A DNA repair protein appears to have limited use for determining response to cisplatin-based adjuvant chemotherapy for non–small cell lung cancer, according to the results of an international study.
"We were unable to validate the predictive effect of immunostaining for ERCC1 protein," Dr. Jean-Charles Soria of the Institut Gustave-Roussy, Villejuif, France, and his associates reported in the New England Journal of Medicine (2013;368:1101-10).
The absence of excision repair cross-complementation group 1 (ERCC1) protein expression and better response to platinum-based chemotherapy were first linked 7 years ago in a biology substudy of the IALT (International Adjuvant Lung Cancer Trial) (N. Engl. J. Med. 2006;355:983-91).
Dr. Soria and his team were unable to replicate these findings, however, in the LACE (Lung Adjuvant Cisplatin Evaluation) Biology biomarker project. In fact, they found contrary evidence, suggesting that the presence rather than the absence of ERCC1 might confer a slight overall survival advantage with cisplatin-based chemotherapy.
The hazard ratio (HR) for death in patients with ERCC1-negative tumors was 1.16 (P = .62), and for ERCC1-positive tumors it was 0.78 (P = .09), but there was no overall predictive value of the marker (P = .23).
The LACE Biology biomarker project used the 8F1 mouse monoclonal antibody to detect ERCC1 expression in tumor samples taken from two independent, randomized, phase III trials of postoperative adjuvant cisplatin-based chemotherapy. The aim was to confirm ERCC1 as a predictive biomarker as seen in the IALT substudy.
A total of 494 whole-tissue sections were obtained from the Cancer and Leukemia Group B (CALGB) 9633 trial and the National Cancer Institute of Canada Clinical Trials Group JBR.10 trials. A lack of confirmatory findings prompted a reanalysis of the entire original set of tissue samples taken from 589 patients who had participated in the 2006 IALT.
"Repeated staining showed important discrepancies between the ERC1 immunohistochemical results obtained in 2006 and those obtained in 2011," Dr. Soria and his team reported. They found that tumors previously classified as ERCC1-negative were ERCC1-positive on reexamination. The discrepancies might be explained by changes in the 8F1 antibody between 2006 and 2011, although the researchers were unable to test this hypothesis.
Other antibodies have been proposed to detect ERCC1 expression, but testing a further 15 of these antibodies showed that none was specific for any of the four known isoforms of ERCC1.
Results obtained using reverse transcriptase–polymerase chain reaction highlighted the fact that ERCC1 isoform transcripts and proteins are heterogeneously expressed in cell lines and tumor samples.
"We were unable to validate ERCC1 protein expression as a predictive marker in a new, independent series of homogeneously treated patients with NSCLC," the researchers commented.
This could be because there are currently inadequate tools to detect expression levels of the protein or because the biologic complexity of the protein’s expression has been underestimated.
A third explanation is that the ERCC1 biomarker is not an efficient predictor of the response to cisplatin-based chemotherapy.
"Immunohistochemical analysis with the use of currently available ERCC1 antibodies did not specifically detect the unique functional ERCC1 isoform," the researchers concluded.
"As a result, its usefulness in guiding therapeutic decision making is limited."
The research was supported by various grants associated with the clinical trials involved: an unrestricted educational grant from Eli Lilly and grants from l’Institut National du Cancer Programme National d’Excellence Spécialisé and Programme Hospitalier de Recherche Clinique (for the IALT); a grant from La Ligue Nationale contre le Cancer and an unrestricted grant from Sanofi-Aventis (for the LACE Biology project); and a grant from the European Union Seventh Framework Program. Support also came from a translational research fellowship from Roche.