Pancreatic Cancer
Pancreatic ductal adenocarcinoma has a well-described but largely undruggable core mutational landscape. The clinically consequential findings tend to sit in the minority of cases carrying DNA damage repair alterations, mismatch repair deficiency or rare fusions — which is precisely why comprehensive profiling is discussed.
Disease categories
Major disease categories
- Pancreatic ductal adenocarcinoma
- Pancreatic neuroendocrine tumours
- Acinar cell carcinoma
- Intraductal papillary mucinous neoplasms
Molecular
Molecular considerations
KRAS alterations are present in the large majority of pancreatic ductal adenocarcinomas, with TP53, CDKN2A and SMAD4 frequently co-occurring. The minority of cases with BRCA1, BRCA2 or PALB2 alterations, mismatch repair deficiency, or NTRK and other fusions are of particular interest.
Markers commonly discussed in pancreatic cancer
- KRAS (including G12C and other specific alterations)
- BRCA1/2
- PALB2
- MMR / MSI
- NTRK fusions
- CA 19-9
Not exhaustive, and not every marker is assessed in every patient. Which of these is relevant depends on the individual case and should be discussed with the treating team.
Testing
Genomic testing considerations
Comprehensive somatic profiling is frequently discussed in advanced disease, precisely because the actionable minority is difficult to identify otherwise.
Germline
Germline considerations
Germline testing is widely discussed in pancreatic cancer irrespective of family history, given the recognised frequency of DNA damage repair gene alterations and their implications for relatives.
Molecular monitoring
ctDNA and liquid biopsy considerations
ctDNA is studied for molecular monitoring, though shedding varies and a negative result requires careful interpretation.
Single-cell & computation
Single-cell and algorithmic approaches
In gastrointestinal and hepatobiliary disease, single-cell sequencing is used chiefly to characterise the tumour microenvironment and to resolve clonal structure in tumours that are heterogeneous between regions. Single-cell DNA analysis helps establish whether a RAS or driver alteration is clonal or subclonal, which bears directly on how much weight it should carry. Algorithm work here includes molecular residual disease detection from serial samples, mismatch repair classification from sequencing data, and pipelines that reconcile findings across multiple biopsy sites.
In practice
What a review of this disease typically surfaces
Reviews frequently find comprehensive profiling was never performed, on the reasoning that the yield in pancreatic cancer is low. That reasoning misses the point: the actionable findings sit in a minority of cases and cannot be identified without looking. Germline testing is the other consistent gap, despite the recognised frequency of DNA damage repair alterations in this disease and their implications for relatives.
Patterns observed across precision oncology case reviews. Every case differs; these are the questions worth checking, not conclusions about any individual patient.
Decisions
Treatment decision questions
Questions worth raising with a treating team when a decision is being made:
- Has comprehensive somatic profiling been performed?
- Has germline testing been discussed?
- Is the specific KRAS alteration recorded rather than only its presence?
Resistance
Resistance and recurrence questions
- Has the molecular profile changed on repeat sampling?
- Is there evidence of a specific resistance mechanism?
Trials
Clinical trial considerations
Trial questions frequently turn on specific KRAS alterations, DNA damage repair status and rare fusions.
When a precision oncology review may help
A review is most useful where the standard pathway has been exhausted or where the picture is more complicated than a protocol accounts for — rare presentations, treatment resistance, complex or apparently contradictory molecular findings, or a decision between several defensible options.
The output is a structured analysis and a set of questions for the treating team. It is not treatment, and it does not replace the treating oncologist.