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High ERCC1 Levels Predict Cisplatin Resistance

High ERCC1 Levels Predict Cisplatin Resistance

ISTANBUL, Turkey--A phase III multicenter study has confirmed that high tumor tissue expression of the gene ERCC1 in patients with metastatic nonsmall- cell lung cancer (NSCLC) is predictive of resistance to cisplatin. In the study, Rafael Rosell, MD, PhD, and his coinvestigators customized therapy to doublets with or without cisplatin, based on patients' levels of ERCC1 expression.

The findings are important in that they could enable clinicians to identify patients more likely to do well on cisplatin and, conversely, potentially would alert them to subsets of NSCLC patients in whom non-cisplatinbased regimens might be more effective, with the added benefit that these patients could avoid toxic side effects of an agent unlikely to be helpful.

The 444-patient trial was presented at the 31st Congress of the European Society for Medical Oncology (ESMO) (Late Breaking Abstract 1). ERCC1 (excision repair cross-complementing 1), a nucleotide excision repair gene, has been associated with resistance to cisplatin, said Dr. Rosell, scientific director for oncology research, Catalan Institute of Oncology, Barcelona, Spain. Dr. Rosell, with colleagues from the University of California at Davis Cancer Center and the Spanish Lung Cancer Group, conducted the trial at 24 study sites. Before treating the patients, the researchers isolated ERCC1 mRNA from biopsies of their tumors, and then used quantitative real-time reverse transcriptase PCR to assess ERCC1 expression levels.

Patients were then randomized in a 1:2 ratio to a control arm, in which they received chemotherapy with docetaxel (Taxotere) and cisplatin, or to a genotypic arm, in which patients with low ERCC1 expression received docetaxel/ cisplatin as in the control arm, but those with high ERCC1 expression were treated with docetaxel and gemcitabine (Gemzar). A total of 366 patients completed the study; all were evaluable for progression- free and overall survival, and 346 were evaluable for overall response.

In the control arm, 53 patients (39.3%) had a response to treatment (95% CI 31.4% to 47.8%). Response to chemotherapy was significantly higher in the genotypic (ERCC1-expression stratified) arm, with 107 patients (50.7%) achieving a response (95% CI 44% to 57.5%, P = .019).

"Patients in the control arm with high levels of ERCC1 would have done better with the docetaxel/gemcitabine regimen," Dr. Rosell said.

The results, he concluded, "provide a proof-of-principle for the practicality and usefulness of tailoring chemotherapy for individual patients," and also provide a path for future research into chemotherapy customization in patients wtih NSCLC.

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