Lifetime caffeine intake and the risk of epithelial ovarian cancer

1

Introduction

Ovarian cancer, the most deadly of the gynecologic cancers [1] , is the eighth most common cancer worldwide [2] with an increasing incidence in several countries [3] . Prognosis is poor and modalities to detect disease early in the general population are limited, thus, primary prevention is important, and can be improved with knowledge of modifiable risk factors. Caffeine is one such potential factor, which is found in a variety of foods and beverages, most frequently in coffees, teas, and cola sodas [4] . Approximately 90% of the North American adult population consume caffeinated beverages daily, making this a highly prevalent exposure [4] . In two expert evaluations carried out by the International Agency for Research on Cancer, the evidence to classify the carcinogenicity of caffeine [5] and the caffeine-containing beverages coffee and maté [6] was insufficient. Caffeine may contribute to ovarian cancer risk through an influence on the cell cycle [78] , DNA repair [9] or on levels of gonadotropins [1011] or estrogen [712] . On the other hand, caffeine may play a preventive role through its antioxidant properties and ability to interfere with proinflammatory processes [1314] .

While several studies have examined intake of coffee [1516] and tea [17] in relation to ovarian cancer risk, only twelve have assessed caffeine exposure that includes intake from both coffee and non-coffee sources 181920212223242526272829 . In meta-analyses [1516] that included all but one [25] of these 12 studies, the summary relative risk (RR) estimates for the highest versus lowest intakes suggested an 11% reduced risk among the case-control studies [16] and a 10% reduced risk among the cohort studies [15] . However, in both meta-analyses, the RR estimates were significantly heterogeneous, with individual studies suggesting positive [1819] , null 222324252728] and inverse [20212629] associations with risk. Interestingly, 4 studies examining associations by menopausal status [18192425] reported an increased ovarian cancer risk with caffeine intake among premenopausal women, whereas among postmenopausal women the associations were null [182425] or less strong [19] .

Measurement of caffeine intake has been hindered in some studies, where questionnaires have not distinguished between decaffeinated vs. caffeinated coffee [202126] or tea [222628] , and only three studies included caffeine from green tea intake [192123] . Also, the time period for which caffeine intake has been assessed was often a single time point in late adulthood (i.e., in the last year before diagnosis or interview in the case-control studies or at baseline in the cohort studies). As the induction period for a potential effect of an exposure on ovarian cancer development likely occurs over decades, the measurement of exposure in most studies likely missed the etiologically relevant period.

The PRevention of OVArian Cancer in Quebec (PROVAQ) Study is a population-based case-control study that was conducted in Montreal, Canada. Using data from this study, we investigated lifetime caffeine intake in relation to epithelial ovarian cancer overall, and by menopausal status. Associations were also examined for invasive vs. borderline tumors, and for high-grade serous carcinomas (HGSC), the most common epithelial ovarian cancer type.