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Interpretive Handbook

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Test 61247 :
EGFR Gene, Mutation Analysis, 29 Mutation Panel, Tumor

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Lung cancer is the leading cause of cancer-related deaths in the world. Non-small cell lung cancer (NSCLC) represents 70% to 85% of all lung cancer diagnoses. Small molecular agents that target the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) protein are approved for the treatment of locally advanced or metastatic NSCLC as a second- or third-line regimen. Subsequently, randomized trials have suggested that targeted agents alone or combined with chemotherapy may be beneficial in maintenance and first-line settings. Because the combination of targeted therapy and standard chemotherapy leads to an increase in toxicity and cost, strategies that help to identify the individuals most likely to benefit from targeted therapies are desirable.

 

EGFR is a growth factor receptor that is activated by the binding of specific ligands, resulting in activation of the RAS/MAPK pathway. Activation of this pathway induces a signaling cascade ultimately leading to cell proliferation. Dysregulation of the RAS/MAPK pathway is a key factor in tumor progression for many solid tumors. Targeted therapies directed to tumors harboring activating mutations within the EGFR tyrosine kinase domain (exons 18-21) have demonstrated some success in treating a subset of patients with NSCLC by preventing ATP-binding at the active site. Gefitinib and erlotinib have been approved by the FDA for use in treating patients with NSCLC who previously failed to respond to the traditional platinum-based doublet chemotherapy. These 2 drugs have also recently been shown to increase progression-free and overall survival in patients who receive EGFR-tyrosine kinase inhibitor therapy as a first-line therapy for the treatment of NSCLC.

Agents such as gefitinib and erlotinib, which prevent ATP binding to EGFR kinase, do not appear to have any meaningful inhibitor activity on tumors that demonstrate the presence of the specific drug-resistant EGFR mutation T790M. Therefore, current data suggest that the efficacy of EGFR-targeted therapies in NSCLC is confined to patients with tumors demonstrating the presence of EGFR- activating mutations such as L858R, L861Q, G719A/S/C, S768I or small deletions within exon 19 and the absence of the drug-resistant mutation T790M. As a result, the mutation status of EGFR can be a useful marker by which patients are selected for EGFR-targeted therapy.

Useful For Suggests clinical disorders or settings where the test may be helpful

Identifying non-small cell lung cancers that may respond to epidermal growth factor receptor-tyrosine kinase inhibitor therapies

Interpretation Provides information to assist in interpretation of the test results

An interpretive report will be provided.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

A negative (wild type) result does not rule out the presence of a mutation that may be present but below the limits of detection for this assay (approximately 10%).  

 

A negative (wild type) result does not rule out the presence of other activating mutations in the EGFR gene.

 

The predictive value of epidermal growth factor receptor (EGFR) testing applies to EGFR-TKI therapies, not to other therapeutic agents.

 

Not all patients that have activating EGFR mutations detected by this assay respond to EGFR-TKI therapies.

 

Rare polymorphisms exist that could lead to false-negative or false-positive results.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Clinical References Provides recommendations for further in-depth reading of a clinical nature

1. Sharma SV, Bell DW, Settleman J, Haber DA: Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007;7(3):169-181

2. Gao G, Ren S, Li A, et al: Epidermal growth factor receptor-tyrosine kinase inhibitor therapy is effective as first-line treatment of advanced non-small-cell lung cancer with mutated EGFR: a meta-analysis from six phase III randomized controlled trials. Int J Cancer 2011;131(5):E822-829

3. Mok TS: Personalized medicine in lung cancer: what we need to know. Nat Rev Clin Oncol 2011;8:661-668


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