Cetuximab has shown clinical benefit in patients with metastatic colorectal cancer (mCRC) harbouring wild-type RAS. HER2 amplification has been suggested as one of the resistant mechanisms of cetuximab treatment. We evaluated association between HER2 amplification and cetuximab efficacy in mCRC patients harbouring extended RAS wild-type.
Between December 2003 and June 2013, we found 253 mCRC patients whose tumor harboured wild type in exon 2/3/4 both of KRAS and NRAS by high throughput sequencing (OncoMap version 4.0) and were treated with cetuximab as 2nd or later-line. We finally included 243 mCRC cases whose HER2 status could be determined by both immunohistochemical (IHC) scoring according to HERACLES criteria and silver in-situ hybridisation (SISH). Progression-free survival (PFS) and overall survival (OS) were analysed in homogenous group (n = 149) who were progressed after oxaliplatin, irinotecan and fluoropyrimidines.
The median age was 55 years (range 19–76 years); 168 patients (69.1%) were male. Of the 243 RAS wild-type tumor, we observed 11 cases (4.5%) of HER2 amplification (table). After the median follow-up of 13.5 months (range, 0.4–78.1), median PFS was statistically different according to the HER2 status: 3.1 months in patients harbouring HER2 amplification vs 5.7 months in those harbouring non-amplified HER2 (p = 0.013). OS was not statistically different according to the HER2 status although there was a tendency towards shorter OS in patients harbouring HER2 amplification (10.1 vs 13.5 months, p = 0.408).
|HER2 IHC (HERACLES criteria)|
† HER2/CEP17 ratio 3.3, †† HER2/CEP17 ratio 2.7, ††† HER2/CEP17 ratio >5 (all cases)
HER2 amplification is associated with shorter PFS after cetuximab in mCRC patients harbouring extended RAS wild-type. Recent study of dual targeting of EGFR and HER2 demonstrated promising result; further study is warranted for this population.
Clinical trial identification
Legal entity responsible for the study
Asan Medical Center
All authors have declared no conflicts of interest.