High epiregulin ( EREG ) gene expression plus K-ras wild-type (WT) status as predictors of cetuximab benefit in the treatment of advanced colorectal cancer (ACRC): Results from NCIC CTG CO.17—A phase III trial of cetuximab versus best supportive care (BSC)

作者：Derek J. Jonker, Christos S. Karapetis, Christopher Harbison, Chris J. O’Callaghan, Dehao Tu, R. J. Simes, L. Xu, Malcolm J. Moore, John Zalcberg, Shirin Khambata‐Ford · 发表于：Journal of Clinical Oncology · 年份：2009 · DOI：10.1200/jco.2009.27.15_suppl.4016 · 被引用次数：39 · 研究领域：Colorectal Cancer Treatments and Studies、Lung Cancer Treatments and Mutations、Cancer Treatment and Pharmacology

4016 Background: Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), improves overall survival (OS) and progression free survival (PFS) in patients with K-ras WT chemotherapy refractory ACRC. Gene expression of the EGFR ligand epiregulin (EREG) may further predict benefit from cetuximab. Methods: CRC tumour samples were analyzed from a phase III clinical trial of cetuximab plus BSC vs BSC alone (NEJM 2007; 357(20)). EREG gene expression was detected in tumour-derived genomic RNA blinded to clinical outcome by quantitative real time-PCR. Using a pre-specified threshold for “high” EREG derived from a prior study (CA225–045), the predictive effect of (1) high vs low EREG among K-ras WT and (2) high EREG/K-ras WT status (“Combimarker”) versus all other patients on OS and PFS was examined using a Cox model with tests for treatment-biomarker interaction. Results: Both EREG gene expression levels and K-ras mutation status were ascertained in 385 (67%) of the total study population (193 cetuximab, 192 BSC). In the K-ras WT subset, OS was better for cetuximab than BSC among patients with high EREG (HR 0.43; p<0.0001) but not for low EREG patients (HR 0.77, p=0.28). The test for interaction showed a non-significantly larger treatment effect in the high EREG group (HR 0.62, p=0.13). High EREG AND K-ras WT status (“Combimarker”) was present in 139 (36%). Within the Combimarker positive group the median PFS was 5.4 vs 1.9 months (HR, 0.31; p<0.000...