Table 2.
Selected actionable genomic alterations and examples of possible targeted therapies in patients with carcinoma of unknown primary (N = 442).
| Genomic alteration | No. % | Example of possible targeted therapies* |
|---|---|---|
| Tyrosine kinase families (N=79, 17.9%) | ||
| EGFR substitutions/amplification | 26 (5.9%) | Afatinib, cetuximab, erlotinib |
| ERBB2 substitutions/amplification/indel | 16 (3.6%) | Afatinib, trastuzumab, lapatinib |
| FGFR1 amplification | 19 (4.3%) | Lenvatinib |
| FGFR2 substitutions/amplification | 4 (0.9%) | |
| FGFR3 substitutions | 3 (0.7%) | |
| JAK2 substitutions | 1 (0.2%) | Ruxolitinib |
| KIT substitutions/amplification | 5 (1.1%) | Dasatinib, imatinib, sunitinib |
| MET amplification | 15 (3.4%) | Cabozantinib, crizotinib |
| PDGFRA amplification | 4 (0.9%) | Dasatinib, imatinib, sunitinib |
| RET fusion | 3 (0.7%) | Cabozantinib, lenvatinib, vandetanib |
| MAPK signaling (N=138, 31.2%) | ||
| HRAS substitution | 3 (0.7%) | MEK inhibitor (e.g. Trametinib or cobimetinib) |
| KRAS substitution/amplification | 82 (18.6%) | |
| NRAS substitution | 8 (1.8%) | |
| NF1 substitution | 16 (3.6%) | |
| GNAS substitution | 10 (2.3%) | |
| RAF1 substitution/amplification | 8 (1.8%) | |
| MAP2K1 substitution | 2 (0.5%) | |
| BRAF substitution/amplification | 33 (7.5%) | BRAF inhibitor (e.g. Dabrafenib, vemurafenib), MEK inhibitor (e.g. trametinib or cobimetinib) |
| PI3K signaling (N=80, 18.1%) | ||
| PIK3CA substitution/amplification | 68 (15.4%) | mTOR inhibitor (e.g. everolimus, temsirolimus) |
| PTEN substitution | 10 (2.3%) | |
| AKT1 substitution | 2 (0.5%) | |
| STK11 substitution | 4 (0.9%) | |
| TSC1 substitution | 1 (0.2%) | |
| Cell cycle associated genes (N=46, 10.4%) | ||
| CDKN2A substitution | 8 (1.8%) | Cyclin-dependent kinase inhibitor (e.g. Palbociclib) |
| CCND1 substitution/amplification | 3 (0.7%) | |
| CCND2 substitution/amplification | 2 (0.5%) | |
| CDK4 amplification | 5 (1.1%) | |
| CDK6 amplification | 18 (4.1%) | |
| CCNE1 amplification | 16 (3.6%) | Proteasome inhibitor (e.g. Bortezomib) |
| TP53 associated genes (N=167, 37.8%) | ||
| TP53 substitution | 164 (37.1%) | Anti-VEGF (e.g. bevacizumab), WEE1 inhibitor (e.g. AZ1775, NCT01748825) |
| ATM substitution | 4 (0.9%) | PARP inhibitor (e.g. olaparib) |
| Mismatch Repair Gene Alterations (N = 7, 1.6%) | ||
| MLH1 gene** | 7 (1.6%) | Immunotherapy with check point inhibitors (50) |
*
See Supplemental Table 3 for the rationale for possible targeted therapies.
**
MLH1 was the only mismatch repair gene tested in the ctDNA assay used.