Table 3.
Molecular landscape of non-small cell lung carcinoma (NSCLC) with the available treatment options, on the basis of [68].
| Gene | Type of Genomic Aberrations | Frequency [%] | Currently Available Targeted Therapy * | Diagnostic Approaches | Ref. |
|---|---|---|---|---|---|
| Adenocarcinomas (ADC) | |||||
| EGFR | EGFR-TKI sensitizing mutations: EGFR exon 21, EGFR exon 19, G719X, L861Q point mutations Copy number variations (gains) |
30–40 | pemetrexed or bevacizumab therapy, afatinib, erlotinib, gefitinib, dacomitinib, osimertinib | PCR: sanger, real-time PCR, ddPCR, and NGS; IHC | [67,72,73,74,75,76,77] |
| KRAS | G12C mutation in KRAS gene | 20–30 | AMG-510 | PCR, DNA sequencing | [67,72,73,74,77] |
| MET | MET exon 14 mutation (MET ex14), skipping mutations, overexpression, amplifications | 2–5 3–4 |
skipping mutations—crizotinib, tepotinib; amplifications—crizotinib, capmatinib | mutations: sanger sequencing, NGS; amplifications: FISH, PCR, real-time PCR, NGS |
[67,72,73,74,76,78] |
| ALK | ALK fusions | 3–7 | crizotinib, alectinib, ceritinib, brigatinib, lorlatinib | FISH (the gold standard); ALK-IHC has become a widely used technique with two validated antibodies in lung cancer (D5F3, 5A4) | [67,72,73,74,76,77,79] |
| BRAF | V600E mutation in BRAF gene; can co-exist with KRAS mutation | 0.5–5 | trametinib, dabrafenib | PCR: sanger, real-time PCR, and NGS | [67,72,73,74,76,78] |
| ROS1 | ROS fusions | 2–3 | crizotinib | ROS1-IHC (screening) is still evolving (the use of the D4D6 rabbit monoclonal antibody) **; FISH; NGS | [67,72,73,74,76,77,80] |
| RET | RET rearrangements, gene fusion of KIF5B-RET; point mutations | 1–2 | vandetanib, cabozantinib, alectinib, BLU-667, LOXO-292 | RT-PCR is typically combined with FISH; FISH; NGS | [67,72,73,74,76,78] |
| NTRK | NTRK rearrangements, gene fusions of NTRK1 (NTRKA), NTRK2 (NTRKB), NTRK3 (NTRKC) | 1–2 | entrectinib, larotrectinib, LOXO-195, repotrectinib | NGS with a panel that includes testing for NTRK1, NTRK2, NTRK3; IHC with subsequent confirmation by FISH or NGS | [67,72,73,74,76,78] |
| HER2 *** | mutations in the kinase domain (exon 20), the most frequent is p.A775_G776insYVMA insertion amplifications, overexpressions |
1–5 2–5 |
afatinib, dacomitinib, neratinib, trastuzumab, trastuzumab-emtansine, DS-8201a, poziotinib | mutations: PCR: sanger, real-time PCR and NGS; amplifications: FISH, NGS, real-time PCR |
[72,74,76,78,81] |
|
PTEN
PDGFRA PIK3CA TP53 ERBB2 TERT CDKN2A |
mutations copy number variations—gains losses |
1.7 6–7 5 52 2–5 75 7 |
NA NA NA NA NA NA NA |
- **** | [59,67,68] |
| Squamous cell carcinoma (SCC) | |||||
|
FGFR
TP53 NF1 DDR2 PDGFRA PIK3CA PTEN SOX2 CDKN2A |
gene fusion of FGFR3-TACC3, mutations of FGFR1, FGFR2 tumor suppressor mutations, copy number variations (gains) mutations of NF1 point mutations of DDR2 amplification amplification tumor suppressor mutations, copy number variations (losses) amplification and copy number variation (gain) copy number variation (loss) |
23 79 10 2–3 4 15 10 8 65 15 |
NA NA NA NA NA NA NA NA NA |
[59,67,68] | |
* platinum-based chemotherapy (+/- pembrolizumab) is still the treatment of choice for patients without targetable mutations [82]; ** screening with ROS1-IHC and subsequent confirmation of IHC-positive cases with the use of FISH; ROS1-inhibitors should only be given to patients whose tumors are double positive according to IHC and FISH; *** HER2 may be present in SCC but outside the kinase domain, with certain clinical benefit data when treating with afatinib; **** NGS can potentially test for all molecular alterations; NA—not available.