A Pooled Analysis of 25-hydroxyvitamin D and Colorectal Cancer Survival

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DESCRIPTION (provided by applicant): Despite advances in prevention, screening, early detection, and treatment, colorectal cancer (CRC) remains the 3rd most commonly diagnosed cancer and the 2nd leading cause of cancer death in the US, with approximately 142,820 new cases and 50,830 deaths expected in 2013. Although advances in CRC early detection and treatment have resulted in relatively longer survival, the impact of modifiable dietary and lifestye factors that may contribute to survival has not been sufficiently explored. Vitamin D is a potentia agent for the chemoprevention of cancer progression, recurrence and death in CRC patients, possibly through mechanisms related to its direct effects on the cell cycle, modulation of growth factor signaling, estrogen and androgen receptor pathways, inflammation, oxidative stress, and immune function, as well as inhibition of invasion, metastasis, and angiogenesis. Higher circulating vitamin D levels are consistently associated with lower risk for CRC, but their association with CRC survival is relatively unexplored. Based on basic science and limited human evidence, we hypothesize that higher levels of prospectively collected, pre-diagnostic circulating vitamin D [25(OH)D, the best indicator of vitamin D status] are associated with lower CRC-specific and overall mortality among CRC cases. We will investigate this in an adjunct study to the ongoing, NCI-funded (R01 CA152071) Vitamin D Pooling Project of Breast and Colorectal Cancer (VDPP), which pools comprehensive primary data from 21 prospective cohort studies from the US, Europe, and Asia to investigate associations between 25(OH)D levels and risk of these cancer sites overall, by tumor subtype, and by population subgroups defined by personal characteristics, lifestyle factors, vitamin D receptor (VDR) polymorphisms, and other biomarkers. We will analyze (using traditional and competing risk survival analyses) the association between pre-diagnostic 25(OH) D levels and risk of CRC-specific and overall mortality in 5,795 CRC cases (among which there were 2,627 deaths) in 16 cohort studies conducted in the US, Europe, and Asia. As part of the parent grant, the 25(OH) D levels have been calibrated to a common standard laboratory to enable categorization of 25(OH)D levels using not only study-specific quintiles, but also consortium-wide quintiles and common absolute cut points. This adjunct study offers a unique, cost-effective and resource-efficient opportunity i the largest pooled study currently available to investigate an association between pre-diagnostic 25(OH)D levels and CRC-specific and overall mortality, with particular emphasis on potential lifestyle (body mass index, physical activity, calcium intake) and genetic (variation in the VDR in a sub-set of cohorts) effect modifiers, and examine the effects of vitamin D on CRC survival by colon sub-site, sex, and tumor characteristics. This study will provide an important step forward in understanding whether vitamin D affects CRC progression and survival, as well as insight into the potential application of this important compound in CRC treatment regimens.