Table:
Genetic mutations present in pancreatic cancer
| Frequency (%)* | Role in tumorigenesis | Potential targeted approaches | Level of clinical evidence | |
|---|---|---|---|---|
| KRAS | 91% | Constitutive activation of RAS–MAPK pathway promoting proliferation | KRAS inhibitors, vaccines, bispecific antibodies, MEK inhibitors | Ongoing trials, encouraging early phase data in other cancer types |
| TP53 | 70% | Impaired recognition of DNA damage and cell cycle arrest | None currently available | NA |
| CDKN2A | 46% | Loss of regulation of the CDK4 and CDK6 growth checkpoint | CDK4 and CDK6 inhibitors | Ongoing trials |
| SMAD | 38% | Alteration in TGFβ signalling permitting increased proliferation | TGFβ inhibitors | Encouraging phase 2 data |
| ATM | 3% | Dysfunctional homologous recombination repair | ATR inhibitors, platin chemotherapy, PARP inhibitors† | Ongoing trials |
| BRAF | 2·2% | Constitutive activation of RAS–MAPK pathway promoting proliferation | BRAF inhibitors with or without MEK inhibitors | Case reports and series suggest efficacy |
| BRCA1 | 1·3% | Dysfunctional homologous recombination repair | Platin chemotherapy, PARP inhibitors† | Positive phase 3 data for PARP inhibitors in germline mutations |
| BRCA2 | 1·3% | Dysfunctional homologous recombination repair | Platin chemotherapy, PARP inhibitors† | Positive phase 3 data for PARP inhibitors in germline mutations |
| MSI family | 0·8% | Impaired mismatch repair | PD-1 blockade | FDA-approved |
| PALB2 | 0·7% | Dysfunctional homologous recombination repair | Platin chemotherapy, PARP inhibitors† | Ongoing trials |
| NRG1 fusion | 0·5% | Increased HER3 dimerisation with HER2 causing RAS–MAPK activation | EGFR inhibitors: afatinib or pertuzumab | Case reports and series suggest efficacy |
| NTRK fusion | 0·3% | Upregulation of TRK activity | TRK inhibitors: larotrectinib | FDA-approved |
| ALK amplification | 0·16% | Constitutive activation of RAS–MAPK pathway promoting proliferation | ALK inhibitors: crizotinib | Case reports and series suggest efficacy |
FDA=US Food and Drug Administration. PARP=poly (ADP-ribose) polymerase.
*
Percentage of pancreatic cancers with genomic aberrations.
†
PARP inhibitors include olaparib or veliparib.