IJC International Journal of Cancer

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1 IJC International Journal of Cancer Cigarette smoking and risk of histological subtypes of epithelial ovarian cancer in the EPIC cohort study Inger T. Gram 1,2, Annekatrin Lukanova 3, Ilene Brill 4, Tonje Braaten 1, Eiliv Lund 1, Eva Lundin 5, Kim Overvad 6, Anne Tjønneland 7, Francoise Clavel-Chapelon 8,9, Nathalie Chabbert-Buffet 10, Christina Bamia 11, Antonia Trichopoulou 11,12, Dimosthenis Zylis 11,12, Giovanna Masala 13, Franco Berrino 14, Rocco Galasso 15, Rosario Tumino 16, Carlotta Sacerdote 17,18, Oxana Gavrilyuk 1, Steinar Kristiansen 1, Laudina Rodríguez 19, Catalina Bonet 20, José María Huerta 21,22, Aurelio Barricarte 23,24, Maria-José Sánchez 22,25, Miren Dorronsoro 26, Karin Jirström 27, Martin Almquist 28, Annika Idahl 29,30, H. Bas Bueno-de-Mesquita 31,32, Marie Braem 33, Charlotte Onland-Moret 33, Konstantinos K. Tsilidis 34, Naomi E. Allen 34, Veronika Fedirko 35, E. Riboli 36 and Rudolf Kaaks 3 1 Institute of Community Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway 2 Norwegian Centre for Integrated Care and Telemedicine, University Hospital of North Norway, Tromsø, Norway 3 Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany 4 Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL 5 Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden 6 Department of Epidemiology, School of Public Health, Aarhus University, DK-8000 Aarhus C, Denmark 7 Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark 8 Inserm, Centre for Research in Epidemiology and Population Health, U1018, Institut Gustave Roussy, F-94805, Villejuif, France 9 Paris South University, UMRS 1018, F-94805, Villejuif, France 10 Ob-Gyn Department, APHP Hospital Tenon and UMR S_938 University P and M Curie, Paris, France 11 WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece 12 Hellenic Health Foundation, Athens, Greece 13 Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Ponte Nuovo, Via delle Oblate n.2, Florence, Italy 14 Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy 15 Istituto di Ricovero e Cura a Carattere Scientifico - Centro di Riferimento Oncologico di Basilicata, Unit of Clinical Epidemiolgy, Biostatistics and Cancer Registry, Rionero in Vulture, Italy 16 Cancer Registry and Histopathology Unit, Civile M.P.Arezzo, Hospital ASP 7, Ragusa, Italy 17 Center for Cancer Prevention (CPO-Piemonte), Torino, Italy 18 Human Genetic Foundation, (HuGeF), Torino, Italy 19 Public Health and Participation Directorate, Health and Health Care Services Council, Asturias, Spain 20 Unit of Nutrition, Environment and Cancer, Catalan Institute of Oncology, Barcelona, Spain 21 Department of Epidemiology, Murcia Regional Health Authority, Murcia, Spain 22 CIBER Epidemiología y Salud Pública (CIBERESP), Spain 23 Navarra Public Health Institute, Pamplona, Spain 24 Consortium for Biomedical Research in Epidemiology and Public Health, Spain 25 Andalusian School of Public Health, Granada, Spain 26 Epidemiology and Health Information, Public Health Division of Gipuzkoa, Basque Regional Health Department, Avda. San Sebastian, Spain 27 Department of Clinical Sciences, Pathology, Lund University, Skåne University Hospital, Lund, Sweden 28 Department of Surgery, University Hospital Lund, Lund, Sweden 29 Department of Public Health and Clinical Medicine, Nutritional Research, Umeå University, Umeå, Sweden 30 Department of Clinical Sciences, Obstetris and Gynecology, Umeå University, Umeå, Sweden 31 National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands 32 Department of Gastroenterology and Hepatology, University Medical Centre Utrecht (UMCU), Utrecht, The Netherlands 33 Julius Center for Health Sciences and Primary Care, University Medical Centre Utrecht (UMCU), Utrecht, The Netherlands 34 Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom 35 International Agency for Research on Cancer, Lyon, France 36 Department of Cancer Epidemiology and Prevention, School of Public Health, Imperial College, London, United Kingdom Key words: ovarian cancer, smoking, mucinous, serous, EPIC cohort Abbreviations: BMI: body mass index; CI: confidence interval; EOC: epithelial ovarian cancer; EPIC: European Prospective Investigation into Cancer and Nutrition; HR: hazard ratio; HT: hormone therapy; IARC: International Agency for Research on Cancer; OC: oral contraceptive DOI: /ijc History: Received 13 Apr 2011; Accepted 26 May 2011; Online 15 Jun 2011 Correspondence to: Inger Torhild Gram, Institute of Community Medicine, University of Tromsø, N-9037 Tromsø, Norway, Tel.: þ[ ], Faxþ[ ], inger.gram@uit.no

2 Gram et al New data regarding a positive association between smoking and risk of epithelial ovarian cancer (EOC), especially the mucinous tumor type, has started to emerge. The purpose of this study was to examine the association between different measures of smoking exposures and subtypes of EOC in a large cohort of women from 10 European countries. The European Prospective Investigation into Cancer and Nutrition (EPIC) cohort is a multicenter prospective study initiated in The questionnaires included data about dietary, lifestyle, and health factors. Information about cigarette smoking was collected from individuals in all participating countries. We used Cox proportional hazard regression models to estimate hazard ratio (HR) of EOC overall and serous, mucinous, and endometroid histological subtypes, with 95% confidence intervals (CIs) associated with different measures of smoking exposures adjusting for confounding variables. Altogether 836 incident EOC cases were identified among 326,831 women. The tumors were classified as 400 serous, 83 mucinous, 80 endometroid, 35 clear cell, and 238 unspecified. Compared with never smokers, current smokers had a significantly increased risk for mucinous tumors [HR (95% CI )] and those smoking more than 10 cigarettes per day had a doubling in risk [HR (95% CI )] as did those who had smoked less than 15 pack-years of cigarettes [HR (95% CI )]. The results from the EPIC study add further evidence that smoking increases risk of mucinous ovarian cancer and support the notion that the effect of smoking varies according to histological subtype. Ovarian cancer is the fifth most common cancer among women in Europe with an estimated number of 67,000 (4.5%) new cases, and the sixth most common cause of cancer death with an estimated number of 42,000 (5.5 %) deaths in Except for the well-established protection by parity and oral contraceptive use, relatively little is known about other factors that may influence the risk of developing the disease. 2,3 In 2004, the Monograph on Tobacco smoke and involuntary smoking from the International Agency for Research on Cancer (IARC) reported that there was insufficient evidence to draw conclusions regarding the possible effect of smoking on ovarian cancer risk. 4 However, new data regarding a positive association between smoking and risk of epithelial ovarian cancer (EOC), especially with the mucinous tumor type, have started to emerge. A systematic review from 2006, 5 including a meta-analysis on the association of smoking and ovarian cancer, with data from one cohort study 6 and 18 case control studies, showed a significant twofold increased risk of mucinous tumors among current compared with never smokers. Since then, three 7 9 cohort and two case control 10,11 studies have examined the relationship between smoking and histological subtypes of EOC, all supporting the notion that the histologic subtypes of EOC may represent different entities. In the most recent summary statement from IARC in 2009, both colorectal cancer and mucinous EOC are reported as new tumor sites for which there is sufficient evidence to list tobacco smoke as a cause of carcinogenicity in humans. 12 The purpose of this study was to examine the association between different measures of smoking exposures and subtypes of EOC in a large cohort of women from 10 European countries. Material and Methods The European Prospective Investigation into Cancer and Nutrition (EPIC) cohort population and the procedures of data collection have been described elsewhere. 13 In brief, approximately 370,000 women and 150,000 men were recruited between 1992 and 2000 from 23 centers in 10 European countries (France, Italy, Spain, United Kingdom (UK), The Netherlands, Greece, Germany, Sweden, Denmark, and Norway). Approval for the study was obtained from the local ethics committees in the participating countries and the internal review board of the International Agency for Research on Cancer. The following women were excluded: 19,707 with prevalent cancer other than nonmelanoma skin cancer, 2,209 with incomplete follow-up data, 10,500 with bilateral oophorectomy, 28 with a nonepithelial ovarian cancer, 509 lacking baseline questionnaire, and 8,209 with missing information on smoking status, leaving 326,831 women in the analytical cohort. Incident cancer cases were identified through linkage to population cancer registries in Denmark, Italy, The Netherlands, Spain, Sweden, UK, and Norway, or using a combination of methods including linkage to health insurance records, cancer and pathology registries, and active follow-up of study participants or their next of kin in France, Germany, and Greece. Invasive and borderline surface epithelial-stromal ovarian tumors were referred to as EOC. They were further categorized according to histology as serous, mucinous, endometroid, clear cell, and others, including those with unspecified/missing information. The baseline questionnaires elicited the following information on cigarette smoking: smoking status at baseline (current, former, or never), age started smoking, age quitting (former smokers), number of cigarettes per day currently smoked (current smokers), and number of cigarettes smoked per day during different periods of life. Based on this information, the following variables were calculated; duration of smoking in years, defined as the current age (or age at quitting for former smokers) minus age at start, intensity of smoking, as the lifetime average number of cigarettes smoked and pack-years of smoking as the lifetime average number of cigarettes smoked multiplied by the number of years smoked

3 2206 Smoking and subtypes of ovarian cancer divided by 20 (1 pack ¼ 20 cigarettes). For former smokers, the number of years since quitting was calculated as the difference between current age and the age at which they quit smoking. The questionnaires also asked about lifestyle and reproductive factors. Information on body height and body weight was collected allowing us to calculate body mass index (BMI) as weight in kilograms divided by height in meters squared. Statistical analysis We used T-Test and v 2 test for differences in distribution of selected characteristics between cases/non-cases and between current and never smokers and current and former smokers. We used the Cox proportional hazards model with age as the underlying time scale to estimate multivariate adjusted hazard ratios (HR) with 95% confidence intervals associated with different measures of smoking exposure for EOC overall, serous, mucinous, and endometroid tumors, with never smokers as the reference group. Entry time was defined as age at recruitment and exit time was age at diagnosis of EOC, the date of any incident cancer (except basal cell carcinoma) diagnosis, death, or the end of follow-up, whichever occurred first. All models were stratified by recruitment center to control for center effects such as follow-up procedures and questionnaire design and age at recruitment (in 1-year interval) to account for duration of follow-up. Each of the following factors was evaluated as a potential confounder of the relation between cigarette smoking and EOC: four levels of education (none or primary school, technical or professional, secondary school, university degree), postmenopausal (yes/no), age at menopause (premenopausal/ perimenopausal, postmenopausal: 45, 46 50, 51 52, >52), parous (yes/no), number of full-term pregnancies (0, 1, 2, 3, 4þ), ever oral contraceptive (OC) use(yes/no), duration of OC use (never; ever: 4, 5 9, 10 years), ever postmenopausal hormonal therapy (HT) use (yes/no), duration of HT use (never, ever: 4, 5þ), nondrinkers (yes/no), life-time alcohol consumption in grams per day (0,<5, 5þ), simple hysterectomy (yes, no), unilateral ovariectomy (yes/no), fertility problems (yes/no), and BMI (in quartiles). For each covariate missing values were assigned to separate categories. We included number of full-term pregnancies and duration of OC use as established risk factors for EOC in the multivariate model. After including these covariates, none of the factors listed above changed the HR estimates materially and was therefore not included in the final models. Tests for linear trend were obtained by creating an ordinal exposure variable with equally spaced scores and including it in the model. We tested for heterogeneity between different histological tumor types with Wald chi-square statistics. Two-sided p-values <0.05 were considered statistically significant. All analyses were conducted using the SAS version 9.2 (SAS Institute, Cary, North Carolina, USA). Results Altogether 836 incident EOC (87% invasive, 8% borderline, and 5% unclassified) cases were identified during a median follow-up time of 8.8 years. The tumors were classified as 400 (47.8%) serous, 83 (9.9%) mucinous, 80 (9.6%) endometroid and 35 (4.2%) clear cell, while 238 (28.5%) cases were undefined, not otherwise specified or had missing data on histology. EOC cases were older, had less years of education, were more likely to be postmenopausal, and if so older at menopause. Cases were younger at age of last birth, were less likely to have a history of ever OC use, and duration of OC use was shorter among ever users compared with noncases. Cases were more likely to be ever HT users, duration of HT use was longer among ever users, they reported to be heavier, and to consume less alcohol compared with noncases (all p s <0.05; data not shown). Women with mucinous tumors were younger at enrolment and at diagnosis, fewer were postmenopausal and fewer were ever HT users compared with those with serous tumors (all p s <0.05; data not shown). Forty-three percent of the women reported being ever smokers. Current smokers were younger at enrolment and at diagnosis of ovarian cancer and compared with never smokers more were postmenopausal and menopause was reached at an earlier age, on average. Compared with never smokers, current smokers also had fewer children and a lower BMI and were more likely to be ever users of OC and HT, and to be longterm users for both medications. Fewer current smokers were non-drinkers, and current smokers had higher average alcohol consumption compared with never smokers. Compared with former smokers, current smokers reported to have smoked on average more cigarettes per day, on a lifetime basis, and for more years (all p-values <0.001; data not shown). Table 1 shows that current smokers had an 85% increased risk of mucinous [HR ¼ 1.85 (95% CI )], while both former [HR ¼ 0.83 (95% CI )] and current [HR ¼ 0.58 (95% CI )] smokers had a nonsignificantly decreased risk of endometroid tumors compared with never smokers. Compared with never smokers, current smokers, and those smoking more than 10 cigarettes per day had a doubling in risk [HR ¼ 2.25 (95% CI )] of mucinous tumors as did those who had smoked less than 15 pack-years of cigarettes [HR ¼ 2.18 (95% CI )]. No consistent dose response relationship was found between the different measures of smoking exposure and the histological subtypes (Table 1). The multivariate adjusted HR s for current versus never smokers did not differ significantly between mucinous and serous (p for heterogeneity ¼ 0.06) while it did for mucinous and endometroid tumors (p for heterogeneity ¼ 0.009). Discussion Our study finds that current smokers have an increased risk of mucinous EOC compared with never smokers. We Int. J. Cancer: 130, (2012) VC 2011 UICC

4 Gram et al Table 1. Multivariate 1 adjusted hazard ratio (HR) estimates of epithelial ovarian cancer with 95% confidence intervals (CI) overall and histological subtype among smokers compared with never smokers: The EPIC Cohort Study All tumors (N 5 836) Serous (N 5 400) Mucinous (N 5 83) Endometroid (N 5 80) Smoking status Cases/Noncases HR CI Cases HR CI Cases HR CI Cases HR CI Never 479/184, (ref) (ref) (ref) (ref) Former 193/75, Current 164/65, Trend test 2 p Former Age started smoking 20þ < Trend test 2 p Smoking duration (years) þ Trend test 2 p Life time number of cigarettes per day þ Trend test 2 p Pack-years of smoking þ Trend test 2 p Time since quitting (years) þ Trend test 2 p Current Age started smoking 20þ < Trend test 2 p < Smoking duration (years) þ Trend test 2 p Life time number of cigarettes per day þ Trend test 2 p Current number of cigarettes per day þ Trend test 2 p <

5 2208 Smoking and subtypes of ovarian cancer Table 1. Multivariate 1 adjusted hazard ratio (HR) estimates of epithelial ovarian cancer with 95% confidence intervals (CI) overall and histological subtype among smokers compared with never smokers: The EPIC Cohort Study (Continued) All tumors (N 5 836) Serous (N 5 400) Mucinous (N 5 83) Endometroid (N 5 80) Smoking status Cases/Noncases HR CI Cases HR CI Cases HR CI Cases HR CI Pack years of smoking þ Trend test 2 p Stratified by center and age, adjusted for number of full-term pregnancies and duration of oral contraceptives use, all at enrolment. 2 Includes never smokers. 3 Women from Sweden and France excluded due to missing data on this variable. observed a doubling in risk among those smoking more than 10 cigarettes daily as well as among those who had smoked less than 15 pack-years of cigarettes. However, we did not reveal any consistent dose response relationship between the different measures of smoking exposure and mucinous tumors. The present study has the largest numbers of cases among all prospective cohort studies so far that focused on the relationship between smoking and EOC. The prospective design, the large sample size, the classification according to histological subtype, and the relatively large proportion of women being ever smokers at enrolment are strengths of our study. Data on daily smoking were standardized across study centers, and data on a wide range of potential confounders was also collected in a similar way. The fact that known risk factors for ovarian cancer differed between cases and non-cases in the expected way clearly indicates high internal validity of our cohort study. A remaining limitation of this study, in spite of the very large cohort size overall, is the small number of ovarian cancer cases by histological subtype. Other limitations are that borderline tumors were clearly under-reported and that for a rather large proportion of cases histological subtype data was missing. We did not have information on changes in smoking habits during follow-up, but we find it likely that any misclassification of smoking exposure and tumor histology will have attenuated the reported associations. Although we adjust for potential confounders, we cannot rule out the presence of residual confounding. The four cohort studies summarized in Table 2 also had fewer than 100 mucinous cases. 6 9 The Canadian Study 6 reported a significant doubling in risk of mucinous tumors among current smokers, while the Nurses Health Study I 8 found an association of this magnitude among both former and current compared with never smokers. In a subsequent report, 9 which included the Nurses Health Study I & II, these associations were no longer significant and were of similar magnitude as those reported from Scandinavia by Gram et al. 7 (Table 2). The results from the present study are in agreement with those of the other cohort studies and contribute to strengthening the evidence. The previously mentioned meta analysis, including a total of 910 women with mucinous and 5,564 with non-mucinous ovarian cancers, found that the risk of mucinous tumors among current smokers increased with increasing amount smoked but returned to that of never smokers within years of quitting smoking, while current smokers had a risk estimate close to unity for serous and a nonsignificantly decreased risk of endometroid tumors. 5 The two more recent case control studies 10,11 also found that smokers had a significantly increased risk of mucinous and a nonsignificant decrease in risk of endometroid tumors. Emerging data on molecular features do support the hypothesis that mucinous EOC is different from other subtypes. Differences in genetic alterations that have been found as mucinous have a significantly higher prevalence of KRAS mutation and a lower frequency of BRCA and p53 abnormalities compared with serous tumors. These subtypes have also been found to differ in gene expression analyses and in immunohistochemical studies. 14 Gene expression studies have shown that mucinous and endometorid histotypes of EOC correlated with changes in normal colonic mucosa and endometrium, respectively. 15 We have previously found that smoking increased the risk of colorectal cancer in both the Norwegian Women and Cancer Study 16 and EPIC cohorts. 17 Furthermore, we have observed a reduced risk of endometrial cancer with smoking among postmenopausal and an increased risk among premenopausal women, in another report from the EPIC study. 18 Our finding suggesting that smoking may influence mucinous and endometroid EOC in opposite direction is supported by the significant test for heterogeneity, although this may still be due to chance, given the relatively small numbers of ovarian cancer cases by histological sub-type. The available data obtained from past decades show that DNA adduct formation is a key step in tobacco carcinogenesis. 19 Benzo(a) pyrene [B(a)p] is a potent carcinogen present in cigarettes that acts locally. 20 B(a)p adducts have been found in ovarian follicular cells among women exposed to cigarette smoke. Presence of these adducts may increase the risk for DNA damage through a direct carcinogenic effect. 21 This supports the biological plausibility of a positive association between smoking and any of the subtypes of EOC. The results of the current study lend further support to the heterogeneity of epithelial ovarian cancer and that

6 Gram et al Table 2. Previous cohort studies of cigarette smoking and histological type of epithelial ovarian cancer (EOC) First author, study year, (Ref.) country All tumors, N, Smoking status RR 1 (95%CI) Serous RR 1 (95%CI) Mucinous RR 1 (95%CI) Endometroid RR 1 (95%CI) Terry, N ¼ 454 2, N ¼ N ¼ 32 2 N ¼ , Never (6) Ref Ref Ref Ref Canada Former ( ) ( ) ( ( ) Current ( ) ( ) ( ) ( ) Gram, N ¼ N ¼ N ¼ 55 3 NA 2008 Never (7) Ref Ref Ref Norway Former /Sweden ( ) ( ) ( ) Current ( ) ( ) ( ) Tworoger, N ¼ NA 69 3 NA 2008 Never (8), NHS I Ref Ref USA Former ( ) ( ) Current < 15/d 1.08 ( ) Current 15/d 1.06 ( ) ( ) Gates, N ¼ N ¼ N ¼ 84 3 N ¼ Never (9 ) Ref Ref Ref Ref NHS I & II Former USA ( ) ( ) ( ) ( ) Current ( ) ( ) ( ) ( ) 1 Multivariate adjusted. 2 Invasive tumors. 3 Include invasive and borderline tumors. 4 Includes all current smokers. smoking may influence the subtypes differently. It will take many years before the respective cohorts have enough cases to explore these associations in greater detail. To better understand the risks revealed in the meta-analyses of case controls studies, 5 we suggest a pooling of the available data from the cohort studies together with new updates of EOC cases. Acknowledgements The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue contre le Cancer, Mutuelle Générale de l Education Nationale, Institut National de la Santé et de la Recherche Medicale (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); Ministry of Health and Social Solidarity, Stavros Niarchos Foundation and Hellenic Health Foundation (Greece); Sicilian Government, AIRE-ONLUS Ragusa, AVIS-Ragusa, Italian Association for Research on Cancer (AIRC) and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF); Statistics Netherlands (The Netherlands); Norwegian Cancer Society (Norway); Health Research Fund (FIS), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council and Regional Government of Skåne and Västerbotten (Sweden); Cancer Research UK, Medical Research Council UK (United Kingdom).

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