Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients.
Giulia SiravegnaBenedetta MussolinMichela BuscarinoGiorgio CortiAndrea CassingenaGiovanni CrisafulliAgostino PonzettiChiara CremoliniAlessio AmatuCalogero LauricellaSimona LambaSebastijan HoborAntonio AvalloneEmanuele ValtortaGiuseppe RospoEnzo MedicoValentina MottaCarlotta AntoniottiFabiana TatangeloBeatriz BellosilloSilvio VeroneseAlfredo BudillonClara MontagutPatrizia RaccaSilvia MarsoniAlfredo FalconeRyan B CorcoranFederica Di NicolantonioFotios LoupakisSalvatore SienaAndrea Sartore-BianchiAlberto BardelliPublished in: Nature medicine (2015)
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. 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.
Keyphrases
- epidermal growth factor receptor
- tyrosine kinase
- circulating tumor
- wild type
- small cell lung cancer
- advanced non small cell lung cancer
- cell free
- end stage renal disease
- squamous cell carcinoma
- single molecule
- acute myeloid leukemia
- emergency department
- drug induced
- bone marrow
- peritoneal dialysis
- young adults
- locally advanced
- mesenchymal stem cells
- clinical decision support
- cell cycle arrest