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Folate and lung cancer risk
Lung Cancer 67 (2010) 380–381
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Letter to the Editor Folate and lung cancer risk Keywords: Lung neoplasms Dietary supplements Micronutrients Prospective cohort study Randomized controlled trials as topic Folic acid Folate
Dear Sir, In our paper published in Lung Cancer, we found a significantly increased lung cancer risk with dietary folate in a prospective Danish cohort study of 55,557 men and women aged 50–64 years: RR 1.15; 95% CI (1.03–1.28) [1]. Since no study had previously reported a positive association between folate intake and lung cancer, this surprising result led us to reanalyze the data, to evaluate if this was an erroneous finding or if we could reveal a confounder accounting for the association. However, the association remained significant, and we hence reported it in our paper, stating concern that it might be due to confounding, which we had not been able to account for. In a recently published article in JAMA, however, Ebbing et al. [2] found a tendency towards an increased lung cancer risk with folic acid supplementation of 0.8 mg/day in a double-blinded, placebocontrolled trial of 6837 Norwegian men and women, based on the occurrence of 92 lung cancer cases: RR 1.59; 95% CI (0.92–2.75). The authors report this as a surprising finding, stating that no previous epidemiological studies have found folate or folic acid to increase lung cancer risk [2]. Our finding of an increased lung cancer risk with dietary but not supplemental folate, as should be expected from the Norwegian trial, may be explained by the fact that the dietary intake in our cohort is more that 3-fold that of supplemental intake (0.33 mg/day vs. 0.1 mg/day). In comparison, the participants in the Norwegian trial received supplements containing 0.8 mg/day. It has been suggested that the harmful effects of folate in carcinogenesis appear only at significantly high doses [3], and it is possible, that a threshold value is not reached with the supplemental intake in our cohort. A search of Medline revealed only two previous experimental trials testing the effect of folic acid in relation to lung cancer. Both used a combination of 2.5 mg folic acid, 50 mg B6 vitamin and 1 mg B12 vitamin daily or placebo. The Women’s Antioxidant and Folic Acid Cardiovascular Study (WAFACS) found no effect (RR: 1.04; 95% CI: 0.58–1.87) in a population of 5442 American women aged 40 years or above. This result is however based on only 45 cases [4]. The Heart Outcomes Prevention Evaluation 2 (HOPE-2) also found no significant effect (RR: 1.16; 95% CI: 0.78–1.73) in a population of 5522 men and women from Canada, United States, Brazil, Western Europe and Slovakia, aged 55 years or above, based on 97 cases 0169-5002/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2009.12.006
[5]. Though not significant, it is however worth noting, that both relative risk estimates are above 1. There seems to be two important differences between the Norwegian study and WAFACS and HOPE-2: First, the fraction of smokers differed very much from the Norwegian study (39.2%) to the two other studies (11.5 and 11.9%, respectively). And second, the WAFACS study is conducted in The United States, where folate fortification of flour and grains began in 1996 and became mandatory by 1998, before the study was initiated [6]. The HOPE-2 study consists mostly (72.1%) of participants from The United States and Canada, where folate fortification has also been mandatory since 1998 [6]. This led to considerably higher circulating folate concentrations at baseline in WAFACS (8.8 ng/mL and 8.9 ng/mL in the active and placebo group, respectively) [4] and HOPE-2 (12.2 ng/mL and 12.0 ng/mL in the active and placebo group, respectively) [5] compared to the Norwegian study (3.9 ng/mL in both active and placebo group) [2]. The percentage of current smokers in our Danish cohort was 36.3% [1] and thus very similar to the Norwegian study and very far from WAFACS and HOPE-2. Circulating folate levels have not been measured for the entire Danish cohort, but for a sub-sample of 824 individuals, showing an average concentration of 4.6 ng/mL, a value similar to the Norwegian, and much lower than the two other studies (unpublished results). It is possible that a higher baseline concentration, due to fortification, may obscure the association between folate and lung cancer compared to the effect folate may have in populations with lower baseline concentrations. The effect of folate on other cancers, primarily colorectal cancer [7] but also prostate cancer [8] has been heavily scrutinized in the previous years after finding of increased risk in intervention studies, with seemingly accumulation of evidence that folate plays a dual role in carcinogenesis with not only beneficial but also harmful effects [3,9]. It has been hypothesized, that the timing of folate in carcinogenesis is important: Administration of folate before development of preneoplastic lesions may prevent tumour growth whereas administration after occurrence may instead promote their growth [3,10]. It is possible, that this is also relevant for lung cancer, so that low circulating folate concentrations in the Norwegian and Danish populations combined with a high frequency of smoking has led to a higher number of preneoplastic lung cancer lesions, whose growth are promoted by a high intake of folate, resulting in increased lung cancer risk with high folate intake. Though not significant, we did see a tendency towards an interaction between dietary folate intake and smoking status in our cohort (p = 0.13), with a borderline protective effect among never smokers (RR: 0.68; 95% CI: 0.46–1.01), but not former and current smokers. Blood concentrations of folate have been shown to be affected by smoking, with lower levels measured among smokers [11–13], and it is possible, that former and current smokers presented lower blood folate concentrations as well as higher
Letter to the Editor / Lung Cancer 67 (2010) 380–381
occurrence of preneoplastic lesions, which obscured the potentially beneficial effects of folate. These are speculative considerations and neither of the two studies presents evidence to deem folate a lung carcinogen. They do however parallel the findings of increased lung cancer risk in large intervention studies of beta-carotene among smokers [14,15] but not non-smokers [16] in the 1990s, and further fuel the speculations that folate may play a harmful role in the cancer process under certain circumstances, seemingly not only in relation to colorectal cancer, but may have harmful effects at a more systemic level. In light of the widespread use of folate supplements and folate fortification, we thus encourage further studies to rapidly assess the association. Conflict of interest None declared. Acknowledgments This work was supported by grants from The Danish Cancer Society. The study sponsors played no role in planning the study design, in collection, analysis or interpretation of data, and in writing and submitting the manuscript. References [1] Roswall N, Olsen A, Christensen J, Dragsted LO, Overvad K, Tjonneland A. Source-specific effects of micronutrients in lung cancer prevention. Lung Cancer (2009), doi:10.1016/j.lungcan.2009.11.010. [2] Ebbing M, Bonaa KH, Nygard O, Arnesen E, Ueland PM, Nordrehaug JE, et al. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA 2009;302:2119–26. [3] Kim YI. Folate: a magic bullet or a double edged sword for colorectal cancer prevention? Gut 2006;55:1387–9. [4] Zhang SM, Cook NR, Albert CM, Gaziano JM, Buring JE, Manson JE. Effect of combined folic acid, vitamin B6, and vitamin B12 on cancer risk in women: a randomized trial. JAMA 2008;300:2012–21. [5] Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006;354:1567–77.
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[6] Mason JB, Dickstein A, Jacques PF, Haggarty P, Selhub J, Dallal G, et al. A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis. Cancer Epidemiol Biomarkers Prev 2007;16:1325–9. [7] Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ, Bresalier RS, et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 2007;297:2351–9. [8] Figueiredo JC, Grau MV, Haile RW, Sandler RS, Summers RW, Bresalier RS, et al. Folic acid and risk of prostate cancer: results from a randomized clinical trial. J Natl Cancer Inst 2009;101:432–5. [9] Ulrich CM, Potter JD. Folate supplementation: too much of a good thing? Cancer Epidemiol Biomarkers Prev 2006;15:189–93. [10] Kim YI. Folate and colorectal cancer: an evidence-based critical review. Mol Nutr Food Res 2007;51:267–92. [11] Stark KD, Pawlosky RJ, Beblo S, Murthy M, Flanagan VP, Janisse J, et al. Status of plasma folate after folic acid fortification of the food supply in pregnant African American women and the influences of diet, smoking, and alcohol consumption. Am J Clin Nutr 2005;81:669–77. [12] Gabriel HE, Crott JW, Ghandour H, Dallal GE, Choi SW, Keyes MK, et al. Chronic cigarette smoking is associated with diminished folate status, altered folate form distribution, and increased genetic damage in the buccal mucosa of healthy adults. Am J Clin Nutr 2006;83:835–41. [13] Vardavas CI, Linardakis MK, Hatzis CM, Malliaraki N, Saris WH, Kafatos AG. Smoking status in relation to serum folate and dietary vitamin intake. Tob Induc Dis 2008;4:8. [14] The Alpha-Tocopherol Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 1994;330:1029–35. [15] Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334:1150–5. [16] Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR, et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 1996;334:1145–9.
Nina Roswall ∗ Institute of Cancer Epidemiology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen Ø, Denmark ∗ Tel.:
+45 35 25 77 14. E-mail address: [email protected] 7 December 2009
Contents lists available at ScienceDirect
Lung Cancer journal homepage: www.elsevier.com/locate/lungcan
Letter to the Editor Folate and lung cancer risk Keywords: Lung neoplasms Dietary supplements Micronutrients Prospective cohort study Randomized controlled trials as topic Folic acid Folate
Dear Sir, In our paper published in Lung Cancer, we found a significantly increased lung cancer risk with dietary folate in a prospective Danish cohort study of 55,557 men and women aged 50–64 years: RR 1.15; 95% CI (1.03–1.28) [1]. Since no study had previously reported a positive association between folate intake and lung cancer, this surprising result led us to reanalyze the data, to evaluate if this was an erroneous finding or if we could reveal a confounder accounting for the association. However, the association remained significant, and we hence reported it in our paper, stating concern that it might be due to confounding, which we had not been able to account for. In a recently published article in JAMA, however, Ebbing et al. [2] found a tendency towards an increased lung cancer risk with folic acid supplementation of 0.8 mg/day in a double-blinded, placebocontrolled trial of 6837 Norwegian men and women, based on the occurrence of 92 lung cancer cases: RR 1.59; 95% CI (0.92–2.75). The authors report this as a surprising finding, stating that no previous epidemiological studies have found folate or folic acid to increase lung cancer risk [2]. Our finding of an increased lung cancer risk with dietary but not supplemental folate, as should be expected from the Norwegian trial, may be explained by the fact that the dietary intake in our cohort is more that 3-fold that of supplemental intake (0.33 mg/day vs. 0.1 mg/day). In comparison, the participants in the Norwegian trial received supplements containing 0.8 mg/day. It has been suggested that the harmful effects of folate in carcinogenesis appear only at significantly high doses [3], and it is possible, that a threshold value is not reached with the supplemental intake in our cohort. A search of Medline revealed only two previous experimental trials testing the effect of folic acid in relation to lung cancer. Both used a combination of 2.5 mg folic acid, 50 mg B6 vitamin and 1 mg B12 vitamin daily or placebo. The Women’s Antioxidant and Folic Acid Cardiovascular Study (WAFACS) found no effect (RR: 1.04; 95% CI: 0.58–1.87) in a population of 5442 American women aged 40 years or above. This result is however based on only 45 cases [4]. The Heart Outcomes Prevention Evaluation 2 (HOPE-2) also found no significant effect (RR: 1.16; 95% CI: 0.78–1.73) in a population of 5522 men and women from Canada, United States, Brazil, Western Europe and Slovakia, aged 55 years or above, based on 97 cases 0169-5002/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2009.12.006
[5]. Though not significant, it is however worth noting, that both relative risk estimates are above 1. There seems to be two important differences between the Norwegian study and WAFACS and HOPE-2: First, the fraction of smokers differed very much from the Norwegian study (39.2%) to the two other studies (11.5 and 11.9%, respectively). And second, the WAFACS study is conducted in The United States, where folate fortification of flour and grains began in 1996 and became mandatory by 1998, before the study was initiated [6]. The HOPE-2 study consists mostly (72.1%) of participants from The United States and Canada, where folate fortification has also been mandatory since 1998 [6]. This led to considerably higher circulating folate concentrations at baseline in WAFACS (8.8 ng/mL and 8.9 ng/mL in the active and placebo group, respectively) [4] and HOPE-2 (12.2 ng/mL and 12.0 ng/mL in the active and placebo group, respectively) [5] compared to the Norwegian study (3.9 ng/mL in both active and placebo group) [2]. The percentage of current smokers in our Danish cohort was 36.3% [1] and thus very similar to the Norwegian study and very far from WAFACS and HOPE-2. Circulating folate levels have not been measured for the entire Danish cohort, but for a sub-sample of 824 individuals, showing an average concentration of 4.6 ng/mL, a value similar to the Norwegian, and much lower than the two other studies (unpublished results). It is possible that a higher baseline concentration, due to fortification, may obscure the association between folate and lung cancer compared to the effect folate may have in populations with lower baseline concentrations. The effect of folate on other cancers, primarily colorectal cancer [7] but also prostate cancer [8] has been heavily scrutinized in the previous years after finding of increased risk in intervention studies, with seemingly accumulation of evidence that folate plays a dual role in carcinogenesis with not only beneficial but also harmful effects [3,9]. It has been hypothesized, that the timing of folate in carcinogenesis is important: Administration of folate before development of preneoplastic lesions may prevent tumour growth whereas administration after occurrence may instead promote their growth [3,10]. It is possible, that this is also relevant for lung cancer, so that low circulating folate concentrations in the Norwegian and Danish populations combined with a high frequency of smoking has led to a higher number of preneoplastic lung cancer lesions, whose growth are promoted by a high intake of folate, resulting in increased lung cancer risk with high folate intake. Though not significant, we did see a tendency towards an interaction between dietary folate intake and smoking status in our cohort (p = 0.13), with a borderline protective effect among never smokers (RR: 0.68; 95% CI: 0.46–1.01), but not former and current smokers. Blood concentrations of folate have been shown to be affected by smoking, with lower levels measured among smokers [11–13], and it is possible, that former and current smokers presented lower blood folate concentrations as well as higher
Letter to the Editor / Lung Cancer 67 (2010) 380–381
occurrence of preneoplastic lesions, which obscured the potentially beneficial effects of folate. These are speculative considerations and neither of the two studies presents evidence to deem folate a lung carcinogen. They do however parallel the findings of increased lung cancer risk in large intervention studies of beta-carotene among smokers [14,15] but not non-smokers [16] in the 1990s, and further fuel the speculations that folate may play a harmful role in the cancer process under certain circumstances, seemingly not only in relation to colorectal cancer, but may have harmful effects at a more systemic level. In light of the widespread use of folate supplements and folate fortification, we thus encourage further studies to rapidly assess the association. Conflict of interest None declared. Acknowledgments This work was supported by grants from The Danish Cancer Society. The study sponsors played no role in planning the study design, in collection, analysis or interpretation of data, and in writing and submitting the manuscript. References [1] Roswall N, Olsen A, Christensen J, Dragsted LO, Overvad K, Tjonneland A. Source-specific effects of micronutrients in lung cancer prevention. Lung Cancer (2009), doi:10.1016/j.lungcan.2009.11.010. [2] Ebbing M, Bonaa KH, Nygard O, Arnesen E, Ueland PM, Nordrehaug JE, et al. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA 2009;302:2119–26. [3] Kim YI. Folate: a magic bullet or a double edged sword for colorectal cancer prevention? Gut 2006;55:1387–9. [4] Zhang SM, Cook NR, Albert CM, Gaziano JM, Buring JE, Manson JE. Effect of combined folic acid, vitamin B6, and vitamin B12 on cancer risk in women: a randomized trial. JAMA 2008;300:2012–21. [5] Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006;354:1567–77.
381
[6] Mason JB, Dickstein A, Jacques PF, Haggarty P, Selhub J, Dallal G, et al. A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis. Cancer Epidemiol Biomarkers Prev 2007;16:1325–9. [7] Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ, Bresalier RS, et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 2007;297:2351–9. [8] Figueiredo JC, Grau MV, Haile RW, Sandler RS, Summers RW, Bresalier RS, et al. Folic acid and risk of prostate cancer: results from a randomized clinical trial. J Natl Cancer Inst 2009;101:432–5. [9] Ulrich CM, Potter JD. Folate supplementation: too much of a good thing? Cancer Epidemiol Biomarkers Prev 2006;15:189–93. [10] Kim YI. Folate and colorectal cancer: an evidence-based critical review. Mol Nutr Food Res 2007;51:267–92. [11] Stark KD, Pawlosky RJ, Beblo S, Murthy M, Flanagan VP, Janisse J, et al. Status of plasma folate after folic acid fortification of the food supply in pregnant African American women and the influences of diet, smoking, and alcohol consumption. Am J Clin Nutr 2005;81:669–77. [12] Gabriel HE, Crott JW, Ghandour H, Dallal GE, Choi SW, Keyes MK, et al. Chronic cigarette smoking is associated with diminished folate status, altered folate form distribution, and increased genetic damage in the buccal mucosa of healthy adults. Am J Clin Nutr 2006;83:835–41. [13] Vardavas CI, Linardakis MK, Hatzis CM, Malliaraki N, Saris WH, Kafatos AG. Smoking status in relation to serum folate and dietary vitamin intake. Tob Induc Dis 2008;4:8. [14] The Alpha-Tocopherol Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 1994;330:1029–35. [15] Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334:1150–5. [16] Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR, et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 1996;334:1145–9.
Nina Roswall ∗ Institute of Cancer Epidemiology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen Ø, Denmark ∗ Tel.:
+45 35 25 77 14. E-mail address: [email protected] 7 December 2009