EGFR, DCC, and K-RAS mutations as predictive factors for cetuximab sensitivity in metastatic colorectal cancer (mCRC)

Abstract

4128 Background: Several studies suggest that increased gene copy number of the Epidermal Growth Factor Receptor (EGFR) or presence of mutations of the K-ras oncogene are associated with cetuximab response or resistance in patients (pts) with mCRC. In this setting data are not yet available regarding deleted in colorectal cancer (DCC), a tumor-suppressor gene located at chromosome 18q21, although DCC could theoretically modulate the EGFR/K-RAS pathway. This study aimed to identify biological predictors for sensitivity and resistance to cetuximab in pts with mCRC. Methods: Paraffin embedded tumor blocks from 31 mCRC pts treated with cetuximab-based regimens (Table 1) were retrospectively analyzed for EGFR (immunohistochemical staining - IHC and fluorescence in situ hybridization - FISH), DCC (Fragment analysis), and K-RAS (exon 12 mutation). Results: EGFR FISH positive patients (n=18), defined as ratio EGFR/nucleus =3, had a significantly higher time to progression -TTP (6.2 versus 3.2 months, p = 0.003) than EGFR FISH negative (n=13). The concordance rate of IHC-positive cases with cases positive for EGFR gene amplification by FISH was 55% (17/31) but EGFR expression assessed by IHC was not associated with any clinical end-point. Allelic losses (LOH) at the DCC locus were observed in 45% of pts. The median TTP was 6.6 months in pts without LOH and 2.7 months in pts with DCC-LOH (log-rank test, p =.04). Compared to pts with wild type K-RAS (n=21), K-RAS mutation carriers (n=10) had a significantly lower objective response rate (PR + SD, 3% versus 42%, p = 0.02), shorter TTP (2.3 versus 6.6 months, p = 0.06) and shorter survival which was not statistically significant (p = 0.2). Multivariate analysis showed that TTP was not correlated with treatment lines, sex, age and objective response rate. Conclusions: This study suggests that there is a significant benefit in TTP for EGFR FISH positive patients treated with cetuximab. DCC allelic losses could predict early resistance to cetuximab therapy and K-RAS mutation analysis identifies a group of pts with the lowest chance of benefiting from therapy. No significant financial relationships to disclose.