Abstract
Personalized medicine shows promise for maximizing efficacy and minimizing toxicity of anti-cancer treatment. KRAS exon 2 mutations are predictive of resistance to epidermal growth factor receptor-directed monoclonal antibodies in patients with metastatic colorectal cancer. Recent studies have shown that broader RAS testing (KRAS and NRAS) is needed to select patients for treatment. While Sanger sequencing is still used, approaches based on various methodologies are available. Few CE-approved kits, however, detect the full spectrum of RAS mutations. More recently, “next-generation” sequencing has been developed for research use, including parallel semiconductor sequencing and reversible termination. These techniques have high technical sensitivities for detecting mutations, although the ideal threshold is currently unknown. Finally, liquid biopsy has the potential to become an additional tool to assess tumor-derived DNA. For accurate and timely RAS testing, appropriate sampling and prompt delivery of material is critical. Processes to ensure efficient turnaround from sample request to RAS evaluation must be implemented so that patients receive the most appropriate treatment. Given the variety of methodologies, external quality assurance programs are important to ensure a high standard of RAS testing. Here, we review technical and practical aspects of RAS testing for pathologists working with metastatic colorectal cancer tumor samples. The extension of markers from KRAS to RAS testing is the new paradigm for biomarker testing in colorectal cancer.
Highlights
Personalized medicine and tailoring of therapy to individual patients is a promising approach for maximizing efficacy and minimizing the toxicity of anti-cancer treatment [1]
In the phase III, first-line PRIME study, oxaliplatin, 5-fluorouracil (5-FU), and leucovorin (FOLFOX4) plus panitumumab was associated with a median progression-free survival (PFS) of 9.6 versus 8.0 months for FOLFOX4 alone (p = 0.02), while median overall survival [OS] was 23.9 and 19.7 months, respectively (p = 0.072) [8]
In patients with mutant KRAS tumors, combination of anti-Epidermal growth factor receptor (EGFR) therapy with irinotecan-based chemotherapy is associated with little or no benefit [9, 12, 13], while combination of anti-EGFR therapy with oxaliplatin-based chemotherapy in such patients may be detrimental to both PFS and OS [8, 14, 15]
Summary
Personalized medicine and tailoring of therapy to individual patients is a promising approach for maximizing efficacy and minimizing the toxicity of anti-cancer treatment [1]. A few molecular tumor biomarkers—characteristics “that can be objectively measured and evaluated as an indicator of pathogenic processes or treatment response” [3]—have been identified, enabling anti-cancer treatments to be better tailored to individual patients’ tumors [1]. Those molecular biomarkers have provided alternative therapeutic options and improved patient outcomes, especially in metastatic colorectal cancer (mCRC). KRAS mutations, Virchows Arch (2016) 468:383–396 those in exon 2 (detectable in about 30–40 % of patients with mCRC) [5, 6] were identified as a predictive biomarker of resistance to the EGFR-targeted antibodies. In patients with mutant KRAS tumors, combination of anti-EGFR therapy with irinotecan-based chemotherapy is associated with little or no benefit [9, 12, 13], while combination of anti-EGFR therapy with oxaliplatin-based chemotherapy in such patients may be detrimental to both PFS and OS [8, 14, 15]
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