TABLE 1.
Predictive Genetic Biomarkers in Lung Cancer
| Molecular Alterationsa | Recommended Method of Detection | Role of IHC as a Surrogate Predictive Biomarker |
|---|---|---|
| EGFR mutations (“hot spot” mutations with ≥1% prevalence) | Any molecular method with ability to detect mutations in histology or cytology samples with ≥20% tumor cells within a turnaround time of 10 working days | Not appropriate for treatment selection |
| ALK rearrangements | Cytogenetic (FISH) or IHCb | Appropriate for treatment selection |
| ROS1 rearrangements | Molecular (RT-PCR or sequencing) or cytogenetic (FISH/ISH) | Appropriate for initial screening |
| BRAF (p.V600E and non-p.V600E mutations) | Molecular (sequencing with evaluation of at least exons 11 and 15) | Not defined as yet |
| MET alterations (exon 14 skipping mutations, amplification) | Molecular (RNA-based assay confirmatory); FISH is widely used for amplification but no specific cut-off validated | Not defined as yet |
| RET rearrangements | Molecular (sequencing preferable to targeted RT-PCR) or cytogenetic (FISH) | Not defined as yet |
| ERBB2/HER2 mutations | Molecular (sequencing, particularly for exon 20 alterations) | No role for IHCc |
| KRAS mutationsd | Molecular (targeted analysis of hot spots in codons 12, 13, 61, and 146) | No role for IHC |
Modified from Lindeman et al.2Abbreviations: ALK, anaplastic lymphoma kinase; BRAF, V-raf murine sarcoma homolog b; EGFR, epidermal growth factor receptor; ERBB2/HER2, human epidermal growth factor receptor 2 gene; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; ISH, in situ hybridization; KRAS, Kirsten rat sarcoma viral oncogene homolog; MET, mesenchymal epithelial transition receptor tyrosine kinase; NGS, next-generation sequencing; RET, rearranged during transfection; ROS1, ROS-associated oncogene 1; RT-PCR, reverse transcription–polymerase chain reaction.
EGFR, ALK and ROS1 alterations must be tested in all patients with advanced NSCLC for receiving approved targeted therapy; BRAF, MET, RET, HER2, and KRAS alterations should be tested only in extended gene panels for inclusion of patients who are wild-type for EGFR, ALK and ROS1 in clinical trials.
IHC has been found to be predictive of tumor response to crizotinib even in FISH-negative cases.
Protein expression by IHC is not predictive of therapy response.
KRAS testing may be performed as a single gene assay and if positive, may serve to exclude the patients from extended panel gene testing. Targeted therapeutic regimens for KRAS mutations have not shown clinical benefit.