Innocenti(ChemotherapyAdvisor) – Patients with pancreatic cancer and two variant alleles of a single-nucleotide polymorphism (SNP) in VDR, the gene coding for the vitamin D receptor, have higher rates of overall survival (OS), a study presented June 19 at the American Association for Cancer Research’s Pancreatic Cancer: Progress and Challenges conference, Lake Tahoe, NV, has found.
This study aimed to identify novel genes associated with OS by replicating the most statistically significant SNPs for OS identified in the phase 3 randomized CALGB80303 trial, which randomly assigned patients with advanced pancreatic cancer of European descent to gemcitabine plus bevacizumab or gemcitabine alone, noted Federico Innocenti, MD, PhD, of the University of North Carolina at Chapel Hill Eshelman School of Pharmacy.
They tested the association of the top 300 SNPs in CALBG80303 in 408 patients with advanced pancreatic cancer—half with locally advanced disease and half with metastatic disease—from the Mayo Clinic who were also of European descent. Approximately 30% of patients had received prior radiation and 60%, gemcitabine. Each was genotyped for about 550,000 SNPs using the same DNA sequencing platform of CALGB80303.
A total of 10 SNPs with an effect on OS concordant with CALGB80303 (P<0.05) were selected; 4 were located in genes VDR, CMYA5, C7orf58, and CAMK4. A SNP in VDR (rs2853564) was associated with OS in both the Mayo Clinic patients (HR 0.82 [95 % CI, 0.71–0.95], P=0.0077) as well as in those in the CALGB80303 trial (HR 0.74 [0.63–0.87], P=0.0002).
Results showed that patients with two variant alleles of rs2853564 had a median OS of 10.5 months in the Mayo Clinic group and 8.9 months in the CALGB803030 study, whereas those with one variant allele had a median OS of 8.34 months in the Mayo Clinic group and 5.9 months in the CALGB 803030 study, they reported. This contrasted with a median OS of 6.6 months in the Mayo Clinic group and 4.7 months in the CALGB 803030 study among patients without copies of the variant allele.
The minor allele of rs2853564 was found to increase luciferase expression by 22% (P<0.05) and 37% (P<0.05) in HEK293 and PANC-1 cells, respectively. “PANC-1 cells exposed to calcitriol, the hormonally active form of vitamin D, were up to 38% (P=0.0005) less viable than PANC-1 cells which had a siRNA-mediated knockdown of VDR expression,” he reported.
While Dr. Innocenti said he does not see this study having any immediate clinical implications, he believes it provides additional information about the link between vitamin D biology and pancreatic cancer. Noting that modulation of VDR expression results in differences in behavior of pancreatic cancer, the “putative prognostic role of VDR germline SNPs should be replicated in additional cohorts of patients with advanced pancreatic cancer,” he concluded.
[see PDF of abstract – we have permission from AACR provide a link to these on CTA.com. The conference abstracts will not be up on the AACR Web site for 6 to 8 weeks.]