Antoine Italiano MD, PhD1,2,†, Armelle Laurand PhD2,†, Audrey Laroche PhD2, Paolo Casali MD3, Roberta Sanfilippo MD3, Axel Le Cesne MD4, Ian Judson MD5, Jean-Yves Blay MD, PhD6,7, Isabelle Ray-Coquard MD, PhD6, Binh Bui MD1, Jean-Michel Coindre MD1,2, Antonio Nieto Bsc8, Juan-Carlos Tercero PhD8, Jose Jimeno MD, PhD9, Jacques Robert MD, PhD1,2, Philippe Pourquier PharmD, PhD1,2,* .
Keywords:Sarcoma;Polymorphism;ERCC5;ERCC1;BRCA1;DNA repair;predictive markers.
Abstract
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.