BC) risk is still unclear. Methods: Breast camcer risk associations were estimated from OCP data on 6030 BRCA1 and 3809 BRCA2 mutation carriers using age-dependent Cox regression, stratified by study and birth cohort. Prospective, left-truncated retrospective and full-cohort retrospective analyses were performed. Results: For BRCA1 mutation carriers, OCP use was not associated with BC risk in prospective analyses (hazard ratio [HR] = 1.08, 95% confidence interval [CI] = 0.75 to 1.56), but in the left-truncated and full-cohort retrospective analyses, risks were increased by 26% (95% CI = 6% to 51%) and 39% (95% CI = 23% to 58%), respectively. For BRCA2 mutation carriers, OCP use was associated with BC risk in prospective analyses (HR = 1.75, 95% CI = 1.03 to 2.97), but retrospective analyses were inconsistent (left-truncated: HR = 1.06, 95% CI = 0.85 to 1.33; full cohort: HR = 1.52, 95% CI = 1.28 to 1.81). There was evidence of increasing risk with duration of use, especially before the first full-term pregnancy (BRCA1: both retrospective analyses, P < .001 and P = .001, respectively; BRCA2: full retrospective analysis, P = .002). Conclusions: Prospective analyses did not show that past use of OCP is associated with an increased BC risk for BRCA1 mutation carriers in young middle-aged women (40-50 years). For BRCA2 mutation carriers, a causal association is also not likely at those ages. Findings between retrospective and prospective analyses were inconsistent and could be due to survival bias or a true association for younger women who were underrepresented in the prospective cohort. Given the uncertain safety of long-term OCP use for BRCA1/2 mutation carriers, indications other than contraception should be avoided and nonhormonal contraceptive methods should be discussed.

20.
BMC Womens Health ; 17(1): 132, 2017 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-29246147

RESUMO

BACKGROUND: Ovarian cancer is usually diagnosed at a late stage when outcomes are poor. Personalised ovarian cancer risk prediction, based on genetic and epidemiological information and risk stratified management in adult women could improve outcomes. Examining health care professionals' (HCP) attitudes to ovarian cancer risk stratified management, willingness to support women, self-efficacy (belief in one's own ability to successfully complete a task), and knowledge about ovarian cancer will help identify training needs in anticipation of personalised ovarian cancer risk prediction being introduced. METHODS: An anonymous survey was distributed online to HCPs via relevant professional organisations in the UK. Kruskal-Wallis tests and pairwise comparisons were used to compare knowledge and self-efficacy scores between different types of HCPs, and attitudes toward population-based genetic testing and risk stratified management were described. Content analysis was undertaken of free text responses concerning HCPs willingness to discuss risk management options with women. RESULTS: One hundred forty-six eligible HCPs completed the survey: oncologists (31%); genetics clinicians (30%); general practitioners (22%); gynaecologists (10%); nurses (4%); and 'others'. Scores for knowledge of ovarian cancer and genetics, and self-efficacy in conducting a cancer risk consultation were generally high but significantly lower for general practitioners compared to genetics clinicians, oncologists, and gynaecologists. Support for population-based genetic testing was not high (<50%). Attitudes towards ovarian cancer risk stratification were mixed, although the majority of participants indicated a willingness to discuss management options with patients. CONCLUSIONS: Larger samples are required to investigate attitudes to population-based genetic testing for ovarian cancer risk and to establish why some HCPs are hesitant to offer testing to all adult female patients. If ovarian cancer risk assessment using genetic testing and non-genetic information including epidemiological information is rolled out on a population basis, training will be needed for HCPs in primary care to enable them to provide appropriate support to women at each stage of the process.


Assuntos
Atitude do Pessoal de Saúde , Testes Genéticos , Conhecimentos, Atitudes e Prática em Saúde , Pessoal de Saúde/psicologia , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Genética Populacional , Humanos , Masculino , Pessoa de Meia-Idade , Atenção Primária à Saúde , Qualidade da Assistência à Saúde , Inquéritos e Questionários
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