Cancer Causes & Control (2019) 30:603–615 https://doi.org/10.1007/s10552-019-01170-6 ORIGINAL PAPER Baseline serum folate, vitamin B12 and the risk of prostate and breast cancer using data from the Swedish AMORIS cohort Anneli Essén1 · Aida Santaolalla1 · Hans Garmo1,2 · Niklas Hammar3,4 · Göran Walldius5 · Ingmar Jungner6 · Håkan Malmström3,7 · Lars Holmberg1,8 · Mieke Van Hemelrijck1,3 Received: 9 July 2018 / Accepted: 11 April 2019 / Published online: 24 April 2019 © The Author(s) 2019 Abstract Purpose The roles of folate and vitamin B12 in prostate cancer (PCa) or breast cancer (BC) development are unclear. We investigated their roles using the prospective Swedish Apolipoprotein MOrtality RISk (AMORIS) study. Methods 8,783 men and 19,775 women with vitamin B12 and folate serum measurements were included. Their associations with PCa and BC risk categories were evaluated using Cox proportional hazards regression. Results During mean follow-up of 13 years, 703 men developed PCa. There was an inverse association between folate > 32 nmol/L and high-risk PCa [hazard ratio (HR) 0.12, 95% confdence interval (CI) 0.02–0.90], and a positive asso- ciation between folate < 5 nmol/L and metastatic PCa (HR 5.25, 95% CI 1.29–21.41), compared with folate 5–32 nmol/L. No associations with vitamin B12 were found. 795 women developed BC during mean follow-up of 14 years. When restricting to the fasting population, there was a positive association between folate > 32 nmol/L and BC (HR 1.47, 95% CI 1.06–2.04). Conclusion High folate levels may protect against PCa and low folate levels may increase risk of metastatic PCa. High fast- ing folate levels may be associated with an increased BC risk. Vitamin B12 was not found to be linked with risk of PCa or BC. Longitudinal studies with serum and dietary information could help defne new prevention targets and add information on the role of folate fortifcation. Keywords Prostate cancer (PCa) · Breast cancer (BC) · Vitamin B12 · Folate · Severity Abbreviations GGT​ Gamma glutamyl transferase 95% CI 95% Confdence interval HR Hazard ratio AMORIS Apolipoprotein MOrtality RISk NPCR National Prostate Cancer Register BC Breast cancer PCa Prostate cancer CALAB Central Automation Laboratory SES Socioeconomic status CCI Charlson comorbidity index Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s1055 2-019-01170 -6) contains supplementary material, which is available to authorized users. * Mieke Van Hemelrijck 5 Department of Cardiovascular Epidemiology, Institute [email protected] of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden 1 Research Oncology, Translational Oncology & Urology 6 Department of Clinical Epidemiology, Karolinska Institutet Research (TOUR), Guy’s Hospital, School of Cancer and CALAB Research, Stockholm, Sweden and Pharmaceutical Sciences, King’s College London, 3rd Floor, Bermondsey Wing, London SE1 9RT, UK 7 Biostatistics, Research & Development, Swedish Orphan Biovitrum AB, Stockholm, Sweden 2 Regional Cancer Centre, Uppsala, Sweden 8 Department of Surgical Sciences, Uppsala University, 3 Unit of Epidemiology, Institute of Environmental Medicine, Uppsala, Sweden Karolinska Institutet, Stockholm, Sweden 4 Medical Evidence & Observational Research, Global Medical Afairs, AstraZeneca, Mölndal, Sweden Vol.:(0123456789)1 3 604 Cancer Causes & Control (2019) 30:603–615 Introduction study in the US, with 712 cases and controls, found that high folate levels may reduce the risk of BC, especially Folate and vitamin B12 are important for cell growth and in women with high alcohol consumption [19]. Studies division. Abnormal levels of these vitamins have long on the efects of vitamin B12 on BC risk have also been been associated with the development of several malignan- inconclusive. A weak positive association between vitamin cies, such as colorectal [1, 2], pancreatic [3], lung [4] and B12 levels and BC risk in women who had a high con- cervix cancer [5]. Their potential role in carcinogenesis sumption of alcohol was found in one nested case–control is thought to be due to their part in the so-called “one- study, which included 2,491 cases and 2,521 controls from carbon metabolism pathway”. This pathway is important Europe [20]. However, another US nested case–control for DNA synthesis, repair and methylation [6]. Epigenetic study with 195 cases and controls found that low B12 lev- changes such as DNA hypo and hypermethylation, DNA els may increase the risk of BC [21], whereas an additional uracil misincorporation, and chromosomal rearrangements US nested case–control study with 848 cases and controls have been seen in many tumour tissues, including prostate found no association [22]. cancer (PCa) [7–9] and breast cancer (BC) [10]. This sug- In this study, we investigated the associations between gests that altered levels of these vitamins could potentially serum folate, vitamin B12, and risks of PCa and BC further promote cancer development. by including information on tumour characteristics. Some studies have investigated the association between folate, vitamin B12 and the risks of PCa and BC, with inconsistent results. Among other studies [11, 12], a Nor- Materials and methods wegian nested case–control study, which included 3,000 cases and 3,000 controls with blood samples collected Study population and data collection between 1973 and 2004, suggested that high levels of serum folate increase the risk of PCa [13]. A prospective All data were obtained from the Swedish Apolipoprotein- case–control study which included 29,133 male smok- related MOrtality RISk (AMORIS) cohort. This database ers aged 50–69 years in Finland between 1985 and 1988 contains blood samples from 812,073 individuals who did, however, not fnd any association between serum mainly came from the greater Stockholm area and were folate levels and PCa [14]. In another nested case–con- either having a general health check-up or were outpatients trol study, which included 6,875 cases and 8,104 controls, referred for laboratory testing. None of the participants were with blood samples collected between 1981 and 2008 and inpatients at the time of the blood sampling. The blood sam- with an average follow-up of 8.9 years, high folate lev- ples were analysed and evaluated in the Central Automation els were associated with an enhanced risk of high grade Laboratory (CALAB) in Stockholm, Sweden, from 1985 to PCa, suggesting that folate may play a role in the progres- 1996. In the AMORIS cohort, the CALAB database was sion of PCa [11]. In contrast, an Australian prospective linked to several Swedish national registries such as the cohort study, which included 964 men with a follow-up of Swedish National Cancer Register, the Hospital Discharge 20 years, found that decreased folate levels increased PCa Register, the Cause of Death Register, the consecutive Swed- mortality risk [15]. Vitamin B12 has, as well as folate, ish Censuses from 1970 to 1990, and the National Register been associated with the increased PCa risk in some stud- of Emigration using the Swedish 10-digit personal identity ies [11, 12]. A prospective Swedish study found that vita- number. These resources provided complete follow-up infor- min B12 may be associated with up to a threefold increase mation until death or the end of December 2011. A more in PCa risk [16]. Yet, the previously mentioned Finnish detailed description of the AMORIS cohort can be found study also looked at vitamin B12 and found no association elsewhere [23]. The study complies with the Declaration between vitamin B12 and PCa. of Helsinki, and the Ethics Review Board of the Karolinska For BC, both positive and negative associations have Institute has approved the study [23]. been found between serum folate levels and BC risk. Stud- In this study, we particularly used the Swedish National ies have suggested that high folate levels are associated Cancer Register [24], to which reporting is mandated, the with the increased BC risk in women with BRCA1/2 muta- National Prostate Cancer Register (NPCR) [25] and the tions [17] and also in women with estrogen receptor beta Stockholm Clinical Quality Register for Breast Cancer [26, negative BC [18]. The frst study was a prospective study 27], to extract information about the cancer diagnoses. which included 164 women with BRCA1/2 mutations in The NPCR includes 98% of all newly diagnosed PCa cases Canada, whereas the second study was a Swedish nested in the Swedish National Cancer Register. It was estab- case–control study which included 204 cases and 408 con- lished to provide data for quality assurance and has been trols. Conversely, another prospective nested case–control ofering the service nationwide since 1998 [25, 28]. We used data on date of diagnosis, age at diagnosis, serum 1 3 Cancer Causes & Control (2019) 30:603–615 605 concentration of PSA at time of diagnosis, TNM stage and In addition, we used information on a variety of biomark- Gleason score from the NPCR. The Stockholm Clinical ers which may be potential confounders for the associations Quality Register for Breast Cancer started in 1976 and is between vitamin B12, folate, and risk of PCa or BC. Total considered to have 97% coverage having been cross ref- cholesterol and triglycerides were measured enzymatically erenced with the Swedish National Cancer Register. This [34], and serum glucose was also measured enzymatically register was established to record the quality of care based with a glucose/peroxidase method [35]. Serum iron was on regional or national guidelines for BC management. measured via acidifcation with citric acid in order to dis- Individual information about date of diagnosis, detection sociate the Fe3+-transferring complex (coefcient of vari- mode, tumour characteristics, pathological tumour-stage ation < 5%) [36]. A colorimetric method was used for the and treatment for all the newly diagnosed BC patients has measurement of total serum calcium (coefcient of varia- been reported continuously by clinicians to the register.