Korean J Health Promot KJHP Korean Journal of Health Promotion 2234-2141 2093-5676 Korean Society for Health Promotion and Disease Prevention 10.15384/kjhp.2017.17.4.282 Original Article Prognostic Role of Serum Vitamin B12 in Solid Tumor Patients Oh Hye Kyung 1 Lee Jee Young 2 Yoon Seong Woo 2 Eo Wan Kyu 3 Han Sung Nim 1 4 Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul, Korea. Department of Internal Korean Medicine, Korean Medicine Cancer Center, Kyung Hee University Hospital at Gangdong, Seoul, Korea. Department of Hematology/Medical Oncology, Kyung Hee University Hospital at Gangdong, Seoul, Korea. Research Institute of Human Ecology, College of Human Ecology, Seoul National University, Seoul, Korea. Corresponding author: Sung Nim Han, PhD. Department of Food and Nutrition, College of Human Ecology, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea. Tel: +82-2-880-6836, Fax: +82-2-884-0305, snhan@snu.ac.kr 12 2017 28 12 2017 17 4 282 288 30 08 2017 13 10 2017 Copyright © 2017 Korean Society for Health Promotion and Disease Prevention 2017 Korean Society for Health Promotion and Disease Prevention This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Background

Serum vitamin B12 has been suggested as one of the cancer diagnostic markers and predictors for survival in cancer patients. In this study, we investigated the relationship between vitamin B12 and tumor progression.

 Methods

Solid tumor patients who had serum vitamin B12 levels and radiologic test follow-up were included in the study. A total of 55 patients were included. Receiver operating characteristic analysis was performed to determine the cut-off value of vitamin B12 for tumor progression. Kaplan-Meier method and Cox proportional hazard model for time to progression (TTP) were performed. Subgroup analysis was performed on patients with or without liver lesion (hepatocellular carcinoma and liver metastasis).

 Results

The cut-off value of vitamin B12 for tumor progression prediction was 691.4 pg/mL, the sensitivity was 57.1% and the specificity was 59.3%. Patients with vitamin B12≥691.4 pg/mL had shorter median TTP (2.1 months vs. 3.4 months, P=0.011). In subgroup analysis of patients without liver lesion, median TTP was significantly shorter in patients with vitamin B12≥691.4 pg/mL (1.6 months vs. 6.3 months, P=0.021), while there was no significant difference in TTP among the patients with liver lesion. Higher vitamin B12 level (≥691.4 pg/mL) was an independent prognostic factor for tumor progression (adjusted hazard ratio 2.4, 95% confidence interval 1.2–4.8, P=0.019).

 Conclusions

Serum vitamin B12 level can be used as a predictor of tumor progression in patients with solid tumors especially in patients without liver lesion. Additional large scale prospective studies are required to confirm this.

 Vitamin B12 Biomarkers Neoplasms Disease progression Oh R Brown DL Vitamin B12 deficiency Am Fam Physician 2003 67 5 979 986 Lechner K Födinger M Grisold W Püspök A Sillaber C Vitamin B12 deficiency. New data on an old them Wien Klin Wochenschr 2005 117 17 579 591 Arendt JF Nexo E Cobalamin related parameters and disease patterns in patients with increased serum cobalamin levels PLoS One 2012 7 9 e45979 Arendt JF Nexo E Unexpected high plasma cobalamin: proposal for a diagnostic strategy Clin Chem Lab Med 2013 51 3 489 496 Arendt JF Pedersen L Nexo E Sørensen HT Elevated plasma vitamin B12 levels as a marker for cancer: a population-based cohort study J Natl Cancer Inst 2013 105 23 1799 1805 Arendt JF Farkas DK Pedersen L Nexo E Sørensen HT Elevated plasma vitamin B12 levels and cancer prognosis: a population-based cohort study Cancer Epidemiology 2016 40 158 165 Lin CY Kuo CS Lu CL Wu MY Huang RF Elevated serum vitamin B(12) levels in association with tumor markers as the prognostic factors predictive for poor survival in patients with hepatocellular carcinoma Nutr Cancer 2010 62 2 190 197 Kelly L White S Stone PC The B12/CRP index as a simple prognostic indicator in patients with advanced cancer: a confirmatory study Ann Oncol 2007 18 8 1395 1399 Eisenhauer EA Therasse P Bogaerts J Schwartz LH Sargent D Ford R New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer 2009 45 2 228 247 Tavares F Is the B12/CRP index more accurate than you at predicting life expectancy in advanced cancer patients? J Pain Symptom Manage 2010 40 1 e12 e13 Ryg J Nybo M Hallas J Cancer incidence in persons with elevated cobalamin levels Eur J Clin Invest 2013 43 6 557 561 Schwettmann L Berbu S Reference interval and status for serum folate and serum vitamin B12 in a Norwegian population Clin Lab 2015 61 8 1095 1100 Bor MV Lydeking-Olsen E Møller J Nexø E A daily intake of approximately 6 microg vitamin B-12 appears to saturate all the vitamin B-12-related variables in Danish postmenopausal women Am J Clin Nutr 2006 83 1 52 58 Salles N Herrmann F Sakbani K Rapin CH Sieber C High vitamin B12 level: a strong predictor of mortality in elderly inpatients J Am Geriatr Soc 2005 53 5 917 918 Duffy MJ Tumor markers in clinical practice: a review focusing on common solid cancers Med Princ Pract 2013 22 1 4 11 Wu AH Sell S Markers for hepatocellular carcinoma Immunol Ser 1990 53 403 422 Zhang K Song P Gao J Li G Zhao X Zhang S Perspectives on a combined test of multi serum biomarkers in China: towards screening for and diagnosing hepatocellular carcinoma at an earlier stage Drug Discov Ther 2014 8 3 102 109 Daniele B Bencivenga A Megna AS Tinessa V Alpha-fetoprotein and ultrasonography screening for hepatocellular carcinoma Gastroenterology 2004 127 5 suppl 1 S108 S112 Farinati F Marino D De Giorgio M Baldan A Cantarini M Cursaro C Diagnostic and prognostic role of alpha-fetoprotein in hepatocellular carcinoma: both or neither? Am J Gastroenterol 2006 101 3 524 532 Yu J Zhang S Zhao B Differences and correlation of serum CEA, CA19-9 and CA72-4 in gastric cancer Mol Clin Oncol 2016 4 3 441 449 Du R Cheng D Lin L Sun J Peng K Xu Y Association between serum CA 19-9 and metabolic syndrome: a cross-sectional study J Diabetes 2017 9 11 1040 1047 Virgilio E Proietti A D'Urso R Cardelli P Giarnieri E Montagnini M Measuring intragastric tumor markers in gastric cancer patients: a systematic literature review on significance and reliability Anticancer Res 2017 37 6 2817 2821 Solomon LR Disorders of cobalamin (vitamin B12) metabolism: emerging concepts in pathophysiology, diagnosis and treatment Blood Rev 2007 21 3 113 130 Collin SM Metcalfe C Refsum H Lewis SJ Zuccolo L Smith GD Circulating folate, vitamin B12, homocysteine, vitamin B12 transport proteins, and risk of prostate cancer: a case-control study, systematic review, and meta-analysis Cancer Epidemiol Biomarkers Prev 2010 19 6 1632 1642 Lildballe DL Nguyen KQ Poulsen SS Nielsen HO Nexo E Haptocorrin as marker of disease progression in fibrolamellar hepatocellular carcinoma Eur J Surg Oncol 2011 37 1 72 79 Sysel AM Valli VE Nagle RB Bauer JA Immunohistochemical quantification of the vitamin B12 transport protein (TCII), cell surface receptor (TCII-R) and Ki-67 in human tumor xenografts Anticancer Res 2013 33 10 4203 4212 Donkena KV Yuan H Young CY Vitamin Bs, one carbon metabolism and prostate cancer Mini Rev Med Chem 2010 10 14 1385 1392 Ermens AA Vlasveld LT Lindemans J Significance of elevated cobalamin (vitamin B12) levels in blood Clin Biochem 2003 36 8 585 590 Fenech MF Dreosti IE Rinaldi JR Folate, vitamin B12, homocysteine status and chromosome damage rate in lymphocytes of older men Carcinogenesis 1997 18 7 1329 1336 Kapiszewska M Kalemba M Wojciech U Milewicz T Uracil misincorporation into DNA of leukocytes of young women with positive folate balance depends on plasma vitamin B12 concentrations and methylenetetrahydrofolate reductase polymorphisms. A pilot study J Nutr Biochem 2005 16 8 467 478 Progression receiver operating characteristic curve for vitamin B<sub>12</sub>. 691.4 pg/mL was the cut-off value for serum vitamin B<sub>12</sub> level related with tumor progression. Kaplan-Meier curve for time to progression (TTP). (A) All patients. Median TTP in patients with vitamin B<sub>12</sub><691.4 pg/mL and in patients with vitamin B<sub>12</sub>≥691.4 pg/mL was 3.4 months (95% confidence interval [CI] 1.8–5.0) and 2.1 months (1.9–2.3), respectively (<italic>P</italic>=0.011). (B) Non-liver lesion<sup>a</sup> group. Median TTP in patients with vitamin B<sub>12</sub><691.4 pg/mL and in patients with vitamin B<sub>12</sub>≥691.4 pg/mL was 6.3 months (2.9–9.7) and 1.6 months (0.0–3.5), respectively (<italic>P</italic>=0.021). (C) Liver lesion group. Median TTP in patients with vitamin B<sub>12</sub><691.4 pg/mL and in patients with vitamin B<sub>12</sub>≥691.4 pg/mL was 1.8 months (1.0–2.6) and 2.1 months (2.0–2.3), respectively (<italic>P</italic>=0.816). <italic>P</italic> values by log-rank test.

aLiver lesion included hepatocellular carcinoma and liver metastasis.

 Characteristics of patients

Abbreviations: NED, no evidence of disease; ECOG PS, Eastern Cooperative Oncology Group performance status.

Values are presented as number (%) or mean±standard error.

aLiver lesion included hepatocellular carcinoma and liver metastasis.

 Changes in serum vitamin B<sub>12</sub> levels according to tumor response

Abbreviations: PD, progressive disease; SD, stable disease; PR, partial response; NED, no evidence of disease; T1, first measurement; T2, second measurement.

Values are presented as mean±standard error.

P values by Wilcoxon's singed rank test.

 Risk for TTP according to vitamin B<sub>12</sub> level

Abbreviations: TTP, time to progression; HR, hazard ratio; CI, confidence interval.

P values by Cox proportional hazard model.

aLiver lesion included hepatocellular carcinoma and liver metastasis.

bAdjusted for age, sex, Eastern Cooperative Oncology Group Performance Status, and concurrent chemotherapy.