Examining the Role of Vitamin D in Colorectal Cancer Survival

Kimmie Ng, MD, MPH
Published: Monday, Jan 27, 2014
Dana-Farber Cancer Institute Dr.Kimmie Ng
Kimmie Ng, MD, MPH
Assistant Professor of Medicine
Center for Gastrointestinal Oncology
Dana-Farber Cancer Institute
Harvard Medical Center
Boston, Massachusetts Strategic Partnerships
Epidemiologic and scientific research indicates that diet and other lifestyle factors have a significant influence on the risk of developing colorectal cancer. Little is known, however, about how these factors may impact the survival of patients with established colorectal cancer, many of whom seek to understand which diet and lifestyle behaviors—beyond standard treatment with surgery, chemotherapy, or radiation—will improve their outcome.

Following on the recommendation of an American Cancer Society consensus panel highlighting the urgent need for more research on the effect of nutrition and physical activity on the prognosis of cancer survivors, the Center for Gastrointestinal Oncology at Dana-Farber Cancer Institute has developed an innovative, crossdisciplinary, translational research program to elucidate the role of diet and lifestyle behaviors in the survival of colorectal cancer patients.

Among the factors that we have identified as being potentially protective are exercise,1-3 avoiding a Western pattern diet,4 maintaining a normal body-mass index,5 aspirin use,6,7 and vitamin D status. For vitamin D, in particular, abundant data from the laboratory as well as epidemiologic studies support a potential antineoplastic effect. Efforts are underway to further understand the biologic mechanisms by which vitamin D may contribute to colorectal cancer pathogenesis and the potential clinical impact of supplementation on patient management.

The hypothesis that vitamin D status is related to colorectal cancer has received strong experimental support over the past two decades, based on the almost ubiquitous expression in colon cancer cells of the vitamin D receptor (VDR)8,9 and 1-a-hydroxylase (CYP27B1),10 which converts plasma 25-hydroxyvitamin D3 [25(OH)D] into 1,25-dihyroxycholecalciferol [1,25(OH)2D], the active metabolite. Binding of VDR by 1,25(OH)2D leads to transcriptional control of target genes, resulting in induction of differentiation and apoptosis,11,12 and inhibition of proliferation,13 angiogenesis,14,15 and metastatic potential.16,17

Vitamin D inhibits growth and promotes differentiation of colorectal cancer cell lines and xenografts.14,18-21 Rats maintained on a diet enriched in 1,25(OH)2D develop fewer intestinal tumors and metastases compared to control animals.17,22 Treatment of ApcMin mice with vitamin D or a synthetic analog reduces the size of intestinal adenomas,23-25 and epidemiologic data also suggest that vitamin D plays a role in colorectal cancer carcinogenesis. A meta-analysis of nine prospective studies showed that individuals with higher plasma levels of 25(OH)D, the best indicator of vitamin D status, have a significantly reduced risk of developing colorectal cancer.26

The influence of vitamin D on survival of patients with established colorectal cancer remains uncertain, however, and we conducted several studies to try and address this knowledge gap.

Figure. Plasma 25(OH)D and Survival in 304 Colorectal Cancer Patients (NHS/HPFS)

 Plasma 25(OH)D and Survival in 304 Colorectal Cancer
Patients (NHS/HPFS)

Adjusted for age, gender, stage, grade, site, year of diagnosis, season of blood draw, BMI, and post-diagnosis physical activity. (Ng K, et al. J Clin Oncol. 2008;26[18]:2984-2991.)

Among 304 colorectal cancer patients in the Nurses’ Health Study (NHS) and the Health Professionals Follow- Up Study (HPFS) who had blood samples available, we measured 25(OH)D concentrations prior to colorectal cancer diagnosis and assessed for a correlation with survival. We found that higher plasma 25(OH)D levels were associated with a significant reduction in overall mortality (Figure).27 This finding was subsequently confirmed in another study of 1017 colorectal cancer patients in the NHS and HPFS, where higher postdiagnosis vitamin D scores calculated from known clinical determinants of vitamin D status were found to be significantly associated with improved cancer-specific (adjusted hazard ratio [HR] = 0.50; 95% CI, 0.26-0.95; P trend = .02) and overall survival (HR = 0.62; 95% CI, 0.42- 0.93; P trend = .002).28 In subgroup analyses, the benefit of higher plasma 25(OH)D seemed greater in stage III and IV patients than stage I and II (adjusted HR = 0.40 vs 0.90, respectively, comparing extreme quartiles).27

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