Can Super B-complex Give False Psa Readings

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 Take a chance (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 take a chance categories were evaluated using Cox proportional hazards regression.

Results

During mean follow-up of thirteen years, 703 men developed PCa. There was an inverse association between folate > 32 nmol/Fifty and loftier-risk PCa [take chances ratio (60 minutes) 0.12, 95% confidence interval (CI) 0.02–0.90], and a positive association between folate < 5 nmol/50 and metastatic PCa (60 minutes 5.25, 95% CI 1.29–21.41), compared with folate 5–32 nmol/L. No associations with vitamin B12 were constitute. 795 women developed BC during mean follow-up of 14 years. When restricting to the fasting population, there was a positive clan between folate > 32 nmol/50 and BC (Hour 1.47, 95% CI 1.06–ii.04).

Determination

Loftier folate levels may protect against PCa and low folate levels may increase risk of metastatic PCa. High fasting 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 ascertain new prevention targets and add together data on the role of folate fortification.

Introduction

Folate and vitamin B12 are of import for jail cell growth and partitioning. Aberrant levels of these vitamins take long been associated with the evolution of several malignancies, such as colorectal [1, 2], pancreatic [three], lung [4] and cervix cancer [five]. Their potential function in carcinogenesis is idea to exist due to their function in the and then-called "one-carbon metabolism pathway". This pathway is important for DNA synthesis, repair and methylation [six]. Epigenetic changes such as DNA hypo and hypermethylation, Deoxyribonucleic acid uracil misincorporation, and chromosomal rearrangements have been seen in many neoplasm tissues, including prostate cancer (PCa) [7,8,9] and breast cancer (BC) [x]. This suggests that altered levels of these vitamins could potentially promote cancer evolution.

Some studies take investigated the association between folate, vitamin B12 and the risks of PCa and BC, with inconsistent results. Among other studies [11, 12], a Norwegian nested instance–control study, which included iii,000 cases and 3,000 controls with claret samples collected betwixt 1973 and 2004, suggested that high levels of serum folate increase the chance of PCa [xiii]. A prospective case–control study which included 29,133 male person smokers aged 50–69 years in Republic of finland betwixt 1985 and 1988 did, however, not find any association between serum folate levels and PCa [fourteen]. In another nested case–control written report, which included half-dozen,875 cases and eight,104 controls, with blood samples nerveless between 1981 and 2008 and with an boilerplate follow-up of 8.9 years, high folate levels were associated with an enhanced risk of high grade PCa, suggesting that folate may play a role in the progression of PCa [11]. In dissimilarity, an Australian prospective cohort study, which included 964 men with a follow-up of 20 years, found that decreased folate levels increased PCa mortality risk [15]. Vitamin B12 has, too equally folate, been associated with the increased PCa hazard in some studies [11, 12]. A prospective Swedish written report found that vitamin B12 may be associated with upwardly to a threefold increment in PCa risk [16]. Withal, the previously mentioned Finnish study also looked at vitamin B12 and establish no association between vitamin B12 and PCa.

For BC, both positive and negative associations have been found between serum folate levels and BC chance. Studies have suggested that high folate levels are associated with the increased BC risk in women with BRCA1/ii mutations [17] and also in women with estrogen receptor beta negative BC [18]. The start study was a prospective study which included 164 women with BRCA1/2 mutations in Canada, whereas the second report was a Swedish nested case–control report which included 204 cases and 408 controls. Conversely, another prospective nested instance–control written report in the United states of america, with 712 cases and controls, found that high folate levels may reduce the risk of BC, particularly in women with high alcohol consumption [xix]. Studies on the effects of vitamin B12 on BC take a chance take also been inconclusive. A weak positive association betwixt vitamin B12 levels and BC adventure in women who had a high consumption of booze was plant in i nested case–control written report, which included ii,491 cases and 2,521 controls from Europe [xx]. All the same, another Usa nested example–control study with 195 cases and controls found that depression B12 levels may increase the run a risk of BC [21], whereas an additional US nested case–control report with 848 cases and controls found no association [22].

In this study, nosotros investigated the associations betwixt serum folate, vitamin B12, and risks of PCa and BC further by including data on tumour characteristics.

Materials and methods

Report population and information collection

All information were obtained from the Swedish Apolipoprotein-related Mortality Gamble (AMORIS) cohort. This database contains claret samples from 812,073 individuals who mainly came from the greater Stockholm area and were either having a general wellness check-up or were outpatients referred for laboratory testing. None of the participants were inpatients at the time of the blood sampling. The blood samples were analysed and evaluated in the Central Automation Laboratory (CALAB) in Stockholm, Sweden, from 1985 to 1996. In the AMORIS cohort, the CALAB database was linked to several Swedish national registries such as the Swedish National Cancer Register, the Hospital Discharge Register, the Cause of Decease Annals, the consecutive Swedish Censuses from 1970 to 1990, and the National Annals of Emigration using the Swedish 10-digit personal identity number. These resources provided complete follow-up information until death or the finish of December 2011. A more detailed description of the AMORIS accomplice can be constitute elsewhere [23]. The study complies with the Annunciation of Helsinki, and the Ethics Review Board of the Karolinska Institute has approved the study [23].

In this study, we particularly used the Swedish National Cancer Register [24], to which reporting is mandated, the National Prostate Cancer Register (NPCR) [25] and the Stockholm Clinical Quality Register for Breast Cancer [26, 27], to excerpt information nearly the cancer diagnoses. The NPCR includes 98% of all newly diagnosed PCa cases in the Swedish National Cancer Register. It was established to provide information for quality assurance and has been offering the service nationwide since 1998 [25, 28]. We used data on date of diagnosis, historic period at diagnosis, serum concentration of PSA at time of diagnosis, TNM stage and Gleason score from the NPCR. The Stockholm Clinical Quality Register for Breast Cancer started in 1976 and is considered to take 97% coverage having been cross referenced with the Swedish National Cancer Register. This register was established to record the quality of intendance based on regional or national guidelines for BC management. Private information about date of diagnosis, detection mode, tumour characteristics, pathological tumour-phase and treatment for all the newly diagnosed BC patients has been reported continuously by clinicians to the register. To evaluate current vital condition of the registered patients, the register is also updated regularly against the National Population Register [26, 29].

We included all men aged 30 years and older and all women anile 20 years and older. All included participants had baseline serum measurements for both folate and vitamin B12 and were not diagnosed with PCa or BC at the fourth dimension of inclusion. Just those with a diagnosis of invasive BC were included in the BC written report due to lack of data on non-invasive BCs. Follow-upward time was defined equally time from baseline serum measurement until date of PCa or invasive BC diagnosis, death, emigration or study closing time (31 December 2011)—whichever occurred before.

Data on comorbidity was obtained past means of the Charlson comorbidity index (CCI). The CCI accounts for 19 diseases, and each disease is assigned a certain number of points. The sum of these points gives a score on which different comorbidity levels are created, from no comorbidity to severe comorbidity (0, i, two, ≥ three) [30]. CCI was calculated by using information obtained from the National Patient Register. Data on educational levels were taken from the Population and Housing Census for the period 1970–1990. Socioeconomic status (SES) was based on occupational status and categorised gainfully employed individuals into bluish and white collar workers and into manual or non-manual employees [31]. In improver, the CALAB database contained data on age and fasting status at time of claret sampling. All other information was extracted from the registries previously mentioned.

The main exposures of interest were serum levels of folate and vitamin B12. Nosotros used reference ranges from the Karolinska Infirmary, Stockholm, Sweden to divide these into categories [32, 33]. Serum folate levels were categorised every bit low (< 5 nmol/Fifty), normal (5–32 nmol/Fifty) and high levels (> 32 nmol/Fifty). Vitamin B12 serum levels were as categorised into depression (< 150 pmol/50), normal (150–650 pmol/Fifty) and high levels (> 650 pmol/L). Serum folate was measured by means of a competitive assay in which folate from the patient sample competes with the Lite Reagent. Serum vitamin B12 was measured past means of a competitive chemiluminescent sandwich assay in which vitamin B12 from the patient sample competes with the Lite Reagent [23].

In addition, we used data on a variety of biomarkers which may be potential confounders for the associations between vitamin B12, folate, and take a chance of PCa or BC. Full cholesterol and triglycerides were measured enzymatically [34], and serum glucose was also measured enzymatically with a glucose/peroxidase method [35]. Serum iron was measured via acidification with citric acrid in club to dissociate the Feⁱⁱⁱ⁺-transferring complex (coefficient of variation < 5%) [36]. A colorimetric method was used for the measurement of full serum calcium (coefficient of variation < 2.five%) [37]. Gamma-glutamyl transferase (GGT) was also measured by an enzymatic colorimetric method [38]. All methods were fully automated with automatic calibration and performed at the same accredited laboratory [35].

With respect to outcomes, we defined PCa based on hazard categories (low risk, intermediate hazard, loftier risk and regional/distant metastatic) by means of PSA, Gleason score and TNM stage [25]. "Depression risk" was defined as T1–2, Gleason score ii–vi and PSA < 10 ng/mL; "intermediate risk" equally T1–2, Gleason score 7 and/or PSA 10 to < 20 ng/mL; "high risk" equally T3 and/or Gleason score 8–x and/or PSA twenty to < 50 ng/mL "regionally metastatic tumours" as T4 and/or N1 and/or PSA 50 to < 100 ng/mL in the absence of distant metastases (M0 or MX); and "distant metastatic tumours" were defined as M1 and/or PSA > 100 ng/mL and/or expiry inside 4 years afterwards PCa diagnosis, where PCa was the crusade of expiry. As well equally looking at risk categories, we looked at some clinicopathological features separately (PSA levels, Gleason score and TNM stage). PSA concentrations were classified as < 4 μg/Fifty, 4.0–nine.9 μg/L, 10.0–20.0 μg/L and > 20.0 μg/L. Gleason score was categorised as Gleason score ≤ 6 or WHO grade ane; Gleason score 7 or WHO grade 2; and Gleason score ≥ 8 or WHO class three [28].

BC was besides divided into run a risk categories (good, moderate and astringent) based on age, estrogen receptor status, and TNM stage [29]. "Good" was defined as ER+ or ER− and pTNM phase I, "Moderate" every bit ER+, age > 40 years and pTNM stage II, "Severe" as historic period < 40 years and pTNM phase II or ER− and pTNM phase II or pTNM phase III or IV. HER2 status could non exist included due to a lack of information.

Information analysis

All data were analysed with Statistical Assay Software (SAS) release ix.four. Cox proportional hazard regression models were used to guess risk ratios (HRs) and 95% confidence intervals (CIs) for the risk of developing PCa and BC based on serum levels of vitamin B12 and folate. HRs were estimated for the overall PCa and BC risk as well every bit for PCa and BC risk categories.

The multivariate models included covariates for age, education level (low, medium, loftier), SES (low, high), CCI (0, 1, 2, ≥ 3), serum glucose, triglycerides, cholesterol and fasting condition (fasting, not-fasting). Data nearly BMI was missing for a large office of the report population and was therefore not included in the multivariate adjustments. To compensate for the lack of information regarding BMI, nosotros adjusted for triglycerides and cholesterol. Studies have shown that overweight people are more likely to have higher full cholesterol [39] and higher triglycerides than non-overweight people [twoscore].

We too conducted further sensitivity analyses past adding GGT, iron and calcium in the model. Iron and calcium were added as some of the sources for these minerals are the same sources every bit for folate and vitamin B12 and they could therefore be potential confounders [41, 42]. Furthermore, calcium has been associated with PCa risk in some studies [14]. GGT was added since we did not accept data near booze consumption and alcohol may have an touch on on folate levels [fifteen]. In addition, alcohol has been linked to many cancer types, including PCa and BC [43]. GGT is one of the biomarkers that is widely used for indication of a patient's booze intake. Several weeks of high intake of alcohol give ascent to raised GGT levels [44].

Moreover, we conducted a sensitivity analysis exploring the fasting condition including simply the participants that were fasting at time of blood fatigued. Nosotros likewise conducted farther analysis using the continuous log value of folate and vitamin B12 instead of the chiselled groups. Additionally, nosotros looked at reverse causation by excluding those who had a follow-upwardly smaller than three years.

Results

A total number of eight,783 men were included. Nigh of the men had normal B12 (150–650 pmol/L) and folate (5–32 nmol/L) levels (90.seven% and 91.4%, respectively). All characteristics of the male study population are shown in Table one. Almost 703 individuals developed PCa during a mean follow-up fourth dimension of 12.7 years (± 6.two SD). All characteristics of the PCa cases are shown in Tabular array 2. Some differences between the exposure groups can exist found for the main categorical variables studied.

Table one Characteristics of the male person study population

Full size tabular array

Tabular array 2 Characteristics of the study population with PCa

Full size tabular array

HRs and 95% CI for the clan between vitamin B12, folate and PCa gamble categories are shown in Tabular array 3. An inverse statistically meaning association between folate levels > 32 nmol/50 and loftier-risk PCa was seen (HR 0.12, 95% CI 0.02–0.xc), compared to folate levels between five and 32 nmol/L. At that place was also a statistically significant positive clan between regional/distant metastatic PCa and folate levels < 5 nmol/L (HR 4.12, 95% CI 1.01–16.82). For metastatic PCa, this association could non exist analysed multivariately due to low number of cases. No statistically meaning associations were found between vitamin B12 and PCa risk categories. Restricting the study population to fasting men only did not result in statistically significant findings due to a smaller sample size (Supplemental Table 1). However, the observed trends remained the same.

Table 3 Gamble ratios (HRs) and 95% confidence intervals (CIs) for the associations between vitamin B12, folate, and PCa adventure categories

Full size table

A total of xix,775 women were included in the study. During a mean follow-upwardly fourth dimension of 14.3 years (± 5.4 SD), 795 individuals developed BC. Well-nigh women had normal B12 and folate levels (89.7% and 87.nine%, respectively). Further baseline characteristics of the female person study population are shown in Tables four and five. Results from the analyses with Cox proportional chance models are shown in Table 6. We observed no statistically significant associations between folate, vitamin B12 and BC in the total study population. Restricting the study population to fasting women only showed a positive clan between high folate levels > 32 nmol/L and the risk of BC overall (HR 1.47, 95% CI 1.06–2.04) as well equally "adept" BC (Supplemental Table 2).

Table 4 Characteristics of the female study population

Full size table

Table five Characteristics of the study population with BC

Full size table

Table half-dozen Hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations betwixt vitamin B12, folate and BC severity groups

Total size table

The sensitivity analyses including additional adjustments for GGT, iron and calcium, as well every bit the sensitivity analyses excluding those with follow-up times less than 3 years, did not change the results (results not shown). No associations were institute when using the continuous log value of the exposure variables (results not shown).

Discussion

Compared with normal folate levels (5–32 nmol/Fifty), an inverse association between high serum folate levels (> 32 nmol/50) and loftier-hazard PCa was seen, also as a positive association between low serum folate levels (< 5 nmol/L) and metastatic PCa. For BC, there was no indication of an association with folate or vitamin B12 in the total population. However, the fasting population showed a positive clan betwixt serum folate levels (> 32 nmol/L) and take chances of BC in comparison with normal folate levels.

Previous literature has shown inconclusive results for the association between folate, vitamin B12 and the risks of PCa and BC. Some studies have suggested a positive clan between folate and PCa risk [eleven,12,13], while others accept not plant a significant association [45]. This study, on the contrary, suggests that high folate levels may reduce the chance of high grade PCa. This could indicate that folate may play a protective part in both the development and the progression of PCa. Even though the case numbers of people with depression folate levels and metastatic PCa were low, findings from this study likewise suggest that low folate levels may increment the risk of getting metastatic PCa. Like to this, an Australian study looking at folate levels and cancer morbidity and mortality showed that decreased folate levels increased the hazard of PCa mortality [46]. These findings suggest that folate may potentially be a target nutrient for preventing PCa development and progression.

Our hateful follow-upward time in the PCa cohort was 12.7 years (± vi.two SD), which is longer than 1 of the studies with different results [11], only shorter than another study with contradictory results [thirteen]. Hence, differences in results between these ii studies and our study are unlikely to be due to different lengths in follow-upward times. Similarly, information technology is unlikely that these observations explicate the differences between our findings and other studies for the association between vitamin B12 and PCa risk [xi, 12].

For BC, some studies have found that high folate levels may raise the risk of some types of BC [17, eighteen], which was also constitute in our fasting analysis. Conversely, another written report showed that high folate concentrations were inversely associated with BC take chances [19]. For vitamin B12 and BC hazard, one study found a weak positive clan betwixt vitamin B12 levels and BC take chances in women who had a high consumption of booze [20] and another study plant that depression B12 levels may increment the risk of BC [21], suggesting that abnormal levels of B12 could lead to a higher BC risk. Yet, similar some other studies [22], nosotros did not find any significant associations betwixt folate, vitamin B12 and BC in the total study population.

Our mean follow-up time in the BC cohort was fourteen.3 years (± 5.4 SD), which was longer than the follow-upwardly time in the previously mentioned studies, both in those that had similar [17, 18, xx] and contradictory [19, 21] findings. This again suggests that the deviation in findings is unlikely due to differences in follow-upwardly fourth dimension. However, it needs to be noted that we did observe an association between folate and BC take chances when restricting our analyses to the fasting population—this suggests that in addition to the need for a broad variety of confounders (every bit shown likewise past our own rough and multivariate analyses) when analysing B12 and folate in relation to risk of cancer, there is a demand to have clear information on fasting status as this may also impact the findings and hence explain a lot of the heterogeneity observed today.

Results from studies exploring dietary intake of folate and vitamin B12 and PCa and BC hazard, frequently seem to take diverse results compared to studies of serum concentrations of folate and vitamin B12. Adequate folate intake has been suggested to protect confronting BC [47,48,49,50,51], whereas in many studies serum folate has been suggested to accept a positive association with BC risk which is besides supported by our findings from the fasting assay [17, 18]. Equally, an inverse association between folate intake and PCa gamble has been seen [52, 53], while serum folate has been positively associated with PCa risk [11,12,13]. Therefore, studies analysing both dietary intake and serum concentrations are needed, to determine whether findings from studies examining serum concentrations would be applicable to dietary intake.

Some countries take introduced mandatory folate fortification to prevent neural tube defects in newborn babies, whereas others have been more than restrictive because of the limited knowledge almost how folate affects cancer [54]. In Sweden, there is no mandatory fortification [55]. A few products are, all the same, frequently fortified such every bit cereal and juice [56]. The dissimilar policies in folate fortification could be another factor explaining variations in studies performed in different countries.

Categorisation of folate distributions may be some other factor explaining potential differences between studies. Nosotros divided the population into iii different groups depending on whether they had low, normal or high serum levels, based on the reference levels used in Swedish clinics. Other studies, on the other hand, take looked at quartiles or quintiles of serum levels [11, thirteen, 45]. Nevertheless, the trends observed in the various studies were different.

An of import force of this study was the big study population and the prospective measurements of serum concentrations of folate and vitamin B12. All blood tests were analysed at the same clinical laboratory (CALAB) and the analyses were performed on fresh claret. Furthermore, the claret tests were taken in outpatients and there is no indication that they were taken on the ground of illness symptoms. Each person in this study had a consummate follow-up fourth dimension and the linkage with other national registers provided good information about the cancer diagnosis, time of death, and emigration.

A limitation of this study was that near of the written report population had normal serum levels of vitamin B12 and folate and therefore the groups with abnormal levels were relatively minor. The cancer subtype groups were especially affected by this and their case numbers became small. This made the estimation harder and it may have contributed to less statistical ability. Some other limitation was the lack of repeated measurements of folate and vitamin B12. It has been suggested that serum folate concentrations are sensitive to changes in dietary intake and that erythrocyte folate concentration may be a amend indicator of folate concentrations in the long term. Using serum folate could therefore give a false picture of the folate status. Vitamin B12 concentrations take been shown to be more than stable than folate concentrations, nonetheless, the literature on the stability of both folate and vitamin B12 serum concentrations is sparse [57]. Furthermore, we lacked data about some potential confounding factors such equally BMI, alcohol intake and smoking. We compensated this partly by adjusting for CCI, glucose, triglycerides, cholesterol and GGT instead. In improver, there were missing information for some of the variables, such as for fasting status. Finally, for BC we did not have sufficient information on the HER2 receptor condition.

Decision

In contrast to previous studies, we found an inverse clan between loftier folate concentrations and high-adventure PCa, suggesting that folate may exist protecting against PCa development and progression. Nosotros corroborated some previous findings suggesting no association between vitamin B12 and BC take chances; however, we found some positive association between high folate concentrations and BC risk in the fasting population which could suggest a role for folate in BC evolution. Prospective studies with longitudinal measurements of both dietary intake and serum levels as well as detailed information on potential confounders and fasting condition are needed to establish whether folate and vitamin B12 are significant take a chance factors or have potential protective backdrop in the evolution of PCa and BC. This could help define new prevention targets and add information to the discussions of mandatory folate fortification.

Abbreviations

95% CI:

95% Confidence interval

AMORIS:

Apolipoprotein Bloodshed RISk

BC:

Breast cancer

CALAB:

Central Automation Laboratory

CCI:

Charlson comorbidity index

GGT:

Gamma glutamyl transferase

Hr:

Hazard ratio

NPCR:

National Prostate Cancer Register

PCa:

Prostate cancer

SES:

Socioeconomic condition

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Acknowledgments

The research was funded/supported past the Swedish Cancer Society; Grants from the Gunnar and Ingmar Jungner Foundation for Laboratory Medicine, Stockholm, Sweden; and the National Institute for Wellness Enquiry (NIHR) Biomedical Enquiry Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the Cancerfonden, the NHS, the NIHR or the Department of Health.

Author data

Affiliations

1. Research Oncology, Translational Oncology & Urology Enquiry (TOUR), Guy's Infirmary, School of Cancer and Pharmaceutical Sciences, Rex's College London, 3rd Floor, Bermondsey Fly, London, SE1 9RT, UK

   Anneli Essén, Aida Santaolalla, Hans Garmo, Lars Holmberg & Mieke Van Hemelrijck

2. Regional Cancer Eye, Uppsala, Sweden

   Hans Garmo

3. Unit of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

   Niklas Hammar, Håkan Malmström & Mieke Van Hemelrijck

4. Medical Evidence & Observational Enquiry, Global Medical Affairs, AstraZeneca, Mölndal, Sweden

   Niklas Hammar

5. Department of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

   Göran Walldius

6. Department of Clinical Epidemiology, Karolinska Institutet and CALAB Enquiry, Stockholm, Sweden

   Ingmar Jungner

7. Biostatistics, Enquiry & Development, Swedish Orphan Biovitrum AB, Stockholm, Sweden

   Håkan Malmström

8. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden

   Lars Holmberg

Corresponding author

Correspondence to Mieke Van Hemelrijck.

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Essén, A., Santaolalla, A., Garmo, H. et al. Baseline serum folate, vitamin B12 and the risk of prostate and breast cancer using data from the Swedish AMORIS cohort. Cancer Causes Control 30, 603–615 (2019). https://doi.org/10.1007/s10552-019-01170-six

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• Received: 09 July 2018

• Accepted: 11 April 2019

• Published: 24 Apr 2019

• Event Date: 01 June 2019

• DOI : https://doi.org/10.1007/s10552-019-01170-6

Keywords

• Prostate cancer (PCa)
• Breast cancer (BC)
• Vitamin B12
• Folate
• Severity

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