Abstract LB-75: Blood-based molecular detection of acquired resistance to anti-EGFR therapies in colorectal cancer patients.

Abstract

Abstract The anti EGFR monoclonal antibodies cetuximab and panitumumab are used to treat metastatic colorectal cancer patients. The clinical efficacy of EGFR inhibitors is limited by the development of acquired resistance, which typically occurs within 3-12 months since starting of therapy. We recently reported that secondary KRAS mutations are responsible for acquired resistance in approximately 50% of patients (Misale et al.; Diaz et al., Nature 2012). We reasoned that the detection of KRAS mutant alleles in the plasma of cetuximab treated patients may enable the early identification of secondary resistance to anti EGFR blockade before radiographic documentation of relapse. Using the highly sensitive BEAMing approach we have examined cell-free circulating tumor DNA (ctDNA), a form of "liquid biopsy". KRAS mutant alleles emerged in the circulation of approximately 50% of patients treated with anti-EGFR antibodies months before radiographic documentation of disease progression. The liquid biopsy approach was then used to select patients in which KRAS mutations did not emerge during anti-EGFR therapy. Exome sequencing identified amplification of the MET proto-oncogene in biopsies from patients who did not develop KRAS mutations. Using an innovative approach, we find that MET amplification can be identified in a non-invasive manner through the examination of ctDNA months before relapse becomes clinically manifest. As multiple anti-MET therapeutic strategies are available, these findings offer immediate novel opportunities to design clinical studies. Citation Format: Giulia Siravegna, Andrea Sartore Bianchi, Andrea Cassingena, Katia Bencardino, Luis A. Diaz, Mark Sausen, Victor E. Velculescu, Federica Di Nicolantonio, Salvatore Siena, Alberto Bardelli. Blood-based molecular detection of acquired resistance to anti-EGFR therapies in colorectal cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-75. doi:10.1158/1538-7445.AM2013-LB-75