Caffeine, Alcohol, Smoking, and the Risk
of Incident Epithelial Ovarian Cancer
Shelley S. Tworoger, PhD1,2
Dorota M. Gertig, MBBS, ScD3,4
Margaret A. Gates, ScD1,2
Jonathan L. Hecht, MD, PhD5
Susan E. Hankinson, ScD1,2
1Channing Laboratory, Department of Medicine,
Brigham and Women’s Hospital, Harvard Medical
School, Boston, Massachusetts.
2Department of Epidemiology, Harvard School of
Public Health, Boston, Massachusetts.
3Victorian Cytology Service, Carlton South, Vic-
4Centre for Molecular, Environmental, Genetic and
Analytical Epidemiology, University of Melbourne,
Melbourne, Victoria, Australia.
5Department of Pathology, Beth-Israel Deacon-
ess Medical Center, Boston, Massachusetts.
BACKGROUND. Smoking, caffeine, and alcohol intake are all potentially modifiable
factors that have an unclear association with ovarian cancer risk. Therefore, the
associations between these exposures and ovarian cancer risk were prospectively
examined among 110,454 women in the Nurses’ Health Study (NHS) for the
smoking analyses and 80,253 women for the dietary analyses.
METHODS. Women completed biennial questionnaires assessing ovarian cancer
risk factors beginning in 1976, with food frequency questionnaires administered
every 2 to 4 years starting in 1980. For the smoking analyses, 737 confirmed cases
of epithelial ovarian cancer were identified and for the dietary aims, 507 cases
were identified through June 1, 2004.
RESULTS. Compared with never-smokers, neither current nor past smoking was
associated with ovarian cancer risk overall; however, both were associated with
mucinous tumors (n 5 69; rate ratio [RR], past 5 2.02 [95% confidence interval
(CI), 1.15–3.55]; RR, current 5 2.22 [95% CI, 1.16–4.24]). A modest inverse asso-
ciation between caffeine intake and ovarian cancer risk was observed (RR, top vs
bottom quintile 5 0.80; 95% CI, 0.60–1.07 [P 5.03]), which was strongest for
women who had never used either oral contraceptives (RR 5 0.65; 95% CI, 0.46–
0.92 [P for heterogeneity 5 .02]) or postmenopausal hormones (RR 5 0.57; 95%
CI, 0.36–0.91 [P for heterogeneity 5 .13]). Alcohol was not associated with ovarian
CONCLUSIONS. The results of the current study suggest that cigarette smoking
may only increase the risk for mucinous ovarian tumors, and alcohol intake was
not associated with risk. However, an inverse association was observed between
caffeine intake and ovarian cancer risk, particularly in women not using hor-
mones; this finding merits further study. Cancer 2008;112:1169–77. ? 2008
American Cancer Society.
KEYWORDS: ovarian cancer, caffeine, alcohol, smoking, coffee, tea, prospective.
factors are not readily modifiable. The evidence supporting the role
of more modifiable factors, such as smoking or caffeine and alcohol
intake, in ovarian cancer etiology is unclear.
A recent meta-analysis of smoking and ovarian cancer, primarily
consisting of retrospective case-control studies, reported no overall
association between smoking and ovarian cancer risk.2However,
current smokers had a 2-fold risk of mucinous tumors. Two small
prospective studies (?40 cases) and 1 larger study (n 5 454 cases)
observed a suggestive positive association with all subtypes of inva-
sive epithelial ovarian cancer incidence or mortality for current
smoking of long duration.3–5
ncreasing parity and oral contraceptive use have consistently
been inversely associated with ovarian cancer1; however, these
Address for reprints: Shelley S. Tworoger, PhD,
Channing Laboratory, Department of Medicine,
Brigham and Women’s Hospital, Harvard Medical
Boston, MA 02115; Fax: (617) 525-2008; E-mail:
Supported by National Institutes of Health Grants
P01 CA87969, CA105009, CA50385, and P50
September 13, 2007; accepted October 1, 2007.
ª2008 American Cancer Society
Published online 22 January 2008 in Wiley InterScience (www.interscience.wiley.com).
Caffeine was found to be inversely associated
with ovarian cancer risk in a large retrospective case-
control study, with an approximately 40% decrease in
risk in the top versus bottom quartile; this associa-
tion was stronger in postmenopausal women and
never oral contraceptive users.6Two other retrospec-
tive studies reported positive associations for caf-
premenopausal women.7,8Two major food contribu-
tors of caffeine—coffee and tea—have been studied
noted for both.6,8–15One prospective study reported
no association for coffee,16but a significant inverse
association for tea17; however a second smaller pro-
spective study did not find a clear association with
The association between alcohol and ovarian
cancer generally has been found to be modestly
inverse19–25or null8,14,15,26–31in case-control studies.
pooled analysis of 10 cohort studies,32have reported
no clear associations with total alcohol.33–36Associa-
tions by alcohol type have been conflicting.
To help clarify these associations, we prospec-
tively examined the association between caffeine,
alcohol intake, cigarette smoking, and ovarian cancer
risk, overall and by histologic subtype, in the Nurses’
Health Study (NHS). We also assessed whether the
associations varied by menopausal status, hormone
use, and other participant characteristics.
MATERIALS AND METHODS
The NHS cohort was established in 1976 when
121,701 U.S. female registered nurses ages 30 to
55 years completed and returned a questionnaire.
The NHS cohort has been followed by questionnaire
every 2 years since to update exposure variables and
ascertain newly diagnosed disease. Smoking history
was assessed at baseline and every questionnaire
through May 31, 2004. In 1980, we included a 61-
item food frequency questionnaire (FFQ), which was
expanded to 131 items in 1984, 1986, 1990, 1994, and
1998. We used the 1980 FFQ as the baseline for die-
tary analyses because the primary sources of caffeine
and alcohol intake were included. Follow-up for
those completing the 1980 FFQ was 97.8% of person-
years through May 31, 2004. The racial/ethnic profile
is 97% white, 2% African-American, and 1% Asian;
1% of women reported being of Hispanic origin. This
study was approved by the Committee on the Use of
Human Subjects in Research at the Brigham and
95.3% of person-years
Ascertainment of Cases
Incident cases of epithelial ovarian cancer were iden-
tified by biennial questionnaire through 2004. For
women reporting a new ovarian cancer or cases
identified via death certificate,37we obtained pathol-
ogy reports and related medical records. A gyneco-
reviewed the records to confirm the diagnosis and
identify histologic type, subtype, morphology, and
stage. We compared the histologic type from the pa-
thology report with a standardized review of pathol-
ogy slides for a subset of 215 cases. Overall, the
concordance for invasiveness was 98% and that for
histologic type was 83%; histologic type was used
from the medical record review for all cases.
For the smoking analysis, we used the 1976 baseline
cohort after excluding those: reporting any diagnosis
of cancer besides nonmelanoma skin cancer (n 5
3359); with a history of bilateral oophorectomy
(n 5 7665); with a history of pelvic irradiation (n 5
99); and missing year of birth (n 5 124), leaving
110,454 women for this analysis. For the dietary anal-
yses (1980 baseline) we excluded women who did
not respond to the dietary questionnaire in 1980 or
who had implausible dietary intakes (n 5 29,233);
other exclusions were as noted above (with 3661,
8439, 69, and 46 women excluded, respectively), leav-
ing 80,253 women for analysis. Exclusions were
On each questionnaire, women were asked whether
they were current or past smokers and the number
of cigarettes smoked per day. In 1976, smokers were
asked the age at which they commenced smoking.
Pack-years were calculated by multiplying the num-
ber of packs smoked per day by the number of years
Information regarding caffeine and alcohol con-
sumption was obtained from each FFQ. Intake of
alcohol was recorded as average frequency of use of
beer, wine, and liquor over the preceding year. The
estimated alcohol content of each beverage was 13.2 g
per bottle or can of beer, 10.8 g per glass of wine,
and 15.1 g per standard drink of liquor. Total alcohol
intake was recorded as the sum of these 3 beverages.
Caffeine consumption was calculated using U.S.
Department of Agriculture food composition sources.38–40
Respondents were asked the average frequency of
use of caffeine-containing foods and beverages,
including coffee (137 mg caffeine/cup), tea (47 mg
caffeine/cup), soda (46 mg caffeine/can or bottle),
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