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Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

3744 - A Genetic Analysis of Gemcitabine-Induced High-Grade Neutropenia in Pancreatic Cancer Patients

Date

20 Oct 2018

Session

Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

Presenters

Federico Innocenti

Citation

Annals of Oncology (2018) 29 (suppl_8): viii649-viii669. 10.1093/annonc/mdy303

Authors

F. Innocenti1, C. Jiang2, A.B. Sibley3, S. Denning1, A.S. Etheridge1, D. Watson3, D. Niedzwiecki4, A.J. Hatch3, H. Hurwitz5, A. Nixon6, Y. Furukawa7, M. Kubo8, D.J. Crona1, H. Kindler9, H.L. McLeod10, M.J. Ratain9, K. Owzar2

Author affiliations

  • 1 Division Of Pharmacotherapy And Experimental Therapeutics, UNC-Institute for Pharmacogenomics and Individualized Therapy, 27599 - Chapel Hill/US
  • 2 Alliance Statistics And Data Center, Duke Cancer Institute, Durham/US
  • 3 Duke University Medical Center, Duke Cancer Institute, Durham/US
  • 4 Department Of Biostatistics And Bioinformatics, Duke University Medical Center, Durham/US
  • 5 Medical Oncology, Duke University Medical Center, 27710 - Durham/US
  • 6 Duke Cancer Institute, Duke University Medical Center, Durham/US
  • 7 Center For Genomic Medicine, RIKEN, Yokohama/US
  • 8 Center For Integrative Medicine, Riken, Kanagawa/JP
  • 9 Oncology, The University of Chicago Medical Centre, 60637-1470 - Chicago/US
  • 10 Department Of Cancer Epidemiology, Moffit Cancer Center, Tampa/US
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Resources

Abstract 3744

Background

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.

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, 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.

Results

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.

Conclusions

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

NCI-2012-02960; NCT00088894.

Legal entity responsible for the study

Alliance for Clinical Trials in Oncology.

Funding

NIH.

Editorial Acknowledgement

Disclosure

All authors have declared no conflicts of interest.

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