Article first published online: 30 APR 2008
Copyright © 2008 Wiley-Liss, Inc.
International Journal of Cancer
Volume 123, Issue 2, pages 450–456, 15 July 2008
How to Cite
Olsen, C. M., Nagle, C. M., Whiteman, D. C., Purdie, D. M., Green, A. C. and Webb, P. M. (2008), Body size and risk of epithelial ovarian and related cancers: A population-based case-control study. Int. J. Cancer, 123: 450–456. doi: 10.1002/ijc.23509
The Australian Ovarian Cancer Study Group comprises: Management Group: D. Bowtell (Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia), G. Chenevix-Trench, A. Green, P. Webb (Queensland Institute of Medical Research, Brisbane, Queensland, Australia), A. deFazio (Westmead Hospital, Sydney, New South Wales, Australia), D. Gertig (University of Melbourne, Melbourne, Victoria, Australia).
Project Managers: N. Traficante (Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia), S. Moore (Queensland Institute of Medical Research, Brisbane, Queensland, Australia), J. Hung (Westmead Hospital, Sydney, New South Wales, Australia).
Data Managers: S. Fereday (Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia), K. Harrap, T. Sadkowsky (Queensland Institute of Medical Research, Brisbane, Queensland, Australia).
Research Nurses: New South Wales-A. Mellon, R. Robertson (John Hunter Hospital, Newcastle, Australia), T. Vanden Bergh (Royal Hospital for Women, Sydney, Australia), J. Maidens (Royal North Shore Hospital, Sydney, Australia), K. Nattress (Royal Prince Alfred Hospital, Sydney, Australia), Y.E. Chiew, A. Stenlake, H. Sullivan (Westmead Hospital, Sydney, Australia); Queensland-B. Alexander, P. Ashover, S. Brown, T. Corrish, L. Green, L. Jackman, K. Martin, B. Ranieri (Queensland Institute of Medical Research, Brisbane, Australia); South Australia-J. White (Queensland Institute of Medical Research, Brisbane, Australia); Tasmania-V. Jayde (Royal Hobart Hospital, Hobart, Australia), Victoria-L. Bowes (Peter MacCallum Cancer Centre, Melbourne, Australia), P. Mamers (Monash Medical Centre, Melbourne, Australia), Western Australia-T. Schmidt, H. Shirley, S. Viduka, Hoa Tran, Sanela Bilic, Lydia Glavinas (Western Australia Research Tissue Network, Perth, Australia).
Clinical Collaborators: New South Wales-A. Proietto, S. Braye, G. Otton (John Hunter Hospital, Newcastle, Australia); T. Bonaventura, J. Stewart (Newcastle Mater Misericordiae, Newcastle, Australia); M. Friedlander (Prince of Wales Hospital, Sydney, Australia); D. Bell, S. Baron-Hay, A. Ferrier, G. Gard, D. Nevell, B. Young (Royal North Shore Hospital, Sydney, Australia); C. Camaris, R. Crouch, L. Edwards, N. Hacker, D. Marsden, G. Robertson (Royal Hospital for Women, Sydney, Australia); P. Beale, J. Beith, J. Carter, C. Dalrymple, A. Hamilton, R. Houghton, P. Russell (Royal Prince Alfred Hospital, Sydney, Australia); A. Brand, R. Jaworski, P. Harnett, G. Wain (Westmead Hospital, Sydney, Australia); Queensland-A. Crandon, M. Cummings, K. Horwood, A. Obermair, D. Wyld (Royal Brisbane and Women's Hospital, Brisbane, Australia); J. Nicklin (Royal Brisbane and Women's Hospital and Wesley Hospital, Brisbane, Australia), L. Perrin (Royal Brisbane and Women's Hospital and Mater Misericordiae Hospitals, Brisbane, Australia), B. Ward (Mater Misericordiae Hospitals, Brisbane, Australia); South Australia-M. Davy, C. Hall, T. Dodd, T. Healy, K. Pittman (Royal Adelaide Hospital, Burnside Memorial Hospital, Adelaide, Australia); D. Henderson, S. Hyde (Flinders Medical Centre, Adelaide, Australia); J. Miller, J. Pierdes (Queen Elizabeth Hospital, Adelaide, Australia); Tasmania-P. Blomfield, D. Challis, R. Mclntosh, A. Parker (Royal Hobart Hospital, Hobart, Australia); Victoria-B. Brown, R. Rome (Freemasons Hospital, Melbourne, Victoria, Australia); D. Allen, P. Grant, S. Hyde, R. Laurie, M. Robbie (Mercy Hospital for Women, Melbourne, Victoria, Australia), D. Healy, T. Jobling, T. Maniolitas, J. McNealage, P. Rogers, B. Susil, A. Veitch, J. Constable, S. Ping Tong, I. Robinson, I. Simpson (Monash Medical Centre, Melbourne, Australia); K. Phillips, D. Rischin, P. Waring, M. Loughrey, N. O'Callaghan, Bill Murray (Peter MacCallum Cancer Centre, Melbourne, Australia); V. Billson, S. Galloway, J. Pyman, M. Quinn (Royal Women's Hospital, Melbourne, Australia); Western Australia-I. Hammond, A. McCartney, Y. Leung (King Edward Memorial Hospital, St John of God, Perth, Australia).
Scientific Collaborators: I. Haviv (Peter MacCallum Cancer Centre, Melbourne, Australia); D. Purdie, D. Whiteman (Queensland Institute of Medical Research, Brisbane, Australia); N. Zeps (Western Australia Research Tissue Network, Perth, Australia).
Investigators are: A.C. Green, P.G. Parsons, N. Hayward, P. Webb, D. Purdie and D. Whiteman (Queensland Institute of Medical Research, Brisbane, Australia).
- Issue published online: 15 MAY 2008
- Article first published online: 30 APR 2008
- Manuscript Accepted: 30 JAN 2008
- Manuscript Received: 16 OCT 2007
- National Health and Medical Research Council (NHMRC). Grant Number: 199600
- US Army Medical Research and Material Command. Grant Number: DAMD17-01-1-0729
- Cancer Council Tasmania
- Cancer Foundation of Western Australia
- ovarian cancer;
- body weight;
- body mass index
Different subtypes of ovarian cancer appear to have different causes; however, the association between body mass index (BMI) and the different subtypes is unclear. We examined the associations between body-mass index (BMI) and weight gain and risk of the different histological subtypes of epithelial ovarian cancer in a case-control study in Australia. Cases aged 18–79 with a new diagnosis of invasive epithelial ovarian cancer (n = 1,269) or borderline tumor (n = 311) were identified through a network of clinics and cancer registries throughout Australia. Controls (n = 1,509) were selected from the Electoral Roll. Height and weight (1 year previously, at age 20 and maximum weight) and other risk factor information were ascertained via a self-administered questionnaire. Obesity was positively associated with clear cell tumors (Odds Ratio 2.3; 95% confidence interval 1.2–4.2) but not invasive endometrioid or mucinous tumors. Although there was no association with invasive serous tumors overall (0.9; 0.7–1.2), we did see an increased risk of serous peritoneal tumors (2.9; 1.7–4.9), but not of serous tumors of the ovary and fallopian tube. Of the borderline subtypes, obesity was positively associated with serous (1.8; 1.1–2.8) but not mucinous tumors (1.1; 0.7–1.7). Overweight was not associated with any subtype overall. There was no association with BMI at age 20, or weight gain for any of the histological subtypes. These results add to the current evidence that obesity increases a woman's risk of developing distinct histological subtypes of ovarian cancer. © 2008 Wiley-Liss, Inc.
A recent systematic review and meta-analysis of the association between body weight or body mass index (BMI) and ovarian cancer concluded that there is a modest association between high adult BMI and epithelial ovarian cancer.1 However, most studies reviewed had combined the histological subtypes of ovarian cancer despite some known differences in risk factors,2–4 with relatively few studies reporting results for the different histological subtypes of ovarian cancer.5–12 Obesity is a well-established risk factor for endometrial cancer13 and as histologically similar endometrioid tumors also occur in the ovary,14 it could be hypothesized that obesity would also be a strong risk factor for this subtype of ovarian cancer. However, while 2 previous studies9, 15 observed an increased prevalence of overweight amongst women with the endometrioid subtype of ovarian cancer, others have failed to confirm this finding.6–8
Since obesity early in life has been positively associated with other hormone-dependent cancers, and inversely associated with premenopausal breast cancer,16, 17 and adult weight gain has been positively associated with of breast18 and endometrial cancer,19 it is relevant to evaluate the association between BMI in early adulthood, weight gain and risk of ovarian cancer. Only one previous study12 has examined the possible links between BMI in early adulthood by subtype of ovarian cancer, but analysis was limited to the most common serous subtype. Three case-control studies5, 20, 21 and 3 cohort studies12, 22, 23 have examined the association between weight gain from early adulthood and risk of ovarian cancer; however, only one study5 examined the association for the histological subtypes of ovarian cancer; they observed an increased risk of the serous and mucinous subtypes among nulliparous women only.
Three7, 8, 21 of 4 studies7, 8, 12, 21 that have examined the risks of ovarian cancer associated with obesity separately for pre- and postmenopausal women have reported higher risk estimates associated with high BMI among premenopausal women. In contrast high BMI has consistently been shown to be positively associated with post- but not premenopausal breast cancer,24, 25 and it has been hypothesized that this increased risk of breast cancer in postmenopausal women is mediated through oestrogenic effects.26 The relationship between BMI and menopausal status has not been examined for the different histological subtypes of ovarian cancer.
In this report, we describe a detailed analysis of self-reported body size during adult life in relation to risk of the major histological subtypes of ovarian cancer using data collected from an Australia-wide, population-based case-control study. We also examined these associations by menopausal status, parity and use of hormone replacement therapy (HRT) (postmenopausal women). We conducted analyses for all invasive serous tumors combined, and then separately by cancer site, ovary and fallopian tube combined, and peritoneum, because previous research suggested that serous cancers of the peritoneum may differ aetiologically from serous cancers of the ovary and fallopian tube.27
Material and methods
The Australian Ovarian Cancer Study was an Australia-wide population-based case-control study of epithelial ovarian cancer. Cases were women aged 18–79 years living in Australia with newly diagnosed histologically confirmed epithelial ovarian, fallopian tube or primary peritoneal cancer in the period between January 2002 and June 2005. Cases were recruited by nurses who liaised with the treatment clinics, physicians and state cancer registries throughout Australia.
Of 3,553 women identified with suspected ovarian cancer (most women were approached prior to surgery and thus prior to histological diagnosis), 304 died before contact could be made, physicians refused to give consent to contact 133, usually because they were too sick or unable to give informed consent, and 194 women could not be contacted. A further 167 (5%) were excluded on the basis of language difficulties, (70) mental incapacity (33) and illness (64). The remaining 2,755 women were invited to participate and, of these, 2,319 (84%) agreed to take part. Two researchers independently abstracted information on tumor site, histological subtype and tumor behavior (invasive vs. borderline) from the diagnostic histopathology reports and discrepancies were resolved by consensus. For a sample of 200 women, the pathology reports and full set of diagnostic slides were reviewed by a gynecologic pathologist and complete agreement with the original abstracted data was >95% for tumor subtype and site, and 99% for tumor behavior. Following the histopathology review, 624 women were excluded because their final diagnosis was not confirmed as epithelial ovarian cancer, and 10 because their cancer was first diagnosed before the start of the study period. Of the final 1,685 eligible participants, 1,580 (94%) returned a questionnaire.
Controls were randomly selected from the national electoral roll (enrolment is compulsory) and were frequency matched by age (in 5-year age bands) and state of residence to the case group. Selected women were mailed an invitation letter and information brochure explaining the study and then, where possible, followed up by telephone. Of the 3,600 women contacted and invited to participate, 158 were excluded due to illness (n = 61) or language difficulties (n = 97). Of the 3,442 remaining women, 1,612 (47%) agreed to participate and returned a completed questionnaire. Six of them reported a history of ovarian cancer and 97 reported a previous bilateral oophorectomy and thus were excluded from the present study leaving 1,509 population controls.
The study was approved by the ethics committees (institutional review boards) of the Queensland Institute of Medical Research, Peter MacCallum Cancer Centre and all participating hospitals and cancer registries.
After obtaining written informed consent, information was collected by a self-administered questionnaire that included questions about demographic, medical, hormonal, reproductive, diet, family history and other potential risk factors for ovarian cancer. Exposures were assessed prior to a reference date, defined as 1 year before the date of diagnosis for cases (date of first approach for controls). Women self-reported height, weight 1 year ago, weight at age 20 years, maximum nonpregnant weight and age at maximum nonpregnant weight.
Body mass index (BMI), calculated as weight in kilograms divided by the square of height in meters (kg/m2) was classified using the World Health Organization (WHO) definitions of obesity (<18.5 “underweight”; 18.5–24.9 “normal weight”; 25–29.9 “overweight”; and ≥30 “obese”).28 Weight gain was calculated as the difference between maximum adult weight and weight at age 20 years. For analysis, 5 categories were created: loss of any amount or gain of less than 5 kg (reference category), gain of 5–9.9 kg, gain of 10–19.9 kg, gain of 20–29.9 kg and gain of 30 or more kg. To examine the effects of weight loss we categorized women as never overweight, overweight at both maximum and recent weight and overweight at maximum weight but normal weight 1 year ago. For this analysis, we excluded women who reported that their maximum weight occurred more recently than 5 years prior to diagnosis (to exclude women who may have gained or lost weight due to preclinical disease).
Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI). Multivariable logistic regression models were used to adjust for potential confounders, including age at diagnosis/first approach (in 10 year age-groups as this was found to give the most effective control for confounding by age), state of residence, education (secondary school, technical college/apprenticeship, university), parity (0, 1–2, 3 or more pregnancies of ≥6 months duration), hormonal contraceptive use (none, <60 months, ≥60 months use), perineal talc use, history of hysterectomy or tubal sterilization, family history of breast or ovarian cancer in a 1st degree relative, smoking (current, ex-, never), breastfeeding (ever, never), menopausal status (pre, peri, post) and level of recreational physical activity (high, medium, low). We entered covariates individually into the models and also in combination. Only those factors that changed the point estimate of the BMI-related variable of interest by more than 10% were included in the final models. BMI 1 year ago was assessed as a potential confounder in the analyses for BMI at age 20 years and weight gain. Tests for trend were based on ordered continuous variables.
We conducted subgroup analyses to assess the interaction between menopausal status (premenopausal or postmenopausal) and BMI, parity (0, 1–2, 3 or more pregnancies of ≥6 month's duration) and BMI, and HRT use (postmenopausal women) and BMI. The statistical significance of any observed stratum-specific differences was assessed by including a cross-product term in regression models. We classified women as postmenopausal if they reported natural or medical menopause before the reference date. Women who were perimenopausal or for whom menopausal status could not be determined were excluded from this stratified analysis.
All analyses were performed separately by tumor behavior (invasive and borderline) and subtype. We conducted analyses for all invasive serous tumors combined, and then separately by cancer site: ovary and fallopian tube combined, and peritoneum. All statistical analyses were performed using SAS version 9.1 (SAS Institute, Cary, NC).
Based on histopathology review, 1,269 women had invasive cancer classified as follows: serous 846 (67%), endometrioid 138 (11%), clear cell 88 (7%), mucinous 44 (3%) and mixed histopathology 153 (12%). A further 311 women had borderline (low malignant potential) tumors classified as serous 152 (49%), mucinous 147 (47%) and other 12 (4%). Cases with mixed histopathology (and also “other” borderline cases) were excluded from the analyses. Serous invasive cases included 128 primary peritoneal cancers, 680 tumors of the ovary or fallopian tube, and a further 38 tumors for which the primary site could not be identified (these women were excluded from the analyses by cancer site). Table I describes the characteristics of the study participants. Cases with invasive or borderline mucinous tumors and borderline serous tumors were younger than controls (mean 50.9 years, 49.4 years and 50.6 years respectively, vs. 56.4 years for controls). In general, cases were more likely to be nulliparous and less likely to have used oral contraceptives than controls. There was a higher percentage of current smokers amongst the borderline cases compared to the control group of women that persisted after adjustment for age (23% for serous, 30% for mucinous vs. 11% for controls).
|Risk factor||Controls1n = 1509 n (%)||Invasive1||Borderline1|
|Serous (n = 846)||Endometrioid (n = 138)||Clear cell (n = 88)||Mucinous (n = 44)||Serous (n = 152)||Mucinous (n = 147)|
|n (%)||n (%)||n (%)||n (%)||n (%)||n (%)|
|Age2 (mean, SD)||56.4 (12.4)||60.8 (10.2)||57.5 (10.2)||58.3 (10.3)||50.9 (14.5)||50.6 (13.4)||49.4 (13.6)|
|Highest level of education|
|School||735 (49)||477 (57)||65 (47)||54 (61)||20 (45)||79 (52)||70 (48)|
|Technical college/trade||550 (36)||254 (30)||49 (36)||24 (27)||15 (34)||49 (32)||56 (38)|
|University||218 (14)||109 (13)||22 (16)||9 (10)||9 (20)||23 (15)||21 (14)|
|0 fullterm births||181 (12)||111 (13)||33 (24)||31 (35)||10 (23)||37 (25)||40 (27)|
|1–2 fullterm births||644 (43)||343 (41)||52 (38)||35 (40)||22 (50)||67 (45)||57 (39)|
|≥3 fullterm births||683 (45)||390 (46)||53 (38)||22 (25)||12 (27)||46 (30)||49 (34)|
|Hormonal contraceptive use|
|Never||330 (22)||292 (35)||48 (35)||35 (40)||6 (14)||27 (18)||27 (19)|
|<5 years||357 (24)||232 (28)||42 (31)||24 (28)||12 (27)||43 (30)||42 (29)|
|≥5 years||812 (54)||314 (37)||47 (34)||28 (32)||26 (59)||75 (52)||76 (52)|
|Premenopausal||398 (26)||116 (14)||33 (24)||13 (15)||21 (48)||58 (39)||67 (46)|
|Perimenopausal||108 (7)||47 (5)||11 (8)||5 (6)||1 (2)||16 (11)||11 (7)|
|Postmenopausal||1002 (67)||683 (81)||94 (68)||70 (79)||22 (50)||76 (50)||69 (47)|
|History of tubal ligation||406 (27)||212 (25)||19 (14)||15 (17)||8 (18)||40 (27)||31 (21)|
|History of hysterectomy||289 (19)||210 (25)||31 (22)||16 (18)||6 (14)||30 (20)||35 (24)|
|Ever use of talc in the perineum||667 (45)||420 (50)||68 (49)||38 (44)||15 (34)||72 (48)||69 (48)|
|Ever use of HRT3||597 (40)||382 (45)||55 (40)||28 (32)||9 (20)||56 (37)||37 (25)|
|Non-smoker||899 (60)||509 (60)||82 (60)||65 (74)||24 (55)||66 (44)||63 (43)|
|Ex-smoker||437 (29)||215 (26)||40 (29)||10 (11)||9 (20)||49 (33)||39 (27)|
|Current smoker||165 (11)||121 (14)||15 (11)||13 (15)||11 (25)||35 (23)||44 (30)|
|Family history of breast or ovarian cancer in a 1st degreerelative||195 (13)||170 (20)||23 (17)||13 (15)||6 (14)||20 (13)||14 (10)|
Overall, obesity, as defined by recent weight was not significantly positively associated with invasive tumors (OR 1.1; 95% CI 0.9–1.4), but was with borderline tumors (OR 1.4; 95% CI 1.03–1.97). When we considered the different histological subtypes separately, obesity was positively associated with clear cell tumors (OR 2.3; 95% CI 1.2–4.2) but not invasive endometrioid or mucinous tumors (Table II). Although there was no association with invasive serous tumors overall (OR 0.9; 95% CI 0.7–1.2), we did see an increased risk of serous peritoneal tumors (OR 2.9; 95% CI 1.7–4.9), but not of serous tumors of the ovary and fallopian tube (OR 0.8; 95% CI 0.6–1.0) (Table III). Of the borderline subtypes, obesity was positively associated with serous (OR 1.8; 95% CI 1.1–2.8) but not mucinous tumors (OR 1.1; 95% CI 0.7–1.7) (Table II). Being overweight (BMI 25–29.9 kg/m2) 1 year ago was not associated with any subtype overall, however again an increased risk was observed for serous peritoneal tumors (OR 2.2; 95% CI 1.3–3.6). Similar results were seen for maximum BMI.
|Risk factor||Controls2n = 1509||Invasive2||Borderline2|
|Serous (n = 846)||Endometrioid (n = 138)||Clear cell (n = 88)||Mucinous(n = 44)||Serous (n = 152)||Mucinous (n = 147)|
|OR (95% CI)||OR (95% CI)||OR (95% CI)||OR (95% CI)||OR (95% CI)||OR (95% CI)|
|BMI 1yr ago|
|<18.5||32||0.9 (0.4–1.7)||0.8 (0.2–3.5)||2.8 (0.7–11.0)3||0.4 (0.1–3.1)||0.5 (0.1–2.4)|
|25–29.9||435||1.2 (1.0–1.5)||1.3 (0.8–2.0)||1.5 (0.8–2.8)||0.9 (0.4–2.1)||1.4 (0.9–2.2)||0.9 (0.6–1.4)|
|≥30||334||0.9 (0.7–1.2)||1.2 (0.7–1.9)||2.3 (1.2–4.2)||1.5 (0.7–3.1)||1.8 (1.1–2.8)||1.1 (0.7–1.7)|
|Trend p = 0.95||Trend p = 0.16||Trend p = 0.09||Trend p = 0.36||Trend p = 0.04||Trend p = 0.92|
|<18.5||9||0.4 (0.1–1.9)||1.5 (0.2–12.6)4||3.2 (0.3–30.6)3||1.0 (0.1–8.9)||0.5 (0.1–4.8)3|
|25–29.9||525||1.0 (0.8–1.3)||1.1 (0.7–1.7)||1.5 (0.8–2.7)||0.7 (0.3–1.5)||1.2 (0.8–1.9)||0.9 (0.6–1.4)|
|≥30||474||0.9 (0.7–1.2)||1.1 (0.7–1.7)||1.7 (1.0–3.2)||0.9 (0.4–1.9)||1.6 (1.0–2.5)||1.1 (0.7–1.7)|
|Trend p = 0.40||Trend p = 0.58||Trend p = 0.46||Trend p = 0.81||Trend p = 0.08||Trend p = 0.79|
|BMI age 20|
|<18.5||215||0.9 (0.7–1.2)||0.9 (0.5–1.5)||1.0 (0.5–1.9)3||1.8 (0.8–3.9)||1.2 (0.7–2.0)||1.1 (0.6–1.9)3|
|25–29.9||120||1.1 (0.8–1.5)||1.1 (0.6–2.1)||1.8 (0.9–3.7)||0.9 (0.3–3.1)||0.8 (0.4–1.7)||1.4 (0.8–2.5)|
|≥30||40||0.7 (0.4–1.3)||1.1 (0.4–3.3)||0.6 (0.1–4.9)||2.4 (0.7–8.8)||2.0 (0.9–4.5)||1.6 (0.7–3.7)|
|Trend p = 0.84||Trend p = 0.37||Trend p = 0.88||Trend p = 0.74||Trend p = 0.35||Trend p = 0.67|
|Weight gain (kg)|
|loss or gain of <5 (ref)||154||1.0||1.0||1.0||1.0||1.0||1.0|
|5–9.9||253||0.8 (0.6–1.2)||1.0 (0.5–2.1)||0.9 (0.3–2.7)||0.8 (0.2–2.8)||1.2 (0.5–2.5)||1.1 (0.5–2.3)|
|10–19.9||522||0.9 (0.7–1.3)||0.7 (0.3–1.5)||1.1 (0.4–3.0)||1.0 (0.3–3.2)||1.2 (0.6–2.4)||1.3 (0.7–2.7)|
|20–29.9||280||1.1 (0.8–1.7)||1.1 (0.5–2.4)||1.1 (0.4–3.5)||0.6 (0.1–2.3)||0.8 (0.4–2.0)||1.7 (0.7–3.8)|
|≥30||252||0.9 (0.6–1.4)||0.7 (0.3–1.8)||1.2 (0.4–4.2)||0.9 (0.2–3.7)||1.2 (0.5–2.9)||1.2 (0.5–2.9)|
|Trend p = 0.46||Trend p = 0.69||Trend p = 0.66||Trend p = 0.81||Trend p = 0.96||Trend p = 0.98|
|Risk factor||Ovary and fallopian tube (n = 680)2||Peritoneal (n = 128)2|
|Controls||Cases||OR (95% CI)||Cases||OR (95% CI)|
|BMI 1 yr ago|
|<18.5||32||9||0.7 (0.3–1.5)||4||3.0 (0.9–9.3)|
|25–29.9||435||217||1.1 (0.9–1.4)||43||2.2 (1.3–3.6)|
|≥ 30||334||116||0.8 (0.6–1.0)||40||2.9 (1.7–4.9)|
|Trend p = 0.28||Trend p = 0.0006|
|25–29.9||525||248||1.0 (0.8–1.2)||45||1.5 (0.9–2.5)|
|≥30||474||183||0.8 (0.6–1.0)||55||2.1 (1.3–3.5)|
|Trend p = 0.20||Trend p = 0.002|
|BMI age 20|
|<18.5||215||94||0.9 (0.7–1.2)||11||0.5 (0.3–1.0)|
|25–29.9||120||55||1.1 (0.8–1.6)||11||1.1 (0.6–2.2)|
|≥30||40||11||0.7 (0.3–1.3)||3||1.0 (0.3–3.4)|
|Trend p = 0.48||Trend p = 0.10|
|Weight gain (kg)|
|Loss of gain <5 (ref)||154||72||1.0||11||1.0|
|5–9.9||253||91||0.8 (0.5–1.2)||13||0.8 (0.3–1.9)|
|10–19.9||522||233||1.0 (0.7–1.4)||33||0.7 (0.3–2.0)|
|20–29.9||280||152||1.2 (0.8–1.8)||29||0.8 (0.3–2.0)|
|≥30||252||92||0.9 (0.6–1.5)||32||0.8 (0.3–2.0)|
|Trend p = 0.41||Trend p = 0.87|
Significant effect modification by menopausal status was observed for the association between BMI 1 year ago and risk of serous tumors of the ovary or fallopian tube (p = 0.04). After stratifying by menopausal status, it appeared that high BMI was not positively associated with serous tumors of the ovary and fallopian tube in post-menopausal women, however there was a suggestion of an increased risk for pre-menopausal women (Table IV). There was no appreciable effect modification by menopausal status for any other histological subtype (data not shown), though the small sample size in some groups limited our power to detect statistically significant variation. We found no effect modification by parity or use of HRT (postmenopausal women) for any of the histological subtypes of invasive ovarian cancer.
|Controls2 (n = 397)||Cases2 (n = 105)||OR (95% CI)||Controls2 (n = 1004)||Cases2 (n = 536)||OR (95% CI)|
|BMI 1 yr ago|
|<18.5||14||1||0.3 (0.1–2.7)3||18||8||0.8 (0.4–2.0)|
|18.5–24.9||205||47||1.0 (ref)||385||214||1.0 (ref)|
|25–29.9||85||33||2.4 (1.4–4.3)||314||174||1.0 (0.8–1.3)|
|≥30||77||20||1.5 (0.8–2.8)||233||87||0.7 (0.5–0.9)|
|Trend p = 0.09||Trend p = 0.11|
|18.5–24.9||171||39||1.0 (ref)3||288||173||1.0 (ref)|
|25–29.9||108||33||1.5 (0.9–2.7)||377||204||0.9 (0.7–1.2)|
|≥30||110||33||1.7 (1.0–3.0)||325||135||0.7 (0.5–0.9)|
|Trend p = 0.29||Trend p = 0.07|
|BMI age 20|
|<18.5||40||7||0.5 (0.2–1.3)3||166||85||1.0 (0.7–1.4)|
|18.5–24.9||303||85||1.0 (ref)||712||365||1.0 (ref)|
|25–29.9||35||10||1.2 (0.5–2.7)||72||38||1.0 (0.7–1.6)|
|≥30||11||2||1.1 (0.2–5.8)||26||9||0.7 (0.3–1.4)|
|Trend p = 0.10||Trend p = 0.22|
After adjustment for potential confounders, there was little evidence for an association between high BMI at age 20 years and any of the histological subtypes of ovarian cancer, although obesity at age 20 years was associated with a nonsignificant increased risk of invasive and borderline mucinous tumors, and also borderline serous tumors (Table II). It should be noted that the number of women in the obese category at age 20 is small. Adjusting for recent BMI slightly attenuated the relationships. There was also no association between weight gain and any of the histological subtypes (Table II). We also examined relative weight gain (i.e., as a percentage of weight at age 20) but again found no association (results not presented). There was no effect modification by menopausal status or parity for BMI at age 20 or weight gain for any of the histological subtypes.
For the histological subtypes where high BMI was identified as a significant risk factor (invasive serous peritoneal and clear cell tumors, and borderline serous tumors) we examined whether the risk varied for women who had been overweight or obese but had a normal body weight 1 year ago compared to those who remained overweight or obese. The excess risk was restricted to women who were overweight or obese at their maximum weight and remained overweight (OR 1.6, 95% CI 1.0–2.5). The small number of women who were overweight or obese at their maximum weight, but whose BMI was in the “normal” range 1 year prior to diagnosis (19 cases and 110 controls) had a similar cancer risk to women who were never overweight (OR 1.0, 95% CI 0.5–1.9).
In this large population-based study, obesity occurring either recently or in the past (at maximum lifetime weight) was not associated with invasive endometrioid or mucinous tumors, but was positively associated with invasive clear cell tumors. Although there was no association with invasive serous tumors overall, we did see an increased risk of serous peritoneal tumors, but not of serous tumors of the ovary and fallopian tube. Of the borderline tumors, obesity was positively associated with the serous but not the mucinous subtype. When we examined invasive serous tumors by cancer site, we observed an increased risk of serous peritoneal cancers associated with overweight/obesity but not of serous tumors of the ovary and fallopian tube. We observed no association with weight at age 20 years, or weight gain from age 20 years for any of the histological subtypes.
Previous epidemiological studies evaluating the relation between obesity and the different histological subtypes of ovarian cancer have given inconsistent results. Six population-based case-control studies,5–10 2 cohort studies11, 12 and 1 pooled analysis of 10 case-control studies29 have previously examined the association between adult BMI and risk of the major histological subtypes of ovarian cancer; the findings of these studies are summarized in a recent systematic review.1 Three studies reported increased risks associated with the highest category of BMI for the serous subtype5, 8, 9 whilst 5 other studies6, 7, 10–12 and the pooled analysis29 found no association. Unlike the present study, previous investigators did not examine serous tumors by site of origin. The present study also found no association with invasive serous tumors overall, however stratification by site of origin and by menopausal status showed a positive association between high BMI and serous peritoneal tumors and also serous tumors of the ovary and fallopian tube in premenopausal women only. Although serous peritoneal cancer is histologically indistinguishable from serous ovarian carcinoma and the clinical presentation is similar,30 epidemiological27 and molecular studies31, 32 have provided evidence of differences between these cancers that may reflect distinct carcinogenic pathways. We have previously reported similar risk factors for serous tumors of the ovary and fallopian tube and a divergent risk factor profile for serous peritoneal tumors.27 Molecular studies have suggested that whilst serous ovarian cancers are clonal in origin,33 serous peritoneal cancers have a multifocal origin.31, 34 Other molecular genetic evidence for divergence derives from studies of allelic loss.32
Some previous studies have reported a positive association between high BMI and the endometrioid subtype of ovarian cancer5, 9, 15 although for 1 of these studies5 the increased risk was seen for nulliparous women only. Others have failed to confirm this finding.6–8 Despite the strong association between obesity and endometrioid endometrial cancer,35 we observed no association between increasing BMI and the endometrioid subtype of ovarian cancer with no effect modification by menopausal status or parity. We did, however, observe an increased risk associated with both BMI 1 year ago and BMI at maximum lifetime weight for the clear cell subtype of ovarian cancer. This finding is consistent with one6 of 3 previous studies5, 6, 8 We can only speculate as to why we observed a relationship between obesity and the clear cell subtype but not the endometrioid subtype. Histologically similar tumors also occur in the endometrium, and both the oestrogen-sensitive type I endometrial tumors (which are mostly endometrial adenocarcinomas) and type II tumors (including papillary, serous, and clear cell adenocarcinomas) have been associated with obesity,35 although the association was more pronounced for Type 1 tumors. The clear cell and endometrioid subtypes of ovarian cancer have been shown to share many of the same risk factors,2, 36, 37 and have both been associated with endometriosis,38, 39 but there is emerging evidence that differences exist in their aetiology,29 gene expression profiles40 molecular pathogenesis41, 42 and clinical behavior including response to chemotherapy.43, 44 The endocrine consequences of obesity may therefore have differential effects on the pathogenesis of these different subtypes of ovarian cancer. In line with most previous studies that have examined the relationship between obesity and risk of the mucinous subtype of ovarian cancer,1 we found no significant association.
We observed no association between weight gain from age 20 years and any of the histological subtypes of ovarian cancer. Three previous studies have reported modest but nonsignificant increased risks for the highest category of weight gain,20, 22, 23 whilst 2 others12, 21 reported nonsignificant inverse associations between weight gain and risk of ovarian cancer. Greer et al.5 found a significant increased risk in the highest quartile of weight gain for the serous and mucinous subtypes, but not the endometrioid or clear cell subtypes. Interestingly, we observed a potential protective effect of weight loss over time on risk of the histological subtypes where high BMI was identified as a significant risk factor (invasive serous peritoneal and clear cell tumors, and borderline serous tumors of the ovary and fallopian tube). For these tumors we found that the increased risk associated with being obese at maximum weight was nullified if that weight was then lost. Although our analyses were based on small numbers of cases and thus need confirmation, this has important public health implications, since almost all other known risk factors for ovarian cancer are nonmodifiable.
Several biological mechanisms have been proposed to explain the increased risk of hormone-related cancers associated with obesity and these include alterations in endogenous sex hormone levels (oestrogen, progesterone and androgens) and insulin-mediated pathways.26 Obesity is associated with increased insulin levels, which lead to increases in the insulin-like growth factor-1 (IGF-I)26 and high levels of IGF-I have been associated with breast and prostate cancers.45, 46 Endogenous hormones are believed to be involved in the aetiology of ovarian cancer,47 and obesity is a well-established risk factor for 2 other hormone-related cancers in women, namely postmenopausal breast cancer25, 48–51 and endometrial cancer.13, 52, 53
Like our results for invasive serious ovarian cancer, other studies have reported that the risk associated with obesity was higher in premenopausal than in postmenopausal women.1 This result deserves further exploration, since postmenopausal but not premenopausal obesity is associated with higher levels of endogenous oestrogen.45 It is therefore unlikely that endogenous oestrogen levels are responsible for the increased risk of ovarian cancer observed in obese premenopausal women, and other hormonal factors should be considered. There is a significant body of evidence suggesting that androgens may increase ovarian cancer risk while progesterone plays a protective role.47 Compared to women of “normal” weight, premenopausal obese women have reduced serum progesterone levels54 but, although there is some evidence that obesity is associated with increased levels of free testosterone in both premenopausal55 and postmenopausal women,56 the relationship between obesity and serum androgens is less clear.
Strengths of our study include the population-based design, large number of cases and detailed information on multiple exposures. A limitation was the relatively low participation rate among controls (47%) which could have resulted in selection bias and an overrepresentation of more health-conscious control women who are less likely to be overweight or obese. However, a comparison with data from the Australian National Health Survey (NHS) conducted in 2004 (a representative survey of the Australian adult population),57 revealed that the distributions of education level, parity and BMI among our control women were almost identical to those from the NHS,58 and it is therefore unlikely that nonresponse could have resulted in appreciable bias. We relied on retrospective self-reported height, weight, and weight history information and recall of body size from different periods of time, particularly during earlier life is subject to error. Research has also shown that women with higher BMI are more likely to underestimate weight, whereas underweight women are more likely to overestimate body weight.59–62 This might have led to non differential misclassification which would have attenuated the true association between obesity and ovarian cancer.
In summary, these results add to the current evidence that obesity increases a woman's risk of developing distinct histological subtypes of ovarian cancer. Previous reports of weak or null associations between BMI and risk of ovarian cancers overall may mask significant associations for specific subtypes. Further large studies are required to confirm these subtype-specific associations.
David Whiteman and Penelope Webb are supported by Senior Research Fellowships from the National Health and Medical Research Council of Australia and Queensland Cancer Fund, respectively. Catherine Olsen is supported by a University of Queensland Postdoctoral Fellowship. The authors acknowledge the cooperation of the New South Wales, Queensland, South Australian, Victorian and Western Australian Cancer Registries as well as all the collaborating institutions represented within the AOCS Study Group (below). The authors thank all of the women who participated in the study.
- 14Surface epithelial–stromal tumors of the ovary. In: KurmanRJ, ed. Blaustein's pathology of the female genital tract,4th edn. New York: Springer-Verlag, 1994. 705–82..
- 57Australian Bureau of Statistics (ABS). 2004–05 National Health Survey: summary of results, vol. Cat. No. 4364. Australia: Australian Bureau of Statistics, 2006. 92.