Genomic markers of panitumumab resistance including ERBB2/HER2 in a phase II study of KRAS wild-type (wt) metastatic colorectal cancer (mCRC)
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Barry, G. S., Cheang, M. C., Chang, H. L., Kennecke, H. F.
(2016)
Genomic markers of panitumumab resistance including ERBB2/HER2 in a phase II study of KRAS wild-type (wt) metastatic colorectal cancer (mCRC).
Oncotarget, 7 (14).
pp. 18953-18964.
ISSN 1949-2553
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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 6mg/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.
| Item Type: | Article |
|---|---|
| All Authors: | Barry, G. S., Cheang, M. C., Chang, H. L., Kennecke, H. F. |
| Additional Information: | ISI Document Delivery No.: DL5TE Times Cited: 0 Cited Reference Count: 43 Barry, Garrett S. Cheang, Maggie C. Chang, Hector Li Kennecke, Hagen F. AMGEN CANADA; BC Cancer Foundation; BC Cancer Agency; Cancer Research UK (CRUK) Core grant [C1491/A15955] This study was supported by AMGEN CANADA, the BC Cancer Foundation and the BC Cancer Agency. Maggie Chon U Cheang is supported by the Cancer Research UK (CRUK) Core grant (Grant number C1491/A15955) to Clinical Trials and Statistics Unit at The Institute of Cancer Research (ICR-CTSU). 0 IMPACT JOURNALS LLC ALBANY ONCOTARGET |
| Uncontrolled Keywords: | mCRC nanostring ERBB2 HER2 EGFR inhibitor resistance ALPHA-B-CRYSTALLIN BREAST-CANCER RAS MUTATIONS TRIAL BRAF CETUXIMAB OVEREXPRESSION SENSITIVITY POPULATION EXPRESSION |
| Research teams: | ICR divisions > Clinical Studies > Clinical Trials & Statistics Unit |
| Depositing User: | Barry Jenkins |
| Date Deposited: | 06 Jun 2016 14:22 |
| Last Modified: | 06 Jun 2016 14:27 |
| URI: | http://publications.icr.ac.uk/id/eprint/15106 |
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