RAS wild-type (extended KRAS and NRAS testing)

This is a negative selector: the drug is given when nothing is found. Cetuximab and panitumumab only work in metastatic colorectal cancer whose RAS genes are unmutated, because a mutation downstream of the receptor makes blocking the receptor pointless. The definition widened once. The 2012 and 2014 companion diagnostic claims asked only for KRAS codons 12 and 13 (exon 2); the PRIME extended analysis (Douillard, New England Journal of Medicine 2013) then showed that patients with RAS mutations outside exon 2, in KRAS or NRAS exons 3 and 4, did worse when panitumumab was added, so the wild-type definition was extended to KRAS and NRAS exons 2, 3 and 4 and the panitumumab label and its companion diagnostics were rewritten around it. The FDA list now carries both definitions side by side: FoundationOne CDx, xT CDx, the CRCDx RAS Mutation Detection Assay and MI Cancer Seek report KRAS and NRAS wild-type across exons 2, 3 and 4 for panitumumab, while the cetuximab rows on the same devices, on the therascreen KRAS RGQ PCR Kit and on ONCO/Reveal Dx still read codons 12 and 13. An assay that reads codons 12 and 13 alone misses about one KRAS mutation in six and nearly every NRAS mutation, so a codon 12 and 13 wild-type result is not the same claim as an extended RAS wild-type result. Sidedness is read alongside it: in RAS wild-type disease an EGFR antibody improves survival in left-sided tumours and not in right-sided ones. RAS wild-type is also the setting for the HER2-directed colorectal combinations and, with a BRAF V600E mutation, for encorafenib with cetuximab.