Publications by authors named "Marina Kvaskoff"

87 Publications

The Global Impact of COVID-19 on the Care of People With Endometriosis.

Front Glob Womens Health 2021 29;2:662732. Epub 2021 Sep 29.

Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, United Kingdom.

Endometriosis is a chronic condition affecting ~10% of women globally. Little is known about the impact of the coronavirus disease 2019 (COVID-19) pandemic on their care. This brief report is aimed to explore the impact of COVID-19 on the care of people with endometriosis around the world, their priorities in relation to their clinical care during and coming out of the pandemic, and whether they believed that endometriosis makes them more vulnerable to COVID-19. An internet-based survey collected data in five languages between May 11, 2020, and June 8, 2020. Only participants with a surgical or radiological diagnosis of endometriosis aged 18 years or over were included. A total of 6,729 eligible respondents completed the survey with 80.7% [95% CI (79.7, 81.6)] reporting a negative impact on their care. This included difficulties obtaining medication (20.3%), cancelled/postponed gynaecology appointments (50.0%), and cancelled/postponed procedures (37.2%). More than half worried that their endometrioses make them more vulnerable to COVID-19 [54.2%; 95% CI (53.0, 55.4)]. The top three priorities were remarkably consistent around the world: contact with gynaecologists, knowing when procedures would be performed, and support with mental health (20.3% prioritising this aspect during the pandemic and 13.0% as restrictions begin to ease). This study shows the substantial impact the COVID-19 pandemic has had on people with endometriosis and describes how they would like care prioritised moving forwards. The findings regarding significant support needs for mental health add further weight to the growing recognition of attending to such issues as part of good patient-centred care.
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http://dx.doi.org/10.3389/fgwh.2021.662732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8594023PMC
September 2021

Endogenous Circulating Sex Hormone Concentrations and Colon Cancer Risk in Postmenopausal Women: A Prospective Study and Meta-Analysis.

JNCI Cancer Spectr 2021 Dec 28;5(6):pkab084. Epub 2021 Sep 28.

Faculty of Health Sciences, Department of Community Medicine, UiT The Arctic University of Norway, Tromsø, Norway.

Background: Observational studies have consistently reported that postmenopausal hormone therapy use is associated with lower colon cancer risk, but epidemiologic studies examining the associations between circulating concentrations of endogenous estrogens and colorectal cancer have reported inconsistent results.

Methods: We investigated the associations between circulating concentrations of estrone, estradiol, free estradiol, testosterone, free testosterone, androstenedione, dehydroepiandrosterone (DHEA), progesterone, and sex hormone-binding globulin (SHBG) with colon cancer risk in a nested case-control study of 1028 postmenopausal European women (512 colon cancer cases, 516 matched controls) who were noncurrent users of exogenous hormones at blood collection. Multivariable conditional logistic regression models were used to compute odds ratios and 95% confidence intervals to evaluate the association between circulating sex hormones and colon cancer risk. We also conducted a dose-response meta-analysis of prospective studies of circulating estrone and estradiol with colorectal, colon, and rectal cancer risk in postmenopausal women. All statistical tests were 2-sided.

Results: In the multivariable model, a nonstatistically significantly positive relationship was found between circulating estrone and colon cancer risk (odds ratio per log 1-unit increment=1.17 [95% confidence interval=1.00 to 1.38]; odds ratio =1.33 [95% confidence interval=0.89 to 1.97], =.20). Circulating concentrations of estradiol, free estradiol, testosterone, free testosterone, androstenedione, DHEA, progesterone, and SHBG were not associated with colon cancer risk. In the dose-response meta-analysis, no clear evidence of associations were found between circulating estradiol and estrone concentrations with colorectal, colon, and rectal cancer risk.

Conclusion: Our observational and meta-analysis results do not support an association between circulating concentrations of endogenous sex hormones and colon or rectal cancer in postmenopausal women.
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http://dx.doi.org/10.1093/jncics/pkab084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8598284PMC
December 2021

Statin Use and Skin Cancer Risk: A Prospective Cohort Study.

J Invest Dermatol 2021 Oct 23. Epub 2021 Oct 23.

Université Paris-Saclay, UVSQ, Université Paris-Sud, Inserm, Gustave Roussy, "Exposome and Heredity" Team, CESP, F-94805, Villejuif, France. Electronic address:

Epidemiological studies on statin use in relation to skin cancer risk are scarce and yielded conflicting results. We explored this association in Etude Epidémiologique auprès de femmes de l'Education Nationale, a prospective cohort of French women born in 1925-1950. Health and lifestyle data were self-reported biennially and matched with drug reimbursement data, allowing the identification of participants' statin use since 2004. Multivariable cause-specific hazards regression models adjusted for skin cancer risk factors estimated hazard ratios with 95% confidence intervals. Over 2004-2014, 455 cutaneous melanoma, 1,741 basal cell carcinoma, and 268 squamous cell carcinoma cases were ascertained among 62,473 women. Compared with never use, there were no associations between ever use of statins and melanoma (hazard ratio = 1.16, 95% confidence interval = 0.94-1.44) or squamous cell carcinoma (hazard ratio = 0.89, 95% confidence interval = 0.66-1.19) risks and a decrease in basal cell carcinoma risk with ever use of statins (hazard ratio = 0.89, 95% confidence interval = 0.79-0.996). We found no trend of increasing or decreasing risks with dose, duration of use, time since first use, or age at first use and no statistically significant effect modification by pigmentary traits or residential UVR exposure. Because of the limited number of studies evaluating the associations between the use of statins and the risks of melanoma, basal cell carcinoma, and squamous cell carcinoma, these findings would deserve further investigation in other settings.
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http://dx.doi.org/10.1016/j.jid.2021.10.010DOI Listing
October 2021

Polyphenol Intake and Epithelial Ovarian Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study.

Antioxidants (Basel) 2021 Aug 4;10(8). Epub 2021 Aug 4.

Institut Gustave Roussy, 94805 Villejuif, France.

Despite some epidemiological evidence on the protective effects of polyphenol intake on epithelial ovarian cancer (EOC) risk from case-control studies, the evidence is scarce from prospective studies and non-existent for several polyphenol classes. Therefore, we aimed to investigate the associations between the intake of total, classes and subclasses of polyphenols and EOC risk in a large prospective study. The study was conducted in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, which included 309,129 adult women recruited mostly from the general population. Polyphenol intake was assessed through validated country-specific dietary questionnaires and the Phenol-Explorer database. During a mean follow-up of 14 years, 1469 first incident EOC cases (including 806 serous, 129 endometrioid, 102 mucinous, and 67 clear cell tumours) were identified. In multivariable-adjusted Cox regression models, the hazard ratio in the highest quartile of total polyphenol intake compared with the lowest quartile (HR) was 1.14 (95% CI 0.94-1.39; -trend = 0.11). Similarly, the intake of most classes and subclasses of polyphenols were not related to either overall EOC risk or any EOC subtype. A borderline statistically significant positive association was observed between phenolic acid intake (HR = 1.20, 95% CI 1.01-1.43; -trend = 0.02) and EOC risk, especially for the serous subtype and in women with obesity, although these associations did not exceed the Bonferroni correction threshold. The current results do not support any association between polyphenol intake and EOC in our large European prospective study. Results regarding phenolic acid intake need further investigation.
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http://dx.doi.org/10.3390/antiox10081249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389235PMC
August 2021

Hysterectomy, non-malignant gynecological diseases, and the risk of incident hypertension: The E3N prospective cohort.

Maturitas 2021 Aug 12;150:22-29. Epub 2021 Jun 12.

CHU Rennes, Université de Rennes 1-Rennes, France.

Objectives: While it has been reported that women with uterine fibroids or endometriosis are commonly overweight and hypertensive, the association between non-malignant gynecological diseases and the risk of hypertension has been little studied prospectively. The aim of this study was to investigate in a large French cohort of women whether a history of hysterectomy, uterine fibroids, or endometriosis was prospectively related to an increased risk of incident hypertension.

Study Design: We analyzed 50,286 women from the E3N cohort who were free of hypertension at baseline, with a median follow-up of 16.4 years.

Main Outcome Measures: Gynecological diseases were based on self-report. Cox proportional hazards models with age as the timescale were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Covariates included smoking status, body mass index (BMI), physical activity, and hormonal factors.

Results: A total of 12,073 women (24%) developed hypertension during follow-up. Women with a history of hysterectomy had an increased risk of incident hypertension, which persisted after adjustment for potential confounding factors (adjusted HR=1.18, 95% CI 1.12-1.24). Risk was similar in women with hysterectomy with or without oophorectomy. Risk of hypertension was higher in women with a history of endometriosis (HR 1.19, 95%CI 1.11-1.22) or uterine fibroids (HR 1.18, 95%CI 1.13-1.22), irrespective of hysterectomy. Associations were similar after further adjustment for BMI.

Conclusions: Hysterectomy and non-malignant gynecological diseases were associated with an increased risk of hypertension in this large prospective study. Women with these conditions may benefit from blood pressure monitoring. ClinicalTrials.gov identifier: NCT03285230.
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http://dx.doi.org/10.1016/j.maturitas.2021.06.001DOI Listing
August 2021

When mentoring matters: a French mentoring program for women in science.

Nat Biotechnol 2021 06;39(6):776-779

Institut des Biomolécules Max Mousseron, CNRS-UMR 5247, University of Montpellier, Montpellier, France.

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http://dx.doi.org/10.1038/s41587-021-00951-2DOI Listing
June 2021

Background exposure to polychlorinated biphenyls and all-cause, cancer-specific, and cardiovascular-specific mortality: A systematic review and meta-analysis.

Environ Int 2021 09 31;154:106663. Epub 2021 May 31.

Paris-Saclay University, UVSQ, Inserm, Gustave Roussy, "Exposome and Heredity" Team, CESP UMR1018, F-94805 Villejuif, France. Electronic address:

Background: Polychlorinated biphenyls (PCBs) are a large family of man-made organic, ubiquitous, and persistent contaminants with endocrine-disrupting properties. PCBs have been associated with numerous adverse health effects and were classified as carcinogenic to humans, but their long-term impact on mortality risk in the general population is unknown.

Objective: To conduct a systematic review and meta-analysis in order to assess whether background exposure levels of PCBs increase all-cause and cancer- and cardiovascular-specific mortality risk in the general population.

Methods: We searched the Pubmed, Web of Science, Cochrane Library, and Embase databases for eligible studies up to 1st of January, 2021. We included cohort and nested-case control studies comparing the lowest vs. the highest background exposure level of PCBs in the general population and reporting data for all-cause mortality and/or cancer-/cardiovascular-specific mortality. Studies reporting occupational and accidental exposures were excluded. Random-effects meta-analysis was used to estimate summary relative risks (SRRs) and 95% confidence intervals (CIs). Heterogeneity across studies was assessed by I2 statistics, and publication bias both graphically and using Egger's and Begg's tests. Quality of included studies was assessed using the National Toxicology Program/Office of Health Assessment and Translation (NTP/OHAT). Confidence in the body of evidence and related level of evidence were assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) based on the NTP/OHAT framework. The protocol was registered in PROSPERO (CRD42020178079).

Results: The initial search led to 2,132 articles. Eight prospective cohort studies met our inclusion criteria, leading to 72,852 participants including 17,805 deaths. Overall exposure to PCBs was not statistically significantly associated with all-cause mortality (SRR = 1.13, 95% CI = 0.90-1.41, n = 7 studies, low certainty); however, dietary exposure to PCBs was associated with an increased risk of cardiovascular-specific mortality (SRR = 1.38, 95% CI = 1.14-1.66, n = 3 studies, moderate certainty), while no association was found with cancer-specific mortality (SRR = 1.07, 95% CI = 0.72-1.59, n = 5 studies, low certainty).

Conclusion: Our meta-analysis suggests that background exposure to PCBs is associated with an increased risk of cardiovascular-specific mortality in the general population with a "moderate" level of evidence. These findings should be interpreted with caution given the small number of studies on mortality in the general population.
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http://dx.doi.org/10.1016/j.envint.2021.106663DOI Listing
September 2021

Letter to the Editor: Endometriosis and malignancy-The intriguing relationship.

Int J Gynaecol Obstet 2021 06 9;153(3):556-557. Epub 2021 Apr 9.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

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http://dx.doi.org/10.1002/ijgo.13687DOI Listing
June 2021

Recreational and residential sun exposure and risk of endometriosis: a prospective cohort study.

Hum Reprod 2021 01;36(1):199-210

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Study Question: Is recreational and residential sun exposure associated with risk of endometriosis?

Summary Answer: Tanning bed use in early adulthood, sunscreen use and history of sunburns were associated with a greater risk of endometriosis; however, higher residential UV exposure was associated with a lower endometriosis risk.

What Is Known Already: Previous research has reported an association between endometriosis and skin cancer, with evidence of shared risk factors between the two diseases. We investigated the potential associations between ultraviolet radiation and endometriosis risk.

Study Design, Size, Duration: The Nurses' Health Study II is a prospective cohort of 116 429 female US nurses aged 25-42 years at enrolment in 1989. Participants completed self-administered biennial questionnaires through June 2015.

Participants/materials, Settings, Methods: We investigated self-reported measures of recreational sun-exposure and geocoded residential UV exposure in childhood and adulthood in relation to risk of laparoscopically confirmed endometriosis among premenopausal white women. We used Cox proportional hazards models to calculate hazard ratios (HRs) and 95% CIs.

Main Results And The Role Of Chance: During follow-up, 4791 incident cases of laparoscopically confirmed endometriosis were reported among 1 252  248 person-years. Tanning bed use during high school/college (≥6 times per year vs. never use: HR = 1.19, 95% CI = 1.01-1.40; Ptrend = 0.04) and at ages 25-35 (HR = 1.24, 95% CI = 1.12-1.39; Ptrend ≤ 0.0001), number of sunburns during adolescence (Ptrend = 0.03) and percentage of time using sunscreen in adulthood (Ptrend = 0.002) were positively associated with risk of endometriosis. In contrast, residential UV level at birth (highest vs. lowest quintile: HR = 0.81, 95% CI = 0.72-0.92; Ptrend = 0.0001), at age 15 (HR = 0.79, 95% CI = 0.70-0.88; Ptrend ≤ 0.0001) and at age 30 (HR = 0.90, 95% CI = 0.82-0.99; Ptrend = 0.21) were associated with a decreased risk of endometriosis.

Limitations, Reasons For Caution: Self-reported endometriosis diagnosis may be prone to misclassification; however, we restricted our definition to laparoscopically confirmed endometriosis, which has been shown to have high validity compared to medical records.

Wider Implications Of The Findings: Our results suggest that tanning bed use in early adulthood increases endometriosis risk, potentially through a harmful effect of ultraviolet A wavelengths, and that residential UV exposure reduces risk, possibly via optimal vitamin D synthesis. These findings should be investigated further to enhance our understanding of endometriosis aetiology.

Study Funding/competing Interest(s): This project was supported by NICHD grants HD48544 and HD52473, HD57210, NIH grant CA50385, CA176726. M.K. was supported by a Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme (#PIOF-GA-2011-302078) and is grateful to the Philippe Foundation and the Bettencourt-Schueller Foundation for their financial support. H.R.H. is supported by the National Cancer Institute, National Institutes of Health (K22 CA193860). The authors have nothing to disclose.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deaa280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801789PMC
January 2021

Pigmentary traits, sun exposure, and risk of non-Hodgkin's lymphoma/chronic lymphocytic leukemia: A study within the French E3N prospective cohort.

Cancer Med 2021 01 21;10(1):297-304. Epub 2020 Nov 21.

Hematology-Oncology Department, Centre Hospitalier de Versailles, Le Chesnay, France.

To investigate whether risk factors for keratinocyte carcinomas (KCs), namely pigmentary traits and sun exposure, are associated with risk of non-Hodgkin's lymphomas (NHL) and chronic lymphocytic leukemia (CLL). E3N is a prospective cohort of French women aged 40-65 years at inclusion in 1990. Cancer data were collected at baseline and updated every 2-3 years. Hazard Ratios (HRs) and 95% confidence intervals (CIs) for associations between pigmentary traits and sun exposure, and risk of CLL/NHL were estimated using Cox models. With a median follow-up of 24 years, 622 incident cases of CLL/NHL were ascertained among the 92,097 included women. The presence of nevi was associated with CLL/NHL risk: HR for "many or very many nevi" relative to "no nevi": 1.56 [1.15; 2.11]. Such association with number of nevi appears to be mostly limited to risk of CLL: HR for "many or very many nevi": 3.00 [1.38; 6.52]; versus 1.32 [0.94; 1.84] for NHL. Women whose skin was highly sensitive to sunburn also had a higher risk of CLL: HR = 1.96 [1.21; 3.18], while no increase in risk of NHL was observed. Skin or hair color, number of freckles, and average daily ultraviolet (UV) dose during spring and summer in location of residence at birth or at inclusion (kJ/m ) were not associated with CLL/NHL risk. Some pigmentary traits (presence of nevi and skin sensitivity), but not sun exposure, were associated with CLL/NHL. These observations suggest that CLL may share some constitutional risk factors with keratinocyte cancers.
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http://dx.doi.org/10.1002/cam4.3586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826467PMC
January 2021

Endometriosis and cancer: a systematic review and meta-analysis.

Hum Reprod Update 2021 Feb;27(2):393-420

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: Endometriosis is an often chronic, inflammatory gynaecologic condition affecting 190 million women worldwide. Studies have reported an elevated cancer risk among patients with endometriosis. However, prior research has included methodologic issues that impede valid and robust interpretation.

Objective And Rationale: We conducted a meta-analysis of studies investigating the association between endometriosis and cancer risk and analysed the results by methodologic characteristics. We discuss the implications of cancer screening in patients and management challenges faced by clinicians.

Search Methods: We searched PubMed and Embase databases for eligible studies from inception through 24 October 2019. We included cohort and case-control studies examining the association between endometriosis and cancer risk; cross-sectional studies and case reports were excluded. Publications had to present risk/rate/odds estimates with 95% CI. Random effects meta-analysis was used to estimate summary relative risks (SRR) and CIs. Heterogeneity across studies was assessed by the Q test and I2 statistics, and publication bias using Egger's and Begg's tests. Risk of bias and quality of the included studies were assessed using the risk of bias in non-randomized studies of interventions (ROBINS-I) tool.

Outcomes: Forty-nine population-based case-control and cohort studies were included. Twenty-six studies were scored as having a 'serious'/'critical' risk of bias, and the remaining 23 'low'/'moderate'. Cancer-specific analyses showed a positive association between endometriosis and ovarian cancer risk (SRR = 1.93, 95% CI = 1.68-2.22; n = 24 studies) that was strongest for clear cell (SRR = 3.44, 95% CI = 2.82-4.42; n = 5 studies) and endometrioid (SRR = 2.33, 95% CI = 1.82-2.98; n = 5 studies) histotypes (Pheterogeneity < 0.0001), although with significant evidence of both heterogeneity across studies and publication bias (Egger's and Begg's P-values < 0.01). A robust association was observed between endometriosis and thyroid cancer (SRR = 1.39, 95% CI =1.24-1.57; n = 5 studies), a very small association with breast cancer (SRR = 1.04, 95% CI =1.00-1.09; n = 20 studies) and no association with colorectal cancer (SRR = 1.00, 95% CI =0.87-1.16; n = 5 studies). The association with endometrial cancer was not statistically significant (SRR = 1.23, 95% CI =0.97-1.57; n = 17 studies) overall and wholly null when restricted to prospective cohort studies (SRR = 0.99, 95% CI =0.72-1.37; n = 5 studies). The association with cutaneous melanoma was also non-significant (SRR = 1.17, 95% CI =0.97-1.41; n = 7 studies) but increased in magnitude and was statistically significant when restricted to studies with low/moderate risk of bias (SRR = 1.71, 95% CI = 1.24-2.36, n = 2 studies). The most robust finding both in terms of statistical significance and magnitude of effect was an inverse association with cervical cancer (SRR = 0.68, 95% CI =0.56-0.82; n = 4 studies); however, this result has a high potential to reflect heightened access to detection of dysplasia for women who reached an endometriosis diagnosis and is thus likely not causal. Several additional cancer types were explored based on <4 studies.

Wider Implications: Endometriosis was associated with a higher risk of ovarian and thyroid, and minimally (only 4% greater risk) with breast cancer, and with a lower risk of cervical cancer. However, this meta-analysis confirms that: a majority of studies had severe/critical risk of bias; there is impactful heterogeneity across studies-and for ovarian cancer, publication bias; and causal inference requires temporality, which in many studies was not considered. We discuss the implications of these potential associations from the perspectives of patients with endometriosis, clinicians involved in their care, and scientists investigating their long-term health risks.
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http://dx.doi.org/10.1093/humupd/dmaa045DOI Listing
February 2021

Ovarian Cancer Risk Factor Associations by Primary Anatomic Site: The Ovarian Cancer Cohort Consortium.

Cancer Epidemiol Biomarkers Prev 2020 10 30;29(10):2010-2018. Epub 2020 Jul 30.

Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

Background: Epithelial ovarian, fallopian tube, and primary peritoneal cancers have shared developmental pathways. Few studies have prospectively examined heterogeneity in risk factor associations across these three anatomic sites.

Methods: We identified 3,738 ovarian, 337 peritoneal, and 176 fallopian tube incident cancer cases in 891,731 women from 15 prospective cohorts in the Ovarian Cancer Cohort Consortium. Associations between 18 putative risk factors and risk of ovarian, peritoneal, and fallopian tube cancer, overall and for serous and high-grade serous tumors, were evaluated using competing risks Cox proportional hazards regression. Heterogeneity was assessed by likelihood ratio tests.

Results: Most associations did not vary by tumor site ( ≥ 0.05). Associations between first pregnancy ( = 0.04), tubal ligation ( = 0.01), and early-adult (age 18-21 years) body mass index (BMI; = 0.02) and risk differed between ovarian and peritoneal cancers. The association between early-adult BMI and risk further differed between peritoneal and fallopian tube cancer ( = 0.03). First pregnancy and tubal ligation were inversely associated with ovarian, but not peritoneal, cancer. Higher early-adult BMI was associated with higher risk of peritoneal, but not ovarian or fallopian tube, cancer. Patterns were generally similar when restricted to serous and high-grade serous cases.

Conclusions: Ovarian, fallopian tube, and primary peritoneal cancers appear to have both shared and distinct etiologic pathways, although most risk factors appear to have similar associations by anatomic site.

Impact: Further studies on the mechanisms underlying the differences in risk profiles may provide insights regarding the developmental origins of tumors arising in the peritoneal cavity and inform prevention efforts.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541500PMC
October 2020

Citrus intake and risk of skin cancer in the European Prospective Investigation into Cancer and Nutrition cohort (EPIC).

Eur J Epidemiol 2020 Nov 24;35(11):1057-1067. Epub 2020 Jul 24.

CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.

Citrus intake has been suggested to increase the risk of skin cancer. Although this relation is highly plausible biologically, epidemiologic evidence is lacking. We aimed to examine the potential association between citrus intake and skin cancer risk. EPIC is an ongoing multi-center prospective cohort initiated in 1992 and involving ~ 520,000 participants who have been followed-up in 23 centers from 10 European countries. Dietary data were collected at baseline using validated country-specific dietary questionnaires. We used Cox proportional hazards regression models to compute hazard ratios (HR) and 95% confidence intervals (CI). During a mean follow-up of 13.7 years, 8448 skin cancer cases were identified among 270,112 participants. We observed a positive linear dose-response relationship between total citrus intake and skin cancer risk (HR = 1.10, 95% CI 1.03-1.18 in the highest vs. lowest quartile; P = 0.001), particularly with basal cell carcinoma (BCC) (HR = 1.11, 95% CI 1.02-1.20, P = 0.007) and squamous cell carcinoma (SCC) (HR = 1.23, 95% CI 1.04-1.47, P = 0.01). Citrus fruit intake was positively associated with skin cancer risk (HR = 1.08, 95% CI 1.01-1.16, P = 0.01), particularly with melanoma (HR = 1.23, 95% CI 1.02-1.48; P = 0.01), although with no heterogeneity across skin cancer types (P = 0.21). Citrus juice was positively associated with skin cancer risk (P = 0.004), particularly with BCC (P = 0.008) and SCC (P = 0.004), but not with melanoma (P = 0.02). Our study suggests moderate positive linear dose-response relationships between citrus intake and skin cancer risk. Studies with available biomarker data and the ability to examine sun exposure behaviors are warranted to clarify these associations and examine the phototoxicity mechanisms of furocoumarin-rich foods.
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http://dx.doi.org/10.1007/s10654-020-00666-9DOI Listing
November 2020

Dietary and Circulating Fatty Acids and Ovarian Cancer Risk in the European Prospective Investigation into Cancer and Nutrition.

Cancer Epidemiol Biomarkers Prev 2020 09 2;29(9):1739-1749. Epub 2020 Jul 2.

Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology - ICO, Group of Research on Nutrition and Cancer, Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet of Llobregat, Barcelona, Spain.

Background: Fatty acids impact obesity, estrogens, and inflammation, which are risk factors for ovarian cancer. Few epidemiologic studies have investigated the association of fatty acids with ovarian cancer.

Methods: Within the European Prospective Investigation into Cancer and Nutrition (EPIC), 1,486 incident ovarian cancer cases were identified. Cox proportional hazard models with adjustment for ovarian cancer risk factors were used to estimate HRs of ovarian cancer across quintiles of intake of fatty acids. False discovery rate was computed to control for multiple testing. Multivariable conditional logistic regression models were used to estimate ORs of ovarian cancer across tertiles of plasma fatty acids among 633 cases and two matched controls in a nested case-control analysis.

Results: A positive association was found between ovarian cancer and intake of industrial elaidic acid [HR comparing fifth with first quintile = 1.29; 95% confidence interval (CI) = 1.03-1.62; = 0.02, q-value = 0.06]. Dietary intakes of -6 linoleic acid (HR = 1.10; 95% CI = 1.01-1.21; = 0.03) and -3 α-linolenic acid (HR = 1.18; 95% CI = 1.05-1.34; = 0.007) from deep-frying fats were also positively associated with ovarian cancer. Suggestive associations were reported for circulating elaidic (OR comparing third with first tertile = 1.39; 95% CI = 0.99-1.94; = 0.06) and α-linolenic acids (OR = 1.30; 95% CI = 0.98-1.72; = 0.06).

Conclusions: Our results suggest that higher intakes and circulating levels of industrial elaidic acid, and higher intakes of linoleic acid and α-linolenic acid from deep-frying fat, may be associated with greater risk of ovarian cancer.

Impact: If causal, eliminating industrial -fatty acids could offer a straightforward public health action for reducing ovarian cancer risk.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1477DOI Listing
September 2020

Menstrual Factors, Reproductive History, Hormone Use, and Urothelial Carcinoma Risk: A Prospective Study in the EPIC Cohort.

Cancer Epidemiol Biomarkers Prev 2020 08 28;29(8):1654-1664. Epub 2020 May 28.

Hellenic Health Foundation, Kaisareias 13 & Alexandroupoleos, Athens, Greece.

Background: Urothelial carcinoma is the predominant (95%) bladder cancer subtype in industrialized nations. Animal and epidemiologic human studies suggest that hormonal factors may influence urothelial carcinoma risk.

Methods: We used an analytic cohort of 333,919 women from the European Prospective Investigation into Cancer and Nutrition Cohort. Associations between hormonal factors and incident urothelial carcinoma (overall and by tumor grade, tumor aggressiveness, and non-muscle-invasive urothelial carcinoma) risk were evaluated using Cox proportional hazards models.

Results: During a mean of 15 years of follow-up, 529 women developed urothelial carcinoma. In a model including number of full-term pregnancies (FTP), menopausal status, and menopausal hormone therapy (MHT), number of FTP was inversely associated with urothelial carcinoma risk (HR = 0.48; 0.25-0.90; in parous women = 0.010) and MHT use (compared with nonuse) was positively associated with urothelial carcinoma risk (HR = 1.27; 1.03-1.57), but no dose response by years of MHT use was observed. No modification of HRs by smoking status was observed. Finally, sensitivity analyses in never smokers showed similar HR patterns for the number of FTP, while no association between MHT use and urothelial carcinoma risk was observed. Association between MHT use and urothelial carcinoma risk remained significant only in current smokers. No heterogeneity of the risk estimations in the final model was observed by tumor aggressiveness or by tumor grade. A positive association between MTH use and non-muscle-invasive urothelial carcinoma risk was observed.

Conclusions: Our results support that increasing the number of FTP may reduce urothelial carcinoma risk.

Impact: More detailed studies on parity are needed to understand the possible effects of perinatal hormone changes in urothelial cells.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0184DOI Listing
August 2020

Plasma concentration of brominated flame retardants and postmenopausal breast cancer risk: a nested case-control study in the French E3N cohort.

Environ Health 2020 05 20;19(1):54. Epub 2020 May 20.

CESP, Faculté de médecine, Université Paris-Saclay, UVSQ, INSERM, Villejuif, France.

Background: Brominated flame retardants (BFRs) are lipophilic substances with endocrine-disrupting properties. To date, only few investigations, mainly retrospective case-control studies, have explored the link between internal levels of BFRs and the risk of breast cancer, leading to conflicting results. We investigated the associations between plasma concentrations of two main groups of BFRs, PBDEs (pentabromodiphenyl ethers) and PBBs (polybrominated biphenyls), and the risk of breast cancer in a nested case-control study.

Methods: A total of 197 incident breast cancer cases and 197 controls with a blood sample collected in 1994-1999 were included. Plasma levels of PBDE congeners (BDE-28, BDE-47, BDE-99, BDE-100, BDE153, BDE-154) and of PBB-153 were measured by gas chromatography coupled to high-resolution mass spectrometry. Conditional logistic regression models, adjusted for potential confounders, were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).

Results: Women were aged 56 years on average at blood draw. All cases, except for one, were diagnosed after menopause, with an average age at diagnosis of 68 years. Overall, we found no evidence of an association between plasma levels of PBDEs and PBB-153 and postmenopausal breast cancer risk (log-concentrations of BFRs yielding non-statistically significant ORs of 0.87 to 1.07). The analysis showed a non-linear inverse association for BDE-100 and BDE-153 and postmenopausal breast cancer risk; nevertheless, these findings were statistically significant only when the exposure was modeled as ng/L plasma (third vs. first quintile: OR = 0.42, 95%CI = 0.19-0.93 and OR = 0.42, 95%CI = 0.18-0.98, respectively) and not when modeled as ng/gr of lipids (OR = 0.58, 95%CI = 0.27-1.25 and OR = 0.53, 95%CI = 0.25-1.17). These results were unchanged in stratified analyses by tumor hormone receptor expression or body mass index.

Conclusions: Our results suggest no clear association between internal levels of PBDEs and PBB-153 and the risk of breast cancer in postmenopausal women. However, these findings need to be carefully interpreted, taking into account limitations due to the limited number of women included in the study, the lack of information concerning genetic susceptibility of cases, and the unavailability of exposure assessment during critical windows of susceptibility for breast cancer. More studies are warranted to further investigate the relationships between PBDE and PBB exposure and breast cancer risk.
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http://dx.doi.org/10.1186/s12940-020-00607-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238573PMC
May 2020

Serologic markers of Chlamydia trachomatis and other sexually transmitted infections and subsequent ovarian cancer risk: Results from the EPIC cohort.

Int J Cancer 2020 10 24;147(8):2042-2052. Epub 2020 Apr 24.

Clinical Microbiology, Department of Translational Medicine, Lund University, Malmö, Sweden.

A substantial proportion of epithelial ovarian cancer (EOC) arises in the fallopian tube and other epithelia of the upper genital tract; these epithelia may incur damage and neoplastic transformation after sexually transmitted infections (STI) and pelvic inflammatory disease. We investigated the hypothesis that past STI infection, particularly Chlamydia trachomatis, is associated with higher EOC risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort including 791 cases and 1669 matched controls. Serum antibodies against C. trachomatis, Mycoplasma genitalium, herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) 16, 18 and 45 were assessed using multiplex fluorescent bead-based serology. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) comparing women with positive vs. negative serology. A total of 40% of the study population was seropositive to at least one STI. Positive serology to C. trachomatis Pgp3 antibodies was not associated with EOC risk overall, but with higher risk of the mucinous histotype (RR = 2.30 [95% CI = 1.22-4.32]). Positive serology for chlamydia heat shock protein 60 (cHSP60-1) was associated with higher risk of EOC overall (1.36 [1.13-1.64]) and with the serous subtype (1.44 [1.12-1.85]). None of the other evaluated STIs were associated with EOC risk overall; however, HSV-2 was associated with higher risk of endometrioid EOC (2.35 [1.24-4.43]). The findings of our study suggest a potential role of C. trachomatis in the carcinogenesis of serous and mucinous EOC, while HSV-2 might promote the development of endometrioid disease.
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http://dx.doi.org/10.1002/ijc.32999DOI Listing
October 2020

Theoretical potential for endometrial cancer prevention through primary risk factor modification: Estimates from the EPIC cohort.

Int J Cancer 2020 09 18;147(5):1325-1333. Epub 2020 Feb 18.

Nutrition and Metabolism Section, International Agency for Research on Cancer (IARC), Lyon, France.

Endometrial cancer (EC) incidence rates vary ~10-fold worldwide, in part due to variation in EC risk factor profiles. Using an EC risk model previously developed in the European EPIC cohort, we evaluated the prevention potential of modified EC risk factor patterns and whether differences in EC incidence between a European population and low-risk countries can be explained by differences in these patterns. Predicted EC incidence rates were estimated over 10 years of follow-up for the cohort before and after modifying risk factor profiles. Risk factors considered were: body mass index (BMI, kg/m ), use of postmenopausal hormone therapy (HT) and oral contraceptives (OC) (potentially modifiable); and, parity, ages at first birth, menarche and menopause (environmentally conditioned, but not readily modifiable). Modeled alterations in BMI (to all ≤23 kg/m ) and HT use (to all non-HT users) profiles resulted in a 30% reduction in predicted EC incidence rates; individually, longer duration of OC use (to all ≥10 years) resulted in a 42.5% reduction. Modeled changes in not readily modifiable exposures (i.e., those not contributing to prevention potential) resulted in ≤24.6% reduction in predicted EC incidence. Women in the lowest decile of a risk score based on the evaluated exposures had risk similar to a low risk countries; however, this was driven by relatively long use of OCs (median = 23 years). Our findings support avoidance of overweight BMI and of HT use as prevention strategies for EC in a European population; OC use must be considered in the context of benefits and risks.
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http://dx.doi.org/10.1002/ijc.32901DOI Listing
September 2020

The Risk of Ovarian Cancer Increases with an Increase in the Lifetime Number of Ovulatory Cycles: An Analysis from the Ovarian Cancer Cohort Consortium (OC3).

Cancer Res 2020 03 13;80(5):1210-1218. Epub 2020 Jan 13.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, University Utrecht, Utrecht, the Netherlands.

Repeated exposure to the acute proinflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2,045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted HRs between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype. Women in the 90th percentile of LOC (>514 cycles) were almost twice as likely to be diagnosed with ovarian cancer than women in the 10th percentile (<294) [HR (95% confidence interval): 1.92 (1.60-2.30)]. Risk increased 14% per 5-year increase in LOC (60 cycles) [(1.10-1.17)]; this association remained after adjustment for LOC components: number of pregnancies and oral contraceptive use [1.08 (1.04-1.12)]. The association varied by histotype, with increased risk of serous [1.13 (1.09-1.17)], endometrioid [1.20 (1.10-1.32)], and clear cell [1.37 (1.18-1.58)], but not mucinous [0.99 (0.88-1.10), P-heterogeneity = 0.01] tumors. Heterogeneity across histotypes was reduced [P-heterogeneity = 0.15] with adjustment for LOC components [1.08 serous, 1.11 endometrioid, 1.26 clear cell, 0.94 mucinous]. Although the 10-year absolute risk of ovarian cancer is small, it roughly doubles as the number of LOC rises from approximately 300 to 500. The consistency and linearity of effects strongly support the hypothesis that each ovulation leads to small increases in the risk of most ovarian cancers, a risk that cumulates through life, suggesting this as an important area for identifying intervention strategies. SIGNIFICANCE: Although ovarian cancer is rare, risk of most ovarian cancers doubles as the number of lifetime ovulatory cycles increases from approximately 300 to 500. Thus, identifying an important area for cancer prevention research.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-2850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056529PMC
March 2020

Lifestyle factors and risk of multimorbidity of cancer and cardiometabolic diseases: a multinational cohort study.

BMC Med 2020 01 10;18(1). Epub 2020 Jan 10.

Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Background: Although lifestyle factors have been studied in relation to individual non-communicable diseases (NCDs), their association with development of a subsequent NCD, defined as multimorbidity, has been scarcely investigated. The aim of this study was to investigate associations between five lifestyle factors and incident multimorbidity of cancer and cardiometabolic diseases.

Methods: In this prospective cohort study, 291,778 participants (64% women) from seven European countries, mostly aged 43 to 58 years and free of cancer, cardiovascular disease (CVD), and type 2 diabetes (T2D) at recruitment, were included. Incident multimorbidity of cancer and cardiometabolic diseases was defined as developing subsequently two diseases including first cancer at any site, CVD, and T2D in an individual. Multi-state modelling based on Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (95% CI) of developing cancer, CVD, or T2D, and subsequent transitions to multimorbidity, in relation to body mass index (BMI), smoking status, alcohol intake, physical activity, adherence to the Mediterranean diet, and their combination as a healthy lifestyle index (HLI) score. Cumulative incidence functions (CIFs) were estimated to compute 10-year absolute risks for transitions from healthy to cancer at any site, CVD (both fatal and non-fatal), or T2D, and to subsequent multimorbidity after each of the three NCDs.

Results: During a median follow-up of 11 years, 1910 men and 1334 women developed multimorbidity of cancer and cardiometabolic diseases. A higher HLI, reflecting healthy lifestyles, was strongly inversely associated with multimorbidity, with hazard ratios per 3-unit increment of 0.75 (95% CI, 0.71 to 0.81), 0.84 (0.79 to 0.90), and 0.82 (0.77 to 0.88) after cancer, CVD, and T2D, respectively. After T2D, the 10-year absolute risks of multimorbidity were 40% and 25% for men and women, respectively, with unhealthy lifestyle, and 30% and 18% for men and women with healthy lifestyles.

Conclusion: Pre-diagnostic healthy lifestyle behaviours were strongly inversely associated with the risk of cancer and cardiometabolic diseases, and with the prognosis of these diseases by reducing risk of multimorbidity.
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http://dx.doi.org/10.1186/s12916-019-1474-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953215PMC
January 2020

Adherence to the World Cancer Research Fund/American Institute for Cancer Research cancer prevention recommendations and risk of in situ breast cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

BMC Med 2019 12 2;17(1):221. Epub 2019 Dec 2.

Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.

Background: Even though in situ breast cancer (BCIS) accounts for a large proportion of the breast cancers diagnosed, few studies have investigated potential risk factors for BCIS. Their results suggest that some established risk factors for invasive breast cancer have a similar impact on BCIS risk, but large population-based studies on lifestyle factors and BCIS risk are lacking. Thus, we investigated the association between lifestyle and BCIS risk within the European Prospective Investigation into Cancer and Nutrition cohort.

Methods: Lifestyle was operationalized by a score reflecting the adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations. The recommendations utilized in these analyses were the ones pertinent to healthy body weight, physical activity, consumption of plant-based foods, energy-dense foods, red and processed meat, and sugary drinks and alcohol, as well as the recommendation on breastfeeding. Cox proportional hazards regression was used to assess the association between lifestyle score and BCIS risk. The results were presented as hazard ratios (HR) and corresponding 95% confidence intervals (CI).

Results: After an overall median follow-up time of 14.9 years, 1277 BCIS cases were diagnosed. Greater adherence to the WCRF/AICR cancer prevention recommendations was not associated with BCIS risk (HR = 0.98, 95% CI 0.93-1.03; per one unit of increase; multivariable model). An inverse association between the lifestyle score and BCIS risk was observed in study centers, where participants were recruited mainly via mammographic screening and attended additional screening throughout follow-up (HR = 0.85, 95% CI 0.73-0.99), but not in the remaining ones (HR = 0.99, 95% CI 0.94-1.05).

Conclusions: While we did not observe an overall association between lifestyle and BCIS risk, our results indicate that lifestyle is associated with BCIS risk among women recruited via screening programs and with regular screening participation. This suggests that a true inverse association between lifestyle habits and BCIS risk in the overall cohort may have been masked by a lack of information on screening attendance. The potential inverse association between lifestyle and BCIS risk in our analyses is consistent with the inverse associations between lifestyle scores and breast cancer risk reported from previous studies.
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http://dx.doi.org/10.1186/s12916-019-1444-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886197PMC
December 2019

Development and validation of circulating CA125 prediction models in postmenopausal women.

J Ovarian Res 2019 Nov 26;12(1):116. Epub 2019 Nov 26.

CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain.

Background: Cancer Antigen 125 (CA125) is currently the best available ovarian cancer screening biomarker. However, CA125 has been limited by low sensitivity and specificity in part due to normal variation between individuals. Personal characteristics that influence CA125 could be used to improve its performance as screening biomarker.

Methods: We developed and validated linear and dichotomous (≥35 U/mL) circulating CA125 prediction models in postmenopausal women without ovarian cancer who participated in one of five large population-based studies: Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO, n = 26,981), European Prospective Investigation into Cancer and Nutrition (EPIC, n = 861), the Nurses' Health Studies (NHS/NHSII, n = 81), and the New England Case Control Study (NEC, n = 923). The prediction models were developed using stepwise regression in PLCO and validated in EPIC, NHS/NHSII and NEC.

Result: The linear CA125 prediction model, which included age, race, body mass index (BMI), smoking status and duration, parity, hysterectomy, age at menopause, and duration of hormone therapy (HT), explained 5% of the total variance of CA125. The correlation between measured and predicted CA125 was comparable in PLCO testing dataset (r = 0.18) and external validation datasets (r = 0.14). The dichotomous CA125 prediction model included age, race, BMI, smoking status and duration, hysterectomy, time since menopause, and duration of HT with AUC of 0.64 in PLCO and 0.80 in validation dataset.

Conclusions: The linear prediction model explained a small portion of the total variability of CA125, suggesting the need to identify novel predictors of CA125. The dichotomous prediction model showed moderate discriminatory performance which validated well in independent dataset. Our dichotomous model could be valuable in identifying healthy women who may have elevated CA125 levels, which may contribute to reducing false positive tests using CA125 as screening biomarker.
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http://dx.doi.org/10.1186/s13048-019-0591-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878636PMC
November 2019

Fertility drugs and cutaneous melanoma risk: a French prospective cohort study.

Eur J Cancer Prev 2020 03;29(2):182-185

CESP, Fac. de médecine - Univ. Paris-Sud, Fac. de médecine - UVSQ, INSERM, Université Paris-Saclay.

Cutaneous melanoma has been suspected to be influenced by female sex hormones. A review of the literature in 2018 indicated that fertility drug (FD) use was associated with increased melanoma risk among parous women only. However, most studies so far were based on a retrospective design and the current evidence is unclear. We sought to prospectively investigate the associations between FD use and melanoma risk in women. E3N is a prospective cohort of 98 995 French women aged 40-65 years at inclusion in 1990. Information on use of FDs, including duration and time of administration, was assessed through self-administered questionnaires. We used Cox proportional hazards regression models adjusted for age and melanoma risk factors. Over 1990-2008, about 611 melanoma cases were ascertained among 86 653 women. Compared with never use, ever use of FDs was not associated with melanoma risk overall [hazard ratio (HR) = 1.15; 95% confidence interval (CI) = 0.75-1.74], or among parous women (HR = 1.08; 95% CI = 0.67-1.73). Among ever users of FDs, duration of use and age at first use were not associated with melanoma risk. Associations were similar after adjustment for UV exposure, although FD users were more likely to report tanning bed use than never-users (odds ratio = 1.50; CI = 1.01-2.22) in a subsample with recreational UV exposure data. Our data do not support an association between FD use and melanoma risk, but underlie the importance of taking into consideration potential confounding from sun exposure in future research.
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http://dx.doi.org/10.1097/CEJ.0000000000000532DOI Listing
March 2020

Premenopausal Use of Progestogens and Cutaneous Melanoma Risk: A French Prospective Cohort Study.

Am J Epidemiol 2020 04;189(4):314-329

We investigated the influence of premenopausal use of progestogens on melanoma using data from E3N (Etude Epidémiologique Auprès de Femmes de l'Education Nationale), a prospective cohort of 98,995 French women, aged 40-65 years at inclusion. We used Cox models to adjust for age and melanoma risk factors. Over 1992-2008, 540 melanoma cases were ascertained among 79,558 women. We found a modest association between self-reported progestogen use and melanoma risk (hazard ratio (HR) = 1.23, 95% confidence interval (CI) = 1.02, 1.47), which was reduced after adjustment for melanoma risk factors (HR = 1.15, 95% CI: 0.95, 1.39). There was no heterogeneity across types of progestogens (P = 0.22), and use of multiple progestogens was positively associated with melanoma risk (HR = 1.33, 95% CI: 1.04, 1.70). Among users, we found no relationship with duration of progestogen use, age at start and last use, and time since first and last use. Although our results did not show evidence of a confounding effect of sun exposure, progestogen users had lower levels of residential sun exposure and were more likely to report sunscreen use, suggesting specific sun exposure profiles in users. Our findings do not support a strong influence of progestogens on melanoma risk. Further research is needed to confirm these results.
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http://dx.doi.org/10.1093/aje/kwz240DOI Listing
April 2020

Exogenous hormone use and cutaneous melanoma risk in women: The European Prospective Investigation into Cancer and Nutrition.

Int J Cancer 2020 06 10;146(12):3267-3280. Epub 2019 Oct 10.

CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.

Evidence suggests an influence of sex hormones on cutaneous melanoma risk, but epidemiologic findings are conflicting. We examined the associations between use of oral contraceptives (OCs) and menopausal hormone therapy (MHT) and melanoma risk in women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a prospective cohort study initiated in 1992 in 10 European countries. Information on exogenous hormone use at baseline was derived from country-specific self-administered questionnaires. We used Cox proportional hazards regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Over 1992-2015, 1,696 melanoma cases were identified among 334,483 women, whereof 770 cases among 134,758 postmenopausal women. There was a positive, borderline-significant association between OC use and melanoma risk (HR = 1.12, 95% CI = 1.00-1.26), with no detected heterogeneity across countries (p = 0.42). This risk increased linearly with duration of use (p = 0.01). Among postmenopausal women, ever use of MHT was associated with a nonsignificant increase in melanoma risk overall (HR = 1.14, 95% CI = 0.97-1.43), which was heterogeneous across countries (p = 0.05). Our findings do not support a strong and direct association between exogenous hormone use and melanoma risk. In order to better understand these relations, further research should be performed using prospectively collected data including detailed information on types of hormone, and on sun exposure, which may act as an important confounder or effect modifier on these relations.
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http://dx.doi.org/10.1002/ijc.32674DOI Listing
June 2020

High Levels of C-Reactive Protein Are Associated with an Increased Risk of Ovarian Cancer: Results from the Ovarian Cancer Cohort Consortium.

Cancer Res 2019 10 28;79(20):5442-5451. Epub 2019 Aug 28.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Growing epidemiologic evidence supports chronic inflammation as a mechanism of ovarian carcinogenesis. An association between a circulating marker of inflammation, C-reactive protein (CRP), and ovarian cancer risk has been consistently observed, yet, potential heterogeneity of this association by tumor and patient characteristics has not been adequately explored. In this study, we pooled data from case-control studies nested within six cohorts in the Ovarian Cancer Cohort Consortium (OC3) to examine the association between CRP and epithelial ovarian cancer risk overall, by histologic subtype and by participant characteristics. CRP concentrations were measured from prediagnosis serum or plasma in 1,091 cases and 1,951 controls. Multivariable conditional logistic regression was used to estimate ORs and 95% confidence intervals (CI). When CRP was evaluated using tertiles, no associations with ovarian cancer risk were observed. A 67% increased ovarian cancer risk was found for women with CRP concentrations >10 mg/L compared with <1 mg/L (OR = 1.67; 95% CI = 1.12-2.48). A CRP concentration >10 mg/L was positively associated with risk of mucinous (OR = 9.67; 95% CI = 1.10-84.80) and endometrioid carcinoma (OR = 3.41; 95% CI = 1.07-10.92), and suggestively positive, although not statistically significant, for serous (OR = 1.43; 95% CI = 0.82-2.49) and clear cell carcinoma (OR = 2.05; 95% CI = 0.36-11.57; = 0.20). Heterogeneity was observed with oral contraceptive use ( = 0.03), where the increased risk was present only among ever users (OR = 3.24; 95% CI = 1.62-6.47). This study adds to the existing evidence that CRP plays a role in ovarian carcinogenesis and suggests that inflammation may be particularly implicated in the etiology of endometrioid and mucinous carcinoma. SIGNIFICANCE: C-reactive protein is involved in ovarian carcinogenesis, and chronic inflammation may be particularly implicated in the etiology of mucinous and endometrioid carcinomas.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-1554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801098PMC
October 2019

Mediterranean dietary pattern and skin cancer risk: A prospective cohort study in French women.

Am J Clin Nutr 2019 10;110(4):993-1002

Centre for Research in Epidemiology and Population Health (CESP) - School of Medicine, Université Paris Sud - School of Medicine, Université Versailles Saint-Quentin-en-Yvelines (UVSQ); INSERM (French National Institute for Health and Medical Research), Université Paris Saclay, Villejuif, France.

Background: The Mediterranean diet (MD) has been reported to be associated with lower cancer risk. However, while previous studies explored major single components of the MD, only 1 previous study has investigated adherence to the MD in relation to melanoma risk.

Objective: The aim of this study was to explore the relations between adherence to the MD and the risk of skin cancer, including melanomas, basal cell carcinomas (BCCs), and squamous cell carcinomas (SCCs).

Design: Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l'Education Nationale (E3N) is a prospective cohort of 98,995 French women aged 40-65 y in 1990. Dietary data were collected via a validated food questionnaire in 1993. Adherence to the MD was assessed using a 9-unit dietary score that incorporates intakes of fruit, vegetables, legumes, cereal products, olive oil, fish, dairy products, meat products, and alcohol. We used Cox proportional hazards regression models to compute HRs and 95% CIs adjusted for age and main known skin cancer risk factors.

Results: From 1993 to 2008, a total of 2003 skin cancer cases were ascertained among 67,332 women, including 404 melanomas, 1367 BCCs, and 232 SCCs. Score of adherence to the MD was associated with lower risk of skin cancer (HR: 0.83; 95% CI: 0.73, 0.93 for high compared with low score, Ptrend = 0.001). MD score was also inversely and linearly associated with risks of melanoma (HR: 0.72; 95% CI: 0.54, 0.96; Ptrend = 0.02) and BCC (HR: 0.77; 95% CI: 0.66, 0.90; Ptrend = 0.0006) but not SCC (HR: 1.08; 95% CI: 0.75, 1.55; Ptrend = 0.68), although with no heterogeneity across skin cancer types (Pheterogeneity = 0.23).

Conclusion: These findings suggest that adherence to the MD is associated with a lower skin cancer risk in women, particularly melanoma and BCC. If confirmed in future research, these findings may have important implications in skin cancer prevention.
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http://dx.doi.org/10.1093/ajcn/nqz173DOI Listing
October 2019

Reproductive and Lifestyle Factors and Circulating sRANKL and OPG Concentrations in Women: Results from the EPIC Cohort.

Cancer Epidemiol Biomarkers Prev 2019 10 10;28(10):1746-1754. Epub 2019 Jul 10.

Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.

Background: Except for a documented increase in osteoprotegerin (OPG) concentrations with older age, data on determinants of soluble Receptor Activator of Nuclear Factor κB (sRANKL) and OPG concentrations in women are limited. We evaluated reproductive and lifestyle factors as potential sources of variation in circulating sRANKL and OPG concentrations in pre- and postmenopausal women.

Methods: This study includes 2,016 controls [ = 1,552 (76%) postmenopausal, = 757 (38%) using postmenopausal hormone therapy (PMH)] from a breast cancer case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Serum sRANKL was measured using an ELISA and serum OPG using an electrochemiluminescent assay. Generalized linear models were used to evaluate associations between these analytes and reproductive and lifestyle factors.

Results: Older age at blood collection was associated with lower sRANKL concentrations in postmenopausal women ( ≤ 0.03) and higher OPG concentrations in all women ( ≤ 0.01). Longer duration of oral contraceptive use among premenopausal women and postmenopausal PMH users was associated with higher OPG ( ≤ 0.04). In postmenopausal non-PMH users, sRANKL concentrations were lower with longer duration of oral contraceptive use and current (vs. never) smoking ( ≤ 0.01). sRANKL concentrations were higher among women with higher BMI ( ≤ 0.01). The evaluated factors accounted for 12% of the variation in sRANKL concentrations and 21% of the variation in OPG concentrations.

Conclusions: Circulating sRANKL and OPG concentrations are minimally impacted by hormone-related factors in pre- and postmenopausal women.

Impact: This study suggests circulating concentrations of sRANKL and OPG are unlikely to be strongly modified by hormone-related reproductive and lifestyle factors.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0241DOI Listing
October 2019

The association between endometriosis and autoimmune diseases: a systematic review and meta-analysis.

Hum Reprod Update 2019 07;25(4):486-503

Oxford Endometriosis CaRe Centre, Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK.

Background: Endometriosis is a chronic gynaecological disorder that affects 2-10% of women of reproductive age. The aetiology of endometriosis is largely under-explored, yet abnormalities in the immune system have been suggested to explain the origin of ectopic endometrial tissues, and an association between endometriosis and autoimmune diseases has been proposed. Evaluation of current evidence investigating the association between endometriosis and autoimmune diseases from population-based studies will facilitate our understanding of the causes and consequences of endometriosis and provide a reference for better healthcare practices population-wide.

Objective And Rationale: The aim of this study was to systematically review the literature on population-based studies investigating an association between endometriosis and autoimmune diseases and to conduct a meta-analysis of combinable results to investigate the extent and robustness of evidence.

Search Methods: Four electronic databases were searched (MEDLINE, Embase, Web of Science, and CINAHL) from each database inception date until 7 April 2018. Search terms included a combination of database-specific controlled vocabulary terms and free-text terms relating to 'endometriosis' and 'autoimmune diseases'. Study inclusion criteria focused on peer-reviewed published articles that reported an association between endometriosis and autoimmune diseases, excluding case reports/series, review papers, meta-analyses, organizational guidelines, editorial letters, expert opinions, and conference abstracts. Quality assessment of included studies was performed based on GRADE criteria. Key information of eligible studies was abstracted into a standard form. Meta-analysis was performed for autoimmune diseases with combinable study results from at least three studies investigating an association with endometriosis. For cross-sectional studies and case-control studies, raw data from each study were documented to calculate a Mantel-Haenszel odds ratio with 95% CIs. For cohort studies, an inverse variance probability weighted model was used to pool study results to calculate a rate ratio (a hazard ratio or a standardized incidence rate) with 95% CIs.

Outcomes: A total of 26 published population-based cross-sectional, case-control, and cohort studies that investigated the association between endometriosis and autoimmune diseases met all eligible criteria and were included in the review. The studies quantified an association between endometriosis and several autoimmune diseases, including systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), rheumatoid arthritis (RA), autoimmune thyroid disorder, coeliac disease (CLD), multiple sclerosis (MS), inflammatory bowel disease (IBD), and Addison's disease. However, the quality of the evidence was generally poor due to the high risk of bias in the majority of the chosen study designs and statistical analyses. Only 5 of the 26 studies could provide high-quality evidence, and among these, 4 supported a statistically significant association between endometriosis and at least 1 autoimmune disease: SLE, SS, RA, CLD, MS, or IBD.

Wider Implications: The observed associations between endometriosis and autoimmune diseases suggest that clinicians need to be aware of the potential coexistence of endometriosis and autoimmune diseases when either is diagnosed. Scientists interested in research studies on endometriosis or autoimmune diseases should consider the likelihood of comorbidity when studying these two types of health conditions. Well-designed large prospective cohort studies with confounding control and mediation quantification, as well as genetic and biological studies, are needed to generate further insights into whether endometriosis is a risk factor for, or a consequence of, autoimmune diseases, and whether these two types of disorders share pathophysiological mechanisms even if they arise independently. Such insights may offer opportunities for the development of novel non-hormonal medications such as immuno-modulators or repurposing of existing immunomodulatory therapies for endometriosis.
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http://dx.doi.org/10.1093/humupd/dmz014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601386PMC
July 2019

Perfluorinated alkylated substances serum concentration and breast cancer risk: Evidence from a nested case-control study in the French E3N cohort.

Int J Cancer 2020 02 3;146(4):917-928. Epub 2019 May 3.

CESP, Fac. de médecine, Univ. Paris-Sud, Fac. de médecine - UVSQ, INSERM, Université Paris-Saclay, Villejuif, France.

Endocrine-disrupting chemicals are proposed to increase breast cancer (BC) incidence. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), two perfluorinated alkylated substances (PFASs), are suspected to be ubiquitously present in the blood of human population worldwide. We investigated the associations between serum concentrations of these substances and BC risk. Etude Epidémiologique auprès de femmes de l'Education Nationale is a cohort of 98,995 French women born in 1925-1950 and followed up since 1990. We sampled 194 BC cases and 194 controls from women with available blood samples. Serum concentrations of PFASs were measured by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Adjusted conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). All statistical tests were two sided. While PFASs concentrations were not associated with BC risk overall, we found positively linear associations between PFOS concentrations and the risk of ER+ (3rd quartile: OR = 2.22 [CI = 1.05-4.69]; 4th quartile: OR = 2.33 [CI = 1.11-4.90]); P = 0.04) and PR+ tumors (3rd quartile: OR = 2.47 [CI = 1.07-5.65]; 4th quartile: OR = 2.76 [CI = 1.21-6.30]; P = 0.02). When considering receptor-negative tumors, only the 2nd quartile of PFOS was associated with risk (ER-: OR = 15.40 [CI = 1.84-129.19]; PR-: OR = 3.47 [CI = 1.29-9.15]). While there was no association between PFOA and receptor-positive BC risk, the 2nd quartile of PFOA was positively associated with the risk of receptor-negative tumors (ER-: OR = 7.73 [CI = 1.46-41.08]; PR-: OR = 3.44 [CI = 1.30-9.10]). PFAS circulating levels were differentially associated with BC risk. While PFOS concentration was linearly associated with receptor-positive tumors, only low concentrations of PFOS and PFOA were associated with receptor-negative tumors. Our findings highlight the importance of considering exposure to PFASs as a potential risk factor for BC.
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February 2020
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