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 6mg/kg IV q2weeks. Of 34 panitumumabtreated 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.

Targeting HER2 in colorectal cancer: The landscape of amplification and short variant mutations in ERBB2 and ERBB3

“…Recent studies of ERBB2 amplification and sequence mutations in colorectal cancer (CRC) suggest that HER2 is a therapy target in this disease, in addition to being a mechanism of resistance to epidermal growth factor receptor (EGFR)‐targeted therapies such as cetuximab and panitumumab . Similarly, reports of high‐level ERBB3 amplification being a negative prognostic factor within the context of CRC suggest that HER3 may also be a target in this tumor type .…”

“…11,[26][27][28] Recent studies of ERBB2 amplification and sequence mutations in colorectal cancer (CRC) suggest that HER2 is a therapy target in this disease, [29][30][31][32][33] in addition to being a mechanism of resistance to epidermal growth factor receptor (EGFR)-targeted therapies such as cetuximab and panitumumab. [34][35][36][37][38] Similarly, reports of high-level ERBB3 amplification being a negative prognostic factor within the context of CRC suggest that HER3 may also be a target in this tumor type. 27,39,40 These studies encourage continued research into the effects and prevalence of ERBB alterations in patients with recurrent and metastatic CRC, as well as their importance for treatment.…”