ABSTRACT & COMMENTARY
Can Supplementation With Vitamin D Affect PD-L1 Expression in Gastrointestinal Cancers? Results from a post hoc analysis of the AMATERASU trial in Japan REFERENCE
Morita M, Okuyama M, Akutsu T, Ohdaira H, Suzuki Y, Urashima M. Vitamin D supplementation regulates postoperative serum levels of PD-L1 in patients with digestive tract cancer and improves survivals in the highest quintile of PD-L1: a post hoc analysis of the AMATERASU randomized controlled trial. Nutrients. 2021;13(6):1987. STUDY OBJECTIVE
To examine whether vitamin D supplementation regulates serum programmed cell death ligand 1 (PD-L1) and, thus, could alter survival time of gastrointestinal (GI) cancer patients DESIGN
A post hoc analysis of the AMATERASU trial in Japan, which was a randomized, double-blind, placebo-controlled trial conducted at a single university hospital PARTICIPANTS
The study recruited patients aged 30 to 90 years with stage I to III cancers of the digestive tract from the esophagus to the rectum, who were surgical candidates. Of the 439 eligible patients, 15 declined and 7 were excluded after surgery. The investigators included all 417 randomized patients (mean age 66 years; male 66%; esophageal cancer 10%; gastric cancer 42%; colorectal cancer 48%) in the analysis to compare the effects of vitamin D3 supplements (2,000 IU/day) and placebo on relapse and/or death, at an allocation ratio of 3:2, between January 2010 and February 2018. The trial included patients with stage I (44% of participants), II (26%), or III (30%) digestive tract cancers who underwent
curative surgery with complete tumor resection. Only those not taking vitamin D supplements already were included. INTERVENTION
Investigators randomized patients to receive oral supplemental capsules of vitamin D (2,000 IU/d; n=251) or placebo (n=166) from the first postoperative outpatient visit to until the end of the trial. Placebo contained sesame oil, gelatin (swine-derived), and glycerin, and the active supplement contained the same constituents plus vitamin D3 as 25-hydroxycholecalciferol, 25(OH)D. STUDY PARAMETERS ASSESSED
Investigators measured postoperative serum PD-L1 levels using ELISA and divided them into quintiles (Q1– Q5). Serum samples were available for 396 (95.0%) of the original trial participants. Investigators collected serum samples for PD-L1 measurements after the surgery (23 days, interquartile range (IQR): 13–43.5 days) and just before the start of vitamin D/placebo supplementation. They also measured serum PD-L1 levels 1 year after starting vitamin D/ placebo supplements. Subgroups analyzed had baseline serum 25(OH)D levels of 0 to less than 20 ng/mL, 20 to 40 ng/ mL, and greater than 40 ng/mL. Because of small sample size for the highest-baseline-level group, investigators tested interactions between only the low- and middle-baselinelevel serum 25(OH)D groups.
14 ©2021 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2021 SUPPLEMENT—VOL.13, NO. 101 (SUPPL)
By Shauna Birdsall, ND, FABNO PRIMARY OUTCOME MEASURES
The primary outcome was relapse-free survival, time to relapse, or death. The outcome of relapse or death was confirmed by regular outpatient follow-up. The elapsed time to relapse or death was calculated from the time of randomization (ie, time from starting the study supplements). KEY FINDINGS
Vitamin D supplementation significantly (P=0.0008) increased serum PD-L1 levels in the lowest quintile of PD-L1 (Q1; ie, those patients who started out with the lowest levels of PD-L1), whereas it significantly (P=0.0001) decreased PD-L1 levels in the highest quintile of serum PD-L1 levels (Q5), and it neither increased nor decreased PD-L1 levels in the middle quintiles of PD-L1 (Q2–Q4). Significant effects of vitamin D supplementation compared with placebo on death (HR, 0.34; 95% CI, 0.12–0.92) and relapse/death (HR, 0.37; 95% CI, 0.15–0.89) were observed in the highest quintile (Q5) of serum PD-L1, whereas significant effects were not observed in other quintiles (Pinteraction=0.02 for death, Pinteraction=0.04 for relapse/death). Vitamin D supplementation significantly reduced the risk of relapse and/or death by approximately two-thirds in the highest quintile of serum PD-L1.
