What are the recommendations for genetic testing in patients with non-small cell lung cancer (NSCLC)?

Updated: Aug 21, 2019
  • Author: Maurie Markman, MD, MS; Chief Editor: Keith K Vaux, MD  more...
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Testing for activating EGFR mutations in exons 18 through 21 is recommended in all patients with advanced NSCLC adenocarcinoma to help determine whether an EGFR-TKI should be considered. Routine testing for KRAS mutations is not recommended, but it can be considered as a way to help determine whether a patient might be resistant to treatment with an EGFR-TKI. No clear guidelines suggest whether to test for EGFR T790M mutations in patients with acquired resistance to EGFR-TKIs, because the clinical significance of mutation status relative to treatment continuation remains unknown.

The current standard for EGFR and KRAS mutation testing is polymerase chain reaction (PCR) analysis of formalin-fixed paraffin-embedded specimens or fresh-frozen biopsy. The clinical relevance of FISH or IHC testing for EGFR amplification is unknown.

In May 2013, erlotinib was approved for first-line treatment of NSCLC tumors that have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. Until that time, the official indication was second- or third-line use in advanced NSCLC. First-line use includes the use of the cobas EGFR Mutation Test, a companion diagnostic for erlotinib.

The safety and effectiveness of the cobas EGFR Mutation Test was established with clinical data from the EURTAC study and showed progression-free survival in patients with NSCLC who had specific types of EGFR mutations (exon 19 deletions or exon 21 [L858R] substitution mutations) for 10.4 months when they received erlotinib treatment, compared with 5.4 months for those who received standard therapy. [42]

The cobas EGFR Mutation Test v2 is available for the detection of EGFR T790M mutations to determine if osimertinib should be considered for treatment. [43]

In July 2013, afatinib was approved for first-line treatment of NSCLC in patients with metastatic NSCLC with tumors that have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by the diagnostic test, therascreen EGFR RGQ PCR Kit.

Testing for ALK rearrangements to determine potential benefit from crizotinib is recommended in all patients with advanced NSCLC adenocarcinoma using the Vysis ALK Break Apart FISH Probe Kit on formalin-fixed paraffin-embedded tissue specimens.

As of March 2016, there are no FDA-approved tests for detecting ROS-1 mutation. In clinical trials, the ROS-1 status of NSCLC tissue samples was determined by laboratory-developed break-apart FISH (96%) or RT-PCR (4%) clinical trial assays. For assessment by FISH, ROS-1 positivity required that ≥15% of a minimum of 50 evaluated nuclei contained a ROS-1 gene rearrangement. [44]

Regardless of current recommendations, any decision to test for genetic mutations should be individualized for each patient and should take into account considerations such as: (a) the time available before the management decision must be made and the potential delay in obtaining genetic test results; (b) third-party payment for the test; (c) the relative toxicities of alternative therapeutic options in this specific patient; and (d) the availability and quality of the clinical laboratory that will be performing the test.

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