Clinical Research Papers:

Clinical validation of prospective liquid biopsy monitoring in patients with wild-type RAS metastatic colorectal cancer treated with FOLFIRI-cetuximab

Rodrigo A. Toledo, Antonio Cubillo, Estela Vega, Elena Garralda, Rafael Alvarez, Lisardo U. de la Varga, Jesús R. Pascual, Gema Sánchez, Francesca Sarno, Susana H. Prieto, Sofía Perea, Pedro P. Lopéz-Casas, Fernando López-Ríos and Manuel Hidalgo _

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Oncotarget. 2017; 8:35289-35300. https://doi.org/10.18632/oncotarget.13311

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Rodrigo A. Toledo1,4,*, Antonio Cubillo1,2,*, Estela Vega1,2, Elena Garralda1,2, Rafael Alvarez1,2, Lisardo U. de la Varga1,2, Jesús R. Pascual1,2, Gema Sánchez1,4, Francesca Sarno1,4, Susana H. Prieto3, Sofía Perea1,4, Pedro P. Lopéz-Casas4, Fernando López-Ríos3 and Manuel Hidalgo4,5

1 Centro Integral Oncológico Clara Campal (CIOCC), Madrid, Spain

2 Universidad San Pablo CEU, Madrid, Spain

3 Laboratorio de Dianas Terapeúticas, Madrid, Spain

4 Spanish National Cancer Research Centre (CNIO), Madrid, Spain

5 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

* These authors have contributed equally to this manuscript

Correspondence to:

Rodrigo A. Toledo, email:

Manuel Hidalgo, email:

Keywords: colorectal cancer, cfDNA, liquid biopsy, anti-EGFR, cetuximab

Received: October 13, 2016 Accepted: October 24, 2016 Published: November 11, 2016


Cancer genomics and translational medicine rely on the molecular profiling of patient’s tumor obtained during surgery or biopsy. Alternatively, blood is a less invasive source of tumor DNA shed, amongst other ways, as cell-free DNA (cfDNA). Highly-sensitive assays capable to detect cancer genetic events from patient’s blood plasma became popularly known as liquid biopsy (LqB). Importantly, retrospective studies including small number of selected patients with metastatic colorectal cancer (mCRC) patients treated with anti-EGFR therapy have shown LqB capable to detect the acquired clonal mutations in RAS genes leading to therapy resistance. However, the usefulness of LqB in the real-life clinical monitoring of these patients still lack additional validation on controlled studies. In this context, we designed a prospective LqB clinical trial to monitor newly diagnosed KRAS wild-type (wt) mCRC patients who received a standard FOLFIRI-cetuximab regimen. We used BEAMing technique for evaluate cfDNA mutations in KRAS, NRAS, BRAF, and PIK3CA in twenty-five patients during a 2-y period. A total of 2,178 cfDNA mutation analyses were performed and we observed that: a) continued wt circulating status was correlated with a prolonged response; b) smoldering increases in mutant cfDNA were correlated with acquired resistance; while c) mutation upsurge/explosion anticipated a remarkable clinical deterioration. The current study provides evidences, obtained for the first time in an unbiased and prospective manner, that reinforces the utility of LqB for monitoring mCRC patients.

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