Editorial See corresponding articles on pages 1269 and 1344.

Flavonoids and the risk of ovarian cancer1–3 Marta Rossi and Carlo La Vecchia cases, quintiles), derived from fixed-effects models for each class of flavonoids on the basis of all available data, are also shown in Table 1. Five studies, 2 cohorts (including the NHS cohorts) and 3 casecontrol studies, examined flavonols (10–12, 15). Of these, in addition to the NHS cohorts, a case-control study conducted in Italy and including 1031 cases reported a significant inverse association (OR for the highest compared with the lowest quintile: 0.63) (17). Of the remaining 3 studies, 2 gave nonsignificant RRs below unity (10, 15), and one showed RRs above unity (11). The pooled RR for the highest compared with the lowest quintile of flavonol intake from 5 studies on the basis of 3160 cases was 0.88 (95% CI: 0.80, 0.97). Data on flavones were available from 4 studies on a total of 3036 ovarian cancer cases (10–12). The pooled RR for flavones was 0.99 (95% CI: 0.89, 1.09), in line with the absence of association found in the NHS cohorts. In the NHS cohorts, there was an inverse association of borderline significance between flavanones and ovarian cancer risk. The only other study providing data was an Italian casecontrol study, which reported a nonsignificant OR of 1.28 (12). Thus, the pooled analysis, on the basis of 1754 cases, points to no association of flavanones with ovarian cancer risk. Three studies, including the NHS cohorts, provided data on flavanols (7, 12, 16). All of the risk estimates were below unity, but none of these was significant, nor was their pooled estimate (RR for the highest compared with the lowest intake: 0.88; 95% CI: 0.74, 1.05). Data on anthocyanidins were provided by the Italian casecontrol study (12), as well as by the NHS cohorts. None of these showed any material association, and the pooled RR for the highest compared with the lowest quintile of intake was 0.97. The study by Cassidy et al (7) did not include information on isoflavones (mainly derived from soya), for which various biological hypotheses in support of their beneficial effects on ovarian cancer have been proposed (5, 8, 9). In addition to their estrogenic activity, possibly leading to inhibition of growth and 1 From the Department of Epidemiology, IRCCS-Istituto di Ricerche Farmacologiche ‘‘Mario Negri,’’ Milan, Italy (MR), and the Department of Clinical Sciences and Community Health, Universita` degli Studi di Milano, Milan, Italy (CLV). 2 Supported by a contribution from the Italian Foundation for Cancer Research (FIRC). 3 Address correspondence to M Rossi, Department of Epidemiology, IRCCS-Istituto di Ricerche Farmacologiche ‘‘Mario Negri,’’ via G La Masa, 19-20156 Milan, Italy. E-mail: [email protected]. First published online September 24, 2014; doi: 10.3945/ajcn.114.098285.

Am J Clin Nutr 2014;100:1217–9. Printed in USA. Ó 2014 American Society for Nutrition

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The etiology of ovarian cancer is poorly understood. Recognized risk factors include family history of ovarian and/or breast cancer, nulliparity and low parity, and a reduced risk by oral contraceptives, but the relation of ovarian cancer with lifestyle factors, including diet, is still unclear (1). The role of fruit and vegetable consumption is controversial (2). However, the hypothesis that some compounds of plant foods have favorable effects on the risk of ovarian cancer has taken hold in the past decade (3). In particular, flavonoids are a group of .4000 compounds, generally categorized into 6 major classes (flavonols, flavones, flavanones, flavanols, anthocyanidins, and isoflavones) and a class of flavanol polymers. Flavonoids have been reported to have antioxidant, antimutagenic, and antiproliferative properties (4). Among them, isoflavones and some flavones, flavanones, and flavanols also have estrogenic or antiestrogenic activity, which makes these compounds of particular interest for possible effects on ovarian cancer risk (5). In fact, various mechanisms, including modulation of female hormones and their receptors, together with antioxidant and antiinflammatory activities, have been invoked in relation to ovarian cancer risk reduction (5, 6). In this context, in this issue of the Journal, Cassidy et al (7) investigated the role of flavonoids on the risk of epithelial ovarian cancer by analyzing data from the Nurses’ Health Study (NHS) and NHSII cohorts (subsequently referred to as NHS cohorts), which included 171,940 US women, 723 of whom developed ovarian cancer during 16–22 y of follow-up. By using data from validated food-frequency questionnaires and food composition tables to obtain estimates of intakes of flavonols, flavones, flavanones, flavanols, anthocyanidins, and polymers of flavanols, they found inverse associations between flavonol and flavanone intakes and ovarian cancer risk. Suggestive, but not significant, inverse associations were also reported for flavones and flavanol polymers. No association was found with other flavonoid classes or with total flavonoids. This is the largest prospective study to investigate the issue of flavonoids and ovarian cancer, and the first to examine flavanol polymers. At least 9 other studies investigated flavonoids in relation to ovarian cancer risk, but most of them focused on a few classes of flavonoids only (8–16). Of these, 6 were case-control and 3 were cohort investigations. Six were conducted in North America, one in Europe, one in Asia, and one in Australia. Their main results, together with those from the NHS cohorts, are presented in Table 1, to provide a summary view of our current knowledge on the issue. The pooled RR estimates for the highest compared with the lowest amount of intake (in most

11

10

9

8

7

6

5

4

3

2

(723) (1366) (205) (141) (1141) (1031) (280) (254) (124) (151)

0.76 (0.59, 0.98) — — 0.94 (0.83, 1.07)5 1.14 (0.84, 1.56)7 0.63 (0.47, 0.84) — — 0.71 (0.38, 1.32)9 — 5 (3160) 0.88 (0.80, 0.97)

Flavonols 0.87 (0.68, 1.11) — — 1.07 (0.95, 1.22)6 1.01 (0.58, 1.74)8 0.79 (0.60, 1.04) — — — — 4 (3036) 0.99 (0.89, 1.09)

Flavones 0.79 (0.63, 1.00) — — — — 1.28 (0.98, 1.68) — — — — 2 (1754) 0.97 (0.81, 1.15)

Flavanones

Anthocyanidins 0.95 (0.75, 1.21) — — — — 0.99 (0.76, 1.29) — — — — 2 (1754) 0.97 (0.81, 1.16)

Flavanols 0.91 (0.71, 1.16) — — — — 0.89 (0.67, 1.17) — — — 0.73 (0.44, 1.24)10 3 (1905) 0.88 (0.74, 1.05)

ref, reference. Values are for quintiles, unless otherwise specified. For .5 compared with ,0.9 mg/d of intake. For the third compared with the first tertile of intake. Refers to quercetin intake; information was also given for myricetin (RR: 0.97; 95% CI: 0.86, 1.10) and kaempferol (RR: 0.97; 95% CI; 0.86, 1.08). Refers to leuteolin intake; information was also given for apigenin (RR: 0.99; 95% CI: 0.87, 1.12). Refers to quercetin intake; information was also given for myricetin (RR: 1.12; 95% CI: 0.85, 1.49) and kaempferol (RR: 0.98; 95% CI; 0.73, 1.32). Refers to leuteolin intake; information was also given for apigenin (RR: 0.79; 95% CI: 0.59, 1.06). Refers to quercetin intake; information was also given for kaempferol (RR: 0.73; 95% CI; 0.39, 1.34). For the fourth compared with the first quartile of intake. Derived by using the fixed-effects model.

Cohort Case-control Case-control Cohort Case-control Case-control Cohort Case-control Case-control Cohort — —

Study design (no. of cases)

RR (95% CI) for the highest compared with the lowest amount of intake2

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1

Cassidy, 2014 (7) Neill, 2014 (8) Bandera, 2011 (9) Wang, 2009 (10) Gates, 2009 (11) Rossi, 2008 (12) Chang, 2007 (13) Zhang, 2004 (14) McCann, 2003 (15) Arts, 2002 (16) No. of studies (total no. of cases) Pooled RR11 (95% CI)

First author, year (ref)

TABLE 1 Study-specific and pooled estimates according to various classes of flavonoid intake1

— 0.87 (0.66, 1.13)3 0.86 (0.52, 1.42)4 — — 0.51 (0.37, 0.69) 0.71 (0.46, 1.12) 0.51 (0.31, 0.85) — — 5 (3136) 0.69 (0.58, 0.81)

Isoflavones

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EDITORIAL

We thank P Lagiou for her valuable comments and suggestions to improve the manuscript and I Garimoldi for editorial assistance. The authors’ responsibilities were as follows—MR and CLV: designed the structure of the editorial; MR: wrote the manuscript and had primary responsibility for final content; and CLV: revised the manuscript. Both of the authors read and approved the final manuscript. The authors declared no conflicts of interest.

REFERENCES 1. La Vecchia C. Epidemiology of ovarian cancer: a summary review. Eur J Cancer Prev 2001;10:125–9. 2. Webb P, Dorata G, Hunter D. Ovarian cancer. In: Adami H-O, Hunter D, Trichopoulos D, eds. Textbook of cancer epidemiology. 2nd ed. New York, NY: Oxford University Press, 2008:494–516.

3. Crane TE, Khulpateea BR, Alberts DS, Basen-Engquist K, Thomson CA. Dietary intake and ovarian cancer risk: a systematic review. Cancer Epidemiol Biomarkers Prev 2014;23:255–73. 4. Manach C, Scalbert A, Morand C, Remesy C, Jimenez L. Polyphenols: food sources and bioavailability. Am J Clin Nutr 2004;79:727–47. 5. Chen X, Anderson JJ. Isoflavones inhibit proliferation of ovarian cancer cells in vitro via an estrogen receptor-dependent pathway. Nutr Cancer 2001;41:165–71. 6. Shan W, Liu J. Inflammation: a hidden path to breaking the spell of ovarian cancer. Cell Cycle 2009;8:3107–11. 7. Cassidy A, Huang T, Rice MS, Rimm EB, Tworoger SS. Intake of dietary flavonoids and risk of epithelial ovarian cancer. Am J Clin Nutr 2014;100:1344–51. 8. Neill AS, Ibiebele TI, Lahmann PH, Hughes MC, Nagle CM, Webb PM. Dietary phyto-oestrogens and the risk of ovarian and endometrial cancers: findings from two Australian case-control studies. Br J Nutr 2014; 111:1430–40. 9. Bandera EV, King M, Chandran U, Paddock LE, Rodriguez-Rodriguez L, Olson SH. Phytoestrogen consumption from foods and supplements and epithelial ovarian cancer risk: a population-based case control study. BMC Womens Health 2011;11:40. 10. Wang L, Lee IM, Zhang SM, Blumberg JB, Buring JE, Sesso HD. Dietary intake of selected flavonols, flavones, and flavonoid-rich foods and risk of cancer in middle-aged and older women. Am J Clin Nutr 2009;89:905–12. 11. Gates MA, Vitonis AF, Tworoger SS, Rosner B, Titus-Ernstoff L, Hankinson SE, Cramer DW. Flavonoid intake and ovarian cancer risk in a population-based case-control study. Int J Cancer 2009;124:1918–25. 12. Rossi M, Negri E, Lagiou P, Talamini R, Dal Maso L, Montella M, Franceschi S, La Vecchia C. Flavonoids and ovarian cancer risk: A case-control study in Italy. Int J Cancer 2008;123:895–8. 13. Chang ET, Lee VS, Canchola AJ, Clarke CA, Purdie DM, Reynolds P, Anton-Culver H, Bernstein L, Deapen D, Peel D, et al. Diet and risk of ovarian cancer in the California Teachers Study cohort. Am J Epidemiol 2007;165:802–13. 14. Zhang M, Xie X, Lee AH, Binns CW. Soy and isoflavone intake are associated with reduced risk of ovarian cancer in Southeast China. Nutr Cancer 2004;49:125–30. 15. McCann SE, Freudenheim JL, Marshall JR, Graham S. Risk of human ovarian cancer is related to dietary intake of selected nutrients, phytochemicals and food groups. J Nutr 2003;133:1937–42. 16. Arts IC, Jacobs DR Jr, Gross M, Harnack LJ, Folsom AR. Dietary catechins and cancer incidence among postmenopausal women: the Iowa Women’s Health Study (United States). Cancer Causes Control 2002; 13:373–82. 17. Rossi M, Bosetti C, Negri E, Lagiou P, La Vecchia C. Flavonoids, proanthocyanidins, and cancer risk: a network of case-control studies from Italy. Nutr Cancer 2010;62:871–7. 18. van der Velpen V, Geelen A, Hollman PCH, Schouten EG, van ’t Veer P, Afman LA. Isoflavone supplement composition and equol producer status affect gene expression in adipose tissue: a double-blind, randomized, placebo-controlled crossover trial in postmenopausal women. Am J Clin Nutr 2014;100:1269–77. 19. Braem MG, Onland-Moret NC, Schouten LJ, Tjonneland A, Hansen L, Dahm CC, Overvad K, Lukanova A, Dossus L, Floegel A, et al. Coffee and tea consumption and the risk of ovarian cancer: a prospective cohort study and updated meta-analysis. Am J Clin Nutr 2012;95:1172–81.

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proliferation of ovarian cell lines, isoflavones may regulate cancer inflammation pathways. Also in the current issue of the Journal, a randomized trial by Velpen et al (18) in 55 postmenopausal women showed that isoflavone supplementation induces downregulation of expression of energy metabolism–related genes and antiinflammatory gene expression in adipose tissue of equol producers. Five studies evaluated the relation between isoflavone intake and ovarian cancer risk (8, 9, 12–14). In all of them, the RR was below unity (ranging between 0.51 and 0.87). The pooled RR for the highest compared with the lowest amount of isoflavone intake was 0.69 (95% CI: 0.58, 0.81). Epidemiologic studies on dietary flavonoids have limits related to measurement of intake, on the basis of food-frequency questionnaires, and bioavailability in the human body (4, 17). However, studies on biomarkers are few, and nutritional epidemiology studies on this issue are important to formulate and evaluate hypotheses on flavonoids, as well as on major food sources of flavonoids and cancer risk. In the NHS cohorts, the consumption of tea (one of the major source of flavonols in that study, contributing to 31% of the intake) was inversely related to ovarian cancer risk (7). A recent meta-analysis, however, did not support an association between tea and risk of ovarian cancer (19). In the Italian study, flavanol intake was mainly derived from apples, pears, and various common vegetables and ,10% was derived from tea (12). The study by Cassidy et al (7) contributed important data supporting a favorable role of flavonols in ovarian cancer risk. They also reported a significant inverse association for flavanones and suggestive inverse associations for flavones and flavanol polymers. Thus, accumulating evidence points to a possible role of flavonoids, including isoflavones, in reducing the risk of ovarian cancer, which merits further investigation.

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Flavonoids and the risk of ovarian cancer.

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