Is BRAF testing recommended as routine biomarker testing in non-small cell lung cancer?
Yes. The American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) recommend BRAF testing in all patients with advanced lung adenocarcinoma, irrespective of clinical characteristics.
What is the role of cell-free DNA testing in non-small cell lung cancer?
Although cell-free/circulating tumor DNA testing has generally high
specificity, it has low sensitivity (with a false-negative rate of up to
30%) and should not be used in place of tissue-based testing, if tissue
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.
Which emerging biomarkers are on the horizon for non-small cell lung cancer?
RET gene rearrangements, ERBB2 mutations, high-level MET amplifications or MET
exon 14 skipping mutations, and tumor mutational burden (TMB) are
emerging predictive biomarkers. Currently, evaluating these biomarkers
is not considered part of routine care. However, broad molecular
profiling to identify rare targets (such as these) for which effective
drugs may be available is strongly advised, and in that context,
including these biomarkers is appropriate and encouraged.
Testing for NTRK gene fusions can be considered to detect rare driver alterations to determine the potential for effective therapy; NTRK
gene fusions can be detected by fluorescence in situ hybridization
(FISH), immunohistochemistry (IHC), next generation sequencing (NGS),
and polymerase chain reaction (PCR) assays.
Epidermal growth factor receptor (EGFR) mutations occur in approximately 10% of NSCLC adenocarcinomas in the U.S. and are observed more frequently in nonsmokers.
The two most common EGFR
mutations, exon 19 deletions and exon 21 point mutations (L858R), account for approximately 90% of EGFR
-mutated NSCLC cases and are associated with responsiveness to EGFR TKI therapy.
However, there are many other less common EGFR
mutations that are also sensitizing, and patients should be tested for
these, as well. DNA mutational analysis is the preferred method for
status; IHC is not recommended.
ALK Gene Rearrangements
Anaplastic lymphoma kinase (ALK) gene rearrangements are present in roughly 5% of patients with NSCLC. The presence of an ALK gene rearrangement correlates with responsiveness to ALK TKIs.
The U.S. Food and Drug Administration (FDA)-approved IHC assay (D5F3 clone) is an adequate standalone test to detect ALK
alterations, although secondary confirmation is encouraged.
Fluorescence in situ hybridization (FISH) is also widely used for ALK
gene rearrangement detection.
Next generation sequencing (NGS) methodologies may detect ALK
rearrangements, if appropriately designed.
ROS1 Gene Rearrangements
ROS proto-oncogene 1 (ROS1) gene rearrangements are more common in patients who are negative for EGFR mutations, KRAS mutations, and ALK rearrangements.
The presence of a ROS1
gene rearrangement correlates with responsiveness to ROS1 TKIs. FISH is often used to detect ROS1
rearrangements, but may not detect the FIG
IHC testing is also available, but has lower specificity than other
methodologies. Therefore, positive IHC results should be confirmed
molecularly or cytogenetically.
NGS methodologies may detect ROS1
rearrangements, if appropriately designed.
BRAF mutations at amino acid position 600 (BRAF V600E) have been associated with responsiveness to combined therapy with oral inhibitors of BRAF and MEK.
The American Society of Clinical Oncology (ASCO) and NCCN recommend BRAF
testing in all patients with advanced lung adenocarcinoma, irrespective of clinical characteristics.
Testing methodologies include polymerase
chain reaction (PCR), NGS, and Sanger sequencing. IHC, although
available, is not a preferred approach.
The presence of a KRAS mutation, considered a prognostic
biomarker, suggests poor survival for patients with NSCLC and is
associated with reduced responsiveness to EGFR TKI therapy. EGFR, KRAS, ROS1, and ALK genetic alterations do not usually overlap. Therefore, the presence of a KRAS mutation suggests that patients may not benefit from further testing.
Targeted therapy is not currently available for patients with KRAS
mutations, though immune checkpoint inhibitors appear to be effective.
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 PD-L1 Testing
topic for the most up-to-date testing recommendations.