The role of KRAS, BRAF, and PI3K mutations as markers of resistance to cetuximab in metastatic colorectal cancer.

Abstract

3603 Background: KRAS mutations negatively affect outcome after cetuximab (CTX) in metastatic colorectal cancer (mCRC). As only 20% of KRAS wild-type (WT) patients respond it is possible that other mutations, constitutively activating the EGFR pathway, are present in the non-responding WT. We retrospectively correlated KRAS, BRAF and PI3K mutational status with the clinical outcome of 64 mCRC patients treated with CTX plus chemotherapy. Methods: DNA was extracted from 5 mM paraffin-embedded sections containing at least 50% of tumoral cells, derived from primary or metastatic lesions. Exon 2 of KRAS and exon 15 of BRAF were amplified by PCR and analysed by direct sequencing. PIK3CA status was analysed by Pyrosequencing. A two-sided Fisher's exact test was used to evaluate the association between mutations and objective response (OR). Progression-free survival (PFS) was estimated by Kaplan-Meier method and curves were compared by log-rank test. Hazard ratios (HR) were estimated according to Cox multiple regression model. Results: Patient characteristics were as follows: Male/Female = 35/29; primary site: rectum/colon =13/51. KRAS, BRAF and PI3K mutations were present in 28.1%, 21.3% and 15.1% of CRC lesions, respectively. KRAS WT/MUT was associated with OR 28.3/22.2% (p=0.75), median PFS 5.1 (95% CI 3.3-6.2)/3.1 months (95%CI 2.3-5.5), p=0.85. BRAF WT/MUT was associated with OR 33.3/7.7% (p=0.08), PFS 5.1 (95% CI 2.9-6.5)/3.4 months (95%CI 1.4-5.1), p<0.01. PI3K WT/MUT was associated with OR 31.1/12.5% (p=0.41), PFS 5.3(95% CI 3.6-6.5)/2.2 months (95% CI 1.1-3.3), p<0.01. PFS (95% CI) was increasingly worse for patients with tumors harboring none, 1, or ≥ 2 molecular alteration(s): 5.5 (2.7-8.7), 3.5 (2.3-5.5), 2.1 months (1.0-3.9), respectively, p<0.01. Moreover, the multivariate analysis of PFS indicated BRAF and PI3K as potential independent predictors of clinical benefit: HR (95% CI) 2.74 (1.37-5.45), p<0.01 and 3.57 (1.45-8.80), p<0.01, respectively. Conclusions: Our results seem to confirm that comprehensive molecular dissection of the EGFR signaling pathways should be considered to better select mCRC patients for CTX based therapies.