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, Todd Skaar, S. Philips, E. A. Montgomery, M. J. Hafez, M. Powell, G. Liu, A. A. Forastiere, A. B. Benson, L. R. Kleinberg, K. M. Murphy

Research output: Contribution to journalArticle

8 Citations (Scopus)

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
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

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. / Yoon, H. H.; Catalano, P.; Gibson, M. K.; Skaar, Todd; Philips, S.; Montgomery, E. A.; Hafez, M. J.; Powell, M.; Liu, G.; Forastiere, A. A.; Benson, A. B.; Kleinberg, L. R.; Murphy, K. M.

In: Cancer Chemotherapy and Pharmacology, Vol. 68, No. 4, 10.2011, p. 863-870.

Research output: Contribution to journalArticle

Yoon, H. H. ; Catalano, P. ; Gibson, M. K. ; Skaar, Todd ; Philips, S. ; Montgomery, E. A. ; Hafez, M. J. ; Powell, M. ; Liu, G. ; Forastiere, A. A. ; Benson, A. B. ; Kleinberg, L. R. ; Murphy, K. M. / 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. In: Cancer Chemotherapy and Pharmacology. 2011 ; Vol. 68, No. 4. pp. 863-870.
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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.",
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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, Todd

AU - Philips, S.

AU - Montgomery, E. A.

AU - Hafez, M. J.

AU - Powell, M.

AU - Liu, G.

AU - Forastiere, A. A.

AU - Benson, A. B.

AU - Kleinberg, L. 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.

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KW - Esophageal cancer

KW - Radiation toxicity prediction

KW - Single nucleotide polymorphism

KW - Trimodality

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