Kohn, Christine G.

Importance In a phase 2 randomized clinical trial, high-dose vitamin D 3 added to standard treatment improved progression-free survival (PFS) compared with standard-dose vitamin D 3 in patients with metastatic colorectal cancer (mCRC). Objective To determine if high-dose vitamin D 3 added to standard chemotherapy improves outcomes in patients with previously untreated mCRC. Design, Setting, and Participants Double-blind phase 3 randomized clinical trial enrolling 455 patients with previously untreated mCRC, conducted in the US through the National Clinical Trials Network from October 2019 to December 2022 (database freeze: July 15, 2024). Interventions mFOLFOX6 (modified FOLFOX6 [5-fluorouracil, leucovorin, oxaliplatin]) or FOLFIRI (5-fluorouracil, leucovorin, irinotecan) plus bevacizumab every 2 weeks with either high-dose vitamin D 3 (8000 IU daily × 14 days as loading dose followed by 4000 IU daily) or standard-dose vitamin D 3 (400 IU daily) until disease progression, intolerable toxicity, or withdrawal of consent. Main Outcomes and Measures The primary end point was PFS assessed by the unstratified log-rank test. Secondary end points included objective response rate, overall survival, and toxicity. Prespecified subgroup analyses of PFS were performed according to known prognostic factors. Results Among 455 randomized patients (median age, 59 years; 181 [40%] female) with median follow-up 20 months, the median PFS for high-dose vitamin D 3 (n = 228) was 11.8 months (95% CI, 10.3-13.3) vs 10.3 months (95% CI, 9.4-12.2) for standard-dose vitamin D 3 (n = 227) (1-sided log-rank P = .25). There were no significant differences in objective response rate between high-dose and standard-dose vitamin D 3 (51% [95% CI, 44%-58%] vs 44% [95% CI, 37%-50%], respectively; P = .12), or in overall survival (median, 25.6 vs 27.0 months; 1-sided log-rank P = .66). There were no clinically meaningful differences in the most common grade 3 or greater adverse events between the high- and standard-dose groups, including neutropenia (n = 67 [32%] vs n = 62 [30%]) and hypertension (n = 42 [20%] vs n = 49 [23%]) or in incidence of vitamin D–associated toxicities. Conclusions and Relevance Among patients with previously untreated mCRC, addition of high-dose vitamin D 3 , vs standard-dose vitamin D 3 , to standard chemotherapy plus bevacizumab did not improve PFS. Trial Registration ClinicalTrials.gov Identifier: NCT04094688

3553 Background: Higher levels of plasma 25-hydroxyvitamin D [25(OH)D)] are associated with better outcomes in mCRC, but underlying biologic mechanisms are unknown. Key components of the VitD metabolic pathway include CYP27B1 (encodes 1-α-hydroxylase, converts 25(OH)D to active calcitriol), VitD receptor (VDR), and CYP24A1 (encodes 24-hydroxylase, degrades calcitriol and 25(OH)D into excreted metabolites). Since these factors may affect 25(OH)D levels and potentially mediate VitD activity in mCRC, we examined the relationship between tumoral gene expression (GEx) of CYP27B1, VDR, and CYP24A and pt outcome in a study nested in a randomized phase III trial of first-line chemotherapy plus biologics in mCRC pts, CALGB/SWOG 80405. Methods: We determined GEx of CYP27B1, VDR, and CYP24A1 by RNA sequencing (RNA-Seq) of archival tumor samples using the Illumina TruSeq platform. Primary endpoints were overall (OS) and progression-free survival (PFS). Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for prognostic and molecular characteristics. Results: 562 pts with RNA-Seq data were included. Pts with higher CYP27B1 expression (>median) were less likely to have BRAF wild type (WT) (79% vs 90%) compared to pts with lower expression (p=0.0007). Pts with higher VDR expression (>quartile 1 [Q1]) were younger (median age 59 vs 62 years; p=0.03), more likely to have left-sided (63% vs 46%; p=0.0005) and BRAF WT tumors (89% vs 70%; p<0.0001), and less likely to have RAS WT tumors (70% vs 80%; p=0.02) compared to pts with lower VDR. Pts with higher CYP24A1 expression (>median) were more likely to have left-sided tumors compared to pts with lower expression (63% vs 54%; p=0.03). On multivariable analysis, pts with higher CYP27B1 expression had significantly improved OS (HR 0.84; 95% CI, 0.75-0.93; p=0.002) and PFS (HR 0.89; 95% CI, 0.80-0.99; p=0.04). Higher VDR expression (up to Q1) was associated with significantly improved PFS (HR 0.69; 95% CI, 0.53-0.91; p=0.007) but not OS (HR 0.85; 95% CI, 0.66-1.09; p=0.20). Above Q1, this improvement attenuated. Higher CYP24A1 GEx was not associated with improved OS (HR 0.98; 95% CI, 0.88-1.08; p=0.66) or PFS (HR 0.98; 95% CI, 0.89-1.08; p=0.68). We found no significant interactions between GEx of CYP27B1, VDR, or CYP24A with baseline plasma 25(OH)D levels (p for interaction ≥0.10 for all). Conclusions: Our findings suggest an association between GEx of VitD pathway markers, particularly CYP27B1 and VDR, and survival in pts with mCRC, lending biologic plausibility to a role of VitD in CRC pathogenesis. Future studies are needed to confirm these findings and elucidate underlying mechanisms of action. Clinical trial information: NCT00265850 .