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1.
Artigo em Inglês | MEDLINE | ID: mdl-33082203

RESUMO

Women identified with an increased risk of breast cancer due to mutations in cancer susceptibility genes or a familial history of breast cancer undergo tailored screening with the goal of detecting tumors earlier, when potential curative interventions are still possible. Ideally, screening would identify signs of carcinogenesis even before a tumor is detectable by imaging. This could be achieved by timely signaling of altered biomarker levels for precancerous processes in liquid biopsies. Currently, the Nipple Aspirate Fluid (NAF) and the Trial Early Serum Test BREAST cancer (TESTBREAST), both ongoing, prospective, multicenter studies, are investigating biomarkers in liquid biopsies to improve breast cancer screening in high-risk women. The NAF study focuses on changes over time in miRNA expression levels both in blood and NAF samples, whereas the TESTBREAST study analyzes changes in protein levels in blood samples at sequential interval timepoints. These within-subject changes are studied in relation to later occurrence of breast cancer using a nested case-control design. These longitudinal studies face their own challenges in execution, such as hindrances in logistics and in sample processing that were difficult to anticipate. This article offers insight into those challenges and concurrently aims to provide useful strategies for the set-up of similar studies.

2.
J Community Genet ; 2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32880035

RESUMO

Individuals having a genetic predisposition to cancer and their partners face challenging decisions regarding their wish to have children. This study aimed to determine the effects of an online decision aid to support couples in making an informed decision regarding their reproductive options. A nationwide pretest-posttest study was conducted in the Netherlands among 131 participants between November 2016 and May 2018. Couples were eligible for participation if one partner had a pathogenic variant predisposing for an autosomal dominant hereditary cancer syndrome. Participants completed a questionnaire before use (T0), and at 3 months (T3) after use of the decision aid to assess the primary outcome measure informed decision-making, and the secondary outcome measures decisional conflict, knowledge, realistic expectations, level of deliberation, and decision self-efficacy. T0-T3 comparisons show an overall positive effect for all outcome measures (all ps < 0.05; knowledge (ES = - 1.05), decisional conflict (ES = 0.99), participants' decision self-efficacy (ES = -0.55), level of deliberation (ES = - 0.50), and realistic expectations (ES = - 0.44). Informed decision-making increased over time and 58.0% of the participants made an informed reproductive decision at T3. The online decision aid seems to be an appropriate tool to complement standard reproductive counseling to support our target group in making an informed reproductive decision. Use of the decision aid may lessen the negative psychological impact of decision-making on couples' daily life and wellbeing.

3.
JAMA Oncol ; 6(9): 1381-1389, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32729887

RESUMO

Importance: For women with a 20% or more familial risk of breast cancer without a known BRCA1/2 (BRCA1, OMIM 113705; and BRCA2, OMIM 114480) or TP53 (OMIM 151623) variant, screening guidelines vary substantially, and cost-effectiveness analyses are scarce. Objective: To assess the cost-effectiveness of magnetic resonance imaging (MRI) screening strategies for women with a 20% or more familial risk for breast cancer without a known BRCA1/2 or TP53 variant. Design, Setting, and Participants: In this economic evaluation, conducted from February 1, 2019, to May 25, 2020, microsimulation modeling was used to estimate costs and effectiveness on a lifetime horizon from age 25 years until death of MRI screening among a cohort of 10 million Dutch women with a 20% or more familial risk for breast cancer without a known BRCA1/2 or TP53 variant. A Dutch screening setting was modeled. Most data were obtained from the randomized Familial MRI Screening (FaMRIsc) trial, which included Dutch women aged 30 to 55 years. A health care payer perspective was applied. Interventions: Several screening protocols with varying ages and intervals including those of the randomized FaMRIsc trial, consisting of the mammography (Mx) protocol (annual mammography and clinical breast examination) and the MRI protocol (annual MRI and clinical breast examination plus biennial mammography). Main Outcomes and Measures: Costs, life-years, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated and discounted by 3%. A threshold of €22 000 (US $24 795.87) per QALY was applied. Results: This economic evaluation modeling study estimated that, on a lifetime horizon per 1000 women with the Mx protocol of the FaMRIsc trial, 346 breast cancers would be detected, and 49 women were estimated to die from breast cancer, resulting in 22 885 QALYs and total costs of €7 084 767 (US $7 985 134.61). The MRI protocol resulted in 79 additional QALYs and additional €2 657 266 (US $2 994 964.65). Magnetic resonance imaging performed only every 18 months between the ages of 35 and 60 years followed by the national screening program was considered optimal, with an ICER of €21 380 (US $24 097.08) compared with the previous nondominated strategy in the ranking, when applying the National Institute for Health and Care Excellence threshold. Annual screening alternating MRI and mammography between the ages of 35 and 60 years, followed by the national screening program, gave similar outcomes. Higher thresholds would favor annual MRI screening. The ICER was most sensitive to the unit cost of MRI and the utility value for ductal carcinoma in situ and localized breast cancer. Conclusions and Relevance: This study suggests that MRI screening every 18 months between the ages of 35 and 60 years for women with a family history of breast cancer is cost-effective within the National Institute for Health and Care Excellence threshold for all densities. Higher thresholds would favor annual MRI screening. These outcomes support a change of current screening guidelines for this specific risk group and support MRI screening.

4.
Fam Cancer ; 19(4): 281-290, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32323055

RESUMO

There is a disproportionate underuse of genetic testing in breast cancer patients from lower education or migrant background. Within these groups, communication about referral to genetic counseling appears challenging due to limited health literacy and cultural barriers. Our aim was to develop and evaluate a training program for healthcare professionals (breast surgeons and specialized nurses), to increase effective communication. We systematically developed a blended training program based on patients' and healthcare professionals' needs and preferences. Prior to the training, we assessed awareness, knowledge and self-efficacy of healthcare professionals. Acceptability and usefulness of the training program were assessed directly after the training. Healthcare professionals (n = 65) from 17 hospitals showed moderate to high awareness and knowledge about the prevalence and impact of limited health literacy. They were aware of cultural factors that influence communication. However, they did not feel confident in recognizing limited health literacy and their self-efficacy to communicate effectively with these patients was low. The training program was rated as acceptable and useful. Healthcare professionals lack confidence to effectively communicate with patients with limited health literacy or migrant background. The training program offers opportunities to improve communication about referral to breast cancer genetic counseling.

5.
Fam Cancer ; 19(2): 183-187, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32088803

RESUMO

Barrett's oesophagus (BE) has been associated with an increased risk of both colorectal adenomas and colorectal cancer. A recent investigation reported a high frequency of BE in patients with adenomatous polyposis coli (APC)-associated polyposis (FAP). The aim of the present study is to evaluate the prevalence of BE in a large cohort of patients with MUTYH-associated polyposis (MAP) and APC-associated adenomatous polyposis. Patients with a genetically confirmed diagnosis of familial adenomatous polyposis (FAP) or MAP were selected and upper gastrointestinal (GI) endoscopy reports, pathology reports of upper GI biopsies were reviewed to determine the prevalence of BE in these patients. Histologically confirmed BE was found in 7 (9.7%) of 72 patients with MAP. The mean age of diagnosis was 60.2 years (range 54.1-72.4 years). Two patients initially diagnosed with low grade dysplasia showed fast progression into high grade dysplasia and esophageal cancer, respectively. Only 4 (1.4%) of 365 patients with FAP were found to have pathologically confirmed BE. The prevalence of BE in patients with MAP is much higher than reported in the general population. We recommend that upper GI surveillance of patients with MAP should not only focus on the detection of gastric and duodenal adenomas but also on the presence of BE.

7.
Breast Cancer Res ; 22(1): 8, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31948486

RESUMO

BACKGROUND: The effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers is uncertain. Retrospective analyses have suggested a protective effect but may be substantially biased. Prospective studies have had limited power, particularly for BRCA2 mutation carriers. Further, previous studies have not considered the effect of RRSO in the context of natural menopause. METHODS: A multi-centre prospective cohort of 2272 BRCA1 and 1605 BRCA2 mutation carriers was followed for a mean of 5.4 and 4.9 years, respectively; 426 women developed incident breast cancer. RRSO was modelled as a time-dependent covariate in Cox regression, and its effect assessed in premenopausal and postmenopausal women. RESULTS: There was no association between RRSO and breast cancer for BRCA1 (HR = 1.23; 95% CI 0.94-1.61) or BRCA2 (HR = 0.88; 95% CI 0.62-1.24) mutation carriers. For BRCA2 mutation carriers, HRs were 0.68 (95% CI 0.40-1.15) and 1.07 (95% CI 0.69-1.64) for RRSO carried out before or after age 45 years, respectively. The HR for BRCA2 mutation carriers decreased with increasing time since RRSO (HR = 0.51; 95% CI 0.26-0.99 for 5 years or longer after RRSO). Estimates for premenopausal women were similar. CONCLUSION: We found no evidence that RRSO reduces breast cancer risk for BRCA1 mutation carriers. A potentially beneficial effect for BRCA2 mutation carriers was observed, particularly after 5 years following RRSO. These results may inform counselling and management of carriers with respect to RRSO.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/epidemiologia , Mutação , Salpingo-Ooforectomia/métodos , Adulto , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Estudos de Coortes , Feminino , Humanos , Incidência , Agências Internacionais , Menopausa , Pessoa de Meia-Idade , Estudos Prospectivos , Comportamento de Redução do Risco
8.
Fam Cancer ; 19(1): 65-76, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31773425

RESUMO

Pre-test counseling about multigene panel testing involves many uncertainties. Ideally, counselees are informed about uncertainties in a way that enables them to make an informed decision about panel testing. It is presently unknown whether and how uncertainty is discussed during initial cancer genetic counseling. We therefore investigated whether and how counselors discuss and address uncertainty, and the extent of shared decision-making (SDM), and explored associations between counselors' communication and their characteristics in consultations on panel testing for cancer. For this purpose, consultations of counselors discussing a multigene panel with a simulated patient were videotaped. Simulated patients represented a counselee who had had multiple cancer types, according to a script. Before and afterwards, counselors completed a survey. Counselors' uncertainty expressions, initiating and the framing of expressions, and their verbal responses to scripted uncertainties of the simulated patient were coded by two researchers independently. Coding was done according to a pre-developed coding scheme using The Observer XT software for observational analysis. Additionally, the degree of SDM was assessed by two observers. Correlation and regression analyses were performed to assess associations of communicated uncertainties, responses and the extent of SDM, with counselors' background characteristics. In total, twenty-nine counselors, including clinical geneticists, genetic counselors, physician assistants-in-training, residents and interns, participated of whom working experience varied between 0 and 25 years. Counselors expressed uncertainties mainly regarding scientific topics (94%) and on their own initiative (95%). Most expressions were framed directly (77%), e.g. We don't know, and were emotionally neutral (59%; without a positive/negative value). Counselors mainly responded to uncertainties of the simulated patient by explicitly referring to the uncertainty (69%), without providing space for further disclosure (66%). More experienced counselors provided less space to further disclose uncertainty (p < 0.02), and clinical geneticists scored lower on SDM compared with other types of counselors (p < 0.03). Our findings that counselors mainly communicate scientific uncertainties and use space-reducing responses imply that the way counselors address counselees' personal uncertainties and concerns during initial cancer genetic counseling is suboptimal.

9.
Eur Urol ; 76(6): 831-842, 2019 Dec.
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.
Breast Cancer Res Treat ; 177(3): 723-733, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31302855

RESUMO

BACKGROUND: In healthy BRCA1/2 mutation carriers, bilateral risk-reducing mastectomy (BRRM) strongly reduces the risk of developing breast cancer (BC); however, no clear survival benefit of BRRM over BC surveillance has been reported yet. METHODS: In this Dutch multicenter cohort study, we used multivariable Cox models with BRRM as a time-dependent covariable to estimate the associations between BRRM and the overall and BC-specific mortality rates, separately for BRCA1 and BRCA2 mutation carriers. RESULTS: During a mean follow-up of 10.3 years, 722 out of 1712 BRCA1 (42%) and 406 out of 1145 BRCA2 (35%) mutation carriers underwent BRRM. For BRCA1 mutation carriers, we observed 52 deaths (20 from BC) in the surveillance group, and 10 deaths (one from BC) after BRRM. The hazard ratios were 0.40 (95% CI 0.20-0.90) for overall mortality and 0.06 (95% CI 0.01-0.46) for BC-specific mortality. BC-specific survival at age 65 was 93% for surveillance and 99.7% for BRRM. For BRCA2 mutation carriers, we observed 29 deaths (7 from BC) in the surveillance group, and 4 deaths (no BC) after BRRM. The hazard ratio for overall mortality was 0.45 (95% CI 0.15-1.36). BC-specific survival at age 65 was 98% for surveillance and 100% for BRRM. CONCLUSION: BRRM was associated with lower mortality than surveillance for BRCA1 mutation carriers, but for BRCA2 mutation carriers, BRRM may lead to similar BC-specific survival as surveillance. Our findings support a more individualized counseling based on BRCA mutation type.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/etiologia , Neoplasias da Mama/prevenção & controle , Heterozigoto , Mutação , Mastectomia Profilática , Neoplasias da Mama/mortalidade , Neoplasias da Mama/cirurgia , Feminino , Mutação em Linhagem Germinativa , Humanos , Mortalidade , Países Baixos/epidemiologia , Prognóstico , Mastectomia Profilática/métodos , Vigilância em Saúde Pública , Comportamento de Redução do Risco
11.
Lancet Oncol ; 20(8): 1136-1147, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31221620

RESUMO

BACKGROUND: Approximately 15% of all breast cancers occur in women with a family history of breast cancer, but for whom no causative hereditary gene mutation has been found. Screening guidelines for women with familial risk of breast cancer differ between countries. We did a randomised controlled trial (FaMRIsc) to compare MRI screening with mammography in women with familial risk. METHODS: In this multicentre, randomised, controlled trial done in 12 hospitals in the Netherlands, women were eligible to participate if they were aged 30-55 years and had a cumulative lifetime breast cancer risk of at least 20% because of a familial predisposition, but were BRCA1, BRCA2, and TP53 wild-type. Participants who were breast-feeding, pregnant, had a previous breast cancer screen, or had a previous a diagnosis of ductal carcinoma in situ were eligible, but those with a previously diagnosed invasive carcinoma were excluded. Participants were randomly allocated (1:1) to receive either annual MRI and clinical breast examination plus biennial mammography (MRI group) or annual mammography and clinical breast examination (mammography group). Randomisation was done via a web-based system and stratified by centre. Women who did not provide consent for randomisation could give consent for registration if they followed either the mammography group protocol or the MRI group protocol in a joint decision with their physician. Results from the registration group were only used in the analyses stratified by breast density. Primary outcomes were number, size, and nodal status of detected breast cancers. Analyses were done by intention to treat. This trial is registered with the Netherlands Trial Register, number NL2661. FINDINGS: Between Jan 1, 2011, and Dec 31, 2017, 1355 women provided consent for randomisation and 231 for registration. 675 of 1355 women were randomly allocated to the MRI group and 680 to the mammography group. 218 of 231 women opting to be in a registration group were in the mammography registration group and 13 were in the MRI registration group. The mean number of screening rounds per woman was 4·3 (SD 1·76). More breast cancers were detected in the MRI group than in the mammography group (40 vs 15; p=0·0017). Invasive cancers (24 in the MRI group and eight in the mammography group) were smaller in the MRI group than in the mammography group (median size 9 mm [5-14] vs 17 mm [13-22]; p=0·010) and less frequently node positive (four [17%] of 24 vs five [63%] of eight; p=0·023). Tumour stages of the cancers detected at incident rounds were significantly earlier in the MRI group (12 [48%] of 25 in the MRI group vs one [7%] of 15 in the mammography group were stage T1a and T1b cancers; one (4%) of 25 in the MRI group and two (13%) of 15 in the mammography group were stage T2 or higher; p=0·035) and node-positive tumours were less frequent (two [11%] of 18 in the MRI group vs five [63%] of eight in the mammography group; p=0·014). All seven tumours stage T2 or higher were in the two highest breast density categories (breast imaging reporting and data system categories C and D; p=0·0077) One patient died from breast cancer during follow-up (mammography registration group). INTERPRETATION: MRI screening detected cancers at an earlier stage than mammography. The lower number of late-stage cancers identified in incident rounds might reduce the use of adjuvant chemotherapy and decrease breast cancer-related mortality. However, the advantages of the MRI screening approach might be at the cost of more false-positive results, especially at high breast density. FUNDING: Dutch Government ZonMw, Dutch Cancer Society, A Sister's Hope, Pink Ribbon, Stichting Coolsingel, J&T Rijke Stichting.

12.
Br J Cancer ; 121(2): 180-192, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31213659

RESUMO

BACKGROUND: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. METHODS: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction < 0.05). CONCLUSION: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.


Assuntos
Estatura , Índice de Massa Corporal , Genes BRCA1 , Genes BRCA2 , Heterozigoto , Análise da Randomização Mendeliana , Mutação , Neoplasias Ovarianas/etiologia , Adulto , Idoso , Feminino , Humanos , Menopausa , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Modelos de Riscos Proporcionais
13.
Ned Tijdschr Geneeskd ; 1632019 05 20.
Artigo em Holandês | MEDLINE | ID: mdl-31140768

RESUMO

Genetic testing in patients with cancer; new developments About 5% of patients with cancer have a causative germline mutation. When a germline mutation is detected, this may have major implications for treatment and follow-up of the patient, as well as for relatives who are at risk of carrying the mutation. Increasingly, DNA-testing of tumor tissue is being performed to identify potential druggable targets, aiming at personalized medicine. Both germline testing and tissue testing may have consequences for the patient, for treatment and for family members. Currently there is a trend towards mainstreaming of genetic testing, which implies that treating physicians will increasingly be the ones to order DNA tests. This implies that they need to be aware of the (family) consequences and pitfalls of genetic testing. It calls for close collaboration between clinical genetics and regional treating physicians, and adequate referral of patients with abnormal DNA results and those with other clues for a genetic predisposition. The aim being optimal tailored treatment for each patient and adequate cancer prevention for their relatives.

14.
J Genet Couns ; 28(3): 533-542, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30629779

RESUMO

A nationwide pretest-posttest study was conducted in all clinical genetic centres in the Netherlands, to evaluate the effects of an online decision aid to support persons who have a genetic predisposition to cancer and their partners in making an informed decision regarding reproductive options. Main outcomes (decisional conflict, knowledge, realistic expectations, level of deliberation, and decision self-efficacy) were measured before use (T0), immediately after use (T1), and at 2 weeks (T2) after use of the decision aid. Paired sample t tests were used to compute differences between the first and subsequent measurements. T0-T1 and T0-T2 comparisons indicate a significant reduction in mean decisional conflict scores with stronger effects for participants with high baseline decisional conflict. Furthermore, use of the decision aid resulted in increased knowledge levels and improved realistic expectations. Level of deliberation only increased for participants with lower baseline levels of deliberation. Decision self-efficacy increased for those with low baseline scores, whereas those with high baseline scores showed a reduction at T2. It can be concluded that use of the decision aid resulted in several positive outcomes indicative of informed decision-making. The decision aid is an appropriate and highly appreciated tool to be used in addition to reproductive counseling.

15.
J Natl Cancer Inst ; 111(4): 350-364, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30312457

RESUMO

BACKGROUND: BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear. METHODS: We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided. RESULTS: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer. CONCLUSION: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Estatura , Índice de Massa Corporal , Neoplasias da Mama/etiologia , Análise da Randomização Mendeliana , Mutação , Adulto , Neoplasias da Mama/patologia , Feminino , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Prognóstico , Fatores de Risco
16.
Fam Cancer ; 18(1): 137-146, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29846879

RESUMO

An online decision aid to support persons having a genetic predisposition to cancer and their partners during reproductive decision-making was developed. A two-phase usability test was conducted among 12 couples (N = 22; 2 persons participated without their partner) at risk for hereditary cancer and 15 health care providers. Couples and health care providers expressed similar suggestions for improvements, and evaluated the modified decision aid as acceptable, easy to use, and comprehensible. The final decision aid was pilot tested (N = 16) with paired sample t tests comparing main outcomes (decisional conflict, knowledge, realistic expectations regarding the reproductive options and decision self-efficacy) before (T0), immediately (T1) and 2 weeks after (T2) use of the decision aid. Pilot testing indicated decreased decisional conflict scores, increased knowledge, and improved realistic expectations regarding the reproductive options, at T1 and T2. No effect was found for couples' decision self-efficacy. The positive findings during usability testing were thus reflected in the pilot study. The decision aid will be further evaluated in a nationwide pretest-posttest study to facilitate implementation in the onco-genetic counselling setting. Ultimately, it is expected that the decision aid will enable end-users to make an informed decision.


Assuntos
Tomada de Decisões , Técnicas de Apoio para a Decisão , Predisposição Genética para Doença , Síndromes Neoplásicas Hereditárias/genética , Reprodução/genética , Adulto , Feminino , Aconselhamento Genético/métodos , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Internet , Masculino , Projetos Piloto
18.
J Med Genet ; 55(10): 669-674, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29330337

RESUMO

BACKGROUND: In approximately 10% of all gastric cancer (GC) cases, a heritable cause is suspected. A subset of these cases have a causative germline CDH1 mutation; however, in most cases the cause remains unknown. Our objective was to assess to what extent these remaining cases may be explained by germline mutations in the novel candidate GC predisposing genes CTNNA1, MAP3K6 or MYD88. METHODS: We sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without a CDH1germline mutation for germline variants affecting CTNNA1, MAP3K6 and MYD88 using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes. RESULTS: Predicted deleterious germline variants were not encountered in MYD88, but recurrently observed in CTNNA1 (n=2) and MAP3K6 (n=3) in our cohort of patients with GC. In contrast to deleterious variants in CTNNA1, deleterious variants in MAP3K6 also occur frequently in the general population. CONCLUSIONS: Based on our results MAP3K6 should no longer be considered a GC predisposition gene, whereas deleterious CTNNA1 variants are confirmed as an infrequent cause of GC susceptibility. Biallelic MYD88 germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified.


Assuntos
Antígenos CD/genética , Caderinas/genética , MAP Quinase Quinase Quinases/genética , Fator 88 de Diferenciação Mieloide/genética , Neoplasias Gástricas/genética , alfa Catenina/genética , Adulto , Idoso , Estudos de Coortes , Europa (Continente) , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA , Adulto Jovem
19.
JNCI Cancer Spectr ; 2(4): pky078, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30873510

RESUMO

Background: Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers. Methods: Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort. Results: For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] = 0.99, 95% confidence interval [CI] = 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc = 0.79, 95% CI = 0.69 to 0.91; HRc = 0.70, 95% CI = 0.59 to 0.82; HRc = 0.50, 95% CI = 0.40 to 0.63, for 2, 3, and ≥4 FTPs, respectively, P trend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort P trend = .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] = 1.69, 95% CI = 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc = 1.33, 95% CI = 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc = 0.72, 95% CI = 0.54 to 0.98). Conclusions: These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers.

20.
Fam Cancer ; 17(2): 309-316, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28852913

RESUMO

Next-generation sequencing (NGS) can be used to generate information about a patient's tumour and personal genome. This powerful diagnostic tool provides solicited and unsolicited hereditary genetic (risk) information that could have consequences for cancer patients and their quality of life. A well-defined approach for returning appropriate genetic risk information is needed in personalized cancer care. A qualitative design with semi-structured interviews was used. We conducted interviews with 24 Dutch patients with different types of cancer, both NGS-experienced and NGS-inexperienced, to learn their intentions, needs and preferences towards receiving unsolicited genetic information obtained using NGS. Almost all participants had a positive attitude towards receiving unsolicited findings. After receiving comprehensive background information on NGS, including a binning model of four categories of unsolicited findings, most participants preferred to receive only subsets of genetic information. Their main concern was their own and others' (including family members) ability to cope with (the increased risk of having) a genetic disorder. Providing background information gave cancer patients the opportunity to select subsets of findings and increased their ability to make an informed choice. Special attention is needed for social and emotional factors to support the patients themselves and when communicating test results with their family members.


Assuntos
Tomada de Decisões , Testes Genéticos , Síndromes Neoplásicas Hereditárias/genética , Preferência do Paciente/psicologia , Medicina de Precisão , Adaptação Psicológica , Adulto , Idoso , Família/psicologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Intenção , Masculino , Pessoa de Meia-Idade , Países Baixos , Relações Profissional-Paciente , Pesquisa Qualitativa , Revelação da Verdade
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