Precise RAS mutational analysis is required to select candidates for cetuximab in metastatic colorectal cancer (mCRC). Direct sequencing method is conventionally used, however, its sensitivity has been questioned along with its time-consuming process. We performed extended RAS mutational analysis using high-throughput genotyping platform (OncoMap) and evaluated the impact of extended analysis on predicting cetuximab efficacy in patients already known to harbor KRAS exon 2 wild-type tumors by direct sequencing.
A total of 227 mCRC patients with KRAS exon 2 wild-type tumors determined by direct sequencing were included and were treated with cetuximab as at least third-line chemotherapy. Extended RAS analysis was performed using OncoMap (version 4.0) under the SequenomMassARRAY technology platform. Targeted genes included exon 2 (codon 12, 13), exon 3 (codon 59, 61), and exon 3 (codon 117, 146) both in KRAS and NRAS, and also included BRAF exon 15. Survival analysis according to RAS mutation status was performed to assess the impact of the Oncomap.
Among the 227 patients known to harbor wild-type KRAS exon 2 determined by direct sequencing, OncoMap detected 57 additional mutations (25.1%, any RAS mutant group); 25 (11%) in KRAS exon 2 and 32 (14.1%) beyond KRAS exon 2 (9 mutations in KRAS exon 3; 12 in KRAS exon 4; 6 in NRAS exon 2; and 5 in NRAS exon 3). The progression-free (PFS) and overall survival (OS) of all patients was 3.7 and 11.4 months, respectively. Extended RAS analysis using OncoMap discriminated survival outcomes between the RAS wild-type and RAS mutant groups; PFS was 4.8 versus 1.8 months (HR 0.44 [0.32-0.61], p < 0.001) and OS was 11.9 versus 8.4 months (HR 0.65 [0.47-0.88], p = 0.006), in the respective groups.
Due to insufficiency of direct sequencing in determining RAS mutation in mCRC, high-throughput extended RAS genotyping could be considered when selecting candidates for cetuximab treatment.
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T.W. Kim: TW Kim received financial grant to conduct the genetic analysis from Merck.
All other authors have declared no conflicts of interest.