Genetic variation in radiation and platinum pathways predicts severe acute radiation toxicity in patients with esophageal adenocarcinoma treated with cisplatin-based preoperative radiochemotherapy: Results from the Eastern Cooperative Oncology Group

H. H. Yoon, P. Catalano, M. K. Gibson, T. C. Skaar, S. Philips, Elizabeth A Montgomery, M. J. Hafez, M. Powell, G. Liu, Arlene A. Forastiere, A. B. Benson, Lawrence R Kleinberg, K. M. Murphy

Research output: Contribution to journalArticle

Abstract

Purpose: Germline genetic variations may partly explain the clinical observation that normal tissue tolerance to radiochemotherapy varies by individual. Our objective was to evaluate the association between single-nucleotide polymorphisms (SNPs) in radiation/platinum pathways and serious treatment-related toxicity in subjects with esophageal adenocarcinoma who received cisplatin-based preoperative radiochemotherapy. Methods: In a multicenter clinical trial (E1201), 81 eligible treatment-naïve subjects with resectable esophageal adenocarcinoma received cisplatin-based chemotherapy concurrent with radiotherapy, with planned subsequent surgical resection. Toxicity endpoints were defined as grade ≥3 radiation-related or myelosuppressive events probably or definitely related to therapy, occurring during or up to 6 weeks following the completion of radiochemotherapy. SNPs were analyzed in 60 subjects in pathways related to nucleotide/base excision- or double stranded break repair, or platinum influx, efflux, or detoxification. Results: Grade ≥3 radiation-related toxicity (mostly dysphagia) and myelosuppression occurred in 18 and 33% of subjects, respectively. The variant alleles of the XRCC2 5′ flanking SNP (detected in 28% of subjects) and of GST-Pi Ile-105-Val (detected in 65% of subjects) were each associated with higher odds of serious radiation-related toxicity compared to the major allele homozygote (47% vs. 9%, and 31% vs. 0%, respectively; P = 0.005). No SNP was associated with myelosuppression. Conclusions: This novel finding in a well-characterized cohort with robust endpoint data supports further investigation of XRCC2 and GST-Pi as potential predictors of radiation toxicity.

Original languageEnglish (US)
Pages (from-to)863-870
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume68
Issue number4
DOIs
StatePublished - Oct 2011

Fingerprint

Oncology
Chemoradiotherapy
Platinum
Cisplatin
Toxicity
Adenocarcinoma
Polymorphism
Nucleotides
Single Nucleotide Polymorphism
Radiation
Alleles
Detoxification
Chemotherapy
Radiotherapy
Homozygote
Deglutition Disorders
Multicenter Studies
Repair
Therapeutics
Clinical Trials

Keywords

  • Chemoradiation
  • Esophageal cancer
  • Radiation toxicity prediction
  • Single nucleotide polymorphism
  • Trimodality

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

Cite this

@article{6209ba93cf104f89b6df12ffdae5f31a,
title = "Genetic variation in radiation and platinum pathways predicts severe acute radiation toxicity in patients with esophageal adenocarcinoma treated with cisplatin-based preoperative radiochemotherapy: Results from the Eastern Cooperative Oncology Group",
abstract = "Purpose: Germline genetic variations may partly explain the clinical observation that normal tissue tolerance to radiochemotherapy varies by individual. Our objective was to evaluate the association between single-nucleotide polymorphisms (SNPs) in radiation/platinum pathways and serious treatment-related toxicity in subjects with esophageal adenocarcinoma who received cisplatin-based preoperative radiochemotherapy. Methods: In a multicenter clinical trial (E1201), 81 eligible treatment-na{\"i}ve subjects with resectable esophageal adenocarcinoma received cisplatin-based chemotherapy concurrent with radiotherapy, with planned subsequent surgical resection. Toxicity endpoints were defined as grade ≥3 radiation-related or myelosuppressive events probably or definitely related to therapy, occurring during or up to 6 weeks following the completion of radiochemotherapy. SNPs were analyzed in 60 subjects in pathways related to nucleotide/base excision- or double stranded break repair, or platinum influx, efflux, or detoxification. Results: Grade ≥3 radiation-related toxicity (mostly dysphagia) and myelosuppression occurred in 18 and 33{\%} of subjects, respectively. The variant alleles of the XRCC2 5′ flanking SNP (detected in 28{\%} of subjects) and of GST-Pi Ile-105-Val (detected in 65{\%} of subjects) were each associated with higher odds of serious radiation-related toxicity compared to the major allele homozygote (47{\%} vs. 9{\%}, and 31{\%} vs. 0{\%}, respectively; P = 0.005). No SNP was associated with myelosuppression. Conclusions: This novel finding in a well-characterized cohort with robust endpoint data supports further investigation of XRCC2 and GST-Pi as potential predictors of radiation toxicity.",
keywords = "Chemoradiation, Esophageal cancer, Radiation toxicity prediction, Single nucleotide polymorphism, Trimodality",
author = "Yoon, {H. H.} and P. Catalano and Gibson, {M. K.} and Skaar, {T. C.} and S. Philips and Montgomery, {Elizabeth A} and Hafez, {M. J.} and M. Powell and G. Liu and Forastiere, {Arlene A.} and Benson, {A. B.} and Kleinberg, {Lawrence R} and Murphy, {K. M.}",
year = "2011",
month = "10",
doi = "10.1007/s00280-011-1556-5",
language = "English (US)",
volume = "68",
pages = "863--870",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Verlag",
number = "4",

}

TY - JOUR

T1 - Genetic variation in radiation and platinum pathways predicts severe acute radiation toxicity in patients with esophageal adenocarcinoma treated with cisplatin-based preoperative radiochemotherapy

T2 - Results from the Eastern Cooperative Oncology Group

AU - Yoon, H. H.

AU - Catalano, P.

AU - Gibson, M. K.

AU - Skaar, T. C.

AU - Philips, S.

AU - Montgomery, Elizabeth A

AU - Hafez, M. J.

AU - Powell, M.

AU - Liu, G.

AU - Forastiere, Arlene A.

AU - Benson, A. B.

AU - Kleinberg, Lawrence R

AU - Murphy, K. M.

PY - 2011/10

Y1 - 2011/10

N2 - Purpose: Germline genetic variations may partly explain the clinical observation that normal tissue tolerance to radiochemotherapy varies by individual. Our objective was to evaluate the association between single-nucleotide polymorphisms (SNPs) in radiation/platinum pathways and serious treatment-related toxicity in subjects with esophageal adenocarcinoma who received cisplatin-based preoperative radiochemotherapy. Methods: In a multicenter clinical trial (E1201), 81 eligible treatment-naïve subjects with resectable esophageal adenocarcinoma received cisplatin-based chemotherapy concurrent with radiotherapy, with planned subsequent surgical resection. Toxicity endpoints were defined as grade ≥3 radiation-related or myelosuppressive events probably or definitely related to therapy, occurring during or up to 6 weeks following the completion of radiochemotherapy. SNPs were analyzed in 60 subjects in pathways related to nucleotide/base excision- or double stranded break repair, or platinum influx, efflux, or detoxification. Results: Grade ≥3 radiation-related toxicity (mostly dysphagia) and myelosuppression occurred in 18 and 33% of subjects, respectively. The variant alleles of the XRCC2 5′ flanking SNP (detected in 28% of subjects) and of GST-Pi Ile-105-Val (detected in 65% of subjects) were each associated with higher odds of serious radiation-related toxicity compared to the major allele homozygote (47% vs. 9%, and 31% vs. 0%, respectively; P = 0.005). No SNP was associated with myelosuppression. Conclusions: This novel finding in a well-characterized cohort with robust endpoint data supports further investigation of XRCC2 and GST-Pi as potential predictors of radiation toxicity.

AB - Purpose: Germline genetic variations may partly explain the clinical observation that normal tissue tolerance to radiochemotherapy varies by individual. Our objective was to evaluate the association between single-nucleotide polymorphisms (SNPs) in radiation/platinum pathways and serious treatment-related toxicity in subjects with esophageal adenocarcinoma who received cisplatin-based preoperative radiochemotherapy. Methods: In a multicenter clinical trial (E1201), 81 eligible treatment-naïve subjects with resectable esophageal adenocarcinoma received cisplatin-based chemotherapy concurrent with radiotherapy, with planned subsequent surgical resection. Toxicity endpoints were defined as grade ≥3 radiation-related or myelosuppressive events probably or definitely related to therapy, occurring during or up to 6 weeks following the completion of radiochemotherapy. SNPs were analyzed in 60 subjects in pathways related to nucleotide/base excision- or double stranded break repair, or platinum influx, efflux, or detoxification. Results: Grade ≥3 radiation-related toxicity (mostly dysphagia) and myelosuppression occurred in 18 and 33% of subjects, respectively. The variant alleles of the XRCC2 5′ flanking SNP (detected in 28% of subjects) and of GST-Pi Ile-105-Val (detected in 65% of subjects) were each associated with higher odds of serious radiation-related toxicity compared to the major allele homozygote (47% vs. 9%, and 31% vs. 0%, respectively; P = 0.005). No SNP was associated with myelosuppression. Conclusions: This novel finding in a well-characterized cohort with robust endpoint data supports further investigation of XRCC2 and GST-Pi as potential predictors of radiation toxicity.

KW - Chemoradiation

KW - Esophageal cancer

KW - Radiation toxicity prediction

KW - Single nucleotide polymorphism

KW - Trimodality

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U2 - 10.1007/s00280-011-1556-5

DO - 10.1007/s00280-011-1556-5

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