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KRAS mutation spectrum notably diverges between non-small cell lung and colorectal carcinomas.

To the Editor: We read the article entitled “A systematic review and Canadian consensus recommendations on the use of biomarkers in the treatment of non-small cell lung cancer” by Ellis et al. with major interest and would like to address comment on it. Since 2008, clinical research studies on non-small cell lung cancer (NSCLC) have allowed the transfer of EGFR gene mutations testing to the routine analysis for predicting the response to tyrosine kinase inhibitors (TKI) such as gefitinib or erlotinib. Therefore, interest in individualizing patient treatment to maximize clinical benefit has become a focus of scientific investigation. The presence of a translocation involving the anaplastic lymphoma kinase (ALK) gene with EML4 is now admitted to confer a remarkable sensitivity to crizotinib, a specific ALK TKI. In contrast, mutations activating the KRAS oncogene are generally reported as associated with a lack of response to EGFR TKI in several studies, but the mechanism remains unclear and controversial thus insufficient to adopt KRAS mutation detection as a consensual tool for therapeutic decision. When entering into details of KRAS somatic mutations, their predictive value in stage IV colorectal cancer (CRC) patients for treatment with EGFR monoclonal antibodies has been established. RAS mutations are found in 40 to 45% of metastatic colorectal adenocarcinomas, and the mutation spectrum has been extensively studied, mutations involving codon 12 or 13 of KRAS being found in 40% of cases and the remaining 5% being spread over KRAS codons 61 and 146 or NRAS. on KRAS codons 12 and 13, seven mutations have been recognized as the most frequent, leading to the development of commercial kits focusing on these seven mutations. The use of these kits has been extended to other tumor types, in particular NSCLC, as able to predict the absence of EGFR mutation or ALK translocation as these events have been reported as mutually exclusive, instead of predicting a specific resistance to EGFR TKI. Also, the strategy of drug development moves toward the ability of specifically targeting the RAS pathway. Involved in somatic mutations detection in our Cancer Institute, we evaluated the possibility to use those kits targeted on the seven most frequent KRAS mutations that are less expensive and time consuming when compared with nonselective techniques like sequencing. From June 2006 to September 2011, a consecutive series of 1642 histologic samples of metastatic CRC patients has been referred to the bio-pathologic department for sequencing the KRAS codons 12 and 13 mutation status before enrolling patients in cetuximab-based protocols, and 633 mutations were recorded (39%). Since January 2009, an additional 762 samples from patients affected by NSCLC was screened using the same approach, leading to the identification of 186 mutations (24.4%) (Table 1). When comparing the mutation spectra of these two tumor types, no major difference in frequencies is observed except for c.37G>T and for delins mutations that are found in 15 of CRC, i.e., 2.3% of mutated samples, and 27 of NSCLC, i.e., 14.5% of mutated samples. These mutations are not precisely or unreliably detected using the commercial kits. If the proportion of missed mutations is quite low in CRC, it is much higher in NSCLC and cannot be neglected. In those cases, there is a risk to treat with an ineffective therapy, and in the future these patients could lack chance of having a RAStargeted therapy. In summary, meta-analyses on molecular biomarkers usually put together results derived from clinical studies based on heterogeneous molecular approaches, and subsequent conflicting results lead to preclude the use of potential markers in medical practice. When transferring new molecular markers in routine testing, we would like to recommend a scrupulous consideration when choosing the detection technique.