Pre-diagnosis tea and coffee consumption and survival after a diagnosis of ovarian cancer: results from the Ovarian Cancer Association Consortium.

BACKGROUND: Tea and coffee are the most frequently consumed beverages in the world. Green tea in particular contains compounds with potential anti-cancer effects, but its association with survival after ovarian cancer is uncertain. METHODS: We investigated the associations between tea and coffee consumption before diagnosis and survival using data from 10 studies in the Ovarian Cancer Association Consortium. Data on tea (green, black, herbal), coffee and caffeine intake were available for up to 5724 women. We used Cox proportional hazards regression to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI). RESULTS: Compared with women who did not drink any green tea, consumption of one or more cups/day was associated with better overall survival (aHR = 0.84, 95% CI 0.71-1.00, p-trend = 0.04). A similar association was seen for ovarian cancer-specific survival in five studies with this information (aHR = 0.81, 0.66-0.99, p-trend = 0.045). There was no consistent variation between subgroups defined by clinical or lifestyle characteristics and adjustment for other aspects of lifestyle did not appreciably alter the estimates. We found no evidence of an association between coffee, black or herbal tea, or caffeine intake and survival. CONCLUSION: The observed association with green tea consumption before diagnosis raises the possibility that consumption after diagnosis might improve patient outcomes.

Risk of borderline ovarian tumors after fertility treatment - Results from a Danish cohort of infertile women.

OBJECTIVE: Results from previous studies examining the association between fertility treatment and borderline ovarian tumors are inconsistent. The aim of this study was to investigate the association between fertility treatment and borderline ovarian tumors in a cohort of infertile women. METHODS: This cohort study was based on the Danish Infertility Cohort and included all infertile women aged 20-45 years living in Denmark between 1 January 1995 and 31 December 2017 (n = 146,891). Information on use of fertility drugs, borderline ovarian tumors and cancer diagnoses, covariates, emigration, and vital status was obtained by linkage to national registers. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) with adjustment for potential confounders for overall borderline ovarian tumors and for serous- and mucinous borderline ovarian tumors separately. RESULTS: During a median 11.3 years of follow-up, 144 women developed a borderline ovarian tumor. No marked associations between ever use of clomiphene citrate, gonadotropins, gonadotropin-releasing hormone receptor modulators, human chorionic gonadotropin or progesterone and borderline ovarian tumors were observed, neither overall nor for serous and mucinous borderline ovarian tumors analysed separately. Further, no clear associations with borderline ovarian tumors were found according to cumulative dose, time since first use or parity status for any fertility drugs. CONCLUSIONS: No marked associations between use of fertility drugs and borderline ovarian tumors were observed. However, the cohort's relatively young age at end of follow-up emphasizes the importance of extending the follow-up period for women who have used fertility drugs.

Long-Term Health Consequences After Ovarian Removal at Benign Hysterectomy : A Nationwide Cohort Study.

BACKGROUND: More evidence is needed to substantiate current recommendations about removing ovaries during hysterectomy for benign conditions. OBJECTIVE: To compare long-term outcomes in women with and without bilateral salpingo-oophorectomy (BSO) during hysterectomy for benign conditions. DESIGN: Emulated target trial using data from a population-based cohort. SETTING: Women in Denmark aged 20 years or older during 1977 to 2017. PARTICIPANTS: 142 985 women with hysterectomy for a benign condition, 22 974 with BSO and 120 011 without. INTERVENTION: Benign hysterectomy with or without BSO. MEASUREMENTS: The primary outcomes were overall hospitalization for cardiovascular disease (CVD), overall cancer incidence, and all-cause mortality through December 2018. RESULTS: Compared with women without BSO, women with BSO who were younger than 45 years at surgery had a higher 10-year cumulative risk for hospitalization for CVD (risk difference [RD], 1.19 percentage points [95% CI, 0.09 to 2.43 percentage points]). Women with BSO had a higher 10-year cumulative risk for cancer for ages 45 to 54 years (RD, 0.73 percentage point [CI, 0.05 to 1.38 percentage points]), 55 to 64 years (RD, 1.92 percentage points [CI, 0.69 to 3.25 percentage points]), and 65 years or older (RD, 2.54 percentage points [CI, 0.91 to 4.25 percentage points]). Women with BSO had higher 10-year mortality in all age groups, although the differences were statistically significant only for ages 45 to 54 years (RD, 0.79 percentage point [CI, 0.27 to 1.30 percentage points]). The mortality at 20 years was inconsistent with that at 10 years in women aged 65 years or older. LIMITATION: Age was a proxy for menopausal status. CONCLUSION: The authors find that these results support current recommendations for conserving ovaries in premenopausal women without a high risk for ovarian cancer and suggest a cautious approach in postmenopausal women. PRIMARY FUNDING SOURCE: The Danish Cancer Society's Scientific Committee and the Mermaid Project.

Risk of epithelial ovarian tumors among women with polycystic ovary syndrome: A nationwide population-based cohort study.

An association between polycystic ovary syndrome (PCOS) and epithelial ovarian tumors is biologically plausible as conditions inherent to PCOS such as excessive androgenic hormones, reproductive factors and obesity are also risk factors for these hormone-sensitive tumors. However, previous studies have showed conflicting results and have various methodological limitations. This population-based cohort study investigates the association between PCOS and epithelial ovarian tumors and includes all women born in Denmark between January 1, 1940 and December 31, 1993 (n = 1 719 304). PCOS diagnoses, ovarian cancer and borderline ovarian tumor diagnoses, covariates, migration and vital status were obtained from the Danish national registers. Adjusted cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CI) for epithelial ovarian cancer and for borderline ovarian tumors overall as well as for histological subtypes separately. During median 26 years of follow-up we identified 6490 women with ovarian cancer and 2990 women with borderline ovarian tumors. Overall, we observed no marked associations between a diagnosis of PCOS and overall epithelial ovarian cancer or overall epithelial borderline ovarian tumors, irrespective of time since diagnosis. However, we found an increased risk of ovarian cancer among postmenopausal women with PCOS (HR 2.28 95% CI 1.02-5.09) and an increased risk of serous borderline ovarian tumors (HR 2.34 95% CI 1.21-4.53) in women with PCOS compared with women without PCOS. Importantly, low statistical precision is a crucial limitation of our study and in previous studies and larger studies with longer follow-up are therefore warranted.

Ovarian removal and subsequent breast cancer prognosis: a nationwide cohort study.

PURPOSE: To evaluate whether previous ovarian removal concomitant with benign hysterectomy improves prognosis in a cohort of women with breast cancer. METHODS: In this nationwide register-based cohort study, risk of recurrence and mortality were examined in 4563 women with invasive breast cancer and previous bilateral salpingo-oophorectomy (BSO) concomitant with benign hysterectomy, during 1977-2018. Comparing with benign hysterectomy alone, hazard ratios (HRs) and 95% confidence intervals (CIs) were evaluated by Cox-proportional hazards regression models. Analyses were stratified on age at hysterectomy as a proxy for menopausal status (< 45, 45-54 and ≥ 55 years); tumor characteristics, estrogen receptor (ER)-status, and use of hormone therapy (HT) were included in multivariable models. RESULTS: Compared with hysterectomy alone, premenopausal (< 45 years) BSO at benign hysterectomy was associated with an age and calendar period adjusted HR of 1.48 (95% CI 0.83-2.65) for breast cancer recurrence within 10 years of follow-up, a HR of 1.07 (95% CI 0.66-1.72) for overall mortality after breast cancer, and a HR of 0.59 (95% CI 0.26-1.32) for breast cancer-specific mortality. The corresponding HRs for postmenopausal (≥ 55 years) BSO at benign hysterectomy were 1.51 (95% CI 0.73-3.12) for recurrences, 1.34 (95% CI 0.74-2.44) for overall mortality, and 1.78 (95% CI 0.74-4.30) for breast cancer mortality. Adjusting for tumor characteristics, ER-status and HT did not alter the results. CONCLUSION: Results from this cohort study did not indicate an improvement in breast cancer prognosis when removing the ovaries at benign hysterectomy prior to the cancer diagnosis.

Clinical parameters affecting survival outcomes in patients with low-grade serous ovarian carcinoma: an international multicentre analysis.

BACKGROUND: Women with low-grade ovarian serous carcinoma (LGSC) benefit from surgical treatment; however, the role of chemotherapy is controversial. We examined an international database through the Ovarian Cancer Association Consortium to identify factors that affect survival in LGSC. METHODS: We performed a retrospective cohort analysis of patients with LGSC who had had primary surgery and had overall survival data available. We performed univariate and multivariate analyses of progression-free survival and overall survival, and generated Kaplan-Meier survival curves. RESULTS: Of the 707 patients with LGSC, 680 (96.2%) had available overall survival data. The patients' median age overall was 54 years. Of the 659 patients with International Federation of Obstetrics and Gynecology stage data, 156 (23.7%) had stage I disease, 64 (9.7%) had stage II, 395 (59.9%) had stage III, and 44 (6.7%) had stage IV. Of the 377 patients with surgical data, 200 (53.0%) had no visible residual disease. Of the 361 patients with chemotherapy data, 330 (91.4%) received first-line platinum-based chemotherapy. The median follow-up duration was 5.0 years. The median progression-free survival and overall survival were 43.2 months and 110.4 months, respectively. Multivariate analysis indicated a statistically significant impact of stage and residual disease on progression-free survival and overall survival. Platinum-based chemotherapy was not associated with a survival advantage. CONCLUSION: This multicentre analysis indicates that complete surgical cytoreduction to no visible residual disease has the most impact on improved survival in LGSC. This finding could immediately inform and change practice.

Tumors of the central nervous system among women treated with fertility drugs: a population-based cohort study.

PURPOSE: To investigate the association between fertility drugs and tumors of the central nervous system (CNS). METHODS: This cohort study was based on The Danish Infertility Cohort and included 148,016 infertile women living in Denmark (1995-2017). The study cohort was linked to national registers to obtain information on use of specific fertility drugs, cancer diagnoses, covariates, emigration, and vital status. Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for all CNS tumors and separately for gliomas, meningiomas and diverse benign tumors of the brain and other parts of the CNS. RESULTS: During a median 11.3 years of follow-up, 328 women were diagnosed with CNS tumors. No marked associations were observed between use of the fertility drugs clomiphene citrate, gonadotropins, gonadotropin-releasing hormone receptor modulators and progesterone and CNS tumors. However, use of human chorionic gonadotropin was associated with a decreased rate of meningiomas (HR 0.49 95% CI 0.28-0.87). No clear associations with CNS tumors were observed according to time since first use or cumulative dose for any of the fertility drugs. CONCLUSION: No associations between use of most types of fertility drugs and CNS tumors were observed. However, our findings only apply to premenopausal women and additional studies with longer follow-up time are necessary.

Fertility drugs and incidence of thyroid cancer in a Danish nationwide cohort of 146 024 infertile women.

STUDY QUESTION: Do fertility drugs increase the risk of thyroid cancer among infertile women? SUMMARY ANSWER: The use of most types of fertility drugs was not associated with an increased risk of thyroid cancer. WHAT IS KNOWN ALREADY: The incidence of thyroid cancer is higher for women than men, especially during reproductive years, indicating that reproductive hormones may be involved in the development of thyroid cancer. Only a few previous studies have examined the association between the use of fertility drugs and incidence of thyroid cancer and the results are inconclusive. STUDY DESIGN, SIZE, DURATION: A retrospective, population-based cohort study including all 146 024 infertile women aged 20-45 years and living in Denmark in the period 1995-2017. The women were followed from the date of entry in the cohort (i.e. date of first infertility diagnosis) until the occurrence of thyroid cancer or any other cancer (except non-melanoma skin cancer), death, emigration, total thyroidectomy or the end of follow-up (31 December 2018), whichever occurred first. The median length of follow-up was 11.3 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 167 women were diagnosed with thyroid cancer during the follow-up period. Information on the use of specific fertility drugs (clomiphene citrate, gonadotropins, hCGs, GnRH receptor modulators and progesterone), thyroid cancer, covariates and vital status was obtained from the Danish Infertility Cohort and various Danish national registers. Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% CIs for thyroid cancer overall and for papillary thyroid cancer. MAIN RESULTS AND THE ROLE OF CHANCE: After adjustment for the calendar year of infertility diagnosis, the highest obtained level of education, parity status, obesity or thyroid disease and mutual adjustment for other registered fertility drugs, no marked associations were observed between the use of clomiphene citrate, hCG, gonadotropins or GnRH receptor modulators and risk of overall or papillary thyroid cancer. However, ever use of progesterone was associated with an increased rate of both overall (HR 1.63; 95% CI 1.07-2.48) and papillary (HR 1.66, 95% CI 1.04-2.65) thyroid cancer after mutual adjustment for other specific fertility drugs. For most specific fertility drugs, we observed a tendency toward higher associations with thyroid cancer within the first 5 years after the start of drug use than after 5 years from the start of use. No marked associations were detected according to the cumulative dose for any of the specific fertility drugs. LIMITATIONS, REASONS FOR CAUTION: Despite a large study population, the statistical precision in some subgroup analyses may be affected due to the low number of thyroid cancer cases. Although we were able to adjust for a number of potential confounders, residual and unmeasured confounding may potentially have affected the observed associations, as we could not adjust for some factors that may influence the association between fertility drugs and thyroid cancer, including age at menarche and BMI. WIDER IMPLICATIONS OF THE FINDINGS: Although this study, which is the largest to date, provides reassuring evidence that there is no strong link between the use of fertility drugs and thyroid cancer incidence, we observed a modest increased thyroid cancer incidence after the use of progesterone. However, we cannot rule out that this is a chance finding and the potential association between the use of progesterone and thyroid cancer should therefore be investigated further in large epidemiological studies. The results of the present study provide valuable knowledge for clinicians and other health care personnel involved in the diagnosis and treatment of infertility. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by research grants from the Jascha Foundation and the Aase and Ejner Danielsens Foundation. B.N. received honoraria and/or non-financial support by Gedeon Richter Nordics AB, IBSA Nordic APS and Merck KGAA. The remaining authors have no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Endometriosis and menopausal hormone therapy impact the hysterectomy-ovarian cancer association.

OBJECTIVE: To evaluate the association between hysterectomy and ovarian cancer, and to understand how hormone therapy (HT) use and endometriosis affect this association. METHODS: We conducted a pooled analysis of self-reported data from 11 case-control studies in the Ovarian Cancer Association Consortium (OCAC). Women with (n = 5350) and without ovarian cancer (n = 7544) who never used HT or exclusively used either estrogen-only therapy (ET) or estrogen+progestin therapy (EPT) were included. Risk of invasive epithelial ovarian cancer adjusted for duration of ET and EPT use and stratified on history of endometriosis was determined using odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Overall and among women without endometriosis, there was a positive association between ovarian cancer risk and hysterectomy (OR = 1.19, 95% CI 1.09-1.31 and OR = 1.20, 95% CI 1.09-1.32, respectively), but no association upon adjusting for duration of ET and EPT use (OR = 1.04, 95% CI 0.94-1.16 and OR = 1.06, 95% CI 0.95-1.18, respectively). Among women with a history of endometriosis, there was a slight inverse association between hysterectomy and ovarian cancer risk (OR = 0.93, 95% CI 0.69-1.26), but this association became stronger and statistically significant after adjusting for duration of ET and EPT use (OR = 0.69, 95% CI 0.48-0.99). CONCLUSIONS: The hysterectomy-ovarian cancer association is complex and cannot be understood without considering duration of ET and EPT use and history of endometriosis. Failure to take these exposures into account in prior studies casts doubt on their conclusions. Overall, hysterectomy is not risk-reducing for ovarian cancer, however the inverse association among women with endometriosis warrants further investigation.

Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer.

PURPOSE: The known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes. METHODS: We sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics. RESULTS: The ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive. CONCLUSIONS: We have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.

Endometrial cancer risk after fertility treatment: a population-based cohort study.

PURPOSE: Using data from a large population-based cohort of women with fertility problems in Denmark, we examined the association between use of fertility drugs and endometrial cancer incidence. METHODS: Women aged 20-45 years living in Denmark during 1 January 1995-31 December 2017 and diagnosed with fertility problems (i.e., subfertile women) were identified from the Danish Infertility Cohort. Information on use of fertility drugs, endometrial cancer, covariates and vital status was obtained from various Danish national registers. Cox proportional hazard models were used adjusted for calendar year of study entry, highest level of education, parity status, hormonal contraceptive use, obesity and diabetes mellitus. RESULTS: Of the 146,104 subfertile women, 129,478 (88.6%) were treated with fertility drugs. During a median follow-up of 10.1 years, 119 women were diagnosed with endometrial cancer. Use of any fertility drugs was not associated with an increased rate of overall (HR 0.82; 95% CI 0.50-1.34) or type I endometrial cancer (HR 1.08; 95% CI 0.60-1.95). No associations between use of specific types of fertility drugs and endometrial cancer were observed. No marked associations were observed according to cumulative dose of specific fertility drugs, parity status, or with increasing follow-up time. CONCLUSIONS: No marked associations between use of fertility drugs and risk of endometrial cancer were observed. The relatively young age of the cohort at end of follow-up, however, highlights the need for longer follow-up of women after fertility drug use.

Ovarian removal at or after benign hysterectomy and breast cancer: a nationwide cohort study.

PURPOSE: Large-scale population-based registry studies investigating the risk of breast cancer after removal of both ovaries at hysterectomy for benign conditions in women with no known genetic predisposition to cancer are needed. We aimed to perform such a study taking into account the age at surgery status and use of hormone replacement therapy (HRT). METHODS: Within the female population of Denmark born 1937-1996, we evaluated breast cancer incidence after unilateral or bilateral oophorectomy concomitant with or after benign hysterectomy in comparison with no surgery and with hysterectomy alone using health registry data during 1978-2016. In a subpopulation followed from 1996, the analyses were stratified according to use of HRT. RESULTS: We found a reduced risk of breast cancer among women aged < 45 years at bilateral oophorectomy compared with women with hysterectomy alone (HR = 0.78; 95% CI 0.66, 0.92), whereas slightly increased risks were seen in women above 50 years. In the subpopulation, non-users of HRT aged ≥ 50 years at oophorectomy had a HR of 0.74 (95% CI 0.56, 0.98) for breast cancer after bilateral oophorectomy compared with hysterectomy alone. CONCLUSIONS: Our large-scale study covering four decades provides evidence that bilateral oophorectomy performed at young age in women with benign indications for hysterectomy is associated with a reduction in breast cancer risk. The finding of a negative association at older ages in women not using HRT deserves further attention.

Risk of epithelial ovarian cancer among women with benign ovarian tumors: a follow-up study.

PURPOSE: The importance of benign ovarian tumors as precursors or risk markers for ovarian cancer is not fully understood. Studies on the association between benign ovarian tumors and ovarian cancer have provided inconclusive results. We examined the overall and histological type-specific risk of ovarian cancer among 158,221 Danish women diagnosed with a benign ovarian tumor during 1978-2016. METHODS: The study cohort was linked to the Danish Cancer Register to identify all cases of epithelial ovarian cancer, and standardized incidence ratios (SIR) with 95% confidence intervals (CI) were calculated. RESULTS: After excluding the first year of follow-up, women with benign ovarian tumors did not have an increased risk for overall epithelial ovarian cancer (SIR 1.02; 95% CI 0.93-1.11), as compared with women in the general population. However, we found an increased risk for mucinous ovarian cancer (SIR 2.06; 95% CI 1.67-2.52); both solid and cystic benign ovarian tumors were associated with an increased risk. The risk for mucinous ovarian cancer was increased irrespective of the age at benign ovarian tumors diagnosis and persisted for up to 20 years after the benign ovarian tumor diagnosis. No clear associations for other histological types of ovarian cancer were observed, except for an increased risk for serous ovarian cancer among women diagnosed with benign ovarian tumors at an young age. CONCLUSIONS: Benign ovarian tumors may be associated with long-term increased risk for mucinous ovarian cancer.

Estrogen Plus Progestin Hormone Therapy and Ovarian Cancer: A Complicated Relationship Explored.

BACKGROUND: Menopausal estrogen-alone therapy is a risk factor for endometrial and ovarian cancers. When a progestin is included with the estrogen daily (continuous estrogen-progestin combined therapy), there is no increased risk of endometrial cancer. However, the effect of continuous estrogen-progestin combined therapy on risk of ovarian cancer is less clear. METHODS: We pooled primary data from five population-based case-control studies in the Ovarian Cancer Association Consortium, including 1509 postmenopausal ovarian cancer cases and 2295 postmenopausal controls. Information on previous menopausal hormonal therapy use, as well as ovarian cancer risk factors, was collected using in-person interviews. Logistic regression was used to assess the association between use of continuous estrogen-progestin combined therapy and risk of ovarian cancer by duration and recency of use and disease histotype. RESULTS: Ever postmenopausal use of continuous estrogen-progestin combined therapy was not associated with increased risk of ovarian cancer overall (OR = 0.85, 95% CI = 0.72, 1.0). A decreased risk was observed for mucinous ovarian cancer (OR = 0.40, 95% CI = 0.18, 0.91). The other main ovarian cancer histotypes did not show an association (endometrioid: OR = 0.86, 95% CI = 0.57, 1.3, clear cell: OR = 0.68, 95% CI = 0.40, 1.2; serous: OR = 0.98, 95% CI = 0.80, 1.2). CONCLUSIONS: Given that estrogen-alone therapy has been shown to be associated with increased risk of ovarian cancer, these findings are consistent with the hypothesis that adding a progestin each day ameliorates the carcinogenic effects of estrogen on the cells of origin for all histotypes of ovarian cancer.

Menopausal hormone therapy prior to the diagnosis of ovarian cancer is associated with improved survival.

PURPOSE: Prior studies of menopausal hormone therapy (MHT) and ovarian cancer survival have been limited by lack of hormone regimen detail and insufficient sample sizes. To address these limitations, a comprehensive analysis of 6419 post-menopausal women with pathologically confirmed ovarian carcinoma was conducted to examine the association between MHT use prior to diagnosis and survival. METHODS: Data from 15 studies in the Ovarian Cancer Association Consortium were included. MHT use was examined by type (estrogen-only (ET) or estrogen+progestin (EPT)), duration, and recency of use relative to diagnosis. Cox proportional hazards models were used to estimate the association between hormone therapy use and survival. Logistic regression and mediation analysis was used to explore the relationship between MHT use and residual disease following debulking surgery. RESULTS: Use of ET or EPT for at least five years prior to diagnosis was associated with better ovarian cancer survival (hazard ratio, 0.80; 95% CI, 0.74 to 0.87). Among women with advanced stage, high-grade serous carcinoma, those who used MHT were less likely to have any macroscopic residual disease at the time of primary debulking surgery (p for trend <0.01 for duration of MHT use). Residual disease mediated some (17%) of the relationship between MHT and survival. CONCLUSIONS: Pre-diagnosis MHT use for 5+ years was a favorable prognostic factor for women with ovarian cancer. This large study is consistent with prior smaller studies, and further work is needed to understand the underlying mechanism.

Risk of febrile seizures among children conceived following fertility treatment: A cohort study.

BACKGROUND: Studies have shown that fertility treatment in mothers is associated with neurological problems in children. However, knowledge about any association between maternal use of fertility treatment and febrile seizures in children is lacking. OBJECTIVE: To determine whether maternal use of fertility treatment is associated with febrile seizures in children. METHODS: All liveborn children in Denmark during 1996-2012 (n = 1 065 901) were linked with the Danish Infertility Cohort and the Danish national registers and were followed from one year of age until the first episode of a febrile seizure, death, emigration, loss to follow-up, or end of follow-up (December 2015). Cox proportional hazard regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with adjustment for potential confounders. RESULTS: Approximately 16% children (n = 172 140) were conceived by infertile women, and approximately 3% (n = 34 082) were diagnosed with febrile seizures during follow-up. Compared with children conceived by fertile women, children conceived following any fertility treatment (HR 1.11, 95% CI 1.06, 1.16), following specific fertility treatment, for example IVF (HR 1.15, 95% CI 1.05, 1.25), ICSI (HR 1.20, 95% CI 1.10, 1.32), and following fertility drugs (HR 1.06, 95% CI 1.00, 1.11) had slight increase in risk of febrile seizures, after adjusting for calendar year of birth, parental age, education, parity status, and maternal smoking during pregnancy. The associations were unchanged when children conceived naturally by infertile women were used as the reference group. CONCLUSIONS: Children conceived following fertility treatment had slightly increased relative risk for febrile seizures.

High-resolution assessment of road traffic noise exposure in Denmark.

Recent studies show associations between transportation noise and various diseases. However, selection bias remains an inherent limitation in many cohort studies. In this study, we aimed to model road traffic noise exposure across the entire Danish population and investigate its distribution in relation to area-level socioeconomic indicators and green space. Based on the Nordic prediction method, we estimated road traffic noise for all Danish residential addresses, in total 2,761,739 addresses, for the years 1995, 2000, 2005, 2010, and 2015 at the most and least exposed façades. Area-level sociodemographic variables encompassing education, income, and unemployment were collected and residential green within a 150 m radius buffer at the address level was estimated using high-resolution national land use classification data. Median levels of noise at both the most and least exposed facades across Denmark increased slightly from 1995 to 2015. Correlations between most and least exposed façades varied based on population density and building type, with the highest correlations between the most and least exposed façades found for semidetached homes and lowest for multistory buildings. Increasing median noise levels were observed across increasing levels of higher education, lower income, and higher unemployment. A decreasing trend in median noise levels with increasing levels of green space was observed. In conclusion, we showed that it is feasible to estimate nationwide, address-specific exposure over a long time-period. Furthermore, the low correlations found between most and least exposed façade for multistory buildings, which characterize metropolitan centers, suggests that the most exposed façade estimation used in most previous studies and predicts exposure at the silent façade relatively poorly.

A comprehensive gene-environment interaction analysis in Ovarian Cancer using genome-wide significant common variants.

As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well-known ovarian cancer risk factors and their interactions with 28 genome-wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case-control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 × 10-4 ). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46-0.60) compared to 0.71 (95%CI = 0.66-0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1-5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene-environment analysis in ovarian cancer.

Cancer therapy and risk of congenital malformations in children fathered by men treated for testicular germ-cell cancer: A nationwide register study.

BACKGROUND: Because of the potential mutagenic effects of chemo- and radiotherapy, there is concern regarding increased risk of congenital malformations (CMs) among children of fathers with cancer. Previous register studies indicate increased CM risk among children conceived after paternal cancer but lack data on oncological treatment. Increased CM risk was recently reported in children born before paternal cancer. This study aims to investigate whether anti-neoplastic treatment for testicular germ-cell cancer (TGCC) implies additional CM risk. METHODS AND FINDINGS: In this nationwide register study, all singletons born in Sweden 1994-2014 (n = 2,027,997) were included. Paternal TGCC diagnoses (n = 2,380), anti-neoplastic treatment, and offspring CMs were gathered from the Swedish Norwegian Testicular Cancer Group (SWENOTECA) and the Swedish Medical Birth Register. Children were grouped based on +/- paternal TGCC; treatment regimen: surveillance (n = 1,340), chemotherapy (n = 2,533), or radiotherapy (n = 360); and according to time of conception: pre- (n = 2,770) or post-treatment (n = 1,437). Odds ratios (ORs) for CMs were calculated using logistic regression with adjustment for parental ages, maternal body mass index (BMI), and maternal smoking. Children conceived before a specific treatment acted as reference for children conceived after the same treatment. Among children fathered by men with TGCC (n = 4,207), 184 had a CM. The risk of malformations was higher among children of fathers with TGCC compared with children fathered by men without TGCC (OR 1.28, 95% confidence interval [CI] 1.19-1.38, p = 0.001, 4.4% versus 3.5%). However, no additional risk increase was associated with oncological treatment when comparing post-treatment-to pretreatment-conceived children (chemotherapy, OR = 0.82, 95% CI 0.54-1.25, p = 0.37, 4.1% versus 4.6%; radiotherapy, OR = 1.01, 95% CI 0.25-4.12, p = 0.98, 3.2% versus 3.0%). Study limitations include lack of data on use of cryopreserved or donor sperm and on seminoma patients for the period 1995-2000-both tending to decrease the difference between the groups with TGCC and without TGCC. Furthermore, the power of analyses on chemotherapy intensity and radiotherapy was limited. CONCLUSIONS: No additional increased risk of CMs was observed in children of men with TGCC treated with radio- or chemotherapy. However, paternal TGCC per se was associated with modestly increased risk for offspring malformations. Clinically, this information can reassure concerned patients.

Risk of breast cancer among women with benign ovarian tumors: a Danish nationwide cohort study.

PURPOSE: To assess the association between benign ovarian tumors and subsequent risk of breast cancer, and to examine this association according to type of benign ovarian tumors. METHODS: This nationwide cohort study comprised all Danish women diagnosed with a benign ovarian tumor during 1978-2016 (n = 158,221) identified through the Danish National Patient Register. The cohort was linked to the Danish Cancer Registry to identify all cases of breast cancer, and standardized incidence ratios (SIR) and 95% confidence intervals (CI) were calculated. RESULTS: Overall, women with a benign ovarian tumor were at significantly increased risk of breast cancer. The risk was confined to women with a solid ovarian tumor (SIR 1.09; 95% CI 1.05-1.13), particularly in women ≥ 50 years at benign tumor diagnosis (SIR 1.19; 95% CI 1.12-1.26). The risk remained increased up to 20 years or more after the diagnosis of a solid ovarian tumor (SIR 1.11; 95% CI 1.04-1.18), and women with a solid tumor were at increased risk of ductal, lobular, and other types of breast cancer, although most consistent for the lobular subtype. For cystic tumors, this association was confined to ductal breast cancer in women with the tumor diagnosed at age ≥ 50 years. CONCLUSIONS: Women with a benign ovarian tumor were at increased risk of breast cancer. This association was largely confined to women with a solid ovarian tumor, and the excess risk was present 20 years or more after the ovarian tumor diagnosis. The underlying mechanism is unknown and should be investigated further.