FoundationOneCDx Testing in Pancreatic Cancer
Yes, FoundationOneCDx (320 genes) is indicated for patients with malignant neoplasm of the pancreas, as universal genetic testing is warranted given the considerable rate of predisposing mutations (approximately 10% hereditary component) and the potential to guide treatment decisions, particularly regarding systemic therapy options. 1
Rationale for Comprehensive Genomic Profiling
High Prevalence of Actionable Mutations
- Pancreatic ductal adenocarcinoma harbors multiple genetic mutations that are commonly found, including KRAS (>90% of cases), TP53, p16/CDKN2A, and SMAD4 inactivation 1
- Germline mutations commonly found in pancreatic adenocarcinoma include BRCA1, BRCA2, CDKN2A, mismatch repair genes (MSH2, MLH1, MSH6, PMS2, EPCAM), ATM, PALB2, STK11, and TP53 1
- BRCA2 and CDKN2A are the most prevalent germline mutations, with rates in moderate- to high-risk families ranging from 2% to 6% for BRCA2 and 1.5% to 2.5% for CDKN2A 1
Clinical Utility Despite Current Limitations
- Universal genetic testing for patients with pancreatic cancer is warranted because typical clinical factors (young age of onset, family history) are poorly predictive for identifying mutation carriers 1
- Detecting a germline mutation can potentially aid in treatment decision-making, particularly regarding systemic therapy options such as platinum-based chemotherapy for BRCA2-mutant disease 2
- Real-world data from Japanese PDAC patients showed that 94% had KRAS mutations, 76% had TP53 mutations, 18% had SMAD4 mutations, and 6% had CDKN2A mutations, with all patients having at least one pathogenic or likely pathogenic variant 2
Important Caveats and Considerations
Current Therapeutic Landscape
- While FoundationOneCDx identifies multiple genetic alterations, current data suggests that matched targeted therapies with clinical benefit may be limited in unselected PDAC patients 2
- However, specific mutations like BRCA2 can guide the use of platinum-based chemotherapy, which has demonstrated clinical benefit including successful conversion surgery in previously unresectable cases 2
Timing of Testing
- Given that mortality rates for pancreatic cancer are high, it may be beneficial to test patients near the time of diagnosis, as the option to test the patient may not be available for very long 1
- Early identification of actionable mutations allows for timely treatment planning and potential enrollment in clinical trials targeting specific genetic alterations 1
Emerging Therapeutic Targets
- Recent genetic mutations discovered through whole-genome sequencing, including chromosomal rearrangements affecting KDM6A and PREX2, could become targetable in the near future 1
- Gene therapy approaches targeting TP53 restoration and KRAS silencing are under investigation and may benefit from comprehensive genomic profiling 3
Practical Implementation
- Order FoundationOneCDx testing on tumor tissue obtained via surgical resection, EUS-FNA, or biopsy 2
- The test will assess tumor mutational burden (TMB) and microsatellite instability (MSI) status in addition to the 320-gene panel 2
- Results should be reviewed in a multidisciplinary tumor board to determine if any identified mutations have matched targeted therapies or clinical trial eligibility 2