KRAS mutations in colorectal cancer is a predictive factor of response and progression free survival in patients treated with Cetuximab.

5671 Background: The Cetuximab anti-EGFR (epidermal growth factor receptor) antibody has been shown to be efficient in metastatic colorectal cancer (CRC). We previously showed in 30 CRC patients that KRAS mutations were associated with the absence of response to Cetuximab (1). The aim of this retrospective study was to confirm, in a larger series of pts treated with Cetuximab, the predictive value of KRAS mutations in comparison with that of skin toxicity and its impact on progression free survival (PFS). Patients and Methods: A series of 76 EGFR+ metastatic CRC patients treated with Cetuximab in 7 centers were analyzed for KRAS mutation (exon 2). The mutational analysis was performed by direct sequencing on DNA extracted from fresh frozen or paraffin-embedded tissues. The association between tumor response (RECIST criteria) and KRAS mutations and skin toxicity was analyzed, as PFS of the patients according to the presence or absence of KRAS mutation. Results : Among the 76 patients analyzed (M/F: 39/37; mean age: 60.1 years), 24 (31.5%) had an objective response to Cetuximab (CR : 2, PR : 22), administered in monotherapy (n=2) or in combination with irinotecan (alone, n=66 ; FOLFIRI regimen, n=8). A KRAS mutation was present in 35.5% of the cases (n=27) and was significantly associated with the absence of response to Cetuximab (0 responder among the 27 mutated patients vs 24 (49%) among the 49 non-mutated patients; p=10-5). A severe skin toxicity was more frequent in responder compared to non responder patients (grade 2-3 toxicity in CR/PR/SD/PD groups: 100%/64%/52%/35%; p=0.02 trend test). Median PFS was 19.2 weeks. In univariate analysis, PFS was longer when tumor was not mutated (median: 32 vs 8.6 weeks, Log-rank p Conclusion : These results confirm the high predictive value of KRAS mutations for the reponse to Cetuximab in CRC and show their association with a shorter PFS, which could be relevant in clinical practice by allowing the identification of patients that could benefit from Cetuximab and those (with KRAS mutation) for whom Cetuximab is likely to be inefficient, and potentially toxic. (1) Lievre et al. Cancer Res 2006 ; 66 : 3992-95