High ERCC1 Levels Predict Cisplatin Resistance

November 1, 2006

A phase III multicenter study has confirmed thathigh tumor tissue expression of the geneERCC1 in patients with metastatic nonsmall-cell lung cancer (NSCLC) is predictiveof resistance to cisplatin.

ISTANBUL, Turkey--A phase IIImulticenter study has confirmed thathigh tumor tissue expression of the geneERCC1 in patients with metastatic nonsmall-cell lung cancer (NSCLC) is predictiveof resistance to cisplatin. Inthe study, Rafael Rosell, MD,PhD, and his coinvestigatorscustomized therapy to doubletswith or without cisplatin,based on patients' levelsof ERCC1 expression.

The findings are importantin that they could enable cliniciansto identify patients more likely todo well on cisplatin and, conversely, potentiallywould alert them to subsets ofNSCLC patients in whom non-cisplatinbasedregimens might be more effective,with the added benefit that these patientscould avoid toxic side effects of an agentunlikely to be helpful.

The 444-patient trial was presented atthe 31st Congress of the European Societyfor Medical Oncology (ESMO) (LateBreaking Abstract 1). ERCC1 (excisionrepair cross-complementing1), a nucleotide excisionrepair gene, has been associatedwith resistance to cisplatin,said Dr. Rosell, scientificdirector for oncologyresearch, Catalan Institute ofOncology, Barcelona, Spain. Dr.Rosell, with colleagues from the Universityof California at Davis Cancer Centerand the Spanish Lung Cancer Group,conducted the trial at 24 study sites.Before treating the patients, the researchersisolated ERCC1 mRNA frombiopsies of their tumors, and then usedquantitative real-time reverse transcriptasePCR to assess ERCC1 expressionlevels.

Patients were then randomized in a1:2 ratio to a control arm, in which theyreceived chemotherapy with docetaxel(Taxotere) and cisplatin, or to a genotypicarm, in which patients with lowERCC1 expression received docetaxel/cisplatin as in the control arm, but thosewith high ERCC1 expression were treatedwith docetaxel and gemcitabine (Gemzar).A total of 366 patients completedthe study; all were evaluable for progression-free and overall survival, and 346were 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 chemotherapywas significantly higher in thegenotypic (ERCC1-expression stratified)arm, with 107 patients (50.7%) achievinga response (95% CI 44% to 57.5%,P = .019).

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

The results, he concluded, "provide aproof-of-principle for the practicality andusefulness of tailoring chemotherapy forindividual patients," and also provide apath for future research into chemotherapycustomization in patients wtihNSCLC.