Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients

By monitoring ctDNA, the authors reveal the dynamic adaption of clonal populations in colorectal cancer patients treated with anti-EGFR therapy, suggesting that therapeutic re-challenge may have some benefit. Colorectal cancers (CRCs) evolve by a reiterative process of genetic diversification and cl...

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Veröffentlicht in:Nature medicine Jg. 21; H. 7; S. 795 - 801
Hauptverfasser: Siravegna, Giulia, Mussolin, Benedetta, Buscarino, Michela, Corti, Giorgio, Cassingena, Andrea, Crisafulli, Giovanni, Ponzetti, Agostino, Cremolini, Chiara, Amatu, Alessio, Lauricella, Calogero, Lamba, Simona, Hobor, Sebastijan, Avallone, Antonio, Valtorta, Emanuele, Rospo, Giuseppe, Medico, Enzo, Motta, Valentina, Antoniotti, Carlotta, Tatangelo, Fabiana, Bellosillo, Beatriz, Veronese, Silvio, Budillon, Alfredo, Montagut, Clara, Racca, Patrizia, Marsoni, Silvia, Falcone, Alfredo, Corcoran, Ryan B, Di Nicolantonio, Federica, Loupakis, Fotios, Siena, Salvatore, Sartore-Bianchi, Andrea, Bardelli, Alberto
Format: Journal Article
Sprache:Englisch
Veröffentlicht: New York Nature Publishing Group US 01.07.2015
Nature Publishing Group
Schlagworte:
45/22
45/23
45/62
45/77
631/67/2329
Alleles
Antibodies - pharmacology
Antibodies - therapeutic use
Antibodies, Neoplasm - blood
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Biomedicine
Blood
Cancer Research
Care and treatment
Clonal Evolution
Clone Cells
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - blood
Colorectal Neoplasms - drug therapy
Colorectal Neoplasms - genetics
Colorectal Neoplasms - pathology
Development and progression
DNA, Neoplasm - blood
Drug Resistance, Neoplasm - genetics
Genetic aspects
Heterogeneity
Humans
Infectious Diseases
letter
Metabolic Diseases
Molecular Medicine
Mutation - genetics
Neurosciences
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins p21(ras)
ras Proteins - genetics
Receptor, Epidermal Growth Factor - antagonists & inhibitors
Receptor, Epidermal Growth Factor - genetics
Receptor, Epidermal Growth Factor - immunology
Italy
United Kingdom
ISSN:1078-8956, 1546-170X
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Zusammenfassung:By monitoring ctDNA, the authors reveal the dynamic adaption of clonal populations in colorectal cancer patients treated with anti-EGFR therapy, suggesting that therapeutic re-challenge may have some benefit. Colorectal cancers (CRCs) evolve by a reiterative process of genetic diversification and clonal evolution. The molecular profile of CRC is routinely assessed in surgical or bioptic samples 1 . Genotyping of CRC tissue has inherent limitations; a tissue sample represents a single snapshot in time, and it is subjected to spatial selection bias owing to tumor heterogeneity. Repeated tissue samples are difficult to obtain and cannot be used for dynamic monitoring of disease progression and response to therapy. We exploited circulating tumor DNA (ctDNA) to genotype colorectal tumors and track clonal evolution during treatment with the epidermal growth factor receptor (EGFR)-specific antibodies cetuximab or panitumumab. We identified alterations in ctDNA of patients with primary or acquired resistance to EGFR blockade in the following genes: KRAS , NRAS , MET , ERBB2 , FLT3 , EGFR and MAP2K1. Mutated KRAS clones, which emerge in blood during EGFR blockade, decline upon withdrawal of EGFR-specific antibodies, indicating that clonal evolution continues beyond clinical progression. Pharmacogenomic analysis of CRC cells that had acquired resistance to cetuximab reveals that upon antibody withdrawal KRAS clones decay, whereas the population regains drug sensitivity. ctDNA profiles of individuals who benefit from multiple challenges with anti-EGFR antibodies exhibit pulsatile levels of mutant KRAS . These results indicate that the CRC genome adapts dynamically to intermittent drug schedules and provide a molecular explanation for the efficacy of rechallenge therapies based on EGFR blockade.
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ISSN:1078-8956
1546-170X
DOI:10.1038/nm.3870