title: Temporal changes of EGFR mutations and T790M levels in tumour and plasma DNA following AZD9291 treatment.
abstract: AZD9291, a T790M specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has demonstrated impressive response rates in tumours harbouring the EGFR T790M resistance mutation. Emergence of resistance to AZD9291 has been shown to occur through several different mechanisms including the development of new mutations (e.g. C797S) in the EGFR tyrosine kinase domain. We studied two patients with paired tumour biopsies and blood samples pre- and post-progression on AZD9291 to explore possible resistance mechanisms. Pre- and Post-AZD9291 tumour biopsies as well as serial plasma samples were collected from two patients on the AURA clinical study (AZD9291 First Time in Patients Ascending Dose study). Droplet digital PCR (ddPCR) assays were used to quantify T790M, the driver EGFR mutation, and the C797S mutation in genomic DNA from paired tumour biopsies and plasma cell-free DNA. In the first patient, both EGFR T790M and L858R became undetectable in the plasma within 1 month after treatment with AZD9291. However, the T790M and the original L858R mutation re-emerged with radiologically confirmed resistance to AZD9291. In patient two, the levels of T790M were undetectable at the time of radiological resistance to AZD9291 but increasing levels of the original EGFR exon 19 deletion was detected. MET amplification was detected in a biopsy performed on progression. The EGFR C797S mutation was not detected in either patient at the time of relapse. ddPCR of cell free DNA enables real time monitoring of patients on 3rd generation TKIs. As resistance mechanisms are variable, monitoring levels of the initial activating EGFR mutation may facilitate more reliable detection of progression.
authors.affiliation: Department of Medical Oncology, Austin Health, Melbourne, Australia; Olivia Newton-John Cancer Research Institute, Austin Health, Melbourne, Australia. Electronic address: PueyLing.CHIA@onjcri.org.au.
authors.forename: Puey Ling
authors.initials: PL
authors.lastname: Chia
authors.affiliation: Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Victoria 3084, Australia,; Department of Pathology, University of Melbourne, Parkville, Victoria, 3010, Australia; School of Cancer Medicine, La Trobe University, Bundoora, Victoria 3084, Australia.
authors.forename: Hongdo
authors.initials: H
authors.lastname: Do
authors.affiliation: Department of Anatomical Pathology, St Vincent's Hospital, Sydney, Australia.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Morey
authors.affiliation: Department of Medical Oncology, Austin Health, Melbourne, Australia; Olivia Newton-John Cancer Research Institute, Austin Health, Melbourne, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Mitchell
authors.affiliation: Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Victoria 3084, Australia,; Department of Pathology, University of Melbourne, Parkville, Victoria, 3010, Australia; School of Cancer Medicine, La Trobe University, Bundoora, Victoria 3084, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dobrovic
authors.affiliation: Department of Medical Oncology, Austin Health, Melbourne, Australia; Olivia Newton-John Cancer Research Institute, Austin Health, Melbourne, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: John
mesh_terms: D000178:Acrylamides / Q000627:therapeutic use; D000368:Aged; D019943:Amino Acid Substitution; D000814:Aniline Compounds / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D003062:Codon; D004273:DNA, Neoplasm / Q000097:blood; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D008297:Male; D009154:Mutation; D009367:Neoplasm Staging; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D007211:Indoles; D011743:Pyrimidines
chemical_list: D000178:Acrylamides; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D003062:Codon; D004273:DNA, Neoplasm; D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; C000596361:osimertinib; D007211:Indoles; D011743:Pyrimidines