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Clin Cancer Res. 2015 Apr 1;21(7):1583-90. doi: 10.1158/1078-0432.CCR-14-0857. Epub 2015 Jan 14.

Pharmacogenetic Analysis of INT 0144 Trial: Association of Polymorphisms with Survival and Toxicity in Rectal Cancer Patients Treated with 5-FU and Radiation.

Author information

1
University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California.
2
SWOG Statistical Center, Seattle, Washington.
3
SWOG Group Chair's Office/Oregon Health & Science University, Portland, Oregon.
4
University of Washington and Fred Hutchinson Cancer Research Center, Seattle, Washington; and Division of Preventive Oncology at the National Center of Tumor Diseases, Heidelberg, Germany.
5
Radiology Oncology Center of Olathe, Olathe, Kansas.
6
University of Virginia Health System, Charlottesville, Virginia.
7
Mayo Clinic, Rochester, New York.
8
Northwestern University, Chicago, Illinois.
9
Dana-Farber Cancer Institute, Boston, Massachusetts.
10
Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada.
11
Liquid Genomics, Inc., Torrance, California.
12
Fred Hutchinson Cancer Research Center, Seattle, Washington.
13
University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California. lenz@usc.edu.

Abstract

PURPOSE:

We tested whether 18 polymorphisms in 16 genes (GSTP1, COX2, IL10, EGFR, EGF, FGFR4, CCDN1, VEGFR2, VEGF, CXCR2, IL8, MMP3, ICAM1, ERCC1, RAD51, and XRCC3) would predict disease-free survival (DFS), overall survival (OS), and toxicity in the INT0144 trial, which was designed to investigate different postoperative regimens of 5-fluorouracil (5-FU)-based chemoradiation (CRT) in locally advanced rectal cancers: Arm 1 consisted of bolus 5-FU followed by 5-FU protracted venous infusion (PVI) with radiotherapy; arm 2 was induction and concomitant PVI 5-FU with radiotherapy and arm 3 was induction and concomitant bolus 5-FU with radiotherapy.

EXPERIMENTAL DESIGN:

DNA from 746 stage II/III rectal patients enrolled in the Southwest Oncology Group (SWOG) S9304 phase III trial was analyzed. Genomic DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tumor tissue. The polymorphisms were analyzed using direct DNA-sequencing or polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).

RESULTS:

GSTP1-Ile105Val (rs1695) was significantly associated with DFS and OS and its effect did not vary by treatment arm. The five-year DFS and OS were 53% and 58%, respectively, for G/G, 66% and 72% for G/A, and 57% and 66% for A/A patients. In arm 2, IL8-251A/A genotype (rs4073) was associated with a lower risk of toxicities (P = 0.04). The VEGFR2 H472Q Q/Q genotype (rs1870377) was associated with a higher risk of grade 3-5 proximal upper gastrointestinal tract (PUGIT) mucositis (P = 0.04) in arm 2. However, in arm 1, this genotype was associated with a lower risk of PUGIT mucositis (P = 0.004).

CONCLUSION:

rs1695 may be prognostic in patients with rectal cancer treated with adjuvant CRT. rs4073 and rs1870377 may exhibit different associations with toxicity, according to the 5-FU schedule.

PMID:
25589620
PMCID:
PMC4566931
DOI:
10.1158/1078-0432.CCR-14-0857
[Indexed for MEDLINE]
Free PMC Article

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