Abstract
BackgroundAmphiregulin, a ligand of the epidermal growth factor receptor (EGFR), is associated with the efficacy of cetuximab, an antibody against EGFR, as treatment for colorectal cancer (CRC). In contrast, the HER3 ligand heregulin correlates with cetuximab resistance. In this study, we evaluated how the combined levels of circulating amphiregulin and heregulin affect clinical outcomes in patients who receive cetuximab as therapy against advanced CRC.MethodsPlasma levels of amphiregulin and heregulin were measured by enzyme-linked immunosorbent assay in 50 patients with CRC in a training cohort, and in 10 patients in a validation cohort. The combined expression was then assessed with clinical outcome after receiver operating characteristics analysis.ResultsOverall response rate was 26%, and median progression-free survival was 110 days in the training cohort. Patients with high amphiregulin and low heregulin had significantly higher objective response rate at 58% and significantly longer progression-free survival of 216 days. This result was confirmed in the validation cohort.ConclusionA subgroup of CRC patients with high amphiregulin and low heregulin respond to cetuximab therapy better than other patients.
Highlights
Colorectal cancers (CRC) frequently overexpress epidermal growth factor receptor (EGFR), which is associated with tumor progression and poor prognosis [1]
Therapeutic agents that target EGFR are either EGFR-tyrosine kinase inhibitors or monoclonal antibodies [2]. Kinase inhibitors such as gefitinib and erlotinib are highly effective against non-small cell lung cancers with constitutively active EGFR mutations [3]. Monoclonal antibodies such as cetuximab and panitumumab improve the prognosis in patients with CRC and head and neck squamous cell carcinoma that express wild type EGFR [4,5,6,7]
The primary endpoint of this study is to evaluate amphiregulin and heregulin as biomarkers associated with objective response rate to anti-EGFR therapy
Summary
Colorectal cancers (CRC) frequently overexpress epidermal growth factor receptor (EGFR), which is associated with tumor progression and poor prognosis [1]. EGFR is a therapeutic target, not just against CRC, and against other cancers in which it is abundantly expressed. Therapeutic agents that target EGFR are either EGFR-tyrosine kinase inhibitors or monoclonal antibodies [2] Kinase inhibitors such as gefitinib and erlotinib are highly effective against non-small cell lung cancers with constitutively active EGFR mutations [3]. Preclinical studies show that some cancers sensitive to anti-EGFR therapy abundantly express EGFR ligands, especially amphiregulin [8]. Amphiregulin, a ligand of the epidermal growth factor receptor (EGFR), is associated with the efficacy of cetuximab, an antibody against EGFR, as treatment for colorectal cancer (CRC).
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