Foundation One CDx Testing for Pancreatic Cancer
Yes, Foundation One CDx (FoundationOne CDx) comprehensive genomic profiling is indicated for patients with malignant neoplasm of the pancreas to identify actionable mutations that can guide targeted therapy selection and improve treatment outcomes.
Rationale for Comprehensive Genomic Profiling
Universal genetic testing is warranted for all pancreatic cancer patients because typical clinical factors like age of onset and family history are poorly predictive for identifying mutation carriers, and detecting germline mutations can aid in treatment decision-making, particularly regarding systemic therapy options 1. The considerable rate of predisposing mutations in pancreatic cancer patients—with germline mutations commonly including BRCA1, BRCA2, CDKN2A, mismatch repair genes (MSH2, MLH1, MSH6, PMS2, EPCAM), ATM, PALB2, STK11, and TP53—makes comprehensive testing essential 1.
Critical Added Value of Tumor Molecular Profiling
Tumor molecular profiling after germline testing increases the detection of actionable alterations by 5-fold, from 7% to 35% of patients 2. While germline testing alone identifies therapeutic targets in a small subset of patients, adding comprehensive tumor profiling like FoundationOne CDx identifies additional actionable alterations in patients who had negative germline testing and reveals new therapeutic targets even in those with positive germline results 2.
- Most actionable alterations (60%) involve genes associated with the Homologous Recombination DNA Damage Repair pathway, which can guide use of platinum-based chemotherapy and PARP inhibitors 2
- Tumor molecular profiling is a necessary complement to germline genetic testing to fully inform therapeutic decision-making for all pancreatic cancer patients 2
Molecular Landscape Supporting Comprehensive Testing
Pancreatic cancers harbor multiple genetic mutations that can be therapeutically targeted 1:
- KRAS mutations occur in >90% of pancreatic cancers 1
- TP53 mutations are present in approximately 76% of cases 3
- SMAD4 mutations occur in 18% and are associated with widespread metastasis and poor prognosis 4
- CDKN2A/p16 inactivation is common and associated with familial pancreatic cancer risk 1
- DNA repair gene mutations (hMLH1, MSH2) affect treatment response 1
Clinical Implementation
Testing should be performed near the time of diagnosis because mortality rates for pancreatic cancer are high, and the option to test the patient may not be available for long 1. This timing allows:
- Identification of germline mutations that can guide family member testing and surveillance 1
- Detection of somatic alterations that may respond to targeted therapies 2
- Assessment of tumor mutational burden and microsatellite instability status 3
Real-World Evidence
A Japanese single-institution study using FoundationOne CDx on 17 surgically resected PDAC patients found that all patients had at least one pathogenic or likely pathogenic variant 3. Notably, one patient with BRCA2-mutant disease was successfully treated with platinum-based neoadjuvant chemotherapy leading to conversion surgery, demonstrating the clinical utility of identifying actionable mutations 3.
Important Caveats
While FoundationOne CDx identifies genetic alterations in nearly all pancreatic cancer patients, not all identified mutations will have FDA-approved matched targeted therapies available 3. However, this should not deter testing because:
- Identified mutations may qualify patients for clinical trials
- Homologous recombination deficiency mutations guide platinum and PARP inhibitor use 2
- Mismatch repair deficiency identifies patients who may benefit from immunotherapy
- The therapeutic landscape is rapidly evolving with new targeted agents
The test should be ordered on tumor tissue (preferably from surgical resection or biopsy) in addition to germline testing, as the combination provides the most comprehensive assessment of actionable alterations 2.