Abstract

Flavonoids are found in a variety of foods and have anticarcinogenic properties in experimental models. Few epidemiologic studies have examined whether flavonoid intake is associated with breast cancer in humans. In this study, the authors investigated whether dietary flavonoid intake was associated with reduced risk of breast cancer in a population-based sample of US women. They conducted a case-control study among women who resided in Nassau and Suffolk counties on Long Island, New York. Cases and controls were interviewed about known and suspected risk factors and asked to complete a food frequency questionnaire regarding their average intake in the prior 12 months. A total of 1,434 breast cancer cases and 1,440 controls provided adequate responses. A decrease in breast cancer risk was associated with flavonoid intake; the decrease was most pronounced among postmenopausal women for flavonols (odds ratio (OR) = 0.54, 95% confidence interval (CI): 0.40, 0.73), flavones (OR = 0.61, 95% CI: 0.45, 0.83), flavan-3-ols (OR = 0.74, 95% CI: 0.55, 0.99), and lignans (OR = 0.69, 95% CI: 0.51, 0.94). The authors conclude that intake of flavonols, flavones, flavan-3-ols, and lignans is associated with reduced risk of incident postmenopausal breast cancer among Long Island women. These results suggest that US women can consume sufficient levels of flavonoids to benefit from their potential chemopreventive effects.

Flavonoids are a group of more than 4,000 polyphenolic compounds that occur naturally in fruits, vegetables, and beverages of plant origin (1, 2). In numerous laboratory studies, flavonoids have demonstrated the ability to inhibit aromatase activity and thus lower estrogen biosynthesis and circulating estrogen levels (3–7), inhibit tumor cell proliferation (8, 9), and inhibit the formation of reactive oxygen species (10–12), all of which are mechanisms thought to influence breast cancer development (1, 8, 9, 13–18). Furthermore, dietary intake of certain flavonoids has been reported to potentially protect humans from developing certain types of cancer (19–22), including breast cancer (23, 24).

Until very recently, epidemiologic research regarding flavonoids and breast cancer development in women was limited, primarily because of the difficulty in estimating flavonoid intake. Previous hospital-based, case-control studies in Greece (23) and Italy (24) have had their respective dietary data linked with two flavonoid databases from the US Department of Agriculture (USDA) (25, 26). Reduced risks of breast cancer were observed for intake of two classes of flavonoids: flavones (23, 24) and flavonols (24). Whether similar risk reductions are detectable among US women, for whom intake of flavonoid-rich foods is traditionally lower than in Mediterranean women, is unknown (27–29).

In this analysis, we investigated whether breast cancer risk in a population-based case-control study of women in the Long Island Breast Cancer Study Project (LIBCSP) was reduced in relation to flavonoid intake.

MATERIALS AND METHODS

Participants

The LIBCSP was conducted on Long Island, New York, in Nassau and Suffolk counties (26). Cases were English-speaking women with in-situ or invasive breast cancer newly diagnosed between August 1, 1996, and July 31, 1997. Cases were identified using a rapid reporting system developed specifically for the study. Controls were randomly selected through random digit dialing for persons under age 65 years and through Health Care Financing Administration lists for persons aged 65 years or older. Controls were frequency-matched to cases in 5-year age groups (30). The institutional review boards of all participating institutions approved the study protocol, and the individual women all signed informed consent forms.

In-person interviews were completed for 1,508 breast cancer cases (81.2 percent of eligible cases) and 1,556 controls (62.8 percent of eligible controls). Reasons for nonparticipation included subject refusal, illness, cognitive impairment, inability to locate the subject, moving out of the area, and death (26). The average length of time between the reference date (date of diagnosis for cases and date of identification for controls) and the interview date was 96 days for cases and 167 days for controls (30).

Exposure assessment

Women were administered a standardized questionnaire and asked to report on a variety of known and suspected breast cancer risk factors. Cases who signed a medical record release form at the interview had their medical records reviewed for clinical and pathologic characteristics related to the breast cancer diagnosis and treatment, including tumor estrogen receptor (ER) and progesterone receptor (PR) status.

Cases and controls were asked to recall their diet history in the previous 12 months, including assessment of frequency and portion size, with a modified version of the Block food frequency questionnaire (31). A total of 1,481 cases (98.2 percent) and 1,518 controls (97.6 percent) completed this self-administered questionnaire. To facilitate comparison of our results with those of other studies, 18 cases and 18 controls with daily energy intakes above or below three standard deviations of the log-transformed mean (in kcal/day) were excluded from the analysis (32). An additional 29 cases and 60 controls were excluded because their menopausal status was unknown. This resulted in a total of 1,434 cases and 1,440 controls.

Assessment of dietary flavonoid intake

The content of total flavonoids and seven classes of flavonoids (flavonols, flavones, flavan-3-ols, flavanones, anthocyanidins, and isoflavones, as well as lignans) in foods and beverages was estimated with a database created for use in the LIBCSP (33). The LIBCSP database included both the USDA Database for the Flavonoid Content of Selected Foods (26) and the USDA–Iowa State University Database on the Isoflavone Content of Selected Foods (25). Additional sources (34–37) were utilized to include isoflavone content provided by fruits, vegetables, nuts, and grains, which are important dietary contributors among US women (38). These sources also provided content information for lignans, phytochemicals not included in the USDA databases but for which laboratory evidence has demonstrated potential anticarcinogenic properties (1, 39–43).

Using this database, 50 items listed on the modified Block food frequency questionnaire were found to contain measurable amounts of at least one flavonoid class or lignans. Individual foods and beverages were listed under each class they contained, from the richest source to the smallest source (top to bottom) (33). The richest sources of total flavonoids include tea, including herb tea (111.41 mg of flavan-3-ols per 100 g), cherries (116.31 mg of anthocyanidins per 100 g), and grapefruit (54.50 mg of flavanones per 100 g) (26).

Statistical analysis

Odds ratios and 95 percent confidence intervals were estimated using unconditional logistic regression (44), including terms for energy intake (kcal/day) and age (in 5-year age groups). Data on total flavonoids, lignans, and each phytochemical class were categorized into quintiles and deciles based on the distribution of intake among controls, but both categorizations produced similar results; thus, only the results for quintiles are reported here. Tests for trend were conducted using the continuous values in mg/day.

Confounding was assessed using backward elimination with multivariable models. Potential confounders included menopausal status (pre- or postmenopausal at the reference date), age at menarche, lifetime alcohol intake (g/day), cigarette smoking (current, former, never), family history of breast cancer in a mother or sister, benign breast disease, average physical activity level from menarche to the reference date (hours/day), body mass index (weight (kg)/height (m)2) at the reference date (date of interview), household income, education, parity, mammography use, oral contraceptive use, and consumption of fruits, vegetables, and antioxidants in the previous 12 months. None of the potential confounders altered the estimates of effect by more than 10 percent.

Effect modification was first examined through use of stratified analysis and then by comparing log-likelihood statistics for regression models that included a multiplicative interaction term with those without such a term (45). From the covariates listed above, only menopausal status was found to modify the association between flavonoid or lignan intake and breast cancer risk. For the analyses, menopause-specific quintiles were created on the basis of the respective intakes of pre- and postmenopausal control women.

Differences in risk estimates by the hormone receptor status of case tumors were examined in stratified analyses. ER-positive, PR-positive cases were considered as one group and were compared with all other hormone receptor types combined (ER-positive, PR-negative; ER-negative, PR-positive; and ER-negative, PR-negative).

RESULTS

The distribution of flavonoid and lignan intakes among the breast cancer cases and controls is presented in table 1. Overall, postmenopausal cases consumed a smaller amount of total flavonoids per day (mean = 220.74 mg/day; median, 141.78 mg/day) than did postmenopausal controls (mean = 242.66 mg/day; median, 165.00 mg/day). However, among premenopausal women, few or no case-control differences were observed, as cases consumed a mean of 211.12 mg/day (median, 143.14 mg/day) and controls consumed a mean of 212.19 mg/day (median, 137.12 mg/day). Flavan-3-ols were the largest contributor to total intake and were most disparate between postmenopausal cases (mean = 163.29 mg/day) and postmenopausal controls (mean = 182.68 mg/day).

TABLE 1.

Mean intakes (mg/day) of flavonoids and lignans among cases and controls in the Long Island Breast Cancer Study Project, 1996–1997

 Premenopausal cases (n = 457) Premenopausal controls (n = 487) All cases (n = 1,434) p value* p value† p value‡ 
Total flavonoids 211.12 212.19 217.82 0.94 0.53 0.10 
Flavonols 10.09 10.11 9.81 0.96 0.35 0.02 
Flavones 0.14 0.14 0.13 0.91 0.44 0.002 
Flavanones 25.60 27.13 31.29 0.44 0.54 0.91 
Flavan-3-ols 161.00 161.06 162.73 0.99 0.41 0.12 
Anthocyanidins 3.16 3.03 3.15 0.75 0.64 0.23 
Isoflavones 5.50 5.03 0.78 0.37 0.38 0.40 
Lignans 5.97
 
5.92
 
6.00
 
0.85
 
0.50
 
0.04
 
 Postmenopausal cases (n = 977)
 
Postmenopausal controls (n = 953)
 
All controls (n = 1,440)
 
p value§
 
p value¶
 
p value#
 
Total flavonoids 220.74 242.66 230.43 0.02 0.02 0.23 
Flavonols 9.68 10.70 10.44 0.002 0.0003 0.02 
Flavones 0.13 0.15 0.15 0.0002 <0.0001 0.003 
Flavanones 34.12 34.17 31.43 0.97 0.99 0.98 
Flavan-3-ols 163.29 182.68 173.82 0.03 0.009 0.16 
Anthocyanidins 3.14 3.66 3.51 0.17 0.02 0.14 
Isoflavones 4.58 4.86 0.70 0.46 0.69 0.85 
Lignans 6.01 6.62 6.36 0.005 0.002 0.03 
 Premenopausal cases (n = 457) Premenopausal controls (n = 487) All cases (n = 1,434) p value* p value† p value‡ 
Total flavonoids 211.12 212.19 217.82 0.94 0.53 0.10 
Flavonols 10.09 10.11 9.81 0.96 0.35 0.02 
Flavones 0.14 0.14 0.13 0.91 0.44 0.002 
Flavanones 25.60 27.13 31.29 0.44 0.54 0.91 
Flavan-3-ols 161.00 161.06 162.73 0.99 0.41 0.12 
Anthocyanidins 3.16 3.03 3.15 0.75 0.64 0.23 
Isoflavones 5.50 5.03 0.78 0.37 0.38 0.40 
Lignans 5.97
 
5.92
 
6.00
 
0.85
 
0.50
 
0.04
 
 Postmenopausal cases (n = 977)
 
Postmenopausal controls (n = 953)
 
All controls (n = 1,440)
 
p value§
 
p value¶
 
p value#
 
Total flavonoids 220.74 242.66 230.43 0.02 0.02 0.23 
Flavonols 9.68 10.70 10.44 0.002 0.0003 0.02 
Flavones 0.13 0.15 0.15 0.0002 <0.0001 0.003 
Flavanones 34.12 34.17 31.43 0.97 0.99 0.98 
Flavan-3-ols 163.29 182.68 173.82 0.03 0.009 0.16 
Anthocyanidins 3.14 3.66 3.51 0.17 0.02 0.14 
Isoflavones 4.58 4.86 0.70 0.46 0.69 0.85 
Lignans 6.01 6.62 6.36 0.005 0.002 0.03 
*

t test comparing mean values among premenopausal women.

Wilcoxon rank-sum test comparing median values among premenopausal women.

t test comparing mean values among all cases and all controls.

§

t test comparing mean values among postmenopausal women.

Wilcoxon rank-sum test comparing median values among postmenopausal women.

#

Wilcoxon rank-sum test comparing median values among all cases and all controls.

As is shown in table 2, the odds ratios for breast cancer were reduced in relation to intakes of flavones (for the highest quintile of intake versus the lowest, odds ratio (OR) = 0.73, 95 percent confidence interval (CI): 0.57, 0.93) and flavonols (OR = 0.75, 95 percent CI: 0.59, 0.95). When the associations were stratified by menopausal status, breast cancer risk was decreased among postmenopausal women in relation to intake of all flavonoids except flavanones, anthocyanidins, and isoflavones. Odds ratios were reduced by 25 percent among postmenopausal women in the highest fifth of intake of total flavonoids (OR = 0.75, 95 percent CI: 0.56, 1.01), by nearly 40 percent for flavones (OR = 0.61, 95 percent CI: 0.45, 0.83), by nearly 50 percent for flavonols (OR = 0.54, 95 percent CI: 0.40, 0.73), by 31 percent for lignans (OR = 0.69, 95 percent CI: 0.51, 0.94), and by 26 percent for flavan-3-ols (OR = 0.74, 95 percent CI: 0.55, 0.99). There was a significant decreasing trend across quintiles for total flavonoids, flavonols, flavones, and lignans. In contrast, among premenopausal women, there was no evidence of a decreased risk of breast cancer for any class of flavonoids or lignans.

TABLE 2.

Age- and energy-adjusted odds ratios for the associations between menopausal status-specific flavonoid and lignan intakes and breast cancer incidence in the Long Island Breast Cancer Study Project, 1996–1997

Premenopausal women (n = 944) Postmenopausal women (n = 1,930) All women (n = 2,874) 
Intake (mg/day) OR*,† 95% CI* Intake (mg/day) OR† 95% CI Intake (mg/day) OR† 95% CI 
Total flavonoids 
0–34.5 1.00  0–51.8 1.00  0–44.6 1.00  
34.6–84.5 1.20 0.79, 1.84 51.8–119.1 0.94 0.71, 1.24 44.7–101.2 1.01 0.80, 1.27 
84.6–199.5 1.29 0.84, 1.97 119.2–253.3 0.79 0.60, 1.05 101.3–230.2 0.98 0.78, 1.23 
199.6–343.0 1.46 0.96, 2.22 253.4–377.2 0.80 0.60, 1.06 230.3–364.7 0.95 0.76, 1.20 
≥343.1 1.12 0.72, 1.74 ≥377.3 0.75 0.56, 1.01 ≥364.8 0.88 0.69, 1.12 
    p for trend‡ 0.95   0.05   0.14  
Flavonols 
0–3.7 1.00  0–4.3 1.00  0–4.0 1.00  
3.8–6.0 1.32 0.86, 2.03 4.4–6.8 0.56 0.42, 0.74 4.1–6.4 0.80 0.64, 1.01 
6.1–10.2 1.48 0.97, 2.27 6.9–11.1 0.62 0.47, 0.82 6.5–10.7 0.83 0.66, 1.04 
10.3–15.1 1.53 0.99, 2.35 11.2–17.1 0.63 0.47, 0.83 10.8–16.2 0.87 0.69, 1.09 
≥15.2 1.38 0.88, 2.15 ≥17.2 0.54 0.40, 0.73 ≥16.3 0.75 0.59, 0.95 
    p for trend 0.92   <0.001   0.05  
Flavones 
0–0.04 1.00  0–0.04 1.00  0–0.05 1.00  
0.05–0.07 0.94 0.62, 1.43 0.05–0.08 0.90 0.68, 1.19 0.06–0.09 0.94 0.75, 1.18 
0.08–0.12 1.29 0.86, 1.84 0.09–0.14 0.95 0.72, 1.26 0.10–0.14 0.99 0.79, 1.25 
0.13–0.21 1.07 0.70, 1.63 0.15–0.21 0.70 0.52, 0.94 0.15–0.22 0.83 0.66, 1.05 
≥0.22 1.07 0.70, 1.65 ≥0.22 0.61 0.45, 0.83 ≥0.23 0.73 0.57, 0.93 
    p for trend 0.94   <0.001   0.004  
Flavanones 
0–3.1 1.00  0–5.3 1.00  0–4.5 1.00  
3.2–10.8 0.69 0.46, 1.04 5.4–18.8 1.09 0.82, 1.46 4.6–15.2 0.90 0.71, 1.13 
10.9–24.5 0.69 0.46, 1.04 18.9–32.1 1.10 0.83, 1.46 15.3–30.0 0.93 0.74, 1.17 
24.6–40.3 0.85 0.57, 1.26 32.2–54.2 1.08 0.81, 1.43 30.1–50.3 0.99 0.79, 1.25 
≥40.4 0.80 0.53, 1.21 ≥54.3 1.00 0.75, 1.34 ≥50.4 0.89 0.70, 1.12 
    p for trend 0.34   0.87   0.64  
Flavan-3-ols 
0–5.1 1.00  0–7.6 1.00  0–6.5 1.00  
5.2–26.4 1.22 0.80, 1.87 7.7–54.0 0.94 0.72, 1.24 6.6–39.5 0.96 0.76, 1.21 
26.5–120.8 1.32 0.87, 2.01 54.1–192.0 0.80 0.60, 1.06 39.6–189.8 0.99 0.79, 1.24 
120.9–264.1 1.52 1.00, 2.30 192.1–277.9 0.82 0.62, 1.08 189.9–267.9 1.00 0.80, 1.26 
≥264.2 1.21 0.78, 1.86 ≥278.0 0.74 0.55, 0.99 ≥268.0 0.85 0.67, 1.08 
    p for trend 0.87   0.06   0.17  
Anthocyanidins 
0–0.04 1.00  0–0.03 1.00  0–0.04 1.00  
0.05–0.56 1.15 0.77, 1.72 0.04–0.56 1.09 0.83, 1.44 0.05–0.56 1.10 0.88, 1.38 
0.57–1.60 0.77 0.50, 1.17 0.57–1.84 0.97 0.73, 1.28 0.57–1.75 0.95 0.76, 1.19 
1.61–4.19 1.07 0.71, 1.61 1.85–4.84 0.82 0.62, 1.09 1.76–4.57 0.87 0.69, 1.10 
≥4.20 1.08 0.71, 1.63 ≥4.85 0.85 0.64, 1.14 ≥4.58 0.91 0.72, 1.15 
    p for trend 0.81   0.23   0.27  
Isoflavones 
0–0.31 1.00  0–0.27 1.00  0–0.17 1.00  
0.32–1.10 1.03 0.68, 1.56 0.28–0.62 0.97 0.72, 1.30 0.18–0.26 0.86 0.68, 1.09 
1.11–3.17 0.98 0.65, 1.47 0.63–1.94 1.16 0.87, 1.55 0.27–0.38 1.00 0.79, 1.26 
3.18–7.62 0.88 0.58, 1.33 1.95–7.63 1.14 0.85, 1.53 0.39–0.61 0.96 0.75, 1.22 
≥7.63 1.14 0.76, 1.72 ≥7.64 1.02 0.76, 1.38 ≥0.62 0.95 0.74, 1.22 
    p for trend 0.56   0.72   0.31  
Lignans 
0–2.0 1.00  0–2.4 1.00  0–2.3 1.00  
2.1–4.0 1.43 0.95, 2.17 2.5–4.2 1.07 0.81, 1.40 2.4–4.2 1.13 0.90, 1.42 
4.1–5.4 0.98 0.63, 1.51 4.3–6.4 0.82 0.61, 1.09 4.3–6.2 0.86 0.68, 1.09 
5.5–9.3 1.62 1.07, 2.45 6.5–10.2 0.79 0.59, 1.05 6.3–9.8 0.97 0.77, 1.23 
≥9.4 1.24 0.81, 1.92 ≥10.3 0.69 0.51, 0.94 ≥9.9 0.82 0.64, 1.04 
    p for trend 0.72   0.01   0.06  
Premenopausal women (n = 944) Postmenopausal women (n = 1,930) All women (n = 2,874) 
Intake (mg/day) OR*,† 95% CI* Intake (mg/day) OR† 95% CI Intake (mg/day) OR† 95% CI 
Total flavonoids 
0–34.5 1.00  0–51.8 1.00  0–44.6 1.00  
34.6–84.5 1.20 0.79, 1.84 51.8–119.1 0.94 0.71, 1.24 44.7–101.2 1.01 0.80, 1.27 
84.6–199.5 1.29 0.84, 1.97 119.2–253.3 0.79 0.60, 1.05 101.3–230.2 0.98 0.78, 1.23 
199.6–343.0 1.46 0.96, 2.22 253.4–377.2 0.80 0.60, 1.06 230.3–364.7 0.95 0.76, 1.20 
≥343.1 1.12 0.72, 1.74 ≥377.3 0.75 0.56, 1.01 ≥364.8 0.88 0.69, 1.12 
    p for trend‡ 0.95   0.05   0.14  
Flavonols 
0–3.7 1.00  0–4.3 1.00  0–4.0 1.00  
3.8–6.0 1.32 0.86, 2.03 4.4–6.8 0.56 0.42, 0.74 4.1–6.4 0.80 0.64, 1.01 
6.1–10.2 1.48 0.97, 2.27 6.9–11.1 0.62 0.47, 0.82 6.5–10.7 0.83 0.66, 1.04 
10.3–15.1 1.53 0.99, 2.35 11.2–17.1 0.63 0.47, 0.83 10.8–16.2 0.87 0.69, 1.09 
≥15.2 1.38 0.88, 2.15 ≥17.2 0.54 0.40, 0.73 ≥16.3 0.75 0.59, 0.95 
    p for trend 0.92   <0.001   0.05  
Flavones 
0–0.04 1.00  0–0.04 1.00  0–0.05 1.00  
0.05–0.07 0.94 0.62, 1.43 0.05–0.08 0.90 0.68, 1.19 0.06–0.09 0.94 0.75, 1.18 
0.08–0.12 1.29 0.86, 1.84 0.09–0.14 0.95 0.72, 1.26 0.10–0.14 0.99 0.79, 1.25 
0.13–0.21 1.07 0.70, 1.63 0.15–0.21 0.70 0.52, 0.94 0.15–0.22 0.83 0.66, 1.05 
≥0.22 1.07 0.70, 1.65 ≥0.22 0.61 0.45, 0.83 ≥0.23 0.73 0.57, 0.93 
    p for trend 0.94   <0.001   0.004  
Flavanones 
0–3.1 1.00  0–5.3 1.00  0–4.5 1.00  
3.2–10.8 0.69 0.46, 1.04 5.4–18.8 1.09 0.82, 1.46 4.6–15.2 0.90 0.71, 1.13 
10.9–24.5 0.69 0.46, 1.04 18.9–32.1 1.10 0.83, 1.46 15.3–30.0 0.93 0.74, 1.17 
24.6–40.3 0.85 0.57, 1.26 32.2–54.2 1.08 0.81, 1.43 30.1–50.3 0.99 0.79, 1.25 
≥40.4 0.80 0.53, 1.21 ≥54.3 1.00 0.75, 1.34 ≥50.4 0.89 0.70, 1.12 
    p for trend 0.34   0.87   0.64  
Flavan-3-ols 
0–5.1 1.00  0–7.6 1.00  0–6.5 1.00  
5.2–26.4 1.22 0.80, 1.87 7.7–54.0 0.94 0.72, 1.24 6.6–39.5 0.96 0.76, 1.21 
26.5–120.8 1.32 0.87, 2.01 54.1–192.0 0.80 0.60, 1.06 39.6–189.8 0.99 0.79, 1.24 
120.9–264.1 1.52 1.00, 2.30 192.1–277.9 0.82 0.62, 1.08 189.9–267.9 1.00 0.80, 1.26 
≥264.2 1.21 0.78, 1.86 ≥278.0 0.74 0.55, 0.99 ≥268.0 0.85 0.67, 1.08 
    p for trend 0.87   0.06   0.17  
Anthocyanidins 
0–0.04 1.00  0–0.03 1.00  0–0.04 1.00  
0.05–0.56 1.15 0.77, 1.72 0.04–0.56 1.09 0.83, 1.44 0.05–0.56 1.10 0.88, 1.38 
0.57–1.60 0.77 0.50, 1.17 0.57–1.84 0.97 0.73, 1.28 0.57–1.75 0.95 0.76, 1.19 
1.61–4.19 1.07 0.71, 1.61 1.85–4.84 0.82 0.62, 1.09 1.76–4.57 0.87 0.69, 1.10 
≥4.20 1.08 0.71, 1.63 ≥4.85 0.85 0.64, 1.14 ≥4.58 0.91 0.72, 1.15 
    p for trend 0.81   0.23   0.27  
Isoflavones 
0–0.31 1.00  0–0.27 1.00  0–0.17 1.00  
0.32–1.10 1.03 0.68, 1.56 0.28–0.62 0.97 0.72, 1.30 0.18–0.26 0.86 0.68, 1.09 
1.11–3.17 0.98 0.65, 1.47 0.63–1.94 1.16 0.87, 1.55 0.27–0.38 1.00 0.79, 1.26 
3.18–7.62 0.88 0.58, 1.33 1.95–7.63 1.14 0.85, 1.53 0.39–0.61 0.96 0.75, 1.22 
≥7.63 1.14 0.76, 1.72 ≥7.64 1.02 0.76, 1.38 ≥0.62 0.95 0.74, 1.22 
    p for trend 0.56   0.72   0.31  
Lignans 
0–2.0 1.00  0–2.4 1.00  0–2.3 1.00  
2.1–4.0 1.43 0.95, 2.17 2.5–4.2 1.07 0.81, 1.40 2.4–4.2 1.13 0.90, 1.42 
4.1–5.4 0.98 0.63, 1.51 4.3–6.4 0.82 0.61, 1.09 4.3–6.2 0.86 0.68, 1.09 
5.5–9.3 1.62 1.07, 2.45 6.5–10.2 0.79 0.59, 1.05 6.3–9.8 0.97 0.77, 1.23 
≥9.4 1.24 0.81, 1.92 ≥10.3 0.69 0.51, 0.94 ≥9.9 0.82 0.64, 1.04 
    p for trend 0.72   0.01   0.06  
*

OR, odds ratio; CI, confidence interval.

Adjusted for age (years) and energy intake (kcal/day).

p for trend for continuous variable.

When all potential confounders were included in the model (age at menarche, lifetime alcohol intake, cigarette smoking, family history of breast cancer in a mother or sister, benign breast disease, average physical activity level from menarche to the reference date, body mass index at the reference date, household income, education, parity, mammography use, oral contraceptive use, and consumption of fruits, vegetables, and antioxidants in the previous 12 months), similar odds ratios were observed among postmenopausal women for the highest fifth of intake of total flavonoids (OR = 0.69, 95 percent CI: 0.49, 0.98), flavonols (OR = 0.48, 95 percent CI 0.34, 0.68), flavones (OR = 0.59, 95 percent CI: 0.41, 0.84), flavan-3-ols (OR = 0.63, 95 percent CI: 0.45, 0.88), and lignans (OR = 0.62, 95 percent CI: 0.43, 0.87).

When results were stratified by ER/PR status, there was little or no heterogeneity in breast cancer risk in relation to flavonoid intake for postmenopausal women. A consistent trend towards a reduced risk was found for all hormone receptor types in relation to flavonols, flavones, and total flavonoids (table 3). The number of premenopausal women in the study limited our ability to stratify the results by hormone receptor status in these younger women.

TABLE 3.

Age- and energy-adjusted odds ratios for the associations between flavonoid and lignan intakes and breast cancer incidence among postmenopausal women in the Long Island Breast Cancer Study Project, by tumor hormone receptor status, 1996–1997

Variable and intake (mg/day) No. of controls (n = 953) Hormone receptor status 
ER*-positive, PR*-positive All others† 
No. of cases (n = 378) OR*,‡ 95% CI* No. of cases (n = 274) OR‡ 95% CI 
Total flavonoids        
    0–51.7 190 89 1.00  72 1.00  
    51.8–119.0 192 78 0.90 0.62, 1.31 62 0.89 0.59, 1.32 
    119.1–253.2 190 72 0.83 0.57, 1.21 42 0.60 0.39, 0.93 
    253.3–377.1 191 77 0.86 0.59, 1.25 49 0.68 0.44, 1.04 
    ≥377.2 190 62 0.75 0.50, 1.12 49 0.72 0.47, 1.11 
        p for trend§   0.35   0.09  
Flavonols        
    0–4.2 191 113 1.00  93 1.00  
    4.3–6.7 190 66 0.59 0.41, 0.86 47 0.51 0.34, 0.78 
    6.8–11.0 190 67 0.60 0.41, 0.87 42 0.46 0.30, 0.71 
    11.1–17.0 191 74 0.66 0.46, 0.96 46 0.49 0.32, 0.75 
    ≥17.1 191 58 0.55 0.37, 0.82 56 0.51 0.33, 0.79 
        p for trend   0.12   0.03  
Flavones        
    0–0.04 191 101 1.00  69 1.00  
    0.05–0.08 190 74 0.76 0.52, 1.10 72 1.05 0.71, 1.56 
    0.09–0.14 191 85 0.89 0.62, 1.29 55 0.83 0.54, 1.26 
    0.15–0.21 191 61 0.64 0.43, 0.94 44 0.67 0.43, 1.04 
    ≥0.22 190 57 0.59 0.40, 0.89 34 0.51 0.32, 0.82 
        p for trend   0.02   0.003  
Flavanones        
    0–5.3 190 70 1.00  50 1.00  
    5.4–18.8 192 77 1.18 0.80, 1.74 52 1.05 0.68, 1.63 
    18.9–32.1 189 84 1.21 0.83, 1.78 61 1.20 0.78, 1.84 
    32.2–54.2 191 80 1.14 0.77, 1.67 58 1.16 0.75, 1.80 
    ≥54.3 191 67 0.95 0.63, 1.42 53 1.06 0.68, 1.66 
        p for trend   0.77   0.49  
Flavan-3-ols        
    0–7.6 190 93 1.00  71 1.00  
    7.7–54.0 192 75 0.81 0.56, 1.18 62 0.88 0.59, 1.31 
    54.1–192.0 189 65 0.71 0.49, 1.04 48 0.69 0.45, 1.05 
    192.1–277.9 192 81 0.86 0.60, 1.24 48 0.66 0.43, 1.02 
    ≥278.0 190 64 0.75 0.51, 1.10 45 0.67 0.43, 1.03 
        p for trend   0.45   0.13  
Anthocyanidins        
    0–0.03 189 77 1.00  58 1.00  
    0.04–0.56 192 88 1.19 0.82, 1.73 70 1.22 0.81, 1.84 
    0.57–1.84 190 88 1.25 0.86, 1.81 44 0.80 0.51, 1.24 
    1.85–4.84 191 69 0.93 0.63, 1.37 50 0.90 0.59, 1.39 
    ≥4.85 191 56 0.77 0.51, 1.16 52 0.95 0.62, 1.46 
        p for trend   0.005   0.63  
Isoflavones        
    0–0.27 190 82 1.00  55 1.00  
    0.28–0.62 191 63 0.78 0.52, 1.17 64 1.19 0.78, 1.83 
    0.63–1.94 191 81 1.09 0.75, 1.60 50 0.98 0.62, 1.52 
    1.95–7.63 191 88 1.21 0.83, 1.77 58 1.16 0.75, 1.80 
    ≥7.64 190 64 0.92 0.61, 1.37 47 1.00 0.63, 1.58 
        p for trend   0.91   0.48  
Lignans        
    0–2.4 215 89 1.00  72 1.00  
    2.5–4.2 167 81 1.09 0.76, 1.58 68 1.07 0.72, 1.59 
    4.3–6.4 190 76 0.96 0.66, 1.40 48 0.74 0.48, 1.14 
    6.5–10.2 191 71 0.89 0.60, 1.30 43 0.64 0.41, 0.99 
    ≥10.3 190 61 0.82 0.55, 1.24 43 0.67 0.43, 1.05 
        p for trend   0.35   0.02  
Variable and intake (mg/day) No. of controls (n = 953) Hormone receptor status 
ER*-positive, PR*-positive All others† 
No. of cases (n = 378) OR*,‡ 95% CI* No. of cases (n = 274) OR‡ 95% CI 
Total flavonoids        
    0–51.7 190 89 1.00  72 1.00  
    51.8–119.0 192 78 0.90 0.62, 1.31 62 0.89 0.59, 1.32 
    119.1–253.2 190 72 0.83 0.57, 1.21 42 0.60 0.39, 0.93 
    253.3–377.1 191 77 0.86 0.59, 1.25 49 0.68 0.44, 1.04 
    ≥377.2 190 62 0.75 0.50, 1.12 49 0.72 0.47, 1.11 
        p for trend§   0.35   0.09  
Flavonols        
    0–4.2 191 113 1.00  93 1.00  
    4.3–6.7 190 66 0.59 0.41, 0.86 47 0.51 0.34, 0.78 
    6.8–11.0 190 67 0.60 0.41, 0.87 42 0.46 0.30, 0.71 
    11.1–17.0 191 74 0.66 0.46, 0.96 46 0.49 0.32, 0.75 
    ≥17.1 191 58 0.55 0.37, 0.82 56 0.51 0.33, 0.79 
        p for trend   0.12   0.03  
Flavones        
    0–0.04 191 101 1.00  69 1.00  
    0.05–0.08 190 74 0.76 0.52, 1.10 72 1.05 0.71, 1.56 
    0.09–0.14 191 85 0.89 0.62, 1.29 55 0.83 0.54, 1.26 
    0.15–0.21 191 61 0.64 0.43, 0.94 44 0.67 0.43, 1.04 
    ≥0.22 190 57 0.59 0.40, 0.89 34 0.51 0.32, 0.82 
        p for trend   0.02   0.003  
Flavanones        
    0–5.3 190 70 1.00  50 1.00  
    5.4–18.8 192 77 1.18 0.80, 1.74 52 1.05 0.68, 1.63 
    18.9–32.1 189 84 1.21 0.83, 1.78 61 1.20 0.78, 1.84 
    32.2–54.2 191 80 1.14 0.77, 1.67 58 1.16 0.75, 1.80 
    ≥54.3 191 67 0.95 0.63, 1.42 53 1.06 0.68, 1.66 
        p for trend   0.77   0.49  
Flavan-3-ols        
    0–7.6 190 93 1.00  71 1.00  
    7.7–54.0 192 75 0.81 0.56, 1.18 62 0.88 0.59, 1.31 
    54.1–192.0 189 65 0.71 0.49, 1.04 48 0.69 0.45, 1.05 
    192.1–277.9 192 81 0.86 0.60, 1.24 48 0.66 0.43, 1.02 
    ≥278.0 190 64 0.75 0.51, 1.10 45 0.67 0.43, 1.03 
        p for trend   0.45   0.13  
Anthocyanidins        
    0–0.03 189 77 1.00  58 1.00  
    0.04–0.56 192 88 1.19 0.82, 1.73 70 1.22 0.81, 1.84 
    0.57–1.84 190 88 1.25 0.86, 1.81 44 0.80 0.51, 1.24 
    1.85–4.84 191 69 0.93 0.63, 1.37 50 0.90 0.59, 1.39 
    ≥4.85 191 56 0.77 0.51, 1.16 52 0.95 0.62, 1.46 
        p for trend   0.005   0.63  
Isoflavones        
    0–0.27 190 82 1.00  55 1.00  
    0.28–0.62 191 63 0.78 0.52, 1.17 64 1.19 0.78, 1.83 
    0.63–1.94 191 81 1.09 0.75, 1.60 50 0.98 0.62, 1.52 
    1.95–7.63 191 88 1.21 0.83, 1.77 58 1.16 0.75, 1.80 
    ≥7.64 190 64 0.92 0.61, 1.37 47 1.00 0.63, 1.58 
        p for trend   0.91   0.48  
Lignans        
    0–2.4 215 89 1.00  72 1.00  
    2.5–4.2 167 81 1.09 0.76, 1.58 68 1.07 0.72, 1.59 
    4.3–6.4 190 76 0.96 0.66, 1.40 48 0.74 0.48, 1.14 
    6.5–10.2 191 71 0.89 0.60, 1.30 43 0.64 0.41, 0.99 
    ≥10.3 190 61 0.82 0.55, 1.24 43 0.67 0.43, 1.05 
        p for trend   0.35   0.02  
*

ER, estrogen receptor; PR, progesterone receptor; OR, odds ratio; CI, confidence interval.

ER-positive, PR-negative; ER-negative, PR-positive; and ER-negative, PR-negative.

Adjusted for age (years) and energy intake (kcal/day).

§

p for trend for continuous variable.

DISCUSSION

In this analysis, inverse associations with breast cancer risk were found for intake of total flavonoids and for most flavonoid classes. The associations were most evident in postmenopausal women. These results are consistent with those of two previous hospital-based case-control studies conducted in Greece (21) and Italy (24) that found a slightly more modest reduction in risk with increasing flavones (23, 24) and flavonols (24). Both studies used the same two USDA databases (25, 26) to measure flavonoid intake, and each had a study population size similar to ours. Our enhancement of these US databases to more fully capture intake of flavonoid-rich foods may have improved our ability to detect a stronger association between flavonoid intake and breast cancer risk in our US population.

Among postmenopausal women with ER-positive, PR-positive tumors, we observed a reduced risk of breast cancer for increasing intakes of flavones and flavonols. The ER-positive, PR-positive tumor receptor type is the most common type diagnosed among breast cancer patients in the United States (46, 47). Thus, if replicated in other studies, our findings may be of public health significance. However, because our study population included a limited number of women diagnosed with tumors of other receptor types, results from our subgroup analyses should be interpreted with care.

In contrast, our data do not support an inverse association between isoflavones and breast cancer risk. Previous studies have also not observed an association (48–53), including a study conducted in a multiethnic population in the San Francisco Bay Area (53). The diet history instrument used in the LIBCSP was limited in its coverage of soy products, which may have resulted in a slight underestimation of intake of isoflavone-rich foods. This nondifferential misclassification may have resulted in masking of any potential beneficial effects of these compounds.

While previous efforts have been made to estimate the isoflavone content of soy-based products in the United States (54, 55), the continued introduction of new soy products to the market, as well as nontraditional uses of soy such as inclusion of soy flour in doughnuts and soy protein in fast-food hamburgers, demonstrates the need for their inclusion in future dietary assessment tools. Furthermore, the Block food frequency questionnaire did not include questions on blueberries and raspberries, both rich sources of anthocyanidins (26). Omission of these berries may have contributed to the lower anthocyanidin intake reported in our study as compared with the studies in Greece (23) and Italy (24), although neither of those studies found a risk reduction with anthocyanidins.

Additionally, flavonoid content in foods is variable, influenced in part by environmental conditions (56). In fruits and vegetables, particularly, flavonoid content varies because of differences in cultivars, cultural practices, climatic conditions, geographic location, degree of ripeness, storage conditions, and industrial processing (57–61). Thus, it is possible that there were differences in flavonoid and lignan content in the products consumed by the Long Island study population as compared with the products from which estimates were taken and used to create the databases. However, it is unknown how large or small these differences were and where many of the products, especially fruits and vegetables, were grown or produced. However, this source of variation is common to all studies that rely on nutrient databases to estimate dietary consumption (62).

Our study did, however, expand the coverage of phytochemicals in comparison with previous studies of flavonoids and breast cancer risk (23, 24) by including lignans, which are typically found in the woody portions of plants, the coats of seeds, and the bran layer of grains (34, 63). Lignans are thought to act through the same mechanisms as other flavonoids in preventing breast cancer (63). Our finding of a reduced breast cancer risk for increasing lignan intake among women on Long Island supports other reported data on animals (64–67) and humans (1, 39, 43, 68–71).

Given the hypothesized anticarcinogenic effects of flavonoids and lignans (1, 8–18, 72), consumption would be expected to benefit both premenopausal women and postmenopausal women. However, the biologic mechanism for the effect modification by menopausal status observed in our data is unclear. A previous study of fruit, vegetable, and micronutrient intake in the LIBCSP (32) found a decreased risk of breast cancer among postmenopausal women with increasing levels of intake of vegetables and many micronutrients, including alpha- and beta-carotene. Our findings suggest that the impact of flavonoids and lignans may also be greater in postmenopausal women. It is possible that the antiestrogenic properties of some flavonoid classes or lignans are only effective in the low-endogenous-estrogen environment observed in postmenopausal women and are ineffective in the high-endogenous-estrogen environment of premenopausal women. Further research based on large numbers of both premenopausal women and postmenopausal women is needed to help clarify this issue.

Flavonoids and lignans are found in numerous products, including fruits and vegetables; thus, flavonoid and lignan consumption may reflect part of an overall healthy diet and lifestyle (73, 74). Furthermore, many lifestyle factors that may potentially confound the relation between flavonoids or lignans and breast cancer are highly correlated with fruit and vegetable intake (32, 75, 76), making it difficult to firmly establish their independent effects (77). The main LIBCSP questionnaire extensively assessed exposures throughout the life course, including recreational physical activity levels from menarche to age at diagnosis, lifetime active and passive smoking, and lifetime alcohol consumption (32). However, when we controlled for these factors mutually or individually, our results were not substantially altered.

Our study relied on retrospective reporting of dietary intake, which is subject to error, particularly in the reporting by breast cancer cases as compared with controls. The controls may have overreported consumption of flavonoid-rich foods, such as fruits and vegetables, in an attempt to appear socially correct. This would have overemphasized the benefits of flavonoids or lignans. However, if this had actually occurred, it would be expected that overreporting would occur among all control women, regardless of menopausal status. The lack of an association in premenopausal women argues against this possibility. An additional concern with errors in recall is that case reports of food intake may be affected by whether patients have initiated chemotherapy by the time of the study interview (78). However, in the LIBCSP, most of the case women were interviewed prior to any chemotherapy, and among those who had started chemotherapy, reported intake levels were not found to differ from those of women who had not started (32).

There is a possibility that these results are due to errors in reporting among the postmenopausal controls only. Daily total flavonoid intake was higher among postmenopausal controls than among premenopausal controls or among cases (regardless of cases' menopausal status). The LIBCSP was a federally mandated study (30), and thus it garnered considerable media attention. Therefore, it is possible that some of the control women in this study may have recently chosen to adopt healthier dietary habits as a result of the publicity surrounding the study. However, if dietary changes were made in response to media attention, one would expect that median intake levels would be higher among all controls, not just postmenopausal controls. Furthermore, the LIBCSP was primarily undertaken to examine whether breast cancer was influenced by environmental factors, such as pesticides (30). Media attention during the data collection phase was not focused on potential dietary causes of breast cancer. Thus, whether there was systematic misclassification of exposure among only the postmenopausal control women is unclear, although there is no strong evidence to suggest that this differential error occurred. Nevertheless, our findings should be interpreted cautiously until confirmation is provided from studies conducted in other areas of the country.

As with all epidemiologic studies of cancer that rely on food frequency questionnaires to estimate diet history, it is unknown whether reported recent diet accurately reflected the dietary patterns prevailing during the time periods most relevant to cancer development. Because researchers rarely have accurate information on subjects' lifetime dietary intake patterns, it is unclear whether our findings are overestimates or underestimates of the true association between flavonoids and lignans and breast cancer development.

To our knowledge, very few studies have addressed the impact of dietary flavonoid intake on the risk of breast cancer, particularly in a US population. Only the studies conducted in Greece (23) and Italy (24) have used the USDA Database for the Flavonoid Content of Selected Foods (26) and the USDA–Iowa State University Database on the Isoflavone Content of Selected Foods (25) together. We combined these two databases with additional literature (34–38) to construct a more comprehensive instrument for assessing flavonoid intake, including intake of another phytochemical, lignans. Overall, the mean difference in total flavonoid intake between postmenopausal cases and controls was roughly equivalent to half a glass of tea or one apple per day. However, these absolute differences must be interpreted with care, given that the intake estimates were based on data collected as part of a food frequency questionnaire; the food frequency questionnaire is designed to rank relative intakes rather than identify the absolute amounts of food that must be consumed in order to influence disease outcomes.

This study had the advantage of a large sample size with a population-based design, reducing selection bias and allowing for greater generalizability of results as compared with hospital-based studies. The LIBCSP population consumed a wide variety and significant amounts of flavonoid- and lignan-containing products, such as fruits, vegetables, and tea, enabling us to address our specific aims. Furthermore, the Block food frequency questionnaire utilized in this study is a validated, reliable dietary assessment tool for estimating usual food-group intake and for ranking individuals in categories of intake (78–80).

In summary, this case-control study provides evidence that increased intake of lignans and flavonoids is associated with reduced risk of breast cancer in a population-based sample of US women. When the results were stratified by menopausal status, the inverse associations were restricted to postmenopausal women and were particularly strong for flavones, flavonols, flavan-3-ols, and lignans. These findings support the similar but more modest reductions observed in Greece and Italy (23, 24). Most research to date has not utilized the two recently available USDA databases together, with additional sources, to study flavonoids and breast cancer incidence. Further research using these instruments needs to be conducted, particularly in US populations.

Abbreviations

    Abbreviations
  • CI

    confidence interval

  • ER

    estrogen receptor

  • LIBCSP

    Long Island Breast Cancer Study Project

  • OR

    odds ratio

  • PR

    progesterone receptor

  • USDA

    US Department of Agriculture

This work was supported in part by grants from the National Cancer Institute and the National Institute of Environmental Health Sciences (grants UO1CA/ES66572, UO1CA66572, CA52283, P30ES10126, and 5T32CA009330-25) and from the Lance Armstrong Foundation.

Conflict of interest: none declared.

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