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An initial genetic analysis of gemcitabine-induced high-grade neutropenia in pancreatic cancer patients in CALGB 80303 (Alliance)

Innocenti, Federicoa; Jiang, Chenb; Sibley, Alexander B.b; Denning, Stefaniea; Etheridge, Amy S.a; Watson, Dorothyb; Niedzwiecki, Donnab,c; Hatch, Ace J.b; Hurwitz, Herbert I.b; Nixon, Andrew B.b; Furukawa, Yoichif; Kubo, Michiakig; Crona, Daniel J.a; Kindler, Hedy L.d; McLeod, Howard L.e; Ratain, Mark J.d; Owzar, Kourosb,c

doi: 10.1097/FPC.0000000000000375
ORIGINAL ARTICLE
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Objectives One of the standard of care regimens for advanced pancreatic cancer is gemcitabine-based chemotherapy. The efficacy of gemcitabine is limited by dose-limiting hematologic toxicities especially neutropenia. Uncovering the variability of these toxicities attributed to germline DNA variation is of great importance.

Patients and methods 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, and SLC29A2), as well as a genome-wide analysis. The clinical phenotype was time to early high-grade neutropenia event accounting for progression or death or other treatment-terminating adverse events as competing for informative events. The inference was carried out on the basis of the association between genotype and cause-specific hazard of a neutropenic event.

Results The primary analyses were carried out on the basis of 294 genetically estimated European pancreatic cancer patients. For CDA rs2072671 (A>C), AC and CC patients had a lower risk of neutropenia than AA patients (P=0.01, hazard ratio: 0.61, 95% confidence interval: 0.41–0.89). For SLC28A1 rs3825876 (G>A), AA patients have a higher risk of neutropenia than GA and GG patients (P=0.02, hazard ratio: 1.51, 95% confidence interval: 1.06–2.16). CDA rs2072671 was associated with increased mRNA expression in whole blood in three studies (P=2.7e−14, 6.61e−62, and 9.70e−65). In the genome-wide analysis, variants in TGFB2 were among the top hits (lowest P=1.62e−06) but had no effect in luciferase assays.

Conclusion This is 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. Further confirmation is needed.

aUNC Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill

bDuke Cancer Institute

cDepartment of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina

dUniversity of Chicago Comprehensive Cancer Center, Chicago, Illinois

eDepartment of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, USA

fCenter for Genomic Medicine, RIKEN, Yokohama

gRIKEN Center for Integrative Medical Sciences, Yokohama, Japan

Correspondence to Federico Innocenti, MD, PhD, University of North Carolina at Chapel Hill, Eshelman School of Pharmacy, Lineberger Comprehensive Cancer Center, 1014 Genetic Medicine Building, CB 7361, 120 Mason Farm Road, Chapel Hill, NC 27599-7361, USA Tel: +1 919 966 9422; fax: +1 919 966 5863; e-mail: innocent@email.unc.edu

Received May 22, 2018

Accepted February 11, 2019

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