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

Federico Innocenti, Chen Jiang, Alexander B. Sibley, Stefanie Denning, Amy S. Etheridge, Dorothy Watson, Donna Niedzwiecki, Ace J. Hatch, Herbert I. Hurwitz, Andrew B. Nixon, Yoichi Furukawa, Michiaki Kubo, Daniel J. Crona, Hedy L. Kindler, Howard L. McLeod, Mark J. Ratain, Kouros Owzar

Research output: Contribution to journalArticle

Abstract

ObjectivesOne 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 methodsCALGB 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.ResultsThe 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.ConclusionThis 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.

Original languageEnglish
Pages (from-to)123-131
Number of pages9
JournalPharmacogenetics and Genomics
Volume29
Issue number6
DOIs
Publication statusPublished - 01-08-2019

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gemcitabine
Neutropenia
Pancreatic Neoplasms
Genome
Confidence Intervals
Standard of Care
Luciferases
Genotype

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Innocenti, Federico ; Jiang, Chen ; Sibley, Alexander B. ; Denning, Stefanie ; Etheridge, Amy S. ; Watson, Dorothy ; Niedzwiecki, Donna ; Hatch, Ace J. ; Hurwitz, Herbert I. ; Nixon, Andrew B. ; Furukawa, Yoichi ; Kubo, Michiaki ; Crona, Daniel J. ; Kindler, Hedy L. ; McLeod, Howard L. ; Ratain, Mark J. ; Owzar, Kouros. / An initial genetic analysis of gemcitabine-induced high-grade neutropenia in pancreatic cancer patients in CALGB 80303 (Alliance). In: Pharmacogenetics and Genomics. 2019 ; Vol. 29, No. 6. pp. 123-131.
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abstract = "ObjectivesOne 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 methodsCALGB 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.ResultsThe 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.ConclusionThis 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.",
author = "Federico Innocenti and Chen Jiang and Sibley, {Alexander B.} and Stefanie Denning and Etheridge, {Amy S.} and Dorothy Watson and Donna Niedzwiecki and Hatch, {Ace J.} and Hurwitz, {Herbert I.} and Nixon, {Andrew B.} and Yoichi Furukawa and Michiaki Kubo and Crona, {Daniel J.} and Kindler, {Hedy L.} and McLeod, {Howard L.} and Ratain, {Mark J.} and Kouros Owzar",
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Innocenti, F, Jiang, C, Sibley, AB, Denning, S, Etheridge, AS, Watson, D, Niedzwiecki, D, Hatch, AJ, Hurwitz, HI, Nixon, AB, Furukawa, Y, Kubo, M, Crona, DJ, Kindler, HL, McLeod, HL, Ratain, MJ & Owzar, K 2019, 'An initial genetic analysis of gemcitabine-induced high-grade neutropenia in pancreatic cancer patients in CALGB 80303 (Alliance)', Pharmacogenetics and Genomics, vol. 29, no. 6, pp. 123-131. https://doi.org/10.1097/FPC.0000000000000375

An initial genetic analysis of gemcitabine-induced high-grade neutropenia in pancreatic cancer patients in CALGB 80303 (Alliance). / Innocenti, Federico; Jiang, Chen; Sibley, Alexander B.; Denning, Stefanie; Etheridge, Amy S.; Watson, Dorothy; Niedzwiecki, Donna; Hatch, Ace J.; Hurwitz, Herbert I.; Nixon, Andrew B.; Furukawa, Yoichi; Kubo, Michiaki; Crona, Daniel J.; Kindler, Hedy L.; McLeod, Howard L.; Ratain, Mark J.; Owzar, Kouros.

In: Pharmacogenetics and Genomics, Vol. 29, No. 6, 01.08.2019, p. 123-131.

Research output: Contribution to journalArticle

TY - JOUR

T1 - An initial genetic analysis of gemcitabine-induced high-grade neutropenia in pancreatic cancer patients in CALGB 80303 (Alliance)

AU - Innocenti, Federico

AU - Jiang, Chen

AU - Sibley, Alexander B.

AU - Denning, Stefanie

AU - Etheridge, Amy S.

AU - Watson, Dorothy

AU - Niedzwiecki, Donna

AU - Hatch, Ace J.

AU - Hurwitz, Herbert I.

AU - Nixon, Andrew B.

AU - Furukawa, Yoichi

AU - Kubo, Michiaki

AU - Crona, Daniel J.

AU - Kindler, Hedy L.

AU - McLeod, Howard L.

AU - Ratain, Mark J.

AU - Owzar, Kouros

PY - 2019/8/1

Y1 - 2019/8/1

N2 - ObjectivesOne 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 methodsCALGB 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.ResultsThe 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.ConclusionThis 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.

AB - ObjectivesOne 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 methodsCALGB 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.ResultsThe 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.ConclusionThis 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.

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DO - 10.1097/FPC.0000000000000375

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