Does dietary folate intake modify effect of alcohol consumption on bre
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《英国医生杂志》
1 Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, 100 Drummond Street, Carlton, Victoria 3053, Australia, 2 Centre for Genetic Epidemiology, University of Melbourne, Melbourne
Correspondence to: L Baglietto laura.baglietto@cancervic.org.au
Objective To evaluate the effect of dietary folate intake on the relation between alcohol consumption and breast cancer risk.
Design Prospective cohort study.
Setting Melbourne, Australia.
Participants 17 447 Anglo-Australian women resident in Melbourne, aged 40-69 years at recruitment in 1990-4, and followed up until 31 December 2003.
Main outcome measure Invasive breast cancers diagnosed during follow-up and ascertained through the Victorian cancer registry.
Results 537 invasive breast cancers were diagnosed. Compared with lifetime abstainers, the hazard ratio for breast cancer in women who consumed an average of 40 g or more of alcohol daily at baseline was 1.41 (95% confidence interval 0.90 to 2.23). No direct association was found between dietary folate intake and risk of breast cancer, but a high folate intake mitigated the excess risk associated with alcohol. The estimated hazard ratio of an alcohol consumption of 40 g/day or more was 2.00 (1.14 to 3.49) for women with intakes of 200 μg/day of folate and 0.77 (0.33 to 1.80) for 400 μg/day of folate (P = 0.04 for interaction between alcohol and folate).
Conclusions An adequate dietary intake of folate might protect against the increased risk of breast cancer associated with alcohol consumption.
Alcohol consumption is a known risk factor for breast cancer. Although the strength of the association is modest, its adverse effect on breast cancer is one of the most consistent findings among the many hypothesised dietary risk factors.1 Pooled analyses of both case-control studies and cohort studies confirm a linear dose-response relation between alcohol consumption and risk of breast cancer.2 3 However, the mechanisms involved in alcohol associated carcinogenesis are still unknown. Ethanol itself is not considered a carcinogen, but increasing evidence suggests that its metabolite acetaldehyde is responsible for the co-carcinogenic effects of alcohol consumption.4
Folate is a B vitamin necessary for the production of red blood cells and the synthesis and normal methylation of DNA.5 The role of folate in colorectal carcinogenesis has been widely studied, and an inverse dose dependent relation has been found6-8; studies also fairly consistently show that people with high alcohol intake and low folate intake are at higher risk of colorectal neoplasia compared with those with low alcohol and high folate intake.9 Some studies have also reported an inverse association between folate from diet or dietary supplements and risk of breast cancer10-13; the protective effect of folate on breast cancer is more pronounced for heavy drinkers.14-18 These findings suggest that folate and alcohol act in opposite directions in breast carcinogenesis and may interact with each other. To test this hypothesis, we used the Melbourne collaborative cohort study to investigate if the association between alcohol consumption and risk of breast cancer is modified by intake of dietary folate.
Methods
Participants
The Melbourne collaborative cohort study is a prospective cohort study of 41 528 people (24 479 women) aged between 27 and 75 years at baseline (99.3% aged 40-69). Recruitment took place between 1990 and 1994 in the Melbourne metropolitan area. Participants were recruited through the electoral rolls (registration to vote is compulsory for adults in Australia), advertisements, and community announcements in local media (such as television, radio, newspapers). Participants gave written consent and permission for the investigators to obtain access to their medical records.
We excluded women with a confirmed diagnosis of invasive breast cancer before baseline (n = 381) and women who reported a diagnosis of angina, heart attack, or diabetes at baseline (n = 1461), because their diets were not representative of the whole cohort and we could not rule out the possibility that they had changed their diet in response to a recent diagnosis. Other exclusions included women with missing data on alcohol intake or food items and extreme values for self reported total energy intake (< 1st centile and > 99th centile) (n = 439). Of the 22 198 women left, 4751 (21%) were born in Greece or Italy. These women had a lower incidence of breast cancer than other women; few of them consumed alcohol (61% were lifetime abstainers compared with 31% of other women), and those that did had low levels of consumption (4% consumed at least 20 g/day compared with 13% of other women). Thus, they would have added little information about the association between alcohol consumption and risk of breast cancer. To avoid confounding by country of birth, we restricted the analyses to the 17 447 women born in Australia, New Zealand, or the United Kingdom.
Assessment of alcohol consumption and diet
At baseline we used a structured interview schedule to obtain information on potential risk factors, including age, sex, country of birth, education, reproductive history, and alcohol consumption. We asked participants a series of questions about their intake of alcoholic drinks. People who had never consumed at least 12 alcoholic drinks in a year were considered lifetime abstainers. We asked non-lifetime abstainers at baseline about their current average quantity and frequency of intake of beer, wine, and spirits. We then asked them about the intake of alcoholic beverages on each day during the week before the interview (diary). Participants who were not lifetime abstainers but did not consume alcohol at baseline were classified as ex-drinkers. We used Australian food composition tables to calculate alcohol consumption from alcoholic beverages.19 We categorised total alcohol consumption into lifetime abstainers, ex-drinkers, and current drinkers with low intake (1-19 g/day), medium intake (20-39 g/day), or high intake (40 g/day or more), according to guidelines of the Australian National Health and Medical Research Council.20
Participants completed a dietary questionnaire that included a 121 item food frequency questionnaire without portion sizes, specifically developed for the Melbourne collaborative cohort study.21 The questionnaire had 26 items on intake of vegetables, including fresh and cooked vegetables. We calculated nutrient intakes by using mean sex specific portion sizes from weighed food records. We used British data to calculate intake of folate.22 We calculated intake of energy from Australian food composition tables.19 Total energy intake included energy from the food frequency questionnaire and energy from alcohol. We calculated body mass index from measured height and weight.
Cohort follow-up and ascertainment of invasive breast cancer cases
Cases were women notified to the Victorian cancer registry with a first diagnosis of invasive breast cancer during follow-up to 31 December 2003. We did not count women with in situ breast cancer as cases.
We determined addresses and vital status of all participants by record linkage to electoral rolls, Victorian death records, and the national death index; from electronic phone books; and from responses to mailed questionnaires and newsletters. By the end of follow-up on 31 December 2003, 351 (2%) of the women included in this analysis were known to have left Victoria and 627 (4%) had died.
Statistical analysis
Follow-up began at baseline and continued until diagnosis of breast cancer, death, date of leaving Victoria, or 31 December 2003, whichever came first. We estimated hazard ratios by using Cox regression with age as the time metric. For both alcohol consumption and folate intake, we compared linear and more complex polynomial relations with the log hazard rate using fractional polynomials.23 Fractional polynomials are a method of analysing dose-response curves that make no a priori assumption about the shape of the curves. We also fitted a model in which alcohol intake was categorised according to the National Health and Medical Research Council categories.20 We studied the interaction between alcohol consumption and dietary folate intake. We compared non-nested models with the Akaike information criterion.24
We adjusted all analyses for total energy intake. Other potential confounders examined included education, body mass index, age at menarche, hormone replacement therapy, parity, and use of multivitamins. We did not include any of these variables in the final analyses, as their inclusion changed the estimated hazard ratios for the association with alcohol consumption by less than 5%. We used S-PLUS 6.2 (Insightful Corporation, Seattle, WA) and Stata 8.2 (Stata Corporation, College Station, TX) for all statistical analyses.
Results
We identified 537 incident cases of invasive breast cancer (536 were histologically verified) over an average of 10.1 person years of follow-up between 1990 and 2003 in the 17 447 women eligible for analysis. The mean age at baseline was 54.7 (SD 8.8) years; 36% of the women were under 50, 16% between 50 and 55, and 50% over 55 years.
Table 1 summarises the distribution of alcohol consumption and folate intake at baseline. Most women (86%) drank on average less than 20 g of alcohol a day, and only 538 (3%) reported an average daily intake of alcohol of at least 40 g. The Spearman's correlation coefficient between the reported daily average alcohol consumption during the current decade of age at baseline and that from the diary of the week before baseline was 0.87. The mean folate intake was 330 (SD 124) μg/day.
Table 1 Baseline characteristics of women in the Melbourne collaborative cohort study. Values are numbers (percentages) unless stated otherwise
The comparison between the models of the log hazard rate using linear and fractional polynomials of current alcohol consumption provided no evidence for a departure from linearity (P = 0.64; null hypothesis: the association is linear). From the model in which alcohol consumption was fitted as a linear term, the hazard rate increased by 1.03 (95% confidence interval 0.95 to 1.09) times for each additional 10 g a day intake of alcohol (P = 0.36). Next, we modelled alcohol consumption as a categorical variable using the National Health and Medical Research Council categories20 (table 2). The highest hazard ratio occurred in women who drank 40 g of alcohol a day or more; however, overall, the association of breast cancer incidence with alcohol was not significant (P = 0.29).
Table 2 Hazard ratios for association between average alcohol consumption at baseline and breast cancer in the Melbourne collaborative cohort study
The comparison between the regression models using linear and fractional polynomials of folate intake indicated that the more complex models did not fit better than the simple linear model (P = 0.27; null hypothesis: the association is linear). However, folate was not significantly related to incidence of breast cancer (for 100 μg/day increment of folate, relative risk = 1.01 (0.93 to 1.10); P = 0.79).
We evaluated whether folate modified the association between alcohol and breast cancer by fitting a model with an interaction between alcohol and folate. Our model of choice included alcohol as a categorical variable and folate as a continuous variable. We preferred this model to those including both variables as continuous because its results are easier to interpret. Table 3 shows estimates of the hazard ratios in relation to alcohol consumption for three values of folate intake. The values of folate were 200 μg/day, 330 μg/day (the mean value of folate intake), and 400 μg/day, which is the Australian recommended daily intake for women in childbearing age.25 Compared with abstainers who consumed 200 μg/day of folate, the hazard ratio was twofold higher for those women who consumed the most alcohol (40 g/day or more), but the hazards ratios for lower levels of consumption were not elevated. None of the hazard ratios was elevated for women in any other categories of alcohol consumption or for women in the highest category of consumption who had higher levels of folate intake. The test for the interaction gave P values of 0.04. The model in which alcohol and folate were both linear did not give a better fit (AIC = 9138 v AIC = 9138 for the model with alcohol as categorical and folate as linear). The test for the interaction between alcohol and folate was not significant (P = 0.42), probably because, as table 3 shows, the interaction between alcohol and folate was not a simple linear term.
Table 3 Hazard ratios* (95% confidence intervals) for association between average alcohol consumption at baseline and breast cancer by intake of dietary folate in the Melbourne collaborative cohort study
Discussion
Singletary KW, Gapstur SM. Alcohol and breast cancer: review of epidemiologic and experimental evidence and potential mechanisms. JAMA 2001;286: 2143-51.
Smith-Warner SA, Spiegelman D, Yaun SS, van den Brandt PA, Folsom AR, Goldbohm RA, et al. Alcohol and breast cancer in women: a pooled analysis of cohort studies. JAMA 1998;279: 535-40.
Hamajima N, Hirose K, Tajima K, Rohan T, Calle EE, Heath CW Jr, et al. Alcohol, tobacco and breast cancer—collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. Br J Cancer 2002;87: 1234-45.
Poschl G, Seitz HK. Alcohol and cancer. Alcohol Alcohol 2004;39: 155-65.
Fairfield KM, Fletcher RH. Vitamins for chronic disease prevention in adults: scientific review. JAMA 2002;287: 3116-26.
Kim Y-I. Folate and carcinogenesis: evidence, mechanisms, and implications. J Nutr Biochem 1999;10: 66-88.
Kim YI. Folate and cancer prevention: a new medical application of folate beyond hyperhomocysteinemia and neural tube defects. Nutr Rev 1999;57: 314-21.
Mason JB, Levesque T. Folate: effects on carcinogenesis and the potential for cancer chemoprevention. Oncology 1996;10: 1727-36, 1742-3; discussion 1743-4.
Giovannucci E. Alcohol, one-carbon metabolism, and colorectal cancer: recent insights from molecular studies. J Nutr 2004;134: 2475-81S.
Shrubsole MJ, Jin F, Dai Q, Shu XO, Potter JD, Hebert JR, et al. Dietary folate intake and breast cancer risk: results from the Shanghai breast cancer study. Cancer Res 2001;61: 7136-41.
Ronco A, De Stefani E, Boffetta P, Deneo-Pellegrini H, Mendilaharsu M, Leborgne F. Vegetables, fruits, and related nutrients and risk of breast cancer: a case-control study in Uruguay. Nutr Cancer 1999;35: 111-9.
Freudenheim JL, Marshall JR, Vena JE, Laughlin R, Brasure JR, Swanson MK, et al. Premenopausal breast cancer risk and intake of vegetables, fruits, and related nutrients. J Natl Cancer Inst 1996;88: 340-8.
Graham S, Hellmann R, Marshall J, Freudenheim J, Vena J, Swanson M, et al. Nutritional epidemiology of postmenopausal breast cancer in western New York. Am J Epidemiol 1991;134: 552-66.
Zhang S, Hunter DJ, Hankinson SE, Giovannucci EL, Rosner BA, Colditz GA, et al. A prospective study of folate intake and the risk of breast cancer. JAMA 1999;281: 1632-7.
Negri E, La Vecchia C, Franceschi S. Re: dietary folate consumption and breast cancer risk. J Natl Cancer Inst 2000;92: 1270-1.
Rohan TE, Jain MG, Howe GR, Miller AB. Dietary folate consumption and breast cancer risk. J Natl Cancer Inst 2000;92: 266-9.
Sellers TA, Kushi LH, Cerhan JR, Vierkant RA, Gapstur SM, Vachon CM, et al. Dietary folate intake, alcohol, and risk of breast cancer in a prospective study of postmenopausal women. Epidemiology 2001;12: 420-8.
Sellers TA, Grabrick DM, Vierkant RA, Harnack L, Olson JE, Vachon CM, et al. Does folate intake decrease risk of postmenopausal breast cancer among women with a family history? Cancer Causes Control 2004;15: 113-20.
Lewis J, Milligan G, Hunt A. NUTTAB95 nutrient data table for use in Australia. Canberra: Australian Government Publishing Service, 1995.
Pols RG, Hawks DV. Is there a safe level of daily consumption of alcohol for men and women? Recommendations regarding responsible drinking behaviour. Canberra: National Health and Medical Research Council, 1992.
Ireland P, Jolley D, Giles GG, O'Dea K, Powles J, Rutishauser I, et al. Development of the Melbourne FFQ: a food frequency questionnaire for use in an Australian prospective study involving an ethnically diverse cohort. Asia Pacific J Clin Nutr 1994;3: 19-31.
Holland B, Welch AA, Unwin ID, Buss DH, Paul AA, Southgate DAT. McCance and Widdowson's the composition of foods. 5th ed. Cambridge: Royal Society of Chemistry, 1993.
Altman DG, Royston P. Regression using fractional polynomials of continuous covariates: parsimonious parametric modelling. Appl Stat 1994;43: 429-67.
Akaike H. Information theory and an extension of the maximum likelihood principle. 2nd International Symposium on Information Theory 1973: 267-81.
Abraham B, Webb K. Interim evaluation of the voluntary folate fortification policy. Australian Food and Nutrition Monitoring Unit, 2000. ftp://www.sph.uq.edu.au/pdf.ftp/P08b.pdf (accessed 5 Aug 2005).
Report of the Expert Panel on Folate Fortification. Endorsed at the 117th session of the NHMRC, Sydney, 1-2 June 1994. Canberra: Australian Government Publishing Service, 1995.
Metz J, Sikaris KA, Maxwell EL, Levin MD. Changes in serum folate concentrations following voluntary food fortification in Australia. Med J Aust 2002;176: 90-1.
Seitz HK, Matsuzaki S, Yokoyama A, Homann N, Vakevainen S, Wang XD. Alcohol and cancer. Alcohol Clin Exp Res 2001;25: 137-43.(Laura Baglietto, senior research fellow1)
Correspondence to: L Baglietto laura.baglietto@cancervic.org.au
Objective To evaluate the effect of dietary folate intake on the relation between alcohol consumption and breast cancer risk.
Design Prospective cohort study.
Setting Melbourne, Australia.
Participants 17 447 Anglo-Australian women resident in Melbourne, aged 40-69 years at recruitment in 1990-4, and followed up until 31 December 2003.
Main outcome measure Invasive breast cancers diagnosed during follow-up and ascertained through the Victorian cancer registry.
Results 537 invasive breast cancers were diagnosed. Compared with lifetime abstainers, the hazard ratio for breast cancer in women who consumed an average of 40 g or more of alcohol daily at baseline was 1.41 (95% confidence interval 0.90 to 2.23). No direct association was found between dietary folate intake and risk of breast cancer, but a high folate intake mitigated the excess risk associated with alcohol. The estimated hazard ratio of an alcohol consumption of 40 g/day or more was 2.00 (1.14 to 3.49) for women with intakes of 200 μg/day of folate and 0.77 (0.33 to 1.80) for 400 μg/day of folate (P = 0.04 for interaction between alcohol and folate).
Conclusions An adequate dietary intake of folate might protect against the increased risk of breast cancer associated with alcohol consumption.
Alcohol consumption is a known risk factor for breast cancer. Although the strength of the association is modest, its adverse effect on breast cancer is one of the most consistent findings among the many hypothesised dietary risk factors.1 Pooled analyses of both case-control studies and cohort studies confirm a linear dose-response relation between alcohol consumption and risk of breast cancer.2 3 However, the mechanisms involved in alcohol associated carcinogenesis are still unknown. Ethanol itself is not considered a carcinogen, but increasing evidence suggests that its metabolite acetaldehyde is responsible for the co-carcinogenic effects of alcohol consumption.4
Folate is a B vitamin necessary for the production of red blood cells and the synthesis and normal methylation of DNA.5 The role of folate in colorectal carcinogenesis has been widely studied, and an inverse dose dependent relation has been found6-8; studies also fairly consistently show that people with high alcohol intake and low folate intake are at higher risk of colorectal neoplasia compared with those with low alcohol and high folate intake.9 Some studies have also reported an inverse association between folate from diet or dietary supplements and risk of breast cancer10-13; the protective effect of folate on breast cancer is more pronounced for heavy drinkers.14-18 These findings suggest that folate and alcohol act in opposite directions in breast carcinogenesis and may interact with each other. To test this hypothesis, we used the Melbourne collaborative cohort study to investigate if the association between alcohol consumption and risk of breast cancer is modified by intake of dietary folate.
Methods
Participants
The Melbourne collaborative cohort study is a prospective cohort study of 41 528 people (24 479 women) aged between 27 and 75 years at baseline (99.3% aged 40-69). Recruitment took place between 1990 and 1994 in the Melbourne metropolitan area. Participants were recruited through the electoral rolls (registration to vote is compulsory for adults in Australia), advertisements, and community announcements in local media (such as television, radio, newspapers). Participants gave written consent and permission for the investigators to obtain access to their medical records.
We excluded women with a confirmed diagnosis of invasive breast cancer before baseline (n = 381) and women who reported a diagnosis of angina, heart attack, or diabetes at baseline (n = 1461), because their diets were not representative of the whole cohort and we could not rule out the possibility that they had changed their diet in response to a recent diagnosis. Other exclusions included women with missing data on alcohol intake or food items and extreme values for self reported total energy intake (< 1st centile and > 99th centile) (n = 439). Of the 22 198 women left, 4751 (21%) were born in Greece or Italy. These women had a lower incidence of breast cancer than other women; few of them consumed alcohol (61% were lifetime abstainers compared with 31% of other women), and those that did had low levels of consumption (4% consumed at least 20 g/day compared with 13% of other women). Thus, they would have added little information about the association between alcohol consumption and risk of breast cancer. To avoid confounding by country of birth, we restricted the analyses to the 17 447 women born in Australia, New Zealand, or the United Kingdom.
Assessment of alcohol consumption and diet
At baseline we used a structured interview schedule to obtain information on potential risk factors, including age, sex, country of birth, education, reproductive history, and alcohol consumption. We asked participants a series of questions about their intake of alcoholic drinks. People who had never consumed at least 12 alcoholic drinks in a year were considered lifetime abstainers. We asked non-lifetime abstainers at baseline about their current average quantity and frequency of intake of beer, wine, and spirits. We then asked them about the intake of alcoholic beverages on each day during the week before the interview (diary). Participants who were not lifetime abstainers but did not consume alcohol at baseline were classified as ex-drinkers. We used Australian food composition tables to calculate alcohol consumption from alcoholic beverages.19 We categorised total alcohol consumption into lifetime abstainers, ex-drinkers, and current drinkers with low intake (1-19 g/day), medium intake (20-39 g/day), or high intake (40 g/day or more), according to guidelines of the Australian National Health and Medical Research Council.20
Participants completed a dietary questionnaire that included a 121 item food frequency questionnaire without portion sizes, specifically developed for the Melbourne collaborative cohort study.21 The questionnaire had 26 items on intake of vegetables, including fresh and cooked vegetables. We calculated nutrient intakes by using mean sex specific portion sizes from weighed food records. We used British data to calculate intake of folate.22 We calculated intake of energy from Australian food composition tables.19 Total energy intake included energy from the food frequency questionnaire and energy from alcohol. We calculated body mass index from measured height and weight.
Cohort follow-up and ascertainment of invasive breast cancer cases
Cases were women notified to the Victorian cancer registry with a first diagnosis of invasive breast cancer during follow-up to 31 December 2003. We did not count women with in situ breast cancer as cases.
We determined addresses and vital status of all participants by record linkage to electoral rolls, Victorian death records, and the national death index; from electronic phone books; and from responses to mailed questionnaires and newsletters. By the end of follow-up on 31 December 2003, 351 (2%) of the women included in this analysis were known to have left Victoria and 627 (4%) had died.
Statistical analysis
Follow-up began at baseline and continued until diagnosis of breast cancer, death, date of leaving Victoria, or 31 December 2003, whichever came first. We estimated hazard ratios by using Cox regression with age as the time metric. For both alcohol consumption and folate intake, we compared linear and more complex polynomial relations with the log hazard rate using fractional polynomials.23 Fractional polynomials are a method of analysing dose-response curves that make no a priori assumption about the shape of the curves. We also fitted a model in which alcohol intake was categorised according to the National Health and Medical Research Council categories.20 We studied the interaction between alcohol consumption and dietary folate intake. We compared non-nested models with the Akaike information criterion.24
We adjusted all analyses for total energy intake. Other potential confounders examined included education, body mass index, age at menarche, hormone replacement therapy, parity, and use of multivitamins. We did not include any of these variables in the final analyses, as their inclusion changed the estimated hazard ratios for the association with alcohol consumption by less than 5%. We used S-PLUS 6.2 (Insightful Corporation, Seattle, WA) and Stata 8.2 (Stata Corporation, College Station, TX) for all statistical analyses.
Results
We identified 537 incident cases of invasive breast cancer (536 were histologically verified) over an average of 10.1 person years of follow-up between 1990 and 2003 in the 17 447 women eligible for analysis. The mean age at baseline was 54.7 (SD 8.8) years; 36% of the women were under 50, 16% between 50 and 55, and 50% over 55 years.
Table 1 summarises the distribution of alcohol consumption and folate intake at baseline. Most women (86%) drank on average less than 20 g of alcohol a day, and only 538 (3%) reported an average daily intake of alcohol of at least 40 g. The Spearman's correlation coefficient between the reported daily average alcohol consumption during the current decade of age at baseline and that from the diary of the week before baseline was 0.87. The mean folate intake was 330 (SD 124) μg/day.
Table 1 Baseline characteristics of women in the Melbourne collaborative cohort study. Values are numbers (percentages) unless stated otherwise
The comparison between the models of the log hazard rate using linear and fractional polynomials of current alcohol consumption provided no evidence for a departure from linearity (P = 0.64; null hypothesis: the association is linear). From the model in which alcohol consumption was fitted as a linear term, the hazard rate increased by 1.03 (95% confidence interval 0.95 to 1.09) times for each additional 10 g a day intake of alcohol (P = 0.36). Next, we modelled alcohol consumption as a categorical variable using the National Health and Medical Research Council categories20 (table 2). The highest hazard ratio occurred in women who drank 40 g of alcohol a day or more; however, overall, the association of breast cancer incidence with alcohol was not significant (P = 0.29).
Table 2 Hazard ratios for association between average alcohol consumption at baseline and breast cancer in the Melbourne collaborative cohort study
The comparison between the regression models using linear and fractional polynomials of folate intake indicated that the more complex models did not fit better than the simple linear model (P = 0.27; null hypothesis: the association is linear). However, folate was not significantly related to incidence of breast cancer (for 100 μg/day increment of folate, relative risk = 1.01 (0.93 to 1.10); P = 0.79).
We evaluated whether folate modified the association between alcohol and breast cancer by fitting a model with an interaction between alcohol and folate. Our model of choice included alcohol as a categorical variable and folate as a continuous variable. We preferred this model to those including both variables as continuous because its results are easier to interpret. Table 3 shows estimates of the hazard ratios in relation to alcohol consumption for three values of folate intake. The values of folate were 200 μg/day, 330 μg/day (the mean value of folate intake), and 400 μg/day, which is the Australian recommended daily intake for women in childbearing age.25 Compared with abstainers who consumed 200 μg/day of folate, the hazard ratio was twofold higher for those women who consumed the most alcohol (40 g/day or more), but the hazards ratios for lower levels of consumption were not elevated. None of the hazard ratios was elevated for women in any other categories of alcohol consumption or for women in the highest category of consumption who had higher levels of folate intake. The test for the interaction gave P values of 0.04. The model in which alcohol and folate were both linear did not give a better fit (AIC = 9138 v AIC = 9138 for the model with alcohol as categorical and folate as linear). The test for the interaction between alcohol and folate was not significant (P = 0.42), probably because, as table 3 shows, the interaction between alcohol and folate was not a simple linear term.
Table 3 Hazard ratios* (95% confidence intervals) for association between average alcohol consumption at baseline and breast cancer by intake of dietary folate in the Melbourne collaborative cohort study
Discussion
Singletary KW, Gapstur SM. Alcohol and breast cancer: review of epidemiologic and experimental evidence and potential mechanisms. JAMA 2001;286: 2143-51.
Smith-Warner SA, Spiegelman D, Yaun SS, van den Brandt PA, Folsom AR, Goldbohm RA, et al. Alcohol and breast cancer in women: a pooled analysis of cohort studies. JAMA 1998;279: 535-40.
Hamajima N, Hirose K, Tajima K, Rohan T, Calle EE, Heath CW Jr, et al. Alcohol, tobacco and breast cancer—collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. Br J Cancer 2002;87: 1234-45.
Poschl G, Seitz HK. Alcohol and cancer. Alcohol Alcohol 2004;39: 155-65.
Fairfield KM, Fletcher RH. Vitamins for chronic disease prevention in adults: scientific review. JAMA 2002;287: 3116-26.
Kim Y-I. Folate and carcinogenesis: evidence, mechanisms, and implications. J Nutr Biochem 1999;10: 66-88.
Kim YI. Folate and cancer prevention: a new medical application of folate beyond hyperhomocysteinemia and neural tube defects. Nutr Rev 1999;57: 314-21.
Mason JB, Levesque T. Folate: effects on carcinogenesis and the potential for cancer chemoprevention. Oncology 1996;10: 1727-36, 1742-3; discussion 1743-4.
Giovannucci E. Alcohol, one-carbon metabolism, and colorectal cancer: recent insights from molecular studies. J Nutr 2004;134: 2475-81S.
Shrubsole MJ, Jin F, Dai Q, Shu XO, Potter JD, Hebert JR, et al. Dietary folate intake and breast cancer risk: results from the Shanghai breast cancer study. Cancer Res 2001;61: 7136-41.
Ronco A, De Stefani E, Boffetta P, Deneo-Pellegrini H, Mendilaharsu M, Leborgne F. Vegetables, fruits, and related nutrients and risk of breast cancer: a case-control study in Uruguay. Nutr Cancer 1999;35: 111-9.
Freudenheim JL, Marshall JR, Vena JE, Laughlin R, Brasure JR, Swanson MK, et al. Premenopausal breast cancer risk and intake of vegetables, fruits, and related nutrients. J Natl Cancer Inst 1996;88: 340-8.
Graham S, Hellmann R, Marshall J, Freudenheim J, Vena J, Swanson M, et al. Nutritional epidemiology of postmenopausal breast cancer in western New York. Am J Epidemiol 1991;134: 552-66.
Zhang S, Hunter DJ, Hankinson SE, Giovannucci EL, Rosner BA, Colditz GA, et al. A prospective study of folate intake and the risk of breast cancer. JAMA 1999;281: 1632-7.
Negri E, La Vecchia C, Franceschi S. Re: dietary folate consumption and breast cancer risk. J Natl Cancer Inst 2000;92: 1270-1.
Rohan TE, Jain MG, Howe GR, Miller AB. Dietary folate consumption and breast cancer risk. J Natl Cancer Inst 2000;92: 266-9.
Sellers TA, Kushi LH, Cerhan JR, Vierkant RA, Gapstur SM, Vachon CM, et al. Dietary folate intake, alcohol, and risk of breast cancer in a prospective study of postmenopausal women. Epidemiology 2001;12: 420-8.
Sellers TA, Grabrick DM, Vierkant RA, Harnack L, Olson JE, Vachon CM, et al. Does folate intake decrease risk of postmenopausal breast cancer among women with a family history? Cancer Causes Control 2004;15: 113-20.
Lewis J, Milligan G, Hunt A. NUTTAB95 nutrient data table for use in Australia. Canberra: Australian Government Publishing Service, 1995.
Pols RG, Hawks DV. Is there a safe level of daily consumption of alcohol for men and women? Recommendations regarding responsible drinking behaviour. Canberra: National Health and Medical Research Council, 1992.
Ireland P, Jolley D, Giles GG, O'Dea K, Powles J, Rutishauser I, et al. Development of the Melbourne FFQ: a food frequency questionnaire for use in an Australian prospective study involving an ethnically diverse cohort. Asia Pacific J Clin Nutr 1994;3: 19-31.
Holland B, Welch AA, Unwin ID, Buss DH, Paul AA, Southgate DAT. McCance and Widdowson's the composition of foods. 5th ed. Cambridge: Royal Society of Chemistry, 1993.
Altman DG, Royston P. Regression using fractional polynomials of continuous covariates: parsimonious parametric modelling. Appl Stat 1994;43: 429-67.
Akaike H. Information theory and an extension of the maximum likelihood principle. 2nd International Symposium on Information Theory 1973: 267-81.
Abraham B, Webb K. Interim evaluation of the voluntary folate fortification policy. Australian Food and Nutrition Monitoring Unit, 2000. ftp://www.sph.uq.edu.au/pdf.ftp/P08b.pdf (accessed 5 Aug 2005).
Report of the Expert Panel on Folate Fortification. Endorsed at the 117th session of the NHMRC, Sydney, 1-2 June 1994. Canberra: Australian Government Publishing Service, 1995.
Metz J, Sikaris KA, Maxwell EL, Levin MD. Changes in serum folate concentrations following voluntary food fortification in Australia. Med J Aust 2002;176: 90-1.
Seitz HK, Matsuzaki S, Yokoyama A, Homann N, Vakevainen S, Wang XD. Alcohol and cancer. Alcohol Clin Exp Res 2001;25: 137-43.(Laura Baglietto, senior research fellow1)