The role of sidedness, EGFR gene copy number (GCN) and EGFR promoter methylation in RAS/BRAF wild type (WT) colorectal cancer (CRC) patients receiving irinotecan/cetuximab.

Abstract

628 Background: Data from randomized trials suggested that tumour sidedness could represent a prognostic and predictive factor in CRC patients. Distinctive molecular and clinical features are related to tumour sidedness, however their predictive role has not yet been clearly defined. Methods: Tumour samples from RAS/BRAF WT metastatic CRC patients treated with second-third line irinotecan-cetuximab were analised for EGFR GCN and promoter methylation. Study objective was to evaluate the correlation of tumour sidedness, EGFR promoter methylation and EGFR GCN with clinical outcome. Results: Eighty-eightpatients were included in the study, 24/88 (27.3%) had right sided CRC(RSCC), 64/88 (72.7%) had left sided CRC(LSCC); 32/88 (36.4%) had EGFR GCN < 2.12 tumour, 56/88 (63.6%) had EGFR GCN ≥ 2.12 tumour; 44/88 (50%) had EGFR promoter methylated tumour. RSCC were associated with reduced ORR (4.2% for RSCC vs 35.9% for LSCC, p:0.0030), with shorter PFS (3.0 vs 10.29 months, HR:2.74, p < 0.0001) and shorter OS (8.0 vs 13.6 months, HR:2.83, p < 0.0001). EGFR GCN < 2.12 tumours were associated with reduced ORR (6.2% for EGFR GCN < 2.12 vs 39.3% for ≥ 2.12 tumours, p:0.0009), with shorter PFS (3.8 vs 7.0 months HR:2.15, p = 0.0010) and shorter OS (8.5 vs 14.0 months HR:2.59, p < 0.0001). EGFR methylated tumours were associated with reduced ORR (9.1% for methylated vs 45.5% for unmethylated, p = 0.0001), with shorter PFS (3.0 vs 7.67 months HR:3.23, p < 0.0001) and shorter OS (8.0 vs 17.0 months HR:3.57, p < 0.0001). At multivariate analysis EGFR GCN and EGFR promoter methylation mantained their independent role for ORR (respectively p:0.0082 and p:0.0025), PFS (respectively Exp(b):0.40, p:0.0048 and Exp(b):4.52, p < 0.0001) and OS (respectively Exp(b):0.23, p:0.0001 and Exp(b):5.58, p < 0.0001). Conclusions: In our study an accurate molecular selection based on an all RAS and BRAF analisys along with EGFR GCN and EGFR promoter methylation status resulted more relevant than tumour sidedness for the prediction of clinical outcome during cetuximab/irinotecan. We then suggest that molecular selection might overcome the importance of tumour sidedness in this setting.