KRAS and BRAF mutational status and PTEN, cMET, and IGF1R expression as predictive markers of response to cetuximab plus chemotherapy in metastatic colorectal cancer (mCRC).

Abstract

e14065 Background: KRAS and BRAF mutations are associated with resistance to cetuximab in mCRC. Reduced PTEN expression or over-expression of cMET and IGF1R with activation of cell cascade signaling could represent further mechanisms of resistance to EGFR-blockade. Methods: We retrospectively correlated KRAS and BRAF mutational status and PTEN, cMET and IGF1R expression with the clinical outcome of 60 patients (pts) treated with cetuximab plus chemotherapy in front-line setting or as further line therapy. Results: 23/60 (38.3%) pts were KRAS mutated. 23 of 37 KRAS wild-type pts were evaluated for BRAF and no mutations were found. Reduced PTEN expression was found in 7 (11.7%) while an iperexpression of cMET and IGF1R was found in 40 (72.7%) and in 15 (27.3%) pts, respectively response rate (RR), time to progression (TTP) and overall survival (OS) in KRAS mutated and KRAS wild-type pts were 0% and 24.3% (p = 0.01), 2 and 5 months (p = 0.036), 8 and 13 months (p = 0.015). No difference was observed in terms of TTP and OS according to PTEN status; although not significantly, RR was higher in pts with normal PTEN (12.5%) compared with those with reduced PTEN expression (0%). Pts with low or normal cMET expression achieved a higher RR (26.7% vs. 7.5%, p = 0.079) with a significantly longer TTP (5 vs. 3 months; p = 0.028) and a trend toward a longer OS (p = 0.099) in comparison with pts with a cMET iperexpression. In pts with a higher and with normal/lower IGF1R expression, RR was 20% and 10% (p = 0.376), TTP 5 and 4 month (p = 0.074), respectively; a significantly longer OS was observed in higher versus lower/normal IGF1R expression (24 vs. 10 months; p = 0.036). Conclusions: KRAS mutations are the strongest negative predictive marker of response to cetuximab treatment in mCRC. A cMET iperexpression is related to resistance to cetuximab. Despite a trend of higher RR in pts with normal PTEN, the role of PTEN expression should be further investigated. Interestingly, a IGF1R iperexpression is not associated with resistance to cetuximab but it seems to represent a favorable prognostic factor in mCRC. No significant financial relationships to disclose.