Soy Food Intake and Pancreatic Cancer Risk: the Japan Public Health Center-Based

Home , Miso soup

Author Manuscript Published OnlineFirst on March 13, 2020; DOI: 10.1158/1055-9965.EPI-19-1254 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Title: Soy food intake and pancreatic cancer risk: The Japan Public Health Center-based

Prospective Study

Authors: Yoko Yamagiwa1, Norie Sawada1, Taichi Shimazu1, Taiki Yamaji1, Atsushi

Goto1, Ribeka Takachi2, Junko Ishihara3, Motoki Iwasaki1, Manami Inoue1, and

Shoichiro Tsugane1; for the JPHC Study Group.

1 Epidemiology and Prevention Group, Center for Public Health Science, National

Cancer Center, Tokyo, Japan

2 Department of Food Science and Nutrition, Faculty of Human Life and Environment,

Nara Women’s University, Nara, Japan

3 Department of Food and Life Science, School of Life and Environmental Science,

Azabu University, Kanagawa, Japan

Running title: Soy food intake and pancreatic cancer risk

Keywords: dietary factor; fermentation; Japan Public Health Center-based Prospective

Study; pancreatic cancer; soy.

Additional information:

Grant support: National Cancer Center Research and Development Fund (since 2011), a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of

Downloaded from cebp.aacrjournals.org on September 26, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 13, 2020; DOI: 10.1158/1055-9965.EPI-19-1254 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Japan (from 1989 to 2010), and Ministry of Agriculture, Fishery and Forestry, Japan

(MAFFCPS-2016-1-1).

Corresponding author: Norie Sawada, MD, PhD

Epidemiology and Prevention Group, Center for Public Health Science, National

Cancer Center

Mailing address: 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045 Japan

Tel: +81-3-3547-5201

Fax: +81-3-3547-8578

E-mail: [email protected]

Conflicts of interest: The authors declare no potential conflicts of interest

Word count: 2808

Total number of figures and tables: One figure and four tables

Abstract

Background: Although the poor prognosis and increasing incidence of pancreatic cancer highlight the need for prevention strategies, few lifestyle risk factors for pancreatic cancer have yet been identified. Soybeans contain various bioactive compounds. However, the association between soy food intake and pancreatic cancer risk remains unknown.

Methods: The Japan Public Health Center-based Prospective Study (JPHC Study) is a cohort study conducted in a general Japanese population. To determine the association of soy food intake and pancreatic cancer incidence, we analyzed 90,185 participants who responded to a questionnaire on medical history and lifestyle factors, including dietary factors based on a food-frequency questionnaire in 1995–1998, using Cox proportional hazards models.

Results: During a median follow-up of 16.9 years, 577 cases of pancreatic cancer were identified. In the multivariate-adjusted model, total soy food intake was statistically significantly associated with an increased risk of pancreatic cancer (hazard ratio [HR] for the highest versus lowest intake quartile: 1.48; 95% confidence interval [CI]: 1.15–

1.92; P-trend = 0.007). Among soy foods, non-fermented soy food intake showed a statistically significant positive association with pancreatic cancer (HR: 1.41; 95% CI:

1.09–1.81; P-trend = 0.008), whereas fermented soy food intake showed no association

(HR: 0.96; 95% CI: 0.73–1.26; P-trend = 0.982).

Conclusions: Higher intake of soy foods, particularly non-fermented soy foods, might increase pancreatic cancer risk.

Impact: This study is the first to report an association between the intake of various soy foods and pancreatic cancer risk. Further studies are required to confirm our findings.

Introduction

Outcomes in pancreatic cancer are hampered by a lack of reliable tests for early diagnosis and effective treatments, and the prognosis of this condition remains poor. In

Japan, the 5-year survival rate was only 7.7% in 2010 (1), and mortality has now increased, ranking it as the 4th leading cause of cancer death (2). While previous epidemiological studies have identified some risk factors, including obesity, smoking, history of diabetes, history of chronic pancreatitis, and family history of pancreatic cancer (3,4), no clear prevention strategies for pancreatic cancer have yet been established.

Soybeans contain various bioactive compounds, including isoflavones, polypeptides, lectins, saponins, and enzyme inhibitors. These can have both beneficial and harmful effects on human health (5,6). Soy food intake has been associated with reduced risk of chronic diseases, including cardiovascular diseases; associated risk factors, such as hyperlipidemia and hypertension (7,8); and prostate and breast cancer (8-10). In contrast, animal experiments have shown that consumption of raw soy flour causes hypertrophy, hyperplasia, and neoplasm of the pancreas in some animals (11). To our knowledge, however, only one epidemiological study has demonstrated a positive association

between intake of a soy food – miso soup – and pancreatic cancer (12).

Here, we aimed to identify the association between soy food intake and pancreatic cancer risk in a large-scale, population-based prospective study in Japan.

Methods

Study population

The Japan Public Health Center-based Prospective Study (JPHC Study) is a nationwide, population-based longitudinal study that aims to assess the risk of cancer and cardiovascular disease in the Japanese population. Details of the JPHC Study have been described elsewhere (13,14). Briefly, Cohort I in 1990–1994 and Cohort II in 1993–

1995 enrolled 140,420 baseline participants aged 40–69 years in 11 prefectural public health center (PHC) areas (Fig. 1). The starting point for this study was defined as the

5-year follow-up survey in 1995–1998 due to its more detailed estimation of dietary intake. According to the eligibility criteria, we excluded participants shown in Fig.1.

Consequently, data from 90,185 participants (41,899 men and 48,286 women) were analyzed in this study. During the study period, 5,725 participants (6.3%) emigrated out of their PHC area and 104 (0.1%) were lost to follow-up. This study conformed to the

ethical guidelines of the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board of the National Cancer Center, Japan (Approval number:

2001-021).

Dietary assessment

Dietary factors were estimated based on the average intake frequency and amount consumed relative to a standard portion size during the previous year for 138 food items using the food-frequency questionnaire (FFQ), a validated, self-administered questionnaire, as previously reported (14,15). Of these, we classified soy-based foods into the following groups: total soy foods (eight soy food items), fermented soy foods

(two items: fermented soybeans [natto] and fermented soybean paste [miso]), non-fermented soy foods (six items: tofu [soy curd] in miso soup, boiled or cold tofu

[yudofu, hiyayakko], pre-drained tofu [yushidofu], freeze-dried tofu [koyadofu], deep fried tofu [aburaage], and soy milk), and tofu (three items: tofu in miso soup, boiled or cold tofu, and pre-drained tofu; grouped according to similarities in the manufacturing process). Intake of genistein, an isoflavone in soy foods, was calculated based on the

FFQ and the Standard Tables of Food Composition in Japan (7th revised version, 2015)

(16). Intake of soy foods and genistein was adjusted for total energy intake using the

residual method (17), and participants were divided into quartiles of intake for each food group for analysis. Spearman’s rank correlation coefficient for total soy food intake was 0.45 for men and 0.44 for women in Cohort I (18), and 0.52 for men and

0.54 for women in Cohort II (19) in assessment of the validity of the FFQ using 28-day dietary records.

Identification of pancreatic cancer

Pancreatic cancer incidence was determined from medical records and population-based cancer registries in the PHC areas as previously reported (14). In accordance with the

International Classification of Diseases for Oncology (Third Edition) (20), pancreatic cancer cases were determined by codes C25.0–C25.3 and C25.5–C25.9, but excluded endocrine tumor (C25.4) was excluded due to the difference in etiology. The proportion of pancreatic cancer cases specified by death certificate only was 12.5%.

Statistical analysis

We calculated person-years of follow-up for each participant from the date they completed the 5-year follow-up survey questionnaire to the date of pancreatic cancer diagnosis, emigration from the study area, death, or the end of follow-up on December

31, 2012 (for one PHC area) or December 31, 2013 (for nine PHC areas), whichever came first as previously reported (14).Hazard ratios (HRs) and 95% confidence intervals

(CIs) were calculated with Cox proportional hazards models according to the quartile of intake for each food group with the lowest category as a reference, or an increase in intake of 25 g/day (continuous variable). P-values for linear trends were calculated by assigning ordinal quartile scores to each quartile of intake in the models. P-values for quadratic trends also included a quadratic term in each linear trend model. In Model 1,

HRs were adjusted for sex, age (continuous) and study area. Model 2 was further adjusted for potential confounders: smoking status (non-smoker, past-smoker, current-smoker <20, 20 to <40, >40 cigarettes/day, or unknown), history of diabetes mellitus (yes or no), family history of pancreatic cancer (yes or no), body mass index

(BMI, <20, 20 to <25, 25 to <30, >30 kg/m2, or unknown), ethanol intake (0, <150, 150 to <300, 300 to <450, >450g/wk, or unknown), fish intake (quartile), meat intake

(quartile), vegetable intake (quartile), fruit intake (quartile), physical activity (>1 d/wk; yes, no, or unknown), coffee intake (>1 cup/day; yes, no, or unknown), and log-transformed energy intake (continuous). To reduce the possibility of reverse causation, cases of pancreatic cancer identified during the first 3 years of follow-up were excluded from Model 2. Moreover, we conducted analyses stratified by sex,

smoking status (never [non-smoker] or ever smoker [current and past smoker]) and BMI

(< 25 or > 25 kg/m2) to investigate whether soy food intake affects pancreatic cancer risk according to known risk factors for pancreatic cancer. Furthermore, to reduce the influence of factors associated with total soy food intake shown in Table 1, analyses stratified by age, vegetable intake, and coffee intake were conducted. P-values for interaction were calculated using likelihood ratio tests by comparing Cox proportional hazards models with and without a cross-product term, which was derived by crossing the ordinal quartile scores of the corresponding food intake category with the stratified factor. SAS version 9.3 (SAS Institute Inc, Cary, NC) was used in this study.

Results

During 1,433,854 person-years of follow-up (median 16.9 years), 577 cases of pancreatic cancer were identified, 314 in men and 263 in women. Median intake of total soy foods, fermented soy foods, and non-fermented soy foods in the study population was 69.5 g/day, 27.5 g/day, and 35.5 g/day, respectively. At baseline, participants with higher intake of total soy foods tended to be older, more likely to have diabetes, and have higher BMI. There were no sex differences among the intake quartiles for total soy foods (Table 1). Furthermore, those with higher intake of total soy foods tended to do

more physical activity, have higher intake of vegetables, not be current smokers, and have lower intake of alcohol and meat.

In the multivariate-adjusted model, total soy food intake showed a statistically significant positive association with pancreatic cancer incidence (HR of the highest quartile vs. the lowest; 1.48; 95% CI: 1.15–1.92; P for linear trend = 0.007) (Table 2).

Although P for linear trend was statistically significant in total soy food intake, only the highest category was statistically significantly increased in the point estimation of HR among quartiles compared with the lowest category. However, P for quadratic trend was not statistically significant (Supplementary Table 1). Among soy foods, higher intake of non-fermented soy foods showed a statistically significant positive association with pancreatic cancer (HR 1.41; 95% CI: 1.09–1.81; P for linear trend = 0.008), but fermented soy foods did not (HR 0.96; 95% CI: 0.73–1.26; P for linear trend = 0.982).

Similar findings were observed for an increase in intake of 25 g/day. The highest intake of genistein showed a statistically significant positive association with pancreatic cancer

(vs. the lowest; HR 1.33; 95% CI: 1.03–1.73; P for linear trend = 0.033). These findings did not change even after exclusion of participants diagnosed within the first 3 years of follow-up. However, we did not observed a statistically significant association for any

individual fermented or non-fermented soy food (Table 2, Supplementary Table 2).

In analyses stratified by sex (Table 3), total soy food intake was statistically significantly associated with pancreatic cancer in women (HR 1.73; 95% CI: 1.19–2.50;

P for linear trend = 0.004), but not in men (HR 1.28; 95% CI: 0.90–1.82; P for linear trend = 0.329). In analyses stratified by BMI (Table 4), we observed a statistically significant positive association between the highest intake of total soy foods and pancreatic cancer in participants with BMI ≥25 kg/m2 (HR 2.00, 95% CI: 1.18–3.40, P for linear trend = 0.004), but a non-significant association in participants with BMI <25 kg/m2 (HR 1.32, 95% CI: 0.98–1.79, P for linear trend = 0.220). However, there was no statistically significant interaction between total soy food intake and BMI (P-interaction

= 0.174). In analyses stratified by other factors, the direction of the association did not differ among strata for each factor, and P-values for interaction were not statistically significant in these analyses (Supplementary Table 3–7). Furthermore, the positive association between intake of total soy foods, non-fermented soy foods, and genistein and pancreatic cancer was observed in an analysis which excluded participants with a history of diabetes (Supplementary Table 8).

Discussion

We analyzed the association between soy food intake and pancreatic cancer incidence by detailed estimation of food intake in a large-scale, population-based prospective study in Japan. We found that total soy food intake was associated with increased risk of pancreatic cancer. To date, there is only one epidemiological study to have examined the association between soy food intake and pancreatic cancer: Hirayama showed that the frequency of miso soup intake was positively associated with pancreatic cancer risk (12).

However, we found no association between intake of fermented soy foods (miso and natto) or individual fermented soy foods (miso or natto) and pancreatic cancer risk.

Instead, we observed a positive association between non-fermented soy food intake and pancreatic cancer risk.

In contrast to our study, previous epidemiological studies have shown inverse associations between intake of legumes and pancreatic cancer risk (21,22). In the

Hawaii-Los Angeles Multiethnic Cohort Study (529 pancreatic cancer cases among

183,522 participants during 8.3 years of follow-up), multivariate models showed that higher intake of legumes, including tofu, had a nonsignificant inverse association

(highest vs. lowest; relative risk [RR]: 0.84, 95% CI: 0.62–1.13, P-trend = 0.099) (21).

The researchers suggested that isoflavones, proteinase inhibitors, saponins and dietary fiber may underlie the protective effects of legumes against cancer (21,23). In the

Adventist Health Study (40 pancreatic cancer cases among 34,000 participants during 6 years of follow-up), multivariate models showed that both vegetarian protein products including soy products, and beans/lentils/peas had statistically significant inverse associations (high vs. low; RR: 0.15, 95% CI: 0.03–0.89 for vegetarian protein products;

RR: 0.03, 95% CI: 0.003–0.24 for beans/lentils/peas) (24). There are several possible explanations for the difference between the present and previous findings. First, the previous studies grouped non-soy-based legumes with soy products, whereas our study focused on soy foods. These products differ in their nutrient content and heating methods. Legumes such as beans, lentils, and peas contain more carbohydrates and less fat than soybeans and are heated for longer periods, whereas soy contains more protein and fat and is heated for as long as the taste of the soy food is not adversely affected during the manufacture and cooking process (16). Second, the type and manufacture of soy foods in these countries may differ from those in Japan. Third, the studies differed in the number of cases and follow-up period, which may also have contributed to these discrepancies.

One possible mechanism for the increased incidence of pancreatic cancer following high intake of soy foods may be that the presence of trypsin inhibitors, which are contained in soybeans and are heat sensitive, prevents trypsin from inhibiting the release of cholecystokinin (CCK) (25-27), although the effects of trypsin inhibitors and CCK on the human pancreas are controversial (28,29). Consumption of raw soy flour has been shown to cause indigestion and malnutrition in most animals, as well as hypertrophy, hyperplasia, and cancerous lesions in the pancreas of some animals, including rats, due to trypsin inhibitor (5,11,26,27,30). When trypsin inhibitors in soybeans enable the release of CCK, the binding of CCK to CCK-B receptors causes

GTP-coupled responses that lead to proliferation of both acinar cells and islet cells in humans (29). Moreover, CCK induces the release of insulin in humans (31), which stimulates cell proliferation and mitogenesis (32). This putative involvement of CCK may also be supported by our finding that intake of total soy foods was increased in participants with BMI ≥25 kg/m2. Mechanisms underlying carcinogenesis due to obesity include cell proliferation via insulin and insulin-like growth factor signaling, and direct

DNA damage and chronic inflammation due to oxidative stress (29,33-35). Moreover, in obese mice, CCK is expressed in the pancreatic islets and CCK mRNA expression is upregulated 500-fold compared to that in lean mice (29), leading to accelerated cell

proliferation via autocrine/paracrine mechanisms.

Alternatively, additives to non-fermented soy foods should also be considered. For example, magnesium is used as a coagulant in the production of soy curd. However, magnesium intake was not associated with pancreatic cancer risk in previous cohort studies (36,37), and a deficiency in magnesium has been found to be associated with increased risk of pancreatic cancer (38). Magnesium intake is therefore unlikely to explain the increased risk of pancreatic cancer due to non-fermented soy food intake.

In contrast, certain harmful constituents in soy beans such as trypsin inhibitors may be inactivated by soaking, heating, and fermentation. Most traditional Asian soy foods are fermented to make them digestible (5). This may partly explain the lack of association between fermented soy foods and pancreatic cancer risk.

The increased pancreatic cancer risk following higher intake of total soy foods was more evident in women than in men. This may be supported by the anti-estrogenic properties of genistein, with a prospective study suggesting that female hormones have a protective role against pancreatic cancer (39).

Analyses stratified by sex, BMI, and smoking status suggested that the effect modification was unclear. Furthermore, analyses stratified by age, vegetable intake, and coffee intake suggested that the effect of these factors as confounders was small because the direction of the association was generally consistent between the strata of each factor compared with analysis of the overall population. The nature of this study does not allow a determination of causality. However, because the results remained relatively unchanged after exclusion of participants diagnosed with pancreatic cancer in the first 3 years of follow-up, we propose that reverse causality is unlikely.

The strengths of this study is due to features of JPHC study: prospective design with long follow-up period, large general population of participants with high response rate and high proportion of follow-up participants, and availability of food intake estimation based on a detailed, validated FFQ. Nevertheless, several limitations also warrant mention. First, estimation of lifestyle, including food intake, was conducted at a single time point using a 5-year follow-up survey. In analysis of joint classifications in total soy food intake combined quartile categories in 5-year and 10-year follow-up survey

(70260 participants, 378cases), HR of the highest in the 5-year and highest in the

10-year survey participants did not differ; however, participants whose intake changed did not show a consistent tendency (Supplementary Table 9). The effects of food intake may be better understood by accounting for changes in lifestyle habits, which would require longitudinal estimation. Second, the number of incident cases of pancreatic cancer may not have been sufficient for analyses stratified by exposure subgroup and risk factor, and the stratified analysis findings may in part be due to chance. Finally, our association findings may have been affected by residual confounding effects and unmeasured confounding variables.

In conclusion, higher intake of total soy foods, particularly non-fermented soy foods, might increase the risk of pancreatic cancer. This study is the first to report an association between the intake of various soy foods and pancreatic cancer risk. Further studies are required to confirm our findings.

Acknowledgments

JPHC members are listed at the following site (as of April 2017): http://epi.ncc.go.jp/en/jphc/781/7951.html. This study was supported by the National

Cancer Center Research and Development Fund (since 2011), a Grant-in-Aid for Cancer

Research from the Ministry of Health, Labour and Welfare of Japan (from 1989 to

2010), and the Ministry of Agriculture, Fishery and Forestry, Japan

(MAFF-CPS-2016-1-1).

References

1. Katanoda K, Hori M, Matsuda T, Shibata A, Nishino Y, Hattori M, et al. An

updated report on the trends in cancer incidence and mortality in Japan,

1958-2013. Japanese journal of clinical oncology 2015;45(4):390-401 doi

10.1093/jjco/hyv002.

2. Egawa S, Toma H, Ohigashi H, Okusaka T, Nakao A, Hatori T, et al. Japan

Pancreatic Cancer Registry; 30th year anniversary: Japan Pancreas Society.

Pancreas 2012;41(7):985-92 doi 10.1097/MPA.0b013e318258055c.

3. Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer.

Gastroenterology 2013;144(6):1252-61 doi 10.1053/j.gastro.2013.01.068.

4. Maisonneuve P, Lowenfels AB. Risk factors for pancreatic cancer: a summary

review of meta-analytical studies. Int J Epidemiol 2015;44(1):186-98 doi

10.1093/ije/dyu240.

5. D'Adamo CR, Sahin A. Soy foods and supplementation: a review of commonly

perceived health benefits and risks. Alternative therapies in health and medicine

2014;20 Suppl 1:39-51.

6. Chatterjee C, Gleddie S, Xiao CW. Soybean Bioactive Peptides and Their

Functional Properties. Nutrients 2018;10(9) doi 10.3390/nu10091211.

7. Kokubo Y, Iso H, Ishihara J, Okada K, Inoue M, Tsugane S, et al. Association of

dietary intake of soy, beans, and isoflavones with risk of cerebral and myocardial

infarctions in Japanese populations: the Japan Public Health Center-based

(JPHC) study cohort I. Circulation 2007;116(22):2553-62 doi

10.1161/circulationaha.106.683755.

8. Messina M. Soy and Health Update: Evaluation of the Clinical and

Epidemiologic Literature. Nutrients 2016;8(12) doi 10.3390/nu8120754.

9. Kurahashi N, Iwasaki M, Sasazuki S, Otani T, Inoue M, Tsugane S, et al. Soy

product and isoflavone consumption in relation to prostate cancer in Japanese

men. Cancer Epidemiol Biomarkers Prev 2007;16(3):538-45 doi

10.1158/1055-9965.epi-06-0517.

10. Nagata C, Mizoue T, Tanaka K, Tsuji I, Tamakoshi A, Matsuo K, et al. Soy

intake and breast cancer risk: an evaluation based on a systematic review of

epidemiologic evidence among the Japanese population. Jpn J Clin Oncol

2014;44(3):282-95 doi 10.1093/jjco/hyt203.

11. McGuinness EE, Morgan RG, Wormsley KG. Fate of pancreatic nodules

induced by raw soya flour in rats. Gut 1987;28 Suppl:207-12.

12. Hirayama T. Epidemiology of pancreatic cancer in Japan. Japanese journal of

clinical oncology 1989;19(3):208-15.

13. Tsugane S, Sawada N. The JPHC study: design and some findings on the typical

Japanese diet. Japanese journal of clinical oncology 2014;44(9):777-82 doi

10.1093/jjco/hyu096.

14. Yamagiwa Y, Sawada N, Shimazu T, Yamaji T, Goto A, Takachi R, et al. Fruit

and vegetable intake and pancreatic cancer risk in a population-based cohort

study in Japan. Int J Cancer 2019;144(8):1858-66 doi 10.1002/ijc.31894.

15. Ishihara J, Inoue M, Kobayashi M, Tanaka S, Yamamoto S, Iso H, et al. Impact

of the revision of a nutrient database on the validity of a self-administered food

frequency questionnaire (FFQ). J Epidemiol 2006;16(3):107-16.

16. Ministry of Education C, Sports, Science and Technology (MEXT), Japan.

Standard Tables of Food Composition in Japan - 2015 - (Seventh Revised

Edition). 2015.

17. Willett W, Stampfer MJ. Total energy intake: implications for epidemiologic

analyses. Am J Epidemiol 1986;124(1):17-27.

18. Sasaki S, Kobayashi M, Tsugane S. Validity of a self-administered food

frequency questionnaire used in the 5-year follow-up survey of the JPHC Study

Cohort I: comparison with dietary records for food groups. J Epidemiol

2003;13(1 Suppl):S57-63.

19. Ishihara J, Sobue T, Yamamoto S, Yoshimi I, Sasaki S, Kobayashi M, et al.

Validity and reproducibility of a self-administered food frequency questionnaire

in the JPHC Study Cohort II: study design, participant profile and results in

comparison with Cohort I. J Epidemiol 2003;13(1 Suppl):S134-47.

20. Geneva WHO. International Classification of Diseases for Oncology,third

edition. 2000.

21. Nothlings U, Wilkens LR, Murphy SP, Hankin JH, Henderson BE, Kolonel LN.

Vegetable intake and pancreatic cancer risk: the multiethnic cohort study. Am J

Epidemiol 2007;165(2):138-47 doi 10.1093/aje/kwj366.

22. Fraser GE. Associations between diet and cancer, ischemic heart disease, and

all-cause mortality in non-Hispanic white California Seventh-day Adventists.

Am J Clin Nutr 1999;70(3 Suppl):532s-8s doi 10.1093/ajcn/70.3.532s.

23. Steinmetz KA, Potter JD. Vegetables, fruit, and cancer prevention: a review. J

Am Diet Assoc 1996;96(10):1027-39 doi 10.1016/s0002-8223(96)00273-8.

24. Mills PK, Beeson WL, Abbey DE, Fraser GE, Phillips RL. Dietary habits and

past medical history as related to fatal pancreas cancer risk among Adventists.

Cancer 1988;61(12):2578-85.

25. Roebuck BD, Kaplita PV, Edwards BR, Praissman M. Effects of dietary fats and

soybean protein on azaserine-induced pancreatic carcinogenesis and plasma

cholecystokinin in the rat. Cancer Res 1987;47(5):1333-8.

26. McGuinness EE, Morgan RG, Wormsley KG. Effects of soybean flour on the

pancreas of rats. Environmental health perspectives 1984;56:205-12.

27. Roebuck BD. Enhancement of pancreatic carcinogenesis by raw soy protein

isolate: quantitative rat model and nutritional considerations. Advances in

experimental medicine and biology 1986;199:91-107.

28. Murphy JA, Criddle DN, Sherwood M, Chvanov M, Mukherjee R, McLaughlin

E, et al. Direct activation of cytosolic Ca2+ signaling and enzyme secretion by

cholecystokinin in human pancreatic acinar cells. Gastroenterology

2008;135(2):632-41 doi 10.1053/j.gastro.2008.05.026.

29. Smith JP, Solomon TE. Cholecystokinin and pancreatic cancer: the chicken or

the egg? American journal of physiology Gastrointestinal and liver physiology

2014;306(2):G91-g101 doi 10.1152/ajpgi.00301.2013.

30. Gumbmann MR, Spangler WL, Dugan GM, Rackis JJ. Safety of trypsin

inhibitors in the diet: effects on the rat pancreas of long-term feeding of soy

flour and soy protein isolate. Advances in experimental medicine and biology

1986;199:33-79.

31. Rehfeld JF. Cholecystokinin-From Local Gut Hormone to Ubiquitous Messenger.

Front Endocrinol (Lausanne) 2017;8:47 doi 10.3389/fendo.2017.00047.

32. Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel

LA, et al. Diabetes and cancer: a consensus report. CA Cancer J Clin

2010;60(4):207-21 doi 10.3322/caac.20078.

33. Bracci PM. Obesity and pancreatic cancer: overview of epidemiologic evidence

and biologic mechanisms. Molecular carcinogenesis 2012;51(1):53-63 doi

10.1002/mc.20778.

34. Tahergorabi Z, Khazaei M, Moodi M, Chamani E. From obesity to cancer: a

review on proposed mechanisms. Cell biochemistry and function

2016;34(8):533-45 doi 10.1002/cbf.3229.

35. Murphy N, Jenab M, Gunter MJ. Adiposity and gastrointestinal cancers:

epidemiology, mechanisms and future directions. Nat Rev Gastroenterol Hepatol

2018 doi 10.1038/s41575-018-0038-1.

36. Molina-Montes E, Wark PA, Sanchez MJ, Norat T, Jakszyn P, Lujan-Barroso L,

et al. Dietary intake of iron, heme-iron and magnesium and pancreatic cancer

risk in the European prospective investigation into cancer and nutrition cohort.

Int J Cancer 2012;131(7):E1134-47 doi 10.1002/ijc.27547.

37. Kesavan Y, Giovannucci E, Fuchs CS, Michaud DS. A prospective study of

magnesium and iron intake and pancreatic cancer in men. Am J Epidemiol

2010;171(2):233-41 doi 10.1093/aje/kwp373.

38. Dibaba D, Xun P, Yokota K, White E, He K. Magnesium intake and incidence of

pancreatic cancer: the VITamins and Lifestyle study. Br J Cancer

2015;113(11):1615-21 doi 10.1038/bjc.2015.382.

39. Andersson G, Borgquist S, Jirstrom K. Hormonal factors and pancreatic cancer

risk in women: The Malmo Diet and Cancer Study. Int J Cancer

2018;143(1):52-62 doi 10.1002/ijc.31302.

Table 1. Baseline characteristics of the study participants (N = 90,185) according to quartile of total soy food intake

Quartile of total soy food intake Lowest Second Third Highest P-trend6 No of participants 22546 22546 22547 22546

Person-years 347121 358567 364720 363447 <0.001 Age, years1 55 (49-63) 56 (50-62) 57 (51-63) 58 (52-63) <0.001 Male, % 46.6 45.8 46.3 47.2 0.143 Body mass index (kg/m2)1 23.1 (21.3-25.2) 23.2 (21.4-25.2) 23.3 (21.5-25.3) 23.6 (21.8-25.6) <0.001 History of diabetes mellitus, % 4.6 4.8 5.1 7.0 <0.001 Family history of pancreatic cancer, % 0.3 0.3 0.4 0.3 0.855 Current smoker, % 26.5 24.0 22.2 20.5 <0.001 Ethanol intake > 300g/wk, % 17.1 15.4 14.1 12.3 <0.001 Physical activity >1d/wk, % 18.9 20.2 20.4 22.8 <0.001 Coffee intake > 1cup/day, % 45.5 37.6 34.1 29.6 <0.001 Dietary intake

Total soy foods (g/day)1,2 32 (23-39) 57 (51-63) 84 (76-92) 138 (117-181)

Energy (kcal/day)1,2 1896 (1516-2364) 1933 (1570-2380) 1936 (1570-2391) 1865 (1501-2333) <0.001 Fermented soy foods (g/day)1,2,3 12 (6-20) 27 (17-37) 38 (24-51) 43 (25-62) <0.001 Non-fermented soy foods (g/day)1,2,4 16 (10-23) 29 (20-39) 46 (32-60) 96 (69-140) <0.001 Natto (g/day)1,2 2 (0-6) 7 (1-15) 13 (3-26) 16 (3-36) <0.001 Miso (g/day)1,2 8 (3-14) 16 (9-25) 20 (11-29) 22 (12-31) <0.001 Tofu (g/day)1,2,5 14 (8-21) 25 (16-34) 37 (24-52) 69 (41-102) <0.001 Genistein (mg/day) 1,2 9 (6-12) 17 (14-21) 26 (21-31) 39 (30-50) <0.001 Fish (g/day)1,2 70 (45-102) 78 (54-109) 80 (55-112) 77 (52-111) <0.001 Meat (g/day)1,2 54 (33-82) 51 (33-75) 49 (30-72) 45 (26-70) <0.001 Vegetables (g/day)1,2 150 (96-222) 180 (124-252) 193 (135-270) 209 (142-295) <0.001 Fruits (g/day)1,2 148 (73-252) 172 (96-270) 178 (104-278) 174 (100-271) <0.001

1Data are presented as median (interquartile range). 2Energy-adjusted using the residual method 3Fermented soy foods include fermented soybeans (natto) and fermented soybean paste (miso). 4Non-fermented soy foods include tofu [soy curd] in miso soup, boiled or cold tofu, pre-drained tofu, freeze-dried tofu, deep fried tofu, and soy milk. 5Tofu includes tofu in miso soup, boiled or cold tofu, and pre-drained tofu. 6P-trend was calculated using the Jonckheere-Terpstra trend test for continuous variables and Cochran-Armitage trend test for nominal variables.

Table 2. Hazard ratios and 95% confidence intervals for pancreatic cancer risk according to quartile of soy food intake

Excluding first 3 years Model 1 Model 2

No of No of Person- P for P for No of P for Exposures Intake1 cases participants years HR (95%CI) linear HR (95%CI) linear cases HR (95%CI) linear trend trend trend Total soy foods

Lowest 32 (0-45) 110 22546 347121 Ref 0.006 Ref 0.007 95 Ref 0.002 Second 57 (45-69) 146 22546 358567 1.23 (0.96-1.58) 1.23 (0.96-1.59) 122 1.21 (0.92-1.59)

Third 84 (69-103) 137 22547 364720 1.12 (0.86-1.44) 1.12 (0.86-1.46) 124 1.19 (0.90-1.58)

Highest 138 (103-) 184 22546 363447 1.48 (1.15-1.90) 1.48 (1.15-1.92) 164 1.56 (1.19-2.05)

25 g/day increase 1.03 (1.01-1.04) 0.007 1.02 (1.01-1.04) 0.014 1.03 (1.01-1.05) 0.007

Fermented soy foods

Lowest 8 (0-14) 128 22546 340932 Ref 0.916 Ref 0.982 109 Ref 0.598 Second 21 (14-27) 131 22546 358510 0.94 (0.73-1.21) 0.93 (0.72-1.19) 117 0.99 (0.75-1.30)

Third 35 (27-43) 159 22547 367543 1.06 (0.82-1.37) 1.04 (0.80-1.35) 137 1.08 (0.82-1.43)

Highest 56 (43-) 159 22546 366869 0.98 (0.75-1.28) 0.96 (0.73-1.26) 142 1.06 (0.79-1.42)

25 g/day increase 1.01 (0.92-1.11) 0.825 1.01 (0.92-1.10) 0.907 1.03 (0.94-1.13) 0.543

Non-fermented soy foods

Lowest 13 (0-20) 116 22546 352802 Ref 0.008 Ref 0.008 96 Ref 0.005 Second 27 (20-36) 142 22546 359027 1.21 (0.95-1.55) 1.22 (0.95-1.57) 128 1.33 (1.02-1.75)

Third 47 (36-64) 154 22547 361811 1.29 (1.01-1.64) 1.31 (1.02-1.68) 134 1.37 (1.05-1.80)

Highest 97 (64-) 165 22546 360215 1.40 (1.09-1.78) 1.41 (1.09-1.81) 147 1.51 (1.15-1.98)

25 g/day increase 1.03 (1.01-1.04) 0.006 1.02 (1.01-1.04) 0.012 1.03 (1.01-1.05) 0.009

Natto

Lowest 0 (0-1) 136 22546 347381 Ref 0.656 Ref 0.715 114 Ref 0.428 Second 4 (1-7) 140 22546 359075 1.06 (0.83-1.36) 1.05 (0.82-1.35) 126 1.14 (0.87-1.49)

Third 12 (7-20) 145 22547 366059 1.07 (0.82-1.40) 1.07 (0.82-1.40) 130 1.17 (0.88-1.56)

Highest 32 (20-) 156 22546 361339 1.07 (0.82-1.40) 1.06 (0.80-1.39) 135 1.14 (0.85-1.54)

25 g/day increase 1.01 (0.90-1.12) 0.928 1.00 (0.90-1.12) 0.976 1.02 (0.91-1.15) 0.710

Miso

Lowest 3 (0-8) 122 22546 338881 Ref 0.611 Ref 0.667 102 Ref 0.254 Second 11 (8-16) 133 22546 354040 1.00 (0.78-1.28) 1.00 (0.78-1.29) 113 1.05 (0.80-1.38)

Third 21 (16-25) 158 22547 370254 1.10 (0.86-1.41) 1.10 (0.85-1.41) 145 1.24 (0.95-1.63)

Highest 33 (25-) 164 22546 370679 1.04 (0.81-1.35) 1.04 (0.80-1.34) 145 1.14 (0.86-1.51)

25 g/day increase 1.03 (0.87-1.23) 0.702 1.03 (0.86-1.22) 0.763 1.07 (0.89-1.29) 0.455

Tofu

Lowest 10 (0-16) 121 22546 355724 Ref 0.007 Ref 0.007 98 Ref 0.002 Second 22 (16-28) 139 22546 359758 1.16 (0.91-1.48) 1.17 (0.91-1.50) 126 1.32 (1.01-1.72)

Third 37 (28-50) 154 22547 359251 1.28 (1.01-1.63) 1.30 (1.02-1.67) 135 1.42 (1.09-1.86)

Highest 74 (50-) 163 22546 359121 1.38 (1.08-1.76) 1.39 (1.09-1.79) 146 1.55 (1.18-2.03)

25 g/day increase 1.04 (1.01-1.08) 0.021 1.04 (1.00-1.08) 0.029 1.05 (1.01-1.08) 0.014

Genistein

Lowest 8 (0-12) 118 22546 349160 Ref 0.028 Ref 0.033 102 Ref 0.016 Second 16 (12-20) 137 22546 358444 1.09 (0.85-1.40) 1.09 (0.85-1.40) 121 1.13 (0.87-1.49)

Third 25 (20-31) 139 22547 363182 1.07 (0.83-1.39) 1.08 (0.83-1.40) 119 1.09 (0.82-1.44)

Highest 41 (31-) 183 22546 363067 1.34 (1.04-1.72) 1.33 (1.03-1.73) 163 1.43 (1.08-1.88)

25 mg/day increase 1.12 (1.02-1.23) 0.017 1.11 (1.01-1.23) 0.026 1.13 (1.03-1.25) 0.012

1Energy-adjusted using the residual method and presented as median (range). Unit: g/day for soy foods; mg/day for genistein. 2Cox proportional hazards regression models stratified by 10 study areas and adjusted for sex (men or women) and age (continuous) 3Model 2 was further adjusted for smoking status (non-smoker, past smoker, current smoker <20, 20 to <40, >40 cigarettes/day, or unknown), history of diabetes mellitus (yes or no), family history of pancreatic cancer (yes or no), body mass index (<20, 20 to <25, 25 to <30, and >30 kg/m2, or unknown), ethanol intake (0, <150, 150 to <300, 300 to <450, >450 g/wk, or unknown), fish intake (quartile), meat intake (quartile), vegetable intake (quartile), fruit intake (quartile), physical activity

(≥1 d/wk; yes, no, or unknown), coffee intake (≥1 cup/day; yes, no, or unknown), and log-transformed energy intake (continuous). Abbreviations: CI, confidence interval; HR, hazard ratio; No., number; Ref, reference.

Table 3. Hazard ratios and 95% confidence intervals of pancreatic cancer incidence according to quartile of soy food intake stratified by sex in multivariate-adjusted models

Men Women Quartile of intake P for Quartile of intake P for

linear linear Exposures Lowest Second Third Highest Lowest Second Third Highest P-interaction trend trend Total soy foods

No of cases 59 85 78 92 51 61 59 92

No of participants 10503 10331 10432 10633 12043 12215 12115 11913

Person-years 157922 159579 163461 165544 189198 198988 201258 197903

HR (95%CI)1 Ref 1.28 (0.91-1.80) 1.13 (0.79-1.61) 1.28 (0.90-1.82) 0.329 Ref 1.14 (0.78-1.66) 1.10 (0.74-1.62) 1.73 (1.19-2.50) 0.004 0.295

Fermented soy foods

No of cases 56 77 94 87 72 54 65 72

No of participants 9916 10058 10549 11376 12630 12488 11998 11170

Person-years 145696 154835 166601 179375 195236 203675 200942 187494

HR (95%CI)1 Ref 1.18 (0.83-1.69) 1.23 (0.85-1.77) 0.99 (0.67-1.47) 0.842 Ref 0.70 (0.49-1.01) 0.85 (0.59-1.24) 0.94 (0.64-1.39) 0.958 0.735

Non-fermented soy foods

No of cases 70 77 84 83 46 65 70 82

No of participants 11316 10341 10016 10226 11230 12205 12531 12320

Person-years 173504 159725 155686 157592 179298 199303 206124 202623

HR (95%CI)1 Ref 1.16 (0.83-1.61) 1.27 (0.92-1.77) 1.26 (0.90-1.76) 0.158 Ref 1.30 (0.89-1.91) 1.35 (0.92-1.97) 1.61 (1.10-2.36) 0.018 0.500

Genistein

No of cases 63 81 74 96 55 56 65 87

No of participants 10691 10404 10244 10560 11855 12142 12303 11986

Person-years 161397 160691 160029 164391 187763 197754 203154 198677

HR (95%CI)1 Ref 1.17 (0.84-1.65) 1.04 (0.73-1.49) 1.22 (0.85-1.74) 0.422 Ref 0.97 (0.67-1.42) 1.10 (0.75-1.61) 1.46 (1.00-2.12) 0.028 0.592

1Cox proportional hazards regression models stratified by 10 study areas and adjusted for age (continuous), smoking status (non-smoker, past smoker, current smoker <20, 20 to <40, >40 cigarettes/day, or unknown ), history of diabetes mellitus (yes or no), family history of pancreatic cancer (yes or no), body mass index (<20, 20 to <25, 25 to <30, >30 kg/m2, or unknown), ethanol intake (0, <150, 150 to <300, 300 to <450, >450 g/wk, or unknown ), fish intake (quartile), meat intake (quartile), vegetable intake (quartile), fruit intake (quartile), physical activity (≥1 d/wk; yes, no, or unknown), coffee intake (≥1 cup/day; yes, no, or unknown), and log-transformed energy intake (continuous). Abbreviations: CI, confidence interval; HR, hazard ratio; No., number; Ref, reference.

Table 4. Hazard ratios and 95% confidence intervals of pancreatic cancer incidence according to quartile of soy food intake stratified by BMI in multivariate-adjusted models

BMI <25 kg/m2 BMI >25 kg/m2 Quartile of intake P for Quartile of intake P for

linear linear Exposures Lowest Second Third Highest Lowest Second Third Highest P-interaction trend trend Total soy foods

No of cases 84 111 85 125 22 30 44 52

No of participants 15950 16090 15850 14992 5958 5985 6199 6977

Person-years 244417 254833 255698 241030 93786 97109 102046 114359

HR (95%CI)1 Ref 1.19 (0.89-1.60) 0.89 (0.65-1.22) 1.32 (0.98-1.79) 0.220 Ref 1.27 (0.73-2.22) 1.80 (1.06-3.07) 2.00 (1.18-3.40) 0.004 0.174

Fermented soy foods

No of cases 90 93 112 110 31 32 40 45

No of participants 15478 15669 15926 15809 6424 6341 6185 6169

Person-years 231992 248229 258897 256861 100008 102664 102386 102240

HR (95%CI)1 Ref 0.93 (0.69-1.26) 1.03 (0.76-1.40) 0.95 (0.68-1.32) 0.909 Ref 0.91 (0.55-1.52) 1.06 (0.63-1.77) 1.07 (0.62-1.83) 0.678 0.343

Non-fermented soy foods

No of cases 91 98 103 113 19 38 46 45

No of participants 15968 16190 15839 14885 5877 5890 6244 7108

Person-years 249408 257211 252548 236811 93777 95194 102700 115629

HR (95%CI)1 Ref 1.04 (0.78-1.39) 1.09 (0.81-1.45) 1.22 (0.91-1.64) 0.170 Ref 2.14 (1.23-3.74) 2.46 (1.42-4.27) 2.31 (1.32-4.05) 0.006 0.399

Genistein

No of cases 89 100 91 125 24 31 43 50

No of participants 15557 15847 15912 15566 6359 6193 6176 6391

Person-years 239590 250776 255361 250252 100763 100482 101302 104752

HR (95%CI)1 Ref 1.03 (0.77-1.38) 0.90 (0.66-1.23) 1.19 (0.88-1.62) 0.348 Ref 1.24 (0.72-2.14) 1.71 (1.01-2.91) 1.84 (1.07-3.14) 0.014 0.105 , 1Cox proportional hazards regression models stratified by 10 study areas and adjusted for sex (men or women), age (continuous), smoking status (non-smoker, past smoker, current smoker <20, 20 to <40, >40 cigarettes/day, or unknown ), history of diabetes mellitus (yes or no), family history of pancreatic cancer (yes or no), ethanol intake (0, <150, 150 to <300, 300 to <450, >450 g/wk, or unknown ), fish intake (quartile), meat intake (quartile), vegetable intake (quartile), fruit intake (quartile), physical activity (≥1 d/wk; yes, no, or unknown), coffee intake (≥1 cup/day; yes, no, or unknown), and log-transformed energy intake (continuous). In strata of BMI, further adjusted for BMI (<20 and 20 to <25 kg/m2 in BMI <25 kg/m2; 25 to <30 and >30 kg/m2 in BMI >25 kg/m2). Abbreviations: CI, confidence interval; HR, hazard ratio; No., number; Ref, reference; BMI, body mass index.

Figure legend

Fig 1. Flow diagram showing study participants for current analysis

Soy food intake and pancreatic cancer risk: The Japan Public Health Center-based Prospective Study

Yoko Yamagiwa, Norie Sawada, Taichi Shimazu, et al.

Cancer Epidemiol Biomarkers Prev Published OnlineFirst March 13, 2020.

Updated version Access the most recent version of this article at: doi:10.1158/1055-9965.EPI-19-1254

Supplementary Access the most recent supplemental material at: Material http://cebp.aacrjournals.org/content/suppl/2020/03/13/1055-9965.EPI-19-1254.DC1

Author Author manuscripts have been peer reviewed and accepted for publication but have not yet Manuscript been edited.

E-mail alerts Sign up to receive free email-alerts related to this article or journal.

Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at [email protected].

Permissions To request permission to re-use all or part of this article, use this link http://cebp.aacrjournals.org/content/early/2020/03/13/1055-9965.EPI-19-1254. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.