Table 2.

Selected actionable genomic alterations and examples of possible targeted therapies in patients with CUP (N = 442)

Genomic alterationN (%)Example of possible targeted therapiesa
Tyrosine kinase families (N = 79, 17.9%)
EGFR substitutions/amplification26 (5.9%)Afatinib, cetuximab, erlotinib
ERBB2 substitutions/amplification/indel16 (3.6%)Afatinib, trastuzumab, lapatinib
FGFR1 amplification19 (4.3%)Lenvatinib
FGFR2 substitutions/amplification4 (0.9%)
FGFR3 substitutions3 (0.7%)
JAK2 substitutions1 (0.2%)Ruxolitinib
KIT substitutions/amplification5 (1.1%)Dasatinib, imatinib, sunitinib
MET amplification15 (3.4%)Cabozantinib, crizotinib
PDGFRA amplification4 (0.9%)Dasatinib, imatinib, sunitinib
RET fusion3 (0.7%)Cabozantinib, lenvatinib, vandetanib
MAPK signaling (N = 138, 31.2%)
HRAS substitution3 (0.7%)MEK inhibitor (e.g., trametinib or cobimetinib)
KRAS substitution/amplification82 (18.6%)
NRAS substitution8 (1.8%)
NF1 substitution16 (3.6%)
GNAS substitution10 (2.3%)
RAF1 substitution/amplification8 (1.8%)
MAP2K1 substitution2 (0.5%)
BRAF substitution/amplification33 (7.5%)BRAF inhibitor (e.g., dabrafenib, vemurafenib), MEK inhibitor (e.g., trametinib or cobimetinib)
PI3K signaling (N = 80, 18.1%)
PIK3CA substitution/amplification68 (15.4%)mTOR inhibitor (e.g., everolimus, temsirolimus)
PTEN substitution10 (2.3%)
AKT1 substitution2 (0.5%)
STK11 substitution4 (0.9%)
TSC1 substitution1 (0.2%)
Cell-cycle–associated genes (N = 46, 10.4%)
CDKN2A substitution8 (1.8%)Cyclin-dependent kinase inhibitor (e.g., Palbociclib)
CCND1 substitution/amplification3 (0.7%)
CCND2 substitution/amplification2 (0.5%)
CDK4 amplification5 (1.1%)
CDK6 amplification18 (4.1%)
CCNE1 amplification16 (3.6%)Proteasome inhibitor (e.g., bortezomib)
TP53-associated genes (N = 167, 37.8%)
TP53 substitution164 (37.1%)Anti-VEGF (e.g., bevacizumab), WEE1 inhibitor (e.g., AZ1775, NCT01748825)
ATM substitution4 (0.9%)PARP inhibitor (e.g., olaparib)
Mismatch repair gene alterations (N = 7, 1.6%)
MLH1 geneb7 (1.6%)Immunotherapy with checkpoint inhibitors (50)
  • aSee Supplementary Table S3 for the rationale for possible targeted therapies.

  • bMLH1 was the only mismatch repair gene tested in the ctDNA assay used.