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Contains fulltext : 206539.pdf (Publisher’s version ) (Closed access) 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.

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. 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. 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. 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. The BCFR was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organisations imply endorsement by the US Government or the BCFR. CNIO was partially supported by the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare Diseases (CIBERER). CNIO was also partially supported by FISPI16/00440. INHERIT was supported by the Canadian Institutes of Health Research for the 'CIHR Team in Familial Risks of Breast Cancer' program-grant #CRN-87521-and the Ministry of Economic Development, Innovation and Export Trade-grant #PSR-SIIRI-701. The PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (GPH-129344), the Ministere de l'Economie, de la Science et de l' Innovation du Quebec through Genome Quebec, and The Quebec Breast Cancer Foundation. Jacques Simard is a Chairholder of the Canada Research Chair in Oncogenetics. EMBRACE is supported by the Cancer Research UK grants C1287/A23382 and C1287/A16563. D. Gareth Evans is supported by an NIHR grant to the Biomedical Research Centre, Manchester (IS-BRC-1215-20007). The investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by the Cancer Research UK grant C5047/A8385. Ros Eeles is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Antonis C. Antoniou is funded by Cancer Research UK grants C12292/A20861 and C12292/A11174. MT is funded by the European Union Seventh Framework Program (2007-2013)/European Research Council (310018). The German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) is supported by the German Cancer Aid (grant no 110837, Rita K. Schmutzler). The national French cohort, GENEPSO, had been supported by a grant from the Fondation de France and the Ligue Nationale Contre le Cancer and is being supported by a grant from INCa as part of the European program ERA-NET on Translational Cancer Research (TRANSCAN-JTC2012, no. 2014-008). HCSC was supported by CIBERONC 161200301 from ISCIII (Spain), partially supported by European Regional Development FEDER funds. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organisation of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46, and the Transcan grant JTC 2012 Cancer 12-054. The IHCC was supported by Grant PBZ_ KBN_122/P05/2004 and ERA-NET TRANSAN JTC 2012 Cancer 12-054 (ERA-NET-TRANSCAN/07/2014). This work was supported by grants to kConFab and the kConFab Follow-Up Study from Cancer Australia (809195); the Australian National Breast Cancer Foundation (IF 17); the National Health and Medical Research Council (454508, 288704, 145684); the National Institute of Health U.S.A. (1RO1CA159868); the Queensland Cancer Fund; the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia; and the Cancer Foundation of Western Australia. KAP is an Australian National Breast Cancer Foundation fellow. MODSQUAD-Czech Republic, Brno, was supported by MH CZ -DRO (MMCI, 00209805) and by MEYS -NPS I -LO1413 to LF and MN. The Hungarian Breast and Ovarian Cancer Study was supported by Hungarian Research Grants KTIA-OTKA CK-80745, NKFI OTKA K-112228, and the Norwegian EEA Financial Mechanism HU0115/NA/2008-3/OP-9. Lund-BRCA collaborators are supported by the Swedish Cancer Society, Lund Hospital Funds, and European Research Council Advanced Grant ERC-2011-294576. Stockholm-BRCA collaborators are supported by the Swedish Cancer Society. The funders had no role in the design of the study; the collection, analysis, or interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. Sí

Item does not contain fulltext STUDY QUESTION: Do women treated with ovarian stimulation for IVF have an increased risk of melanoma? SUMMARY ANSWER: Ovarian stimulation for IVF does not increase risk of melanoma, even after a prolonged follow-up. WHAT IS KNOWN ALREADY: Although exposure to ultraviolet radiation is the major risk factor for melanoma, associations between female sex steroids and melanoma risk have also been suggested. The results of available studies on fertility drugs and melanoma risk are inconclusive since most studies had several methodological limitations such as short follow-up, a small number of cases and no subfertile comparison group. STUDY DESIGN, SIZE, DURATION: In 1996, a nationwide historic cohort study (the OMEGA-cohort) was established to examine the risk of cancer after ovarian stimulation for IVF. After a median follow-up of 17 years, cancer incidence was ascertained through linkage with the Netherlands Cancer Registry. Melanoma risk in the cohort was compared with that in the general population and between the IVF group and non-IVF group using multivariable Cox regression analyses. PARTICIPANTS/MATERIALS, SETTING, METHODS: The cohort comprises 19 158 women who received IVF between 1983 and 1995 and a comparison group of 5950 women who underwent subfertility treatments other than IVF. Detailed IVF-treatment data were obtained from the medical records and complete information on parity and age at first birth was obtained through linkage with the Dutch Municipal Personal Records Database. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 93 melanoma cases were observed. The risk of melanoma was not elevated among IVF-treated women, neither when compared with the general population (standardized incidence ratio = 0.89; 95% confidence interval (CI): 0.69-1.12), nor when compared with the non-IVF group (adjusted hazard ratio (HR) = 1.27; 95% CI: 0.75-2.15). A higher number of IVF cycles was associated with apparent but statistically non-significant risk increases (5-6 cycles HR = 1.92; >/=7 cycles HR = 1.79). However, no significant trend emerged. In women with more follicle stimulating hormone/human menopausal gonadotrophin ampoules comparable non-significant risk increases were found. A longer follow-up did not increase melanoma risk. Nulliparous women did not have a significantly higher melanoma risk than parous women (HR = 1.22; 95% CI: 0.81-1.84). However, women who were 30 years of age or older at first birth had a significantly higher melanoma risk than women who were younger than 30 years at first birth (age: 30-34 years HR = 4.57; 95% CI: 2.07-10.08, >34 years HR = 2.98; 95% CI: 1.23-7.21). LIMITATIONS, REASONS FOR CAUTION: Despite our large cohort, the number of melanoma cases was rather small, especially in our comparison group, which hampered subgroup analyses. WIDER IMPLICATIONS OF THE FINDINGS: Our results are reassuring for women who underwent IVF or are contemplating to start IVF. Since our cohort study is one of the largest published so far, with long-term follow-up, a subfertile comparison group, and detailed IVF-treatment data, our results add important information to the available evidence. STUDY FUNDING/COMPETING INTEREST: This study was supported by grants from the Dutch Cancer Society (NKI 2006-3631), the Health Research and Development Counsel (28-2540) and the Dutch Ministry of Health.

Data on survival of BRCA1/2-associated primary breast cancer (PBC) patients who opt for subsequent contralateral risk-reducing mastectomy (CRRM) are scarce and inconsistent. We examined the efficacy of CRRM on overall survival in mutation carriers with a history of PBC. From a Dutch multicentre cohort, we selected 583 BRCA-associated PBC patients, being diagnosed between 1980 and 2011. Over time, 242 patients (42%) underwent CRRM and 341 patients (58%) remained under surveillance. Survival analyses were performed using Cox models, with CRRM as a time-dependent covariate. The median follow-up after PBC diagnosis was 11.4 years. In the CRRM group, four patients developed contralateral breast cancer (2%), against 64 patients (19%) in the surveillance group (p

Item does not contain fulltext BACKGROUND: Dizygotic twin pregnancies after IVF treatment are the result of multiple embryos transferred into the uterine cavity, followed by successful double implantation. Factors that increase the chance of multiple implantation after IVF are relatively unknown. The present study aimed to investigate whether features of body composition, such as maternal height, weight and body mass index (BMI) are associated with an increased chance of dizygotic twinning after IVF with double embryo transfer (DET). METHODS: This study was conducted using data from a large Dutch nationwide cohort that comprised 19 861 women who had IVF or ICSI treatment between 1983 and 1995 (OMEGA study). First 'fresh' IVF and ICSI cycles with DET resulting in a delivery of a singleton or twin (living as well as stillborn) were selected. A multivariable logistic regression analysis was performed, with the delivery of a singleton or twin as the dependent variable and height, weight, BMI, maternal age, number of retrieved oocytes, use of alcohol, smoking, highest level of education and parity as independent variables. RESULTS: Of the 6598 women who completed their first IVF or ICSI cycle, 2375 had DET, resulting in 496 deliveries of 371 singletons and 125 twins. Multivariable regression analysis revealed that tall women (>1.74 cm) and women with a high number of retrieved oocytes (>8) had an increased chance of dizygotic twinning [OR: 1.8 (95% CI: 1.0-3.4) and OR: 2.2 (95% CI: 1.3-3.8), respectively]. CONCLUSIONS: Our data demonstrate that tall stature and increased number of retrieved oocytes independently increase the chance of dizygotic twinning after IVF with DET.