Expanding KRAS Gene Testing: We’re Ready and Here’s Why

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Advancements in molecular testing enable physicians to use precision medicine in treatment of cancer patients harbouring actionable mutation. KRAS is one of the most commonly mutated genes in cancer, along with p53, PIK3CA, ATM, PTEN, APC, BRAF and several others [1]. KRAS mutations are present in three of the most highly prevalent and deadly cancers: lung, colon and pancreas. Recent advances in evidence-based therapeutics presented promising clinical benefits for patients harbouring such tumours. Historically, mutated KRAS has been un-druggable despite the progress in targeted therapies. Recently, however, several KRAS-targeted drugs are the subject of ongoing clinical trials. Thus, it is critical that Brazil sets the stage for adoption and implementation of precision medicine and their associated tests as a model for other countries in similar situations.

KRAS plays an important role in the epidermal growth factor receptor (EGFR) signaling pathway that controls cell growth and proliferation. EGFR pathway signaling is triggered by an alteration in RAS proteins, which is due to activating mutations in KRAS gene. This pathway signaling a common event in several types of cancer and is regarded as a prominent step in tumorigenesis. The most commonly mutated codons in KRAS are 12, 13, and 61, which create drug resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Several studies suggest that KRAS mutations should be known prior to using EGFR-TKI therapies. Although tumor tissue is the standard source for KRAS mutation detection, obtaining tissue samples is invasive, and may be associated with additional cost, which may not always be feasible. Considering the advantages and disadvantages of tissue testing, liquid biopsy offers an opportunity to access tumor tissue not only for diagnosis but also for serial sampling and follow up

Lung cancer is the most frequently diagnosed cancer worldwide and the leading cause of death. In Brazil, as previously stated, it is the second most frequent malignant tumor type among men and the fourth in women, with an estimation of more than 30,000 new cases per year. KRAS mutations are seen in approximately 30% of all lung cancers. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of these tumors. Within NSCLC, KRAS mutations have been reported in 25–34% of adenocarcinomas and in 2-6% of squamous cell carcinomas. In adenocarcinomas, the most common codon 12 substitutions are G12C and G12V, both associated with smoking history, whereas the G12D is more frequent in never smokers. In some series, KRAS mutations have been related to worse treatment outcomes and considered a in depend variable, with deleterious prognostic value.