Acquired RAS or EGFR mutations and duration of response to EGFR blockade in colorectal cancer.
Beth O Van EmburghSabrina ArenaGiulia SiravegnaLuca LazzariGiovanni CrisafulliGiorgio CortiBenedetta MussolinFederica BaldiMichela BuscarinoAlice BartoliniEmanuele ValtortaJoana VidalBeatriz BellosilloGiovanni GermanoFilippo PietrantonioAgostino PonzettiJoan AlbanellSalvatore SienaAndrea Sartore-BianchiFederica Di NicolantonioClara MontagutAlberto BardelliPublished in: Nature communications (2016)
Blockade of the epidermal growth factor receptor (EGFR) with the monoclonal antibodies cetuximab or panitumumab is effective in a subset of colorectal cancers (CRCs), but the emergence of resistance limits the efficacy of these therapeutic agents. At relapse, the majority of patients develop RAS mutations, while a subset acquires EGFR extracellular domain (ECD) mutations. Here we find that patients who experience greater and longer responses to EGFR blockade preferentially develop EGFR ECD mutations, while RAS mutations emerge more frequently in patients with smaller tumour shrinkage and shorter progression-free survival. In circulating cell-free tumour DNA of patients treated with anti-EGFR antibodies, RAS mutations emerge earlier than EGFR ECD variants. Subclonal RAS but not EGFR ECD mutations are present in CRC samples obtained before exposure to EGFR blockade. These data indicate that clonal evolution of drug-resistant cells is associated with the clinical outcome of CRC patients treated with anti-EGFR antibodies.
Keyphrases
- epidermal growth factor receptor
- small cell lung cancer
- tyrosine kinase
- advanced non small cell lung cancer
- drug resistant
- cell free
- wild type
- chronic kidney disease
- end stage renal disease
- multidrug resistant
- squamous cell carcinoma
- gene expression
- oxidative stress
- ejection fraction
- cell death
- copy number
- machine learning
- genome wide
- signaling pathway
- single molecule
- big data
- deep learning
- metastatic colorectal cancer