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1.
J Natl Compr Canc Netw ; 19(1): 77-102, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33406487

RESUMO

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.

2.
Psychooncology ; 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33305520

RESUMO

OBJECTIVE: Many women with breast cancer (BC) hesitate to raise sexual concerns clinically. We evaluated a multimedia intervention to facilitate BC patients' communication about sexual/menopausal health, called Starting the Conversation (STC). METHODS: Female BC patients (N = 144) were randomly assigned to either STC (20-min video, workbook, and resource guide) or control (resource guide only). Audio-recorded dialogue from patients' next oncology clinic encounter was coded for patients' sexual health communication. Self-report surveys assessed patients' beliefs about sexual health communication, self-efficacy for clinical interactions, sexual function/activity, anxiety/depression symptoms, and quality of life at baseline, post-intervention, and 2-month follow-up. T-tests or mixed-effects logistic regression compared study arms. RESULTS: Women in the STC arm were more likely to raise the topic of sexual health (51%; OR = 2.62 [1.02, 6.69], p = 0.04) and ask a sexual health question (40%; OR = 2.85 [1.27, 6.38], p = 0.01) during their clinic encounter than those in the control arm (30% and 19% for raise and ask, respectively). At follow-up, women in the STC arm showed greater improvements in sexual health communication self-efficacy (p = 0.009) and in anxiety symptoms (p = 0.03), and more women were sexually active at follow-up, compared to the control arm (OR = 1.5, 70% vs. 46%, p = 0.04). CONCLUSIONS: The STC intervention facilitated women's clinical communication about sexual health and reduced women's anxiety, possibly due to increased confidence in expressing their medical needs. Helpful information gained from clinical discussions could have improved women's willingness or ability to engage in sexual activity. Future studies should identify aspects of the clinical encounter most critical to improving women's sexual outcomes.

3.
J Natl Cancer Inst ; 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33301022

RESUMO

BACKGROUND: Clinical guidelines often use predicted lifetime risk from birth to define criteria for making decisions regarding breast cancer screening rather than thresholds based on absolute 5-year risk from current age. METHODS: We used the Prospective Family Cohort Study of 14,657 women without breast cancer at baseline in which, during a median follow-up of 10 years, 482 women were diagnosed with invasive breast cancer. We examined the performances of the IBIS and BOADICEA risk models when using alternative thresholds by comparing predictions based on 5-year risk with those based on lifetime risk from birth and remaining lifetime risk. All statistical tests were two-sided. RESULTS: Using IBIS, the areas under the receiver-operating characteristic curves were 0.66 (95% confidence interval = 0.63 to 0.68) and 0.56 (95% confidence interval = 0.54 to 0.59) for 5-year and lifetime risks, respectively (Pdiff<0.001). For equivalent sensitivities, the 5-year incidence almost always had higher specificities than lifetime risk from birth. For women aged 20-39 years, 5-year risk performed better than lifetime risk from birth. For women aged 40 years or more, receiver-operating characteristic curves were similar for 5-year and lifetime IBIS risk from birth. Classifications based on remaining lifetime risk were inferior to 5-year risk estimates. Results were similar using BOADICEA. CONCLUSIONS: Our analysis shows that risk stratification using clinical models will likely be more accurate when based on predicted 5-year risk compared with risks based on predicted lifetime and remaining lifetime, particularly for women aged 20-39 years.

4.
Am J Hum Genet ; 107(5): 837-848, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33022221

RESUMO

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Genoma Humano , Herança Multifatorial , Segunda Neoplasia Primária/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/etnologia , Neoplasias da Mama/terapia , Estudos de Coortes , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Grupo com Ancestrais do Continente Europeu , Feminino , Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/etnologia , Segunda Neoplasia Primária/terapia , Prognóstico , Modelos de Riscos Proporcionais , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Medição de Risco
5.
Am J Epidemiol ; 2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33128063

RESUMO

Earlier pubertal development is only partially explained by childhood body mass index (BMI); the role of other factors like childhood infections is less understood. Using data from the LEGACY Girls Study (2011 - 2016), we prospectively examined the associations between childhood viral infections (Cytomegalovirus (CMV), Epstein Barr Virus (EBV), Herpes Simplex Virus 1 (HSV1), HSV2 and pubertal timing. We measured exposures based on seropositivity in pre-menarcheal girls (n=490). Breast and pubic hair development were classified based on mother-reported Tanner Stage (TS: TS2+ compared with TS1), adjusting for age, BMI, and sociodemographic factors. The average age at first blood draw was 9.8 years (Stdev=1.9 years). The prevalences were 31% CMV+, 37% EBV+, 14% HSV1+, 0.4% HSV2+, and 16% for both CMV+/EBV+. CMV+ infection without co-infection was associated with developing breasts an average of 7 months earlier (Hazard Ratio (HR)=2.12, 95% CI 1.32, 3.40). CMV+ infection without co-infection and HSV1+ and/or HSV2+ infection were associated with developing pubic hair 9 months later (HR 0.41, 95% CI 0.24, 0.71, HR 0.42, 95% CI 0.22, 0.81, respectively). Infection was not associated with menarche. If replicated in larger cohorts with blood collection prior to any breast development, this study supports that childhood infections may play a role in altering pubertal timing.

6.
Am J Epidemiol ; 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33057572

RESUMO

Stressful environments have been associated with earlier menarche. We hypothesized that anxiety, and possibly other internalizing symptoms, are also associated with earlier puberty in girls. The LEGACY Girls Study (2011-2016) includes 1040 girls aged 6 to 13 years at recruitment with growth and development assessed every 6 months. Pre-pubertal maternal reports of daughter's internalizing symptoms were available for breast onset (N=447), pubic hair onset (N=456), and menarche (N=681). Using Cox Proportional Hazard Regression, we estimated prospective hazard ratios (HRs) and 95% confidence intervals (CIs) for the relationship between one standard deviation of the percentiles of pre-pubertal anxiety, depression, and somatization symptoms and the timing of each pubertal outcome. Multivariable models included age, race/ethnicity, study center, maternal education, body mass index percentile, and breast cancer family history. Additional models included maternal self-reported anxiety. One standard deviation increase of maternally-reported anxiety in girls at baseline was associated with earlier subsequent onset of breast (HR 1.22, 95% CI 1.09-1.36) and pubic hair (HR 1.15, 95% CI 1.01-1.30) development, but not menarche (HR 0.94, 95% CI 0.83-1.07). The association of anxiety with earlier breast development persisted after adjustment for maternal anxiety. Increased anxiety in young girls may indicate risk for earlier pubertal onset.

7.
Sci Rep ; 10(1): 13518, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32782288

RESUMO

Pathogenic variants (PVs) in multiple genes are known to increase the risk of early-onset renal cancer (eoRC). However, many eoRC patients lack PVs in RC-specific genes; thus, their genetic risk remains undefined. Here, we determine if PVs in DNA damage response and repair (DDRR) genes are enriched in eoRC patients undergoing cancer risk assessment. Retrospective review of de-identified results from 844 eoRC patients, undergoing testing with a multi-gene panel, for a variety of indications, by Ambry Genetics. PVs in cancer-risk genes were identified in 12.8% of patients-with 3.7% in RC-specific, and 8.55% in DDRR genes. DDRR gene PVs were most commonly identified in CHEK2, BRCA1, BRCA2, and ATM. Among the 2.1% of patients with a BRCA1 or BRCA2 PV, < 50% reported a personal history of hereditary breast or ovarian-associated cancer. No association between age of RC diagnosis and prevalence of PVs in RC-specific or DDRR genes was observed. Additionally, 57.9% patients reported at least one additional cancer; breast cancer being the most common (40.1% of females, 2.5% of males). Multi-gene testing including DDRR genes may provide a more comprehensive risk assessment in eoRC patients. Further validation is needed to characterize the association with eoRC.


Assuntos
Dano ao DNA/genética , Reparo do DNA/genética , Variação Genética , Neoplasias Renais/genética , Adulto , Proteína BRCA1/genética , Proteína BRCA2/genética , Estudos de Coortes , Feminino , Predisposição Genética para Doença/genética , Testes Genéticos , Humanos , Neoplasias Renais/diagnóstico , Masculino , Pessoa de Meia-Idade , Prevalência , Medição de Risco , Adulto Jovem
8.
Genet Med ; 22(10): 1653-1666, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32665703

RESUMO

PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10-72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10-50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10-22) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10-12) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

9.
Sci Rep ; 10(1): 9688, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32546843

RESUMO

In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.


Assuntos
Neoplasias da Mama/genética , Mutação em Linhagem Germinativa/genética , Proteínas de Homeodomínio/genética , Feminino , Predisposição Genética para Doença/genética , Técnicas de Genotipagem , Humanos , Pessoa de Meia-Idade , Fatores de Risco
10.
J Clin Oncol ; 38(24): 2798-2811, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32516092

RESUMO

PURPOSE: Germline testing (GT) is a central feature of prostate cancer (PCA) treatment, management, and hereditary cancer assessment. Critical needs include optimized multigene testing strategies that incorporate evolving genetic data, consistency in GT indications and management, and alternate genetic evaluation models that address the rising demand for genetic services. METHODS: A multidisciplinary consensus conference that included experts, stakeholders, and national organization leaders was convened in response to current practice challenges and to develop a genetic implementation framework. Evidence review informed questions using the modified Delphi model. The final framework included criteria with strong (> 75%) agreement (Recommend) or moderate (50% to 74%) agreement (Consider). RESULTS: Large germline panels and somatic testing were recommended for metastatic PCA. Reflex testing-initial testing of priority genes followed by expanded testing-was suggested for multiple scenarios. Metastatic disease or family history suggestive of hereditary PCA was recommended for GT. Additional family history and pathologic criteria garnered moderate consensus. Priority genes to test for metastatic disease treatment included BRCA2, BRCA1, and mismatch repair genes, with broader testing, such as ATM, for clinical trial eligibility. BRCA2 was recommended for active surveillance discussions. Screening starting at age 40 years or 10 years before the youngest PCA diagnosis in a family was recommended for BRCA2 carriers, with consideration in HOXB13, BRCA1, ATM, and mismatch repair carriers. Collaborative (point-of-care) evaluation models between health care and genetic providers was endorsed to address the genetic counseling shortage. The genetic evaluation framework included optimal pretest informed consent, post-test discussion, cascade testing, and technology-based approaches. CONCLUSION: This multidisciplinary, consensus-driven PCA genetic implementation framework provides novel guidance to clinicians and patients tailored to the precision era. Multiple research, education, and policy needs remain of importance.

11.
Genet Med ; 22(8): 1401-1406, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32376981

RESUMO

PURPOSE: To better understand the longitudinal risks and benefits of telephone disclosure of genetic test results in the era of multigene panel testing. METHODS: Adults who were proceeding with germline cancer genetic testing were randomized to telephone disclosure (TD) with a genetic counselor or in-person disclosure (IPD) (i.e., usual care) of test results. All participants who received TD were recommended to return to meet with a physician to discuss medical management recommendations. RESULTS: Four hundred seventy-three participants were randomized to TD and 497 to IPD. There were no differences between arms for any cognitive, affective, or behavioral outcomes at 6 and 12 months. Only 50% of participants in the TD arm returned for the medical follow-up appointment. Returning was associated with site (p < 0.0001), being female (p = 0.047), and not having a true negative result (p < 0.002). Mammography was lower at 12 months among those who had TD and did not return for medical follow-up (70%) compared with those who had TD and returned (86%) and those who had IPD (87%, adjusted p < 0.01). CONCLUSION: Telephone disclosure of genetic test results is a reasonable alternative to in-person disclosure, but attention to medical follow-up may remain important for optimizing appropriate use of genetic results.

12.
J Natl Compr Canc Netw ; 18(4): 380-391, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32259785

RESUMO

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic provide recommendations for genetic testing and counseling for hereditary cancer syndromes, and risk management recommendations for patients who are diagnosed with syndromes associated with an increased risk of these cancers. The NCCN panel meets at least annually to review comments, examine relevant new data, and reevaluate and update recommendations. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding criteria for high-penetrance genes associated with breast and ovarian cancer beyond BRCA1/2, pancreas screening and genes associated with pancreatic cancer, genetic testing for the purpose of systemic therapy decision-making, and testing for people with Ashkenazi Jewish ancestry.

13.
Cancer Prev Res (Phila) ; 13(3): 219-222, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32132115

RESUMO

The Risk Assessment Program (RAP) at Fox Chase Cancer Center (Philadelphia, PA) is a multi-generational prospective cohort, enhanced for personal and family history of cancer, consisting of over 10,000 individuals for whom data on personal and family history of cancer, risk factors, genetic and genomic data, health behaviors, and biospecimens are available. The RAP has a broad research agenda including the characterization of genes with known or potential relevance to cancer, gene-gene and gene-environment interactions, and their contribution to clinically useful risk assessment and risk reduction strategies. Increasingly, this body of research is identifying genetic changes which may have clinical significance for RAP research participants, leading us to confront the issue of whether to return genetic results emerging from research laboratories. This review will describe some of the important fundamental points that must be debated as we develop a paradigm for return of research results. The key issues to address as the scientific community moves toward adopting a policy of return of research results include the best criteria for determining which results to offer, the consent document components necessary to ensure that the participant makes a truly informed decision about receiving their results, and associated logistical and cost challenges.See all articles in this Special Collection Honoring Paul F. Engstrom, MD, Champion of Cancer Prevention.

15.
Trials ; 21(1): 173, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32051002

RESUMO

BACKGROUND: Sexual concerns are distressing for breast cancer survivors and interfere with their intimate relationships. This study evaluates the efficacy of a four-session couple-based intervention delivered via telephone, called Intimacy Enhancement (IE). The IE intervention is grounded in social cognitive theory and integrates evidence-based techniques from cognitive behavioral couple therapy and sex therapy to address survivors' sexual concerns and enhance their and their partners' sexual, relationship, and psychological outcomes. METHODS: This trial is designed to evaluate the efficacy of the IE intervention in improving survivors' sexual function, the primary study outcome. Secondary outcomes include survivors' sexual distress, partners' sexual function, and survivors' and partners' relationship intimacy and quality as well as psychological distress (depressive symptoms and anxiety symptoms). Additional aims are to examine whether treatment effects on patient sexual function are mediated by sexual communication and self-efficacy for coping with sexual concerns and to explore whether survivor age and race/ethnicity moderate intervention effects on survivors' sexual function. Eligible adult female breast cancer survivors reporting sexual concerns and their intimate partners are recruited from two academic sites in the USA and are randomized to either the IE intervention or to a control condition of equal length offering education and support around breast cancer-related health topics (Living Healthy Together). The target sample size is 120 couples. Self-report outcome measures are administered to participants in both conditions at baseline (T1), post-treatment (T2), 3 months post-treatment (T3), and 6 months post-treatment (T4). DISCUSSION: Evidence-based interventions are needed to address sexual concerns for breast cancer survivors and to enhance their and their intimate partners' sexual, relationship, and psychological well-being. This randomized controlled trial will allow us to examine the efficacy of a novel couple-based intervention delivered via telephone for breast cancer survivors experiencing sexual concerns and their intimate partners, in comparison with an attention control. Findings of this study could influence clinical care for women with breast cancer and inform theory guiding cancer-related sexual rehabilitation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03930797. Registered on 24 April 2019.


Assuntos
Neoplasias da Mama/psicologia , Neoplasias da Mama/reabilitação , Sobreviventes de Câncer/psicologia , Terapia Cognitivo-Comportamental/métodos , Relações Interpessoais , Parceiros Sexuais/psicologia , Cônjuges/psicologia , Adaptação Psicológica , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Autorrelato , Disfunções Sexuais Psicogênicas , Telefone , Estados Unidos , Adulto Jovem
16.
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
17.
Nat Commun ; 11(1): 312, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949161

RESUMO

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.


Assuntos
Neoplasias da Mama/genética , Variação Genética , Estudo de Associação Genômica Ampla , Células Germinativas , Apoptose , Relógios Circadianos , Biologia Computacional , Feminino , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Redes Reguladoras de Genes , Genótipo , Humanos , Prognóstico , Receptores Estrogênicos/genética , Transdução de Sinais
18.
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.

19.
J Natl Cancer Inst ; 112(4): 418-422, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31584660

RESUMO

The performance of breast cancer risk models for women with a family history but negative BRCA1 and/or BRCA2 mutation test results is uncertain. We calculated the cumulative 10-year invasive breast cancer risk at cohort entry for 14 657 unaffected women (96.1% had an affected relative) not known to carry BRCA1 or BRCA2 mutations at baseline using three pedigree-based models (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm, BRCAPRO, and International Breast Cancer Intervention Study). During follow-up, 482 women were diagnosed with invasive breast cancer. Mutation testing was conducted independent of incident cancers. All models underpredicted risk by 26.3%-56.7% for women who tested negative but whose relatives had not been tested (n = 1363; 63 breast cancers). Although replication studies with larger sample sizes are needed, until these models are recalibrated for women who test negative and have no relatives tested, caution should be used when considering changing the breast cancer risk management intensity of such women based on risk estimates from these models.


Assuntos
Neoplasias da Mama/epidemiologia , Modelos Estatísticos , Adulto , Idoso , Austrália/epidemiologia , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Canadá/epidemiologia , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Risco , Estados Unidos/epidemiologia , Adulto Jovem
20.
Cancer Res ; 80(1): 116-125, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31578201

RESUMO

Although physical activity is associated with lower breast cancer risk for average-risk women, it is not known if this association applies to women at high familial/genetic risk. We examined the association of recreational physical activity (self-reported by questionnaire) with breast cancer risk using the Prospective Family Study Cohort, which is enriched with women who have a breast cancer family history (N = 15,550). We examined associations of adult and adolescent recreational physical activity (quintiles of age-adjusted total metabolic equivalents per week) with breast cancer risk using multivariable Cox proportional hazards regression, adjusted for demographics, lifestyle factors, and body mass index. We tested for multiplicative interactions of physical activity with predicted absolute breast cancer familial risk based on pedigree data and with BRCA1 and BRCA2 mutation status. Baseline recreational physical activity level in the highest four quintiles compared with the lowest quintile was associated with a 20% lower breast cancer risk (HR, 0.80; 95% confidence interval, 0.68-0.93). The association was not modified by familial risk or BRCA mutation status (P interactions >0.05). No overall association was found for adolescent recreational physical activity. Recreational physical activity in adulthood may lower breast cancer risk for women across the spectrum of familial risk. SIGNIFICANCE: These findings suggest that physical activity might reduce breast cancer risk by about 20% for women across the risk continuum, including women at higher-than-average risk due to their family history or genetic susceptibility.See related commentary by Niehoff et al., p. 23.


Assuntos
Neoplasias da Mama , Adolescente , Adulto , Estudos de Coortes , Exercício Físico , Feminino , Humanos , Estudos Prospectivos , Fatores de Risco
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