KRAS mutations preclude tumor shrinkage of colorectal cancers treated with cetuximab

Abstract

4132 Background: A recent study has shown that the presence of a KRAS mutation is associated with the absence of objective response to cetuximab (CTX) in advanced colorectal cancers (mCRC). Our hypothesis was that CTX cannot induce any tumor shrinkage in KRAS mutant mCRC. Methods: We analyzed KRAS exon 2 mutation status by Taqman, PCR and sequencing on 37 available tumor samples from patients with mCRC progressive on chemotherapy. Twenty patients received CTX combined with irinotecan (BOND) and 17 received CTX in monotherapy (7 BOND, 10 SALVAGE). We measured the change in tumor size between baseline and the consecutive evaluations. At week 12 and at week 24, we statistically tested the change from baseline between the groups with KRAS wild type (WT) and KRAS mutation (MUT) using the t-test. RECIST criteria for tumor response were used. Results: 3 patients had progressive disease (PD), 26 stable disease (SD), 8 partial response (PR) and 0 complete response. A KRAS MUT was found in 17 tumors (46%): 2 in PD (66.7%), 15 in SD (57.7%) and none in PR patients (p<0.01; responders vs. non responders). At 12 weeks there was a mean decrease in tumor size of 23.1% (SE=7.38) in the KRAS WT and an increase of 2.6% (SE=4.13) in the KRAS MUT mCRC. At 24 weeks KRAS WT and MUT mCRC had a 45.8% (SE=8.61) and a 1.3% (SE=6.67) mean decrease respectively (p= 0.0081 at 12 weeks; p=0.0015 at 24 weeks). The mean tumor size of the KRAS WT did not decrease further after 24 weeks. In the subgroup of SD tumor size regression was observed but only in WT patients. Mean time to progression was 32 (range 12–96) and 30 weeks (range 12–84) for KRAS WT (SD + PR) and MUT respectively. Conclusion: We confirmed KRAS MUT precludes objective response to CTX in mCRC. In addition we found tumor size regression in SD patients being restricted to WT patients. We observed rapid onset of these differences suggesting an important role of KRAS MUT status in early tumor shrinkage. However the onset of progression was not different according to KRAS MUT status. [Table: see text]