title: Genomic markers of panitumumab resistance including ERBB2/ HER2 in a phase II study of KRAS wild-type (wt) metastatic colorectal cancer (mCRC).
abstract: A prospective study was conducted to identify biomarkers associated with resistance to panitumumab monotherapy in patients with metastatic colorectal cancer (mCRC). Patients with previously treated, codon 12/13 KRAS wt, mCRC were prospectively administered panitumumab 6 mg/kg IV q2weeks. Of 34 panitumumab-treated patients, 11 (32%) had progressive disease at 8 weeks and were classified as non-responders. A Nanostring nCounter-based assay identified a 5-gene expression signature (ERBB2, MLPH, IRX3, MYRF, and KLK6) associated with panitumumab resistance (P = 0.001). Immunohistochemistry and in situ hybridization determined that the HER2 (ERBB2) protein was overexpressed in 4/11 non-responding and 0/21 responding cases (P = 0.035). Two non-responding tumors had ERBB2 gene amplification only, and one demonstrated both ERBB2 amplification and mutation. A non-codon 12/13 KRAS mutation occurred in one panitumumab-resistant patient and was mutually exclusive with ERBB2/HER2 abnormalities. This study identifies a 5-gene signature associated with non-response to single agent panitumumab, including a subgroup of non-responders with evidence of aberrant ERBB2/HER2 signaling. KRAS wt tumors resistant to EGFRi may be identified by gene signature analysis, and the HER2 pathway plays an important role in resistance to therapy.
authors.affiliation: Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
authors.forename: Garrett S
authors.initials: GS
authors.lastname: Barry
authors.affiliation: The Institute of Cancer Research, Sutton, London, Surrey SM2 5NG, United Kingdom.
authors.forename: Maggie C
authors.initials: MC
authors.lastname: Cheang
authors.affiliation: Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
authors.forename: Hector Li
authors.initials: HL
authors.lastname: Chang
authors.affiliation: Medical Oncology, BC Cancer Agency, Vancouver, BC V5Z 4E6, Canada.
authors.forename: Hagen F
authors.initials: HF
authors.lastname: Kennecke
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D023281:Genomics / Q000379:methods; D006801:Humans; D008297:Male; D000077544:Panitumumab; D011446:Prospective Studies; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000077544:Panitumumab; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; C117307:KRAS protein, human; C508053:ERBB2 protein, human
keywords: EGFR inhibitor resistance; ERBB2; HER2; mCRC; nanostring