Association of BRAF mutations and EGFR Intron-1 L/L genotype with resistance to cetuximab plus irinotecan treatment in KRAS wild-type metastatic colorectal cancer patients

Abstract

4058 Background: KRAS and BRAF mutations are associated with resistance to anti-EGFR monoclonal antibodies. EGFR Intron-1 (CA)n genotype has been suggested to influence the activity of cetuximab. Methods: We retrospectively assessed KRAS and BRAF mutational status and EGFR Intron-1 (CA)n genotypes in 117 irinotecan-refractory EGFR-positive mCRC patients treated with cetuximab plus irinotecan. We defined short (S) and long (L) allelic variants those presenting < and ≥17 CA repeats respectively. Among KRAS wild-type patients, we investigated the association between BRAF mutational status and EGFR Intron-1 genotype and treatment outcome in terms of RR and PFS. Results: Among 66 (56%) KRAS wild-type patients, BRAF V600E mutation was detected in 9 (14%) patients. BRAF wild-type patients reported improved RR (0/9, 0% vs 19/57, 33%, p = 0.04) and PFS (3.3 vs 5.1 months, p = 0.076; HR = 0.54 [95%CI: 0.18–1.09]) in comparison with BRAF-mutated. EGFR Intron-1 L/L genotype was detected in 13 (20%) KRAS wild-type patients. Objective responses were reported in 1/13 (8%) EGFR Intron-1 L/L patients and in 18/53 (34%) S/L or S/S patients (p = 0.061). Significantly longer PFS was observed among EGFR Intron-1 S/L or S/S patients (5.3 vs 3.3 months, p = 0.0062; HR = 0.45 [95%CI: 0.14–0.72]). Among 57 KRAS and BRAF wild-type patients, 1/11 (9%) EGFR Intron-1 L/L patients and 18/46 (39%) S/L - S/S patients responded to treatment (p = 0.058), achieving median PFS of 3.7 and 5.4 months, respectively (p = 0.022; HR = 0.48 [95%CI: 0.15–0.87]). Conclusions: In KRAS wild-type patients, BRAF mutations are confirmed to predict resistance to cetuximab treatment. EGFR Intron-1 allelic variants are promising markers of benefit in patients with both KRAS and BRAF wild-type and may help to better select mCRC patients candidate to receive cetuximab-containing treatment. No significant financial relationships to disclose.