One of the standard of care regimens for advanced pancreatic cancer is gemcitabine-based chemotherapy. The efficacy of gemcitabine is reduced by dose-limiting hematologic toxicities, especially neutropenia. Uncovering the variability of these toxicities attributed to germline DNA variation is of great importance.
CALGB 80303 was a randomized study in advanced pancreatic cancer patients treated with gemcitabine with or without bevacizumab. The study protocol included genotyping of genes of gemcitabine disposition (CDA, DCTD, SLC29A1, SLC28A1, SLC29A2), as well as a genome-wide analysis. The clinical phenotype was time to high-grade early neutropenia event accounting for progression or death, with other treatment-terminating adverse events as competing informative events. The inference was conducted on the basis of the association between genotype and cause-specific hazard of a neutropenic event.
The primary analyses were conducted on the basis of 294 genetically estimated Europeans. For CDA rs2072671 (A>C), AC and CC patients had a lower risk of neutropenia than AA patients (unadjusted P-value 0.01, HR 0.61, 95% CI 0.41-0.89). For SLC28A1 rs3825876 (G>A), AA patients have a higher risk of neutropenia than GA and GG patients (unadjusted P-value 0.02, HR 1.51, 95% CI 1.06-2.16). The C allele of CDA rs2072671 was associated with increased mRNA expression in whole blood in three studies (unadjusted P-values 2.7e-14, 6.61e-62, 9.70e-65). In the genome-wide analysis, variants in TGFB2 were among the top hits (unadjusted lowest P-value 1.62e-06) but had no effect in luciferase assays.
The first genetic analysis of gemcitabine-induced neutropenia using a competing risk model in a prospective randomized clinical study has proposed a potentially novel mechanism of the protective effect of the CDA rs2072671 variant. We hypothesize that the rs2072671 (A>C) variant acts through a local effect in either the bone marrow or in circulating neutrophils (or both), by protecting neutrophils from the anti-proliferative effects of gemcitabine. Further confirmation is needed.
Clinical trial identification
Legal entity responsible for the study
Alliance for Clinical Trials in Oncology.
All authors have declared no conflicts of interest.