title: Changes in colorectal carcinoma genomes under anti-EGFR therapy identified by whole-genome plasma DNA sequencing.
abstract: Monoclonal antibodies targeting the Epidermal Growth Factor Receptor (EGFR), such as cetuximab and panitumumab, have evolved to important therapeutic options in metastatic colorectal cancer (CRC). However, almost all patients with clinical response to anti-EGFR therapies show disease progression within a few months and little is known about mechanism and timing of resistance evolution. Here we analyzed plasma DNA from ten patients treated with anti-EGFR therapy by whole genome sequencing (plasma-Seq) and ultra-sensitive deep sequencing of genes associated with resistance to anti-EGFR treatment such as KRAS, BRAF, PIK3CA, and EGFR. Surprisingly, we observed that the development of resistance to anti-EGFR therapies was associated with acquired gains of KRAS in four patients (40%), which occurred either as novel focal amplifications (n = 3) or as high level polysomy of 12p (n = 1). In addition, we observed focal amplifications of other genes recently shown to be involved in acquired resistance to anti-EGFR therapies, such as MET (n = 2) and ERBB2 (n = 1). Overrepresentation of the EGFR gene was associated with a good initial anti-EGFR efficacy. Overall, we identified predictive biomarkers associated with anti-EGFR efficacy in seven patients (70%), which correlated well with treatment response. In contrast, ultra-sensitive deep sequencing of KRAS, BRAF, PIK3CA, and EGFR did not reveal the occurrence of novel, acquired mutations. Thus, plasma-Seq enables the identification of novel mutant clones and may therefore facilitate early adjustments of therapies that may delay or prevent disease progression.
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Sumitra
authors.initials: S
authors.lastname: Mohan
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Ellen
authors.initials: E
authors.lastname: Heitzer
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Ulz
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Lafer
authors.affiliation: Department of Pathology, General Hospital Graz West, Graz, Austria.
authors.forename: Sigurd
authors.initials: S
authors.lastname: Lax
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Martina
authors.initials: M
authors.lastname: Auer
authors.affiliation: Division of Oncology, Medical University of Graz, Graz, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Pichler
authors.affiliation: Division of Oncology, Medical University of Graz, Graz, Austria.
authors.forename: Armin
authors.initials: A
authors.lastname: Gerger
authors.affiliation: Division of Oncology, Medical University of Graz, Graz, Austria.
authors.forename: Florian
authors.initials: F
authors.lastname: Eisner
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Gerald
authors.initials: G
authors.lastname: Hoefler
authors.affiliation: Division of Oncology, Medical University of Graz, Graz, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bauernhofer
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Jochen B
authors.initials: JB
authors.lastname: Geigl
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Speicher
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000097:blood; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology; D005260:Female; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000077544:Panitumumab; D019859:Proto-Oncogene Proteins c-met / Q000097:blood; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000097:blood
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D000068818:Cetuximab; D066246:ErbB Receptors; D000077544:Panitumumab; D019859:Proto-Oncogene Proteins c-met; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C491743:MET protein, human