The role of KRAS, BRAF, NRAS, and PIK3CA mutations as markers of resistance to cetuximab in chemorefractory metastatic colorectal cancer

Abstract

4020 Background: KRAS mutations (MUT) negatively affect outcome after cetuximab (CTX) in metastatic colorectal cancer (mCRC). As only 40% of KRAS wild-type (WT) respond it is possible that other MUT, constitutively activating the Ras/Erk or PI3K/Akt pathways, are present in the non-responding KRAS WT. We analyzed the KRAS, BRAF, NRAS & PIK3CA MUT status in 276 chemorefractory CRC treated with CTX +- irinotecan and correlated the MUT status with outcome. Methods: KRAS codon 12,13, 61&146, BRAF V600E, NRAS codon 12&13, PIK3CA E542K, E545K, A, G, V (exon 9), H1047Y, R, L (exon 20), N345K, R88Q and Q546K MUT were evaluated on FFPE primary CRC using the Sequenom MALDI TOF MassArray system. A two- sided Fisher's exact test was used to evaluate the association between PIK3CA, KRAS, BRAF & NRAS MUT and objective response (OR). Progression-free (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results: 116/276 (42%) CRC had a KRAS MUT, 96% of which occurred in codon 12 or 13. KRAS WT was associated with OR (p<.0001), longer median PFS (p<.0001) and OS (p<.0001). 15/153 (9.8%) KRAS WT had a BRAF MUT. BRAF WT was associated with OR (p=.01), longer PFS (p<.0001) and OS (p=.007). 5/98 (5%) KRAS WT had an NRAS MUT and none of these showed OR. KRAS, BRAF and NRAS MUT were mutually exclusive. The combined KRAS/BRAF/NRAS WT state was associated with OR (p<.0001), longer PFS (p<.0001) and OS (p<.0001). 23/200 (12%) CRC carried a PIK3CA mutation: 5/39 (13%) of responders and 18/160 (11%) of non-responders (p=.781). Median PFS and OS were not associated with PIK3CA MUT state (p=.760 & p=.698) overall, nor in the KRAS/BRAF/NRAS WT subgroup (p=.946 & p=.509). 5/13 (38.5%) PIK3CA MUT KRAS/BRAF/NRAS WT CRC showed an OR. 13/107 (12%) of KRAS/BRAF/NRAS WT and 10/93 (11%) of KRAS/BRAF/NRAS MUT tumors harbored a PIK3CA MUT (p=.826). Conclusions: KRAS, BRAF & NRAS MUT are mutually exclusive and occur in at least 47% of CRC. Like KRAS WT, BRAF WT state of the primary is significantly associated with outcome in mCRC treated with CTX. The combined KRAS/BRAF/NRAS WT state is significantly associated with outcome. PIK3CA MUT occur independently of the KRAS/BRAF/NRAS MUT status. We cannot provide any evidence for a strong role of PIK3CA MUT as a marker in determining outcome to CTX. [Table: see text]