Non-Small Cell Lung Cancer Molecular Markers

Last Literature Review: March 2024 Last Update:

Lung cancer is the leading cause of cancer-related mortality in the United States. Diagnosis typically involves a combination of imaging studies, cytologic and/or histopathologic specimen evaluation, and subsequent immunohistochemistry (IHC) and genetic analysis.  The majority of lung cancer cases are classified as non-small cell lung cancers (NSCLCs). Adenocarcinoma is the most common NSCLC subtype in nonsmokers.  Guidelines recommend molecular analysis to identify actionable targets and guide subsequent therapy selection.

Quick Answers for Clinicians

What is the role of cell-free DNA testing in non-small cell lung cancer?

Cell-free/circulating tumor DNA testing should not be used in place of tissue-based testing if tissue is available. , 

Cell-free/circulating tumor DNA testing is appropriate when invasive tissue sampling is not an option for a given patient or when the tissue sample is insufficient for molecular analysis. Negative cell-free/circulating tumor DNA testing results should be confirmed by tissue-based analysis whenever possible. , 

Indications for Testing

Individuals with advanced or metastatic disease should undergo:

Laboratory Testing

Predictive and Prognostic Biomarker Testing

Several oncogenic driver alterations, including alterations in EGFR, ALK, ROS1, BRAF, MET, KRAS, NTRK1/2/3, ERBB2, and RET genes, may inform treatment selection in lung cancer and are considered predictive biomarkers. KRAS oncogenic variants are also prognostic biomarkers, confer a poor prognosis, and predict a lack of benefit from EGFR tyrosine kinase inhibitor (TKI) therapy. 

Genetic testing to detect the following somatic alterations is recommended for adenocarcinoma, large cell carcinoma, and NSCLC not otherwise specified (NOS) and should be considered for squamous cell carcinoma in patients with advanced or metastatic disease :

  • EGFR mutations
  • BRAF mutations
  • KRAS G12C mutation
  • ALK rearrangements
  • ROS1 rearrangements
  • MET exon 14 skipping mutations
  • RET rearrangements
  • NTRK1/2/3 rearrangements
  • ERBB2 (HER2) mutations

The use of broad molecular profiling is strongly recommended.  Broad molecular profiling includes all the biomarkers listed here, preferably in conjunction with any emerging biomarkers (ie, high-level MET amplifications).  These variants may also be detected by a single assay or by a combination of assays. 

Testing for PD-L1 expression by IHC is recommended for all histologic subtypes to guide immunotherapy selection. 

PD-L1 Expression Testing

Testing for PD-L1 expression levels by IHC is recommended before first-line treatment in patients with metastatic NSCLC to assess whether PD-1 or PD-L1 inhibitors are a treatment option.  Refer to the ARUP Consult PD-L1 Testing topic for testing recommendations.

Therapy Resistance Testing

 In some cases, patients can develop resistance over the course of targeted therapy. Profiling at multiple points during treatment may be a useful approach to guide treatment. 

ARUP Laboratory Tests

Recommended (as Standard of Care) Biomarker Tests for Therapy Decisions
Other Individually Orderable Biomarker Tests (Including Biomarker Panels and Tests for Emerging Biomarkers)