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

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 genet...

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Published in:	Oncotarget Vol. 8; no. 21; pp. 35289 - 35300
Main Authors:	Toledo, Rodrigo A, Cubillo, Antonio, Vega, Estela, Garralda, Elena, Alvarez, Rafael, de la Varga, Lisardo U, Pascual, Jesús R, Sánchez, Gema, Sarno, Francesca, Prieto, Susana H, Perea, Sofía, Lopéz-Casas, Pedro P, López-Ríos, Fernando, Hidalgo, Manuel
Format:	Journal Article
Language:	English
Published:	United States Impact Journals LLC 23-05-2017
Subjects:	Antineoplastic Agents, Immunological - therapeutic use Antineoplastic Combined Chemotherapy Protocols - therapeutic use Camptothecin - analogs & derivatives Camptothecin - therapeutic use Cetuximab - therapeutic use Class I Phosphatidylinositol 3-Kinases - genetics Clinical Research Paper Colorectal Neoplasms - drug therapy Colorectal Neoplasms - genetics Colorectal Neoplasms - pathology DNA Mutational Analysis - methods Female Fluorouracil - therapeutic use GTP Phosphohydrolases - genetics Humans Leucovorin - therapeutic use Liquid Biopsy Male Membrane Proteins - genetics Neoplasm Metastasis Prospective Studies Proto-Oncogene Proteins B-raf - genetics Proto-Oncogene Proteins p21(ras) - genetics ras Proteins - genetics Survival Analysis Treatment Outcome anti-EGFR cetuximab colorectal cancer cfDNA liquid biopsy
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Summary:	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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	1949-2553 1949-2553
DOI:	10.18632/oncotarget.13311