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ERCC5 / XPG , ERCC1, and BRCA1 gene status and clinical benefit of trabectedin in patients with soft tissue sarcoma
Author(s) -
Italiano Antoine,
Laurand Armelle,
Laroche Audrey,
Casali Paolo,
Sanfilippo Roberta,
Le Cesne Axel,
Judson Ian,
Blay JeanYves,
RayCoquard Isabelle,
Bui Binh,
Coindre JeanMichel,
Nieto Antonio,
Tercero JuanCarlos,
Jimeno Jose,
Robert Jacques,
Pourquier Philippe
Publication year - 2011
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.25925
Subject(s) - ercc1 , nucleotide excision repair , xeroderma pigmentosum , dna repair , cancer research , trabectedin , single nucleotide polymorphism , medicine , biology , soft tissue sarcoma , microbiology and biotechnology , genetics , sarcoma , gene , genotype , pathology
BACKGROUND: The objective of this study was to determine whether specific single nucleotide polymorphisms (SNPs) from nucleotide excision repair (NER) and homologous recombination (HR) DNA repair pathways are associated with sensitivity to trabectedin in patients with soft tissue sarcoma (STS). METHODS: The authors analyzed excision repair cross‐complementation group 5/xeroderma pigmentosum group G ( ERCC5/XPG ) (NER), excision repair cross‐complementation group 1 ( ERCC1 ) (NER), and breast cancer 1 ( BRCA1 ) (HR) SNPs and messenger RNA expression levels in tumor specimens from 113 patients with advanced STS who were enrolled in previously published phase 2 trials or in a compassionate‐use program. The 6‐month progression‐free rate (PFR), progression‐free survival (PFS), and overall survival (OS) were analyzed according to ERCC5, ERCC1 , and BRCA1 status using log‐rank tests. RESULTS: High expression of the common allele (aspartic acid at codon 1104) of ERCC5 , high expression of ERCC1 , and BRCA1 haplotype were associated significantly with improved PFR, PFS, and OS. The ERCC1 thymine‐to‐cytosine (T→C) SNP at codon 19007 and BRCA1 expression were not associated with outcome. On univariate analysis, tumor histology, favorable NER status (high expression of common ERCC5 and/or high ERCC1 expression status), and favorable BRCA1 haplotype (at least 1 triple‐adenine plus guanine [AAAG] allele) were the sole variables associated significantly with PFS and OS. CONCLUSIONS: In the current study, ERCC5 , ERCC1 , and BRCA1 status represented a potential DNA repair signature that could be used for the prediction of clinical response to trabectedin in patients with STS. Cancer 2011. © 2011 American Cancer Society.