Plasma 25-Hydroxyvitamin D Levels and Survival in Stage III Colon Cancer: Findings from CALGB/SWOG 80702 (Alliance)

Qiao Li Wang; Chao Ma; Chen Yuan; Qian Shi; Brian M. Wolpin; Yin Zhang; Charles S. Fuchs; Jeffrey Meyer; Tyler Zemla; En Cheng; Priya Kumthekar; Katherine A. Guthrie; Felix Couture; Philip Kuebler; Pankaj Kumar; Benjamin Tan; Smitha Krishnamurthi; Richard M. Goldberg; Alan Venook; Charles Blanke; Anthony F. Shields; Eileen M. O’Reilly; Jeffrey A. Meyerhardt; Kimmie Ng

doi:10.1158/1078-0432.CCR-23-0447

Plasma 25-Hydroxyvitamin D Levels and Survival in Stage III Colon Cancer: Findings from CALGB/SWOG 80702 (Alliance)

Qiao Li Wang^*, Chao Ma, Chen Yuan, Qian Shi, Brian M. Wolpin, Yin Zhang, Charles S. Fuchs, Jeffrey Meyer, Tyler Zemla, En Cheng, Priya Kumthekar, Katherine A. Guthrie, Felix Couture, Philip Kuebler, Pankaj Kumar, Benjamin Tan, Smitha Krishnamurthi, Richard M. Goldberg, Alan Venook, Charles BlankeAnthony F. Shields, Eileen M. O’Reilly, Jeffrey A. Meyerhardt, Kimmie Ng

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

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Abstract

Purpose: To assess whether higher plasma 25-hydroxyvitamin D [25(OH)D] is associated with improved outcomes in colon cancer and whether circulating inflammatory cytokines mediate such association. Experimental Design: Plasma samples were collected from 1,437 patients with stage III colon cancer enrolled in a phase III randomized clinical trial (CALGB/SWOG 80702) from 2010 to 2015, who were followed until 2020. Cox regressions were used to examine associations between plasma 25(OH)D and disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR). Mediation analysis was performed for circulating inflammatory biomarkers of C-reactive protein (CRP), IL6, and soluble TNF receptor 2 (sTNF-R2). Results: Vitamin D deficiency [25(OH)D <12 ng/mL] was present in 13% of total patients at baseline and in 32% of Black patients. Compared with deficiency, nondeficient vitamin D status (≥12 ng/mL) was significantly associated with improved DFS, OS, and TTR (all P_log-rank<0.05), with multivariable-adjusted HRs of 0.68 (95% confidence interval, 0.51–0.92) for DFS, 0.57 (0.40–0.80) for OS, and 0.71 (0.52–0.98) for TTR. A U-shaped dose–response pattern was observed for DFS and OS (both P_nonlinearity<0.05). The proportion of the association with survival that was mediated by sTNF-R2 was 10.6% (P_mediation = 0.04) for DFS and 11.8% (P_mediation = 0.05) for OS, whereas CRP and IL6 were not shown to be mediators. Plasma 25(OH)D was not associated with the occurrence of ≥ grade 2 adverse events. Conclusions: Nondeficient vitamin D is associated with improved outcomes in patients with stage III colon cancer, largely independent of circulation inflammations. A randomized trial is warranted to elucidate whether adjuvant vitamin D supplementation improves patient outcomes.

Original language	English (US)
Pages (from-to)	2621-2630
Number of pages	10
Journal	Clinical Cancer Research
Volume	29
Issue number	14
DOIs	https://doi.org/10.1158/1078-0432.CCR-23-0447
State	Published - Jul 2023

Funding

We would like to thank the participants and staff of the clinical trials. The authors assume full responsibility for the analyses and interpretation of these data. Research reported in this publication was supported by the NCI of the NIH under award numbers U10CA180821, U10CA180882, and U24 CA196171 (to the Alliance for Clinical Trials in Oncology), UG1CA189858, UG1CA189960, UG1CA233163 (SWOG), UG1CA233180, UG1CA233290, UG1 CA233320, UG1CA233337, UG1CA233339; https://acknowledgments.alliancefound.org; U10CA180863 and CCS Grant 707213 (CCTG); UG1CA233234 and U10CA180820 (ECOG-ACRIN); U10CA180868 (NRG); U10CA180888; R01CA205406 (to K. Ng); Department of Defense (R33CA160344, to K. Ng), Project P Fund (J.A. Meyerhardt and K. Ng), Douglas Gray Woodruff Chair Fund (J.A. Meyerhardt), Anonymous Family Fund for Innovations in Colorectal Cancer (J.A. Meyerhardt), and Cancer Center Support Grant/Core Grant P30 CA008748 (E.M. O’Reilly). Also supported in part by Pfizer. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Q. Shi reports personal fees from Regeneron Pharmaceuticals, Inc., Kronos Bio, Yiviva Inc., Hoosier Cancer Research Network, and Mirati Therapeutics Inc; grants from Janssen, BMS, Genetech, and Novartis outside the submitted work. C.S. Fuchs

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General Medicine

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10.1158/1078-0432.CCR-23-0447

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Wang, Q. L., Ma, C., Yuan, C., Shi, Q., Wolpin, B. M., Zhang, Y., Fuchs, C. S., Meyer, J., Zemla, T., Cheng, E., Kumthekar, P., Guthrie, K. A., Couture, F., Kuebler, P., Kumar, P., Tan, B., Krishnamurthi, S., Goldberg, R. M., Venook, A., ... Ng, K. (2023). Plasma 25-Hydroxyvitamin D Levels and Survival in Stage III Colon Cancer: Findings from CALGB/SWOG 80702 (Alliance). Clinical Cancer Research, 29(14), 2621-2630. https://doi.org/10.1158/1078-0432.CCR-23-0447

@article{7fa72b52b1a9427a8afcbfccd3b00750,

title = "Plasma 25-Hydroxyvitamin D Levels and Survival in Stage III Colon Cancer: Findings from CALGB/SWOG 80702 (Alliance)",

abstract = "Purpose: To assess whether higher plasma 25-hydroxyvitamin D [25(OH)D] is associated with improved outcomes in colon cancer and whether circulating inflammatory cytokines mediate such association. Experimental Design: Plasma samples were collected from 1,437 patients with stage III colon cancer enrolled in a phase III randomized clinical trial (CALGB/SWOG 80702) from 2010 to 2015, who were followed until 2020. Cox regressions were used to examine associations between plasma 25(OH)D and disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR). Mediation analysis was performed for circulating inflammatory biomarkers of C-reactive protein (CRP), IL6, and soluble TNF receptor 2 (sTNF-R2). Results: Vitamin D deficiency [25(OH)D <12 ng/mL] was present in 13% of total patients at baseline and in 32% of Black patients. Compared with deficiency, nondeficient vitamin D status (≥12 ng/mL) was significantly associated with improved DFS, OS, and TTR (all Plog-rank<0.05), with multivariable-adjusted HRs of 0.68 (95% confidence interval, 0.51–0.92) for DFS, 0.57 (0.40–0.80) for OS, and 0.71 (0.52–0.98) for TTR. A U-shaped dose–response pattern was observed for DFS and OS (both Pnonlinearity<0.05). The proportion of the association with survival that was mediated by sTNF-R2 was 10.6% (Pmediation = 0.04) for DFS and 11.8% (Pmediation = 0.05) for OS, whereas CRP and IL6 were not shown to be mediators. Plasma 25(OH)D was not associated with the occurrence of ≥ grade 2 adverse events. Conclusions: Nondeficient vitamin D is associated with improved outcomes in patients with stage III colon cancer, largely independent of circulation inflammations. A randomized trial is warranted to elucidate whether adjuvant vitamin D supplementation improves patient outcomes.",

author = "Wang, {Qiao Li} and Chao Ma and Chen Yuan and Qian Shi and Wolpin, {Brian M.} and Yin Zhang and Fuchs, {Charles S.} and Jeffrey Meyer and Tyler Zemla and En Cheng and Priya Kumthekar and Guthrie, {Katherine A.} and Felix Couture and Philip Kuebler and Pankaj Kumar and Benjamin Tan and Smitha Krishnamurthi and Goldberg, {Richard M.} and Alan Venook and Charles Blanke and Shields, {Anthony F.} and O{\textquoteright}Reilly, {Eileen M.} and Meyerhardt, {Jeffrey A.} and Kimmie Ng",

note = "Publisher Copyright: {\textcopyright} 2023 American Association for Cancer Research.",

year = "2023",

month = jul,

doi = "10.1158/1078-0432.CCR-23-0447",

language = "English (US)",

volume = "29",

pages = "2621--2630",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "14",

}

Wang, QL, Ma, C, Yuan, C, Shi, Q, Wolpin, BM, Zhang, Y, Fuchs, CS, Meyer, J, Zemla, T, Cheng, E, Kumthekar, P, Guthrie, KA, Couture, F, Kuebler, P, Kumar, P, Tan, B, Krishnamurthi, S, Goldberg, RM, Venook, A, Blanke, C, Shields, AF, O’Reilly, EM, Meyerhardt, JA & Ng, K 2023, 'Plasma 25-Hydroxyvitamin D Levels and Survival in Stage III Colon Cancer: Findings from CALGB/SWOG 80702 (Alliance)', Clinical Cancer Research, vol. 29, no. 14, pp. 2621-2630. https://doi.org/10.1158/1078-0432.CCR-23-0447

TY - JOUR

T1 - Plasma 25-Hydroxyvitamin D Levels and Survival in Stage III Colon Cancer

T2 - Findings from CALGB/SWOG 80702 (Alliance)

AU - Wang, Qiao Li

AU - Ma, Chao

AU - Yuan, Chen

AU - Shi, Qian

AU - Wolpin, Brian M.

AU - Zhang, Yin

AU - Fuchs, Charles S.

AU - Meyer, Jeffrey

AU - Zemla, Tyler

AU - Cheng, En

AU - Kumthekar, Priya

AU - Guthrie, Katherine A.

AU - Couture, Felix

AU - Kuebler, Philip

AU - Kumar, Pankaj

AU - Tan, Benjamin

AU - Krishnamurthi, Smitha

AU - Goldberg, Richard M.

AU - Venook, Alan

AU - Blanke, Charles

AU - Shields, Anthony F.

AU - O’Reilly, Eileen M.

AU - Meyerhardt, Jeffrey A.

AU - Ng, Kimmie

PY - 2023/7

Y1 - 2023/7

N2 - Purpose: To assess whether higher plasma 25-hydroxyvitamin D [25(OH)D] is associated with improved outcomes in colon cancer and whether circulating inflammatory cytokines mediate such association. Experimental Design: Plasma samples were collected from 1,437 patients with stage III colon cancer enrolled in a phase III randomized clinical trial (CALGB/SWOG 80702) from 2010 to 2015, who were followed until 2020. Cox regressions were used to examine associations between plasma 25(OH)D and disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR). Mediation analysis was performed for circulating inflammatory biomarkers of C-reactive protein (CRP), IL6, and soluble TNF receptor 2 (sTNF-R2). Results: Vitamin D deficiency [25(OH)D <12 ng/mL] was present in 13% of total patients at baseline and in 32% of Black patients. Compared with deficiency, nondeficient vitamin D status (≥12 ng/mL) was significantly associated with improved DFS, OS, and TTR (all Plog-rank<0.05), with multivariable-adjusted HRs of 0.68 (95% confidence interval, 0.51–0.92) for DFS, 0.57 (0.40–0.80) for OS, and 0.71 (0.52–0.98) for TTR. A U-shaped dose–response pattern was observed for DFS and OS (both Pnonlinearity<0.05). The proportion of the association with survival that was mediated by sTNF-R2 was 10.6% (Pmediation = 0.04) for DFS and 11.8% (Pmediation = 0.05) for OS, whereas CRP and IL6 were not shown to be mediators. Plasma 25(OH)D was not associated with the occurrence of ≥ grade 2 adverse events. Conclusions: Nondeficient vitamin D is associated with improved outcomes in patients with stage III colon cancer, largely independent of circulation inflammations. A randomized trial is warranted to elucidate whether adjuvant vitamin D supplementation improves patient outcomes.

AB - Purpose: To assess whether higher plasma 25-hydroxyvitamin D [25(OH)D] is associated with improved outcomes in colon cancer and whether circulating inflammatory cytokines mediate such association. Experimental Design: Plasma samples were collected from 1,437 patients with stage III colon cancer enrolled in a phase III randomized clinical trial (CALGB/SWOG 80702) from 2010 to 2015, who were followed until 2020. Cox regressions were used to examine associations between plasma 25(OH)D and disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR). Mediation analysis was performed for circulating inflammatory biomarkers of C-reactive protein (CRP), IL6, and soluble TNF receptor 2 (sTNF-R2). Results: Vitamin D deficiency [25(OH)D <12 ng/mL] was present in 13% of total patients at baseline and in 32% of Black patients. Compared with deficiency, nondeficient vitamin D status (≥12 ng/mL) was significantly associated with improved DFS, OS, and TTR (all Plog-rank<0.05), with multivariable-adjusted HRs of 0.68 (95% confidence interval, 0.51–0.92) for DFS, 0.57 (0.40–0.80) for OS, and 0.71 (0.52–0.98) for TTR. A U-shaped dose–response pattern was observed for DFS and OS (both Pnonlinearity<0.05). The proportion of the association with survival that was mediated by sTNF-R2 was 10.6% (Pmediation = 0.04) for DFS and 11.8% (Pmediation = 0.05) for OS, whereas CRP and IL6 were not shown to be mediators. Plasma 25(OH)D was not associated with the occurrence of ≥ grade 2 adverse events. Conclusions: Nondeficient vitamin D is associated with improved outcomes in patients with stage III colon cancer, largely independent of circulation inflammations. A randomized trial is warranted to elucidate whether adjuvant vitamin D supplementation improves patient outcomes.

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U2 - 10.1158/1078-0432.CCR-23-0447

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AN - SCOPUS:85164843217

SN - 1078-0432

VL - 29

SP - 2621

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JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 14

ER -

Plasma 25-Hydroxyvitamin D Levels and Survival in Stage III Colon Cancer: Findings from CALGB/SWOG 80702 (Alliance)

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