Flavonoids and ovarian cancer risk: A case–control study in Italy
Article first published online: 19 MAY 2008
Copyright © 2008 Wiley-Liss, Inc.
International Journal of Cancer
Volume 123, Issue 4, pages 895–898, 15 August 2008
How to Cite
Rossi, M., Negri, E., Lagiou, P., Talamini, R., Dal Maso, L., Montella, M., Franceschi, S. and La Vecchia, C. (2008), Flavonoids and ovarian cancer risk: A case–control study in Italy. Int. J. Cancer, 123: 895–898. doi: 10.1002/ijc.23549
- Issue published online: 12 JUN 2008
- Article first published online: 19 MAY 2008
- Manuscript Accepted: 15 FEB 2008
- Manuscript Received: 21 DEC 2007
- ovarian cancer;
- case–control study;
- risk factors
Flavonoids belong to a vast group of polyphenols widely distributed in all foods of plant origin. Because of their antioxidant, antimutagenic and antiproliferative properties, they have been hypothesized to contribute to the favorable effects of fruit and vegetables against cancer. The aim of this study is to investigate the relation of 6 classes of flavonoids (flavan-3-ols, flavanones, flavonols, flavones, anthocyanidins and isoflavones) with ovarian cancer risk, using data from a multicentric case–control study conducted in Italy between 1992 and 1999. The study included 1,031 cases with incident, histologically confirmed epithelial ovarian cancer and 2,411 controls admitted for acute, nonneoplastic conditions to major hospitals in the same catchment areas. In logistic regression models including study center, education, year of interview, parity, oral contraceptive use and family history of ovarian or breast cancer or both, an inverse relation with significant trend in risk was found between ovarian cancer and flavonols [odds ratio (OR), 0.63; 95% confidence intervals (CI) 0.47–0.84] as well as isoflavones (OR, 0.51; 95% CI, 0.37–0.69), comparing the highest versus the lowest quintile. Further adjustment for fruit and vegetable intake did not modify these associations, suggesting that isoflavones and flavonols may have a distinct role in explaining the effect of fruit and vegetable against ovarian cancer. On the basis of our findings and the relevant literature, we infer that isoflavones, and perhaps flavonols, may have favorable effects with respect to ovarian cancer risk. © 2008 Wiley-Liss, Inc.
Flavonoids belong to a vast group of polyphenols that are widely distributed in all foods of plant origin such as fruit, vegetable, tea and wine.1, 2 Originally known only for their role in plant pigmentation, flavonoids have been shown to have antioxidant, antimutagenic and antiproliferative properties in vitro3–5 and have thus been hypothesized to contribute to the favorable effects of fruit and vegetable against various chronic diseases including cancer.6–9 Recently, the availability of detailed and reliable food composition tables for flavonoids published by the US Department of Agriculture on their 6 major classes (flavan-3-ols, flavanones, flavonols, flavones, anthocyanidins and isoflavones)10, 11 has allowed epidemiological studies to further investigate the role of flavonoids in cancer etiology. Intake of various flavonoids has been inversely related to the risk of cancers of the upper aerodigestive tract,12–14 stomach,15, 16 colorectum,17 urinary tract18, 19 and breast.20–22 As concerns ovarian cancer, of particular interest are isoflavones given their antiestrogenic effects.23
The aim of this study is to investigate the relation of 6 major classes of flavonoids and total flavonoids with ovarian cancer risk, using data from a large multicentric case–control study conducted in Italy.24
Material and methods
Data were derived from a case–control study of ovarian cancer conducted between January 1992 and September 1999 in 4 Italian areas: the greater Milan area and the provinces of Pordenone, Gorizia and Padua in northern Italy, the province of Latina in central Italy and the urban area of Naples in southern Italy.24 Briefly, cases were 1,031 women (median age 56, range 18–79 years) admitted to the major teaching and general hospitals in the areas under study with incident, histologically confirmed epithelial ovarian cancer. Controls were 2,411 women (median age 57, range 18–79 years) admitted to the same network of hospitals as the cases for acute, nonmalignant and nongynecological conditions, unrelated to hormonal or digestive tract diseases or to long-term modifications of diet. Of these, 26% were admitted for traumas, 28% for nontraumatic orthopedic disorders, 15% for surgical conditions and 31% for miscellaneous other illnesses including eye, ear, nose, throat and dental disorders. Less than 4% of cases and controls approached refused interview.
Centrally trained interviewers administered a standard questionnaire to cases and controls during their hospital stay. The questionnaire included information on sociodemographic factors and life-style habits, anthropometric variables, history of cancer in first-degree relatives, menstrual and reproductive factors, use of oral contraceptives (OC) and hormone replacement therapy. The subjects' usual diet during 2 years before cancer diagnosis or hospital admission was investigated by means of a reproducible and valid food frequency questionnaire (FFQ).25, 26 The FFQ included 78 foods or food groups, plus questions aimed at assessing fat intake and general dietary habits. Subjects were asked to indicate their average weekly consumption of single food items or food groups. Information on occasional intakes, i.e., lower than once a week but at least once per month, was also collected. This was arbitrarily coded as 0.5 per week. Frequencies were translated into daily consumption of each food item or beverage category, and these quantities were converted into average daily intakes of 6 classes of flavonoids (flavan-3-ols, flavanones, flavonols, anthocyanidins, flavones and isoflavones), as well as their total. Food and beverage content of flavonoids were obtained from the US Department of Agriculture databases,10, 11 integrated with other sources.27, 28 Major flavonoids included in these classes were epicatechin and catechin for flavan-3-ols, hesperitin and narigerin for flavanones, quercetin, myricetin and kaempferol for flavonols, cyanidin and malvidin for anthocyanidins, apigenin and luteolin for flavones, and genistein and daidzein for isoflavones. In our control population, flavan-3-ols came mainly from tea, apples, pears and wine; flavanones from oranges and other citrus fruits; flavonols from apples, pears and various common vegetables; anthocyanidins from wine, strawberries, cherries and onions; flavones from cooked vegetables and tea; and isoflavones from soya and bean soups (Table I). Total flavonoids were calculated by summing up the 6 classes. Estimates for energy were based on a Italian food composition database, appropriately checked and supplemented with other published data.29, 30
|Flavonoids||Principal flavonoid food sources|
|Flavan-3-ols||Tea (50%)||Apples and pears (20%)||Wine (15%)|
|Flavanones||Citrus fruit (88%)||Fruit juice (11%)|
|Flavonols||Apples and pears (16%)||Fennels (16%)||Mixed vegetable salad (12%)|
|Anthocyanidins||Wine (46%)||Strawberries and cherries (37%)||Onions (7%)|
|Flavones||Spinaches and Swiss chards (29%)||Vegetable and bean soups (17%)||Tea (15%)|
|Isoflavones||Soya milk (45%)||Soya (21%)||Vegetable and bean soups (12%)|
|Total flavonoids||Citrus fruit (28%)||Tea (22%)||Apples and pears (11%)|
We computed energy-adjusted flavonoid intakes using the residual method suggested by Willett and Stampfer.31 The energy-adjusted flavonoid intakes were categorized into approximate quintiles based on the controls distribution, and the corresponding odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional multiple logistic regression models.32 All models included terms for age (quinquennia, categorically), study center (categorically), education (<7, 7–11, ≥12 years, categorically), year of interview (single years), parity (0, 1–2, >2, categorically), OC use (ever vs. never use), and family history of ovarian or breast cancer or both in first-degree relatives (0, ≥1). Tests for trend for quintiles of flavonoids were based on the likelihood ratio test between the models with and without a linear term for flavonoid quintile.
In Table II, cases and controls are distributed by quintiles of energy-adjusted classes of flavonoids and total flavonoids in the diet. Median daily intake and the upper cutoff points of quintiles among controls are given. The median daily intake was 34.7 mg for flavan-3-ols, 33.6 mg for flavanones, 17.3 mg for flavonols, 9.3 mg for anthocyanidins, 0.4 mg for flavones, 20.6 μg for isoflavones and 111.0 mg for total flavonoids.
|Flavonoids||Median||Quintile of intake|
|Upper cutoff point||34.7||16.3||28.3||42.7||77.0||–|
|Cases||262 (25.4)2||205 (19.9)||170 (16.5)||219 (21.2)||175 (17.0)|
|Upper cutoff point||33.6||12.2||31.3||36.6||67.0||–|
|Cases||195 (18.9)||216 (21.0)||192 (18.6)||189 (18.3)||239 (23.2)|
|Upper cutoff point||17.3||11.6||15.4||20.0||28.8||–|
|Cases||292 (28.3)||214 (20.8)||183 (17.7)||200 (19.4)||142 (13.8)|
|Upper cutoff point||9.3||3.5||7.4||12.3||19.4||–|
|Cases||238 (23.1)||174 (16.9)||191 (18.5)||211 (20.5)||217 (21.0)|
|Upper cutoff point||0.4||0.3||0.4||0.5||0.7||–|
|Cases||242 (23.5)||224 (21.7)||216 (21.0)||182 (17.6)||167 (16.2)|
|Upper cutoff point||20.6||12.8||17.8||23.5||32.5||–|
|Cases||238 (23.1)||269 (26.1)||226 (21.9)||190 (18.4)||108 (10.5)|
|Total flavonoids (mg/day)|
|Upper cutoff point||111.0||67.3||97.2||127.5||173.6||–|
|Cases||241 (23.4)||233 (22.6)||188 (18.2)||170 (16.5)||199 (19.3)|
Table III gives the ORs for ovarian cancer according to quintiles of intake. An inverse relation was found for flavonols (OR for the highest versus the first quintile, 0.63; 95% CI, 0.47–0.84) and isoflavones (OR, 0.51; 95% CI, 0.37–0.69). No significant association emerged for total flavonoids (OR, 1.07; 95% CI, 0.82–1.40), as well as flavan-3-ols (OR, 0.89; 95% CI, 0.67–1.17), flavanones (OR, 1.28; 95% CI, 0.98–1.68), anthocyanidins (OR, 0.99; 95% CI, 0.76–1.29) and flavones (OR, 0.79; 95% CI, 0.60–1.04). A significant trend in risk was observed for isoflavones (p-trend < 0.001), as well as for kaempferol (OR, 0.63, 95% CI, 0.48–0.84; p-trend < 0.001). Further adjustment for fruit and vegetable intake did not modify these associations: the ORs for flavonols and isoflavones became 0.66 (95% CI, 0.49–0.88) and 0.46 (95% CI, 0.33–0.64), respectively.
|Flavonoids||Quintile of intake, OR||χ2 trend|
|Flavan-3-ols||1||0.81 (0.62–1.05)3||0.73 (0.55–0.96)||0.92 (0.71–1.19)||0.89 (0.67–1.17)||0.23 [0.63]4|
|Flavanones||1||1.22 (0.93–1.60)||0.99 (0.75–1.31)||1.07 (0.81–1.41)||1.28 (0.98–1.68)||1.44 [0.23]|
|Flavonols||1||0.78 (0.60–1.01)||0.65 (0.50–0.85)||0.88 (0.67–1.14)||0.63 (0.47–0.84)||6.89 [0.009]|
|Anthocyanidins||1||0.74 (0.56–0.98)||0.90 (0.68–1.18)||1.02 (0.79–1.34)||0.99 (0.76–1.29)||0.68 [0.41]|
|Flavones||1||0.91 (0.70–1.19)||0.95 (0.73–1.24)||0.87 (0.66–1.15)||0.79 (0.60–1.04)||2.62 [0.11]|
|Isoflavones||1||1.12 (0.87–1.45)||0.93 (0.71–1.21)||0.85 (0.64–1.12)||0.51 (0.37–0.69)||19.51 [<0.001]|
|Total flavonoids||1||1.03 (0.80–1.34)||0.94 (0.72–1.24)||0.80 (0.61–1.06)||1.07 (0.82–1.40)||0.12 [0.72]|
Since only intake of isoflavones after the fourth quintile (more than 32.5 μg) appeared to have a protective effect against ovarian cancer, we have also computed the ORs for subjects in the highest quintile of consumption compared with those in the 4 lowest ones combined overall (OR, 0.52; 95% CI, 0.40–0.68) and in strata of selected covariates. No substantial differences were observed across strata of age, menopausal status, parity, education and body mass index. Likewise, the inverse relation between flavonols and ovarian cancer risk was consistent across strata of these covariates (data not shown).
The results of this study indicate that isoflavones and flavonols are inversely related to ovarian cancer risk. No relation was found for other classes of flavonoids and total flavonoids.
In line with our findings, intake of isoflavones was associated with a lower risk in a United States cohort study including 280 incident ovarian cancers (relative risk 0.56 for more than 3 mg/day vs. less than 1 mg/day of intake),33 and in a Chinese case–control study based on 254 cases and 652 controls (OR 0.51 for more than 32.8 mg/day vs. less than 11.6 mg/day of intake).34 Another cohort study from the US, which included 347 women with incident ovarian cancer, reported a significant 40% decrease in ovarian cancer incidence for the highest versus the lowest quintile of kaempferol (a flavonol), in broad agreement with our results.35 No significant associations were found for flavonols in a case–control study from the US.36 In accordance with what we report here, however, no relation for catechin (a flavan-3-ol) was found in the Iowa Women cohort.37 It appears that despite differences in populations and study design, food components and sources in various countries, and levels of intake, the results of various studies on flavonoids in relation to ovarian cancer are largely consistent.
Foods rich in isoflavones, including tea and soya, have been hypothesized to have a role in ovarian cancer,34, 38–40 in particular in Asia, where the consumption of these foods is high and they have been often associated with a lower incidence of hormone-related cancers compared to Western countries.41 Also in our population, isoflavones are derived mainly from soya, beans and pulses. Their intake is much lower than in Asia34 but also lower than in the USA,33 because of the rarity in the Italian diet of some foods appreciably richer in isoflavones than beans and pulses, such as soya-containing foods. In fact, the presence of a few high values in the isoflavone distribution is explained by the reported consumption of soya (in the open questions of our FFQ). However, the exclusion of these outliers in the analyses did not materially modify the relevant OR estimates, since the inverse trend in risk was still significant (χ2 = 19.17, p < 0.001), as was the OR estimate contrasting the fifth to the first quintile (OR, 0.51; 95% CI, 0.37–0.70).
The evidence of an inverse association between isoflavones and ovarian cancer risk is supported by the observation that isoflavones have antiestrogenic effects,2 and hence may inhibit the growth and proliferation of ovarian cell lines.42–44 Other studies in vitro suggested that isoflavones can induce both apoptotic and autophagic cell death, and inhibit angiogenesis.45 A novel approach for the treatment of ovarian cancer based on phenoxiodol consumption, an isoflavone derivative, has also been proposed.46
Flavonols, in particular kaempferol that was inversely associated with ovarian cancer risk in a previous investigation35 as well as in our study, come from various common vegetables and fruit in our population. Several studies reported an inverse association between fruit and vegetable consumption and cancer of the ovary,47–51 although the evidence is still inconclusive.52, 53 Further adjustments for fruit and vegetable intake did not materially modify the association. This suggests that flavonols may have a distinct role in explaining the effect of fruit and vegetable against ovarian cancer.
The use of hospital controls has been widely debated,32 since dietary habits of hospital controls may differ from those of the general population. In this study, we excluded from the control group all diagnoses that might have involved any long-term changes in diet. The interview setting and catchment areas were the same for cases and controls, and the participation rate was almost complete. Among the limitations of the study are the questions concerning the adaptability of US flavonoid food composition tables to the Italian diet and the fact that the questionnaire was not specifically designed to investigate flavonoids. However, use of the US flavonoid food composition tables was necessary in the absence of a relevant Italian database, and the high consumption and diversity of fruits and vegetables in this Mediterranean population54 are reassuring against a major role of biased value for any specific food item.
Among the strengths of the study are the large sample size, the use of a reproducible and valid FFQ,25, 26 and the ability to control for total energy intake. We were able to adjust for major recognized risk factors for ovarian cancer, and the study has generated results on other ovarian cancer risk factors that were in line with other investigations,55 providing assurance that major biases were not operating during implementation of the study. Furthermore, potential recall bias in the intake of flavonoids should be limited, given the limited appreciation by the lay population in Italy of a possible link between various aspects of diet, including vegetables and fruit, and ovarian cancer risk.
This work was conducted with the support of the Italian Association for Cancer Research and the Italian League against Cancer. The work in this paper was undertaken while CLV was a senior fellow at the International Agency for Research on Cancer.
- 10U.S. Department of Agriculture. Iowa State University database on the isoflavone content of foods, Release 1.3. Beltsville, MD: USDA, 2002.
- 11U.S. Department of Agriculture. USDA database for the flavonoid content of selected foods. Beltsville, MD: USDA, 2003.
- 30Banca di composizione degli alimenti per studi epidemiologici in Italia. Milano, Italia: Istituto Europeo di Oncologia, 1998., , , , .
- 32Statistical methods in cancer research, Vol. 1. The analysis of case–control studies. IARC Sci Publ No. 32. Lyon, France: IARC, 1980., .