Moving Forward With Expanding to an “All-RASMutational Analysis” in Metastatic Colorectal Cancer: BeyondKRASMutations

Abstract

The advent of biologic agents such as those that target the epidermal growth factor receptor (EGFR) has favorably impacted outcomes for patients with metastatic colorectal cancer (mCRC). An important downstream component of EGFR is the RAS signaling pathway. RAS proteins mainly include KRAS and NRAS. Activating KRAS mutations occur in 30% to 50% of colorectal tumors, most commonly in exon 2 as point mutations in codon 12 followed by mutations in codon 13. NRAS mutations occur in 3% to 5% of colorectal tumors. Since initial approval of the EGFR-directed monoclonal antibodies cetuximab (2004) and panitumumab (2006) for clinical use in mCRC, strategies to improve selection of the appropriate patients have constantly been refined. In 2005, the first confirmation that immunohistochemical analysis for EGFR expression has no predictive value in selecting or excluding patients allowed the use of these agents to be expanded to all eligible patients. In November 2008, the NCCN Colorectal Panel recommended routine KRAS (exon 2 codons 12/13) mutational testing based on consistent findings from multiple retrospective analyses of large clinical trials confirming that KRAS mutational status had predictive value for the use of antiEGFR monoclonal antibodies in mCRC. This move effectively restricted the use of these agents to approximately 60% of all patients with nonmutated KRAS mCRC, sparing the remainder of patients the risk of toxicities and the cost in the absence of a clear benefit. After this restriction, early reports suggested a possible clinical benefit for cetuximab in patients with mCRC with KRAS G13D mutations. However, another report from 3 randomized trials failed to suggest a similar benefit from panitumumab in the presence of a KRAS G13D mutation. These inconsistent results, the absence of a clear biology, and the overall poor outcome associated with the KRAS G13D mutation made this finding inconsequential to actual clinical practice pending further clinical validation. The NCCN Colorectal Cancer Panel continues to recommend against the use of anti-EGFR therapy in patients with codon 13 mutations. More recent data suggest that testing for additional RAS mutations (KRAS exons 3 or 4 and NRAS exon 1, 2, 3, or 4) present in 16% of tumors previously identified as KRAS (exon 2 codons 12/13) wild-type may allow for further refinement. A predefined retrospective analysis of the large prospective randomized trial PRIME (FOLFOX4 [leucovorin, 5-FU, and oxaliplatin] +/– panitumumab in first-line treatment of mCRC) suggests that the presence of these additional RAS mutations predict for lack of benefit. Data from the large phase II randomized study PEAK (FOLFOX plus panitumumab vs FOLFOX plus bevacizumab in first-line treatment of mCRC) confirmed the results from PRIME. This initiated a label change clarifying that panitumumab in combination with oxaliplatin-based chemotherapy is not indicated in the treatment of patients with RAS (KRAS or NRAS) mutation-positive mCRC. Despite these preliminary findings, there was very little uptake for incorporating an all-RAS mutational analysis before using EGFR inhibitors in mCRC. Why the initial reluctance? In addition to the lack of available standardized testing to include all RAS mutations, additional confirmatory data from studies, especially those incorporating cetuximab or irinotecan (which remains the preferred chemotherapeutic backbone Tanios Bekaii-Saab, MD