Too Much of a Good Thing: The Association of Elevated Vitamin B12 Levels and Outcomes in Patients with Cancer Treated with Immunotherapy

Metabolic pathways may regulate responses to cancer immunotherapy (IO). Due to its immunomodulatory properties, we sought to examine the association between serum vitamin B12 (VitB12) and survival in individuals with cancer treated with immune checkpoint inhibitors, compared with biological and chemotherapy. We collected data on patients with advanced cancer initiating intravenous antineoplastic treatment and a concomitant VitB12 measurement (elevated: >820 ng/L), between January 2010 and January 2022. Patients on IO and other regimens (control) were compared using the Mann-Whitney test for continuous variables, χ²test or Fisher test for categorical variables, and multivariate Cox regression models assessed the effect of VitB12 on overall survival and progression-free survival, adjusting for confounders. Patient groups (control: n = 408; IO: n = 93) were balanced for the treatment line and VitB12 (elevated 29.9% vs 23.7%; mean 762.4 vs 687.6 ng/L). In multivariate analysis, overall survival in all patients was negatively associated with VitB12 [control: hazard ratio (HR): 1.4, 95% CI: 1.01-1.96, P = 0.04, false discovery rate (FDR): 0.069; IO: HR: 2.74 as sum of linear baseline and interaction effects, log scale], age (HR: 1.03, 95% CI: 1.02-1.04, P < 0.01), male sex (HR: 0.66, 95% CI: 0.50-0.88, P < 0.01), and neutrophil-to-lymphocyte ratio (HR: 1.05, 95% CI: 0.48-0.99, P = 0.01). However, VitB12 was significantly negatively associated with progression-free survival only in the IO group (P < 0.001, FDR < 0.001, calculated HR: 8.34; biological treatment P = 0.08; FDR: 0.111; neutrophil-to-lymphocyte ratio, P = 0.07; FDR: 0.09). Taken together, elevated VitB12 was a negative predictor for outcomes on IO, independently of other known prognostic factors. Further research is needed to elucidate the immune-metabolic interplay and its interaction with the gut microbiome, as well as interventional strategies to enhance IO responses.