title: Clinical validation of prospective liquid biopsy monitoring in patients with wild-type RAS metastatic colorectal cancer treated with FOLFIRI-cetuximab.
abstract: 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.
authors.affiliation: Centro Integral Oncológico Clara Campal (CIOCC), Madrid, Spain.|Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Toledo
authors.affiliation: Centro Integral Oncológico Clara Campal (CIOCC), Madrid, Spain.|Universidad San Pablo CEU, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cubillo
authors.affiliation: Centro Integral Oncológico Clara Campal (CIOCC), Madrid, Spain.|Universidad San Pablo CEU, Madrid, Spain.
authors.forename: Estela
authors.initials: E
authors.lastname: Vega
authors.affiliation: Centro Integral Oncológico Clara Campal (CIOCC), Madrid, Spain.|Universidad San Pablo CEU, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Garralda
authors.affiliation: Centro Integral Oncológico Clara Campal (CIOCC), Madrid, Spain.|Universidad San Pablo CEU, Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Alvarez
authors.affiliation: Centro Integral Oncológico Clara Campal (CIOCC), Madrid, Spain.|Universidad San Pablo CEU, Madrid, Spain.
authors.forename: Lisardo U
authors.initials: LU
authors.lastname: de la Varga
authors.affiliation: Centro Integral Oncológico Clara Campal (CIOCC), Madrid, Spain.|Universidad San Pablo CEU, Madrid, Spain.
authors.forename: Jesús R
authors.initials: JR
authors.lastname: Pascual
authors.affiliation: Centro Integral Oncológico Clara Campal (CIOCC), Madrid, Spain.|Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Sánchez
authors.affiliation: Centro Integral Oncológico Clara Campal (CIOCC), Madrid, Spain.|Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Francesca
authors.initials: F
authors.lastname: Sarno
authors.affiliation: Laboratorio de Dianas Terapeúticas, Madrid, Spain.
authors.forename: Susana H
authors.initials: SH
authors.lastname: Prieto
authors.affiliation: Centro Integral Oncológico Clara Campal (CIOCC), Madrid, Spain.|Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Sofía
authors.initials: S
authors.lastname: Perea
authors.affiliation: Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Pedro P
authors.initials: PP
authors.lastname: Lopéz-Casas
authors.affiliation: Laboratorio de Dianas Terapeúticas, Madrid, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: López-Ríos
authors.affiliation: Spanish National Cancer Research Centre (CNIO), Madrid, Spain.|Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
mesh_terms: D000074322:Antineoplastic Agents, Immunological / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000068818:Cetuximab / Q000627:therapeutic use*; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D002955:Leucovorin / Q000627:therapeutic use; D000073890:Liquid Biopsy; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009362:Neoplasm Metastasis; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D016019:Survival Analysis; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000074322:Antineoplastic Agents, Immunological; C117307:KRAS protein, human; D008565:Membrane Proteins; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin
keywords: anti-EGFR; cetuximab; cfDNA; colorectal cancer; liquid biopsy