The authors declare that they have no competing interests.
Conceived and designed the experiments: CH XQ ZJD MMT. Performed the experiments: CH PXL ZQY. Analyzed the data: CH XQ ZQY. Contributed reagents/materials/analysis tools: XQ ZQY PXL. Wrote the paper: CH ZJD MMT.
Studies have suggested the chemopreventive effects of flavonoids on carcinogenesis. Yet numbers of epidemiologic studies assessing dietary flavonoids and breast cancer risk have yielded inconsistent results. The association between flavonoids, flavonoid subclasses (flavonols, flavan-3-ols, etc.) and the risk of breast cancer lacks systematic analysis.
We aimed to examine the association between flavonoids, each flavonoid subclass (except isoflavones) and the risk of breast cancer by conducting a meta-analysis.
We searched for all relevant studies with a prospective cohort or case-control study design published before July 1st, 2012, using Cochrane library, MEDLINE, EMBASE and PUBMED. Summary relative risks (RR) were calculated using fixed- or random-effects models. All analyses were performed using STATA version 10.0.
Twelve studies were included, involving 9 513 cases and 181 906 controls, six of which were prospective cohort studies, and six were case-control studies. We calculated the summary RRs of breast cancer risk for the highest vs lowest categories of each flavonoid subclass respectively. The risk of breast cancer significantly decreased in women with high intake of flavonols (RR = 0.88, 95% CI 0.80–0.98) and flavones (RR = 0.83, 95% CI: 0.76–0.91) compared with that in those with low intake of flavonols and flavones. However, no significant association of flavan-3-ols (RR = 0.93, 95% CI: 0.84–1.02), flavanones (summary RR = 0.95, 95% CI: 0.88–1.03), anthocyanins (summary RR = 0.97, 95% CI: 0.87–1.08) or total flavonoids (summary RR = 0.98, 95% CI: 0.86–1.12) intake with breast cancer risk was observed. Furthermore, summary RRs of 3 case-control studies stratified by menopausal status suggested flavonols, flavones or flavan-3-ols intake is associated with a significant reduced risk of breast cancer in post-menopausal while not in pre-menopausal women.
The present study suggests the intake of flavonols and flavones, but not other flavonoid subclasses or total flavonoids, is associated with a decreased risk of breast cancer, especially among post-menopausal women.
Breast cancer is the leading cause of cancer death among women in Europe and North America. Almost 1.4 million women were diagnosed with breast cancer worldwide in 2008 and approximately 459,000 deaths were recorded
Dietary flavonoids occur ubiquitously in plant foods, and can be categorized into six major subclasses based on their range and structural complexity: flavonols, flavones, flavan-3-ols, flavanones, anthocyanins and isoflavones (
Flavonoid subclasses | Example compounds | Major dietary sources | Estimated daily intakes |
Flavonols | Quercetin, kaempferol, myricetin, and isorhamnetin | Onions, broccoli, tea, and various fruits | mg/d12.9 |
Flavones | Luteolin, apigenin, and tangeretin | Herbs (especially parsley), celery, and chamomile tea | 1.6 |
Flavanones | Naringenin, hesperetin | Citrus fruit including oranges and grape fruit | 14.4 |
Flavan-3-ols | Catechin, epicatechin, epigallocatechin | Cocoa or dark chocolate, apples, grape, red wine, and green tea | 156.9 |
Anthocyanidins | Cyanidin, delphinidin, pelargonidin, andmalvidin | Colored berries and other fruit, especially cranberries, black currants, and blueberries | 3.1 |
Isoflavones | Genistein, daidzein, and glycitein | Soy products including fermented products, eg, tofu, tempeh, miso, and soy protein isolate | 1.2 (US and Netherlands) 25–50 (Asia) |
In decades, studies have suggested the chemopreventive effects of flavonoids on carcinogenesis, the anticancer activity of dietary flavonoids has become an important and interesting topic. Yet in fact, a number of epidemiologic studies assessing the association between dietary flavonoid intake and the risk of breast cancer have yielded inconsistent results and have identified controversial evidence
We conducted a systematic search of literature published before July 1st 2012 using the Cochrane Library, MEDLINE, and EMBASE Databases and the following search terms: “flavonoid”, “flavonols”, “flavones”, “flavanones”, “flavan-3-ols”, “flavanols”, “anthocyanidins”, “phytoestrogens”, “polyphenolic compounds” and “breast cancer”. We also performed a manual search using reference lists of original articles and relevant reviews. Only full-length original journal articles were considered and no attempt was made to include abstracts or unpublished studies.
Studies were eligible for our analysis if: (1) the study design is cohort or case-control study; (2) data related to dietary consumption or exposure assessment (blood/urinary levels) of total flavonoids or one of flavonoid subclasses (isoflavones excluded) were available; (3) the association of flavonoids or one of flavonoid subclasses with breast cancer risk was specifically evaluated; (4) relatively complete assessment of total flavonoids or flavonoid subclass intake was performed; (5) relative risk (RR), hazard ratio (HR), or odds ratio (OR), and corresponding 95% confidence intervals (95% CI) were available. Because isoflavones have been studied extensively, including meta-analysises, studies focusing on isoflavones alone were not included in the present study. Originally, we included RCTs in our search criteria, but because there were no RCTs on flavonoids, no RCTs are included in the present study.
We recorded study characteristics as follows: (1) name of the first author and publication year; (2) country or origin; (3) study design (cohort or case-control study); (4) mean length of follow-up; (5) number of cases and controls; (6) assessment of exposure, especially the database for assessment of flavonoid intake; (7) exposures to flavonoids; (8) media of flavonoids intakes; (9) RR, HR or OR from the most fully adjusted model for the highest versus the lowest flavonoids exposure and their 95% CI; (10) confounders adjusted for in multivariate analysis.
We investigated the associations between intakes of each flavonoid subclass and the risk of breast cancer separately. Homogeneity of effect size across studies was tested by Q statistics (P<0.10). We also computed the I2, a quantitative measure of inconsistency across studies. If substantial heterogeneity exists, the random-effects model is appropriate; otherwise, the fixed-effects model is preferred
The twelve studies
Author, year and region | Study design | Mean follow-up | Cases/controls | Assessment of exposure | Flavonoids exposure and media of intake | OR or RR(95% CI) | Adjustments | ||
(year) | (mg/d) | Total | Premenopausal | Postmenopausal | |||||
Wang L 2009, U.S.A | Cohort | 1995–2007 | 1351 (38408) | SFFQ, Databases published in US and Europe | Total flavonoids(19.13) | 1.03(0.85 1.25) | age, race, energy intake, menopausal status, hormone replacement therapy, intake of fruit and vegetables et al. | ||
Arts ICW 2002,U.S.A | Cohort | 1986–1998 | 1069 (34651) | SFFQ, Database from Netherlands | Flavan-3-ols(14.8) | 1.04(0.84 1.28) | age, education level, race, multivitamin use, menopausal status, BMI, energy intake, smoking habit, physical activity. | ||
Adebamowo CA 2005, U.S.A | Cohort | 1991–1999 | 710 (90630) | FFQ, Databasepublished inEurope | Flavonols(17.1) | 1.05(0.83 1.34) | age, parity, age at first pregnancy, age at menarche, menopausal status, BMI, energy intake, alcohol consumption, height, smoking, et al. | ||
Knekt P 2002, Finland | Cohort | 1967–1994 | 125 (4647) | QFIQ, Databases published in Finland | Total flavonoids(24.2) | 1.23(0.72 2.10) | age, geographic area, occupation, smoking, BMI | ||
Goldbohm 1998, Netherlands | Cohort | 1986–1991 | 605(2 203) | SFFQ, Database from Netherlands | Total flavonoids(29.1) | 1.02(0.72 1.44) | age, education level, race, multivitamin use, menopausal status, BMI, energy intake, smoking habit. | ||
Knekt P 1997, Finland | Cohort | 1967–1991 | 87 (4699) | QFIQ, Databasepublished inNetherland | Total flavonoids(nd) | 0.72(0.36 1.48) | sex, age, geographic area, occupation, BMI, energy intake, smoking, vit C and E, cholesterol, β-carotene, fiber, SFA, MUFA,PUFA | ||
Luo JF 2010, Shanghai China | Nested case-control | 1997–2004 | 352/701 | Urinary excretion analysis | Flavonols(nd) Flavan-3-ols(nd) | 1.04(0.73 1.48)1.12(0.77 1.63) | age, education, age at menarche, age at 1st live birth, months of breastfeeding, smoking, et al. | ||
Dai Q 2002, Shanghai China | Population- based case-control | 1996–1998 | 250/250 | Urinary excretion analysis | Flavanones(nd) | 1.04(0.66 1.63) | 1.53(0.77 3.04) | 0.79(0.41 1.51) | age at first live birth, ever diagnosed with fibroadenoma, total meat intake, and physical activity level. |
Luisa TS 2008, Mexico | Hospital- based case-control | 1994–1996 | 141/141 | SFFQ, Databases published in Mexico | Flavonols(27.8) Flavones(2.5) Flavan-3-ols(7.9) | 0.48(0.21 1.08) 0.60(0.27 1.37) 0.80(0.38 1.70) | 0.49(0.19 1.23) 0.49(0.19 1.29) 1.22(0.48 3.08) | 0.21(0.07 0.60) 0.29(0.10 0.82) 0.63(0.25 1.62) | age, energy intake, lifetime lactation |
Fink BN 2007, New York | Population- based case-control | 1996–1997 | 1434/1440 | FFQ, Database from USDA | Total flavonoids Flavonols(9.8) Flavones(0.13) Flavan-3-ols(162) Flavanones(31.2) Anthocyanidins(3.15) | 0.88(0.69 1.12) 0.75(0.59 0.95) 0.73(0.57 0.93) 0.85(0.67 1.08) 0.89(0.70 1.12) 0.91(0.72 1.15) | 1.12(0.72 1.74) 1.38(0.88 2.15) 1.07(0.70 1.65) 1.21(0.78 1.86) 0.80(0.53 1.21) 1.08(0.71 1.63) | 0.75(0.56 1.01) 0.54(0.40 0.73) 0.61(0.45 0.83) 0.74(0.55 0.99) 1.00(0.75 1.34) 0.85(0.64 1.14) | age,energy intake. |
Bosetti C 2005, Italy | Hospital- based case-control | 1991–1994 | 2569/2588 | FFQ, Database from USDA | Flavonols(18.6) Flavones(0.5) Flavan-3-ols(36.4) Flavanones(33.7) Anthocyanidins(10.4) | 0.80(0.66 0.98) 0.81(0.66 0.98) 0.86(0.71 1.05) 0.95(0.79 1.15) 1.09(0.87 1.36) | 0.90(0.80 1.02) 0.87(0.76 0.99) 0.94(0.85 1.05) 0.98(0.85 1.13) 1.14(1.00 1.31) | 0.97(0.89 1.05) 0.90(0.81 1.00) 0.92(0.84 1.00) 0.93(0.82 1.05) 1.04(0.93 1.17) | age,study center, education, parity, alcohol consumption, nonalcohol energr intake. |
Peterson J 2003, Athens, Greece | Hospital- based case-control | 1989–1991 | 820/1548 | SFFQ, Database from USDA | Flavonols(19.4) Flavones(0.4) Flavan-3-ols(23.5) Flavanones(33.5) Anthocyanidins(20.9) | 0.91(0.78 1.06) 0.87(0.77 0.97) 0.93(0.78 1.11) 0.96(0.87 1.07) 0.94(0.81 1.09) | age, place of birth, parity, age at first pregnancy, age at menarche, menopausal status, BMI, energy intake, alcohol consumption. |
BMI: body mass index; 95% CI: 95% confidence intervals; FFQ: food frequency questionnaire; nd: no detection; QFIQ: quantitative food intake questionnaire; SFFQ: semiquantitative food frequency questionnaire; USDA: U.S.Department of Agriculture; SFA: saturated fatty acids, MUFA: monounsaturated fatty acids, PUFA: polyunsaturated fatty acids.
The selected studies were published between 1997 and 2010 spanning 13 years, and all of them were published in English. Among these 12 studies, 6 were prospective cohort studies, 1 was nested case-control study, 2 were population-based case-control studies, and 3 were hospital-based case-control studies; moreover, 4 studies were from USA, 2 from Finland, 2 from China, and the rest were respectively from Netherlands, Mexico, Italy and Greece. The exposure assessments of flavonoids in 10 studies were made by food frequency questionnaire or by quantitative food intake questionaire, and in 2 studies were measured by urinary excretion analysis. Most individual studies were adjusted for a wide range of potential confounders, including age, race, education, energy intake, BMI, physical activity, parity, smoking, alcohol, and hormone replacement therapy.
We identified 6 studies of flavonols intake and breast cancer risk, 4 studies of flavones, 6 studies of flavan-3-ols, 4 studies of flavanones, 3 studies of anthocyanins, and 5 studies of total flavonoids. We calculated the summary RR using fixed- or random-effects models respectively. As shown in
Summary RRs of 4 case-control studies were stratified by menopausal status
Menopause status | Summary RR(95% CI) | P for heterogeneity | I2, % |
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Pre-menopause | 0.92 (0.82 1.03) | 0.081 | 60.3 |
Post-menopause | 0.92 (0.85 0.99) | 0.000 | 90.4 |
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Pre-menopause | 0.88 (0.77 1.00) | 0.323 | 11.5 |
Post-menopause | 0.86 (0.77 0.94) | 0.008 | 79.3 |
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Pre-menopause | 0.96 (0.86 1.06) | 0.000 | 0.474 |
Post-menopause | 0.90 (0.83 0.98) | 0.286 | 20.2 |
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Pre-menopause | 0.98 (0.86 1.11) | 0.281 | 21.3 |
Post-menopause | 0.94 (0.84 1.05) | 0.791 | 0.0 |
As shown in
Studies have suggested that plant flavonoids have many biological benefits, such as the antioxidant, anti-inflammatory, anti-tumor
In establishing flavonoids as one of the contributors to the protective effects, the very first step is to estimate flavonoid intake from various dietary sources
Menopausal status and estrogen-receptor (ER) status, as effect modifiers, may greatly effect the association between the flavonoid intake and breast cancer risk. Some studies showed that the association between the intake of soy isoflavone and the reduced risk of breast cancer incidence or recurrence was stronger in post-menopausal women than in premenopausal women
The present study suggests the intakes of flavonols and flavones, but not the other flavonoid subclasses or total flavonoids, can potentially contribute to breast cancer prevention, especially among post-menopausal women. More studies are needed to confirm the findings.