Introduction 1 2 3 4 6 7 8 9 10 22 18 23 24 24 22 25 29 29 29 24 24 22 25 29 30 28 29 Since only few prospective cohort studies have investigated the association between alcohol consumption, cigarette smoking, and endometrial cancer comprehensively, important features of this relationship are under-explored. Hence, we aim to provide additional evidence based on prospective data. Moreover, we intend to elucidate the hormonal mechanisms underlying endometrial carcinogenesis by investigating, first, whether BMI and age at menopause might act as intermediary variables in the association between smoking and endometrial cancer and by examining, second, whether there is evidence regarding a potential effect modification by HRT use. Materials and methods 31 32 33 n n n n Questionnaire data 34 35 34 36 Smoking was addressed at baseline by questions on age at first exposure to smoking, age at last exposure to smoking, smoking frequency, and smoking duration of cigarette, cigar, and pipe smokers. As the vast majority of smoking subcohort members was cigarette smokers, analyses were restricted to that particular group. Based on the questionnaire data, the following cigarette smoking variables were constructed: cigarette smoking status (never versus ever and never versus former or current), frequency (number of cigarettes per day), duration (years), age at first exposure (years), and time since cessation (years). Time since cessation was calculated as ‘age at baseline’ minus ‘age at smoking cessation’. 37 39 Data analysis 40 41 42 43 44 p Results The percentage of women reporting alcohol consumption was similar among cases and subcohort members (67.5% and 66.9%, respectively), as was the mean alcohol consumption per day among users in both groups (7.7 g with standard deviation (sd) = 10.8, and 8.5 g (sd = 10.4), respectively). Current smoking was less prevalent among cases than among subcohort members (15.4% vs. 21.8%), but the number of cigarettes smoked per day did not differ considerably between smokers in both groups (13.6 (sd = 8.4) and 13.2 (sd = 8.1), respectively). 1 1 Table 1 n Characteristic Unit Alcohol consumption status Cigarette smoking status n n n n n Mean (sd) Mean (sd) Mean (sd) Mean (sd) Mean (sd) Age Years 61.8 (4.3) 61.4 (4.3) 62.0 (4.3) 61.1 (4.4) 60.7 (4.1) Body Mass Index 2 25.4 (3.9) 24.9 (3.4) 25.3 (3.5) 24.7 (3.3) 24.6 (3.8) Parity Number of children 2.8 (2.4) 2.7 (2.2) 3.0 (2.4) 2.5 (1.8) 2.5 (2.1) Age at 1st child birth Years 22.0 (11.2) 21.9 (11.3) 22.2 (11.2) 22.3 (11.3) 20.8 (11.3) Age at menopause Years 48.3 (4.8) 49.2 (4.3) 49.1 (4.4) 49.2 (4.1) 48.1 (4.8) Total energy intake (including alcohol) kcal 1,628 (415) 1,724 (386) 1,694 (393) 1,676 (406) 1,705 (406) Alcohol consumption  G/day 0 (0) 8.5 (10.4) 5.7 (7.8) 10.4 (11.2) 12.5 (12.8) Cigarettes No./day 13.0 (8.8) 11.1 (8.1) 0 (0) 9.8 (8.0) 13.2 (8.1)   n a n a n a n a n a Oral contraceptive use Ever 124 (20.0) 336 (26.7) 223 (20.6) 127 (32.9) 110 (26.8) Physical activity >30 min/day 425 (69.1) 975 (77.8) 796 (74.1) 306 (79.5) 298 (72.9) Diagnosis of hypertension Yes 198 (31.4) 351 (27.6) 339 (30.8) 107 (27.7) 103 (24.9) Diagnosis of diabetes Yes 33 (5.2) 40 (3.2) 48 (4.4) 13 (3.4) 12 (2.9) Hormone replacement therapy Ever 62 (10.0) 152 (12.1) 107 (9.9) 58 (15.1) 49 (12.0) Family history of endometrial cancer Yes 20 (3.2) 32 (2.5) 23 (2.1) 16 (4.1) 13 (3.1) Alcohol users Yes – – 663 (60.3) 312 (80.6) 296 (71.5) Currently smoking cigarettes Yes 118 (18.7) 296 (23.3) – – – a Based on the literature and based on the methodological criteria specified above, we found the following confounders: age, BMI, parity, oral contraceptive use, non-occupational physical activity, hypertension, age at first child birth, and age at menopause. Alcohol consumption and cigarette smoking status were found to confound each other’s association with endometrial cancer. We controlled for all these confounders in multivariate analyses. In additional analyses, we mutually controlled the age-adjusted risk estimates regarding qualitative smoking measures for the other smoking measures. The multivariate risk estimates did not change substantially when oral contraceptive use (ever/never) was replaced by duration of oral contraceptive use (data not shown). Accordingly, we considered it sufficient to control only for oral contraceptive use (ever/never). 2 p trend  = Table 2 Rate ratios of endometrial cancer according to baseline alcohol consumption in the Netherlands Cohort Study, 1986–1997 Alcohol consumption (g/ day) Age adjusted Multivariate adjusted Categorical median Cases Person-years in subcohort a Cases Person-years in subcohort b Total alcohol     No 0 91 6,641 1 (ref.) 82 5,837 1 (ref.)     Yes 4.0 189 13,746 1.01 (0.77–1.32) 172 12,137 1.06 (0.78–1.43)     0.1–4 1.6 114 7,599 1.10 (0.82–1.48) 105 6,643 1.09 (0.78–1.52)     5–14 9.1 47 3,640 0.94 (0.65–1.37) 39 3,279 0.95 (0.62–1.45)     15–29 20.9 17 1,822 0.69 (0.40–1.18) 17 1,575 0.94 (0.52–1.69)     ≥30 37.3 11 684 1.20 (0.62–2.34) 11 639 1.78 (0.88–3.60)     p    0.49   0.62 Alcohol from wine     Yes 3.2 182 13,009 1.06 (0.81–1.37) 166 11,507 1.13 (0.84–1.52)     0.1–4 1.5 125 8,072 1.17 (0.88–1.55) 112 7,113 1.16 (0.84–1.59)     5–14 8.9 38 3,146 0.91 (0.61–1.36) 35 2,784 1.07 (0.68–1.67)     ≥15 21.8 19 1,791 0.80 (0.48–1.35) 19 1,611 1.11 (0.64–1.93)     p    0.43   0.64 Alcohol from beer     Yes 1.14 29 1,873 1.15 (0.76–1.74) 26 1,629 1.30 (0.82–2.07) Alcohol from liquor     Yes 3.7 34 2,648 0.93 (0.64–1.37) 31 2,349 1.11 (0.73–1.68) a b 2 p trend  3 3 Table 3 Rate ratios of endometrial cancer according to baseline cigarette smoking features in the Netherlands Cohort Study, 1986–1997 Cigarette smoking features Categorical median Adjusted for age Adjusted for age, current smoking status, frequency and duration of smoking Adjusted for all confounders Cases Person-years in subcohort a Cases Person-years in subcohort b Cases Person-years in subcohort c Smoking status d n.a. 187 11,872 1 (ref.) – – – 169 10,330 1 (ref.)     Ever smokers  93 8,516 0.70 (0.54–0.92) – – – 85 7,644 0.71 (0.53–0.95) d  187 11,872 1 (ref.) – – – 169 10,330 1 (ref.)     Former smokers n.a 50 4,181 0.77 (0.55–1.07) – – – 47 3,757 0.83 (0.58–1.20)     Current smokers n.a 43 4,334 0.64 (0.45–0.91) – – – 38 3,888 0.59 (0.40–0.88)     p    0.01      0.01 Frequency  cigarettes/day d 0 187 11,872 1 (ref.) 187 11,872 1 (ref.) 169 10,330 1 (ref.)     0.1–9  4 38 3,719 0.65 (0.45–0.95) 37 3,569 0.86 (0.49–1.50) 33 3,223 1.07 (0.58–1.98)     10–19  12 28 2,438 0.74 (0.48–1.14) 27 2,415 1.02 (0.54–1.92) 25 2,214 1.28 (0.66–2.46)     20+ 20 22 2,014 0.70 (0.44–1.12) 22 2,014 1.03 (0.46–2.29) 21 1,798 1.31 (0.56–3.03)     p    0.04   0.75   0.43 Duration  years d 0 187 11,872 1 (ref.) 187 11,872 1 (ref.) 169 10,330 1.0 (ref.)     0.1–19  10.5 23 2,009 0.74 (0.47–1.17) 22 1,991 0.71 (0.42–1.18) 21 1,848 0.77 (0.43–1.39)     20–39 30 52 4,274 0.79 (0.57–1.10) 51 4,120 0.80 (0.47–1.34) 47 3,690 0.89 (0.51–1.56)     40+ 41 13 1970 0.42 (0.23–0.75 13 1,887 0.44 (0.19–1.02) 11 1,697 0.37 (0.15–0.90)     p    0.00   0.10   0.13 Age at first exposure  years d n.a 187 11,872 1 (ref.) 187 11,872 1 (ref.) 169 10,330 1 (ref.)     <19 17 34 3,098 0.71 (0.48–1.05) 32 2,947 0.78 (0.34–1.80) 28 2,724 0.91 (0.37–2.23)     19–24 20 21 2,524 0.53 (0.33–0.86) 20 2,371 0.60 (0.29–1.27) 20 2,102 0.88 (0.38–2.02)     25+ 30 31 2,691 0.73 (0.49–1.09) 31 2,596 0.82 (0.47–1.46) 28 2,325 1.00 (0.53–1.87)     p    0.01   0.47   0.94 Time since cessation  years d n.a 187 11,872 1 (ref.) 187 11,872 1 (ref.) 169 10,330 1 (ref.) e 26.5 20 1,142 1.11 (0.68–1.84) 17 1,041 0.80 (0.41–1.57) 17 943 1.12 (0.52–2.41) e 14 14 1,459 0.62 (0.35–1.09) 14 1,416 0.38 (0.14–1.03) 13 1,270 0.50 (0.17–1.45) e 5 13 1,392 0.60 (0.33–1.08) 13 1,347 0.32 (0.10–1.06) 12 1,257 0.50 (0.12–2.00)     p    0.03   0.06   0.26 a b c 2 d e When we adjusted for all confounders, multivariate analysis showed a statistically significant 29% reduced risk of endometrial cancer for ever-smokers when contrasted with never-smokers. When considered separately, the risk reduction appeared to be stronger among current smokers (RR = 0.59, 95% CI = 0.40–0.88) than among former smokers (RR = 0.83, 95% CI = 0.58–1.20). Tests for trends were not significant for any of the quantitative smoking variables when these were adjusted for age and additional confounders. The strongest reduction in risk, which could be observed in both univariate and multivariate models, was associated with a smoking history of 40 or more years compared with having never smoked (RR = 0.37, 95% CI = 0.15–0.90). Moreover, we observed a non-significant 50% reduction in risk in women that quit smoking either nine or less years ago or that quit 10–19 years ago. The data indicated no association between age at first smoking exposure and endometrial cancer. p  p  p  p  p  Discussion Our results do not suggest a meaningful association between alcohol consumption and endometrial cancer risk. Current smoking is associated with a reduced risk of endometrial cancer. This inverse relationship is neither mediated by BMI nor by age at menopause. 2 2 13 15 18 3 7 8 13 17 18 23 29 25 26 28 17 45 47 26 28 17 28 29 48 50 48 17 29 47 48 17 22 28 29 45 47 48 51 29 22 25 29 26 28 47 49 28 49 24 2 2 In contrast to smoking, use of unopposed HRT increases endometrial cancer risk in postmenopausal women. Although an interaction between smoking and HRT use seems biologically plausible, the small numbers in our analysis did not allow to draw firm conclusions regarding a possible effect modification by HRT use. Moreover, we had no precise information on what type of HRT women in the NLCS have used. If we could have included such information in our analysis, results might differ according to type of HRT used. 34 33 52 40 To sum up our major findings, we found that alcohol consumption is not associated with endometrial cancer. Current smoking was associated with a reduced risk of endometrial cancer in postmenopausal women. This association was probably not mediated by a decreased BMI or by an earlier age at menopause. Larger prospective studies with information on the type of HRT are needed in order to investigate possible effect modification by different types of HRT. Possibly, the incidence of endometrial cancer could be reduced if smoking was more common in female populations; however, such a reduction would be overshadowed by a dramatically increasing incidence of many other chronic diseases. Thus, individuals should still be encouraged to quit or not to start smoking.