Genomic profiling

Every cancer is unique, and we’re starting to understand why

If you have been diagnosed with colorectal cancer, pancreatic cancer, or a hepatopancreatobiliary (HPB) cancer such as cholangiocarcinoma, it is completely reasonable to ask: “Is there anything specific about my cancer that should change my treatment?” Genomic profiling exists to answer that question.

Modern oncology is no longer just about where a cancer started, or to where in the body it may have spread. It is also about the biological features that drive it, and whether those characteristics can be targeted with specific drugs, guide immunotherapy, or open the door to a clinical trial.

For many people, chemotherapy remains the backbone of treatment. Genomic profiling does not replace that, but it can help us personalise the plan, avoid treatments that are unlikely to help, and identify opportunities that are easy to miss if you follow a one-size-fits-all pathway.

Cancers grow because their internal control systems go wrong. Genomic profiling looks for the specific faults that are keeping the cancer switched on. Some faults are useful because they predict response to a treatment. Others are useful because they predict that a treatment is unlikely to work. Many are useful because they can match you to a clinical trial.

Genomic profiling (also called molecular profiling, tumour sequencing, or next-generation sequencing) is testing that looks for the biological signals driving the growth of your cancer. These signals can include genetic changes within the tumour DNA, as well as other so-called biomarkers within tumour tissue itself or detected in tumour DNA present in the bloodstream.
Somatic mutation: a genetic change found in the tumour only.

Germline mutation: an inherited change present in every cell of the body.
Actionable result: a finding that can guide a treatment, either standard or in a trial.
Biomarker: any measurable feature that guides treatment.

A helpful way to frame it is that genomic profiling can answer three practical questions:

1. Is there a targeted treatment that fits this cancer?
2. Is immunotherapy likely to help?
3. Are there trial options that are worth pursuing now, or later if needed?

Basic genomic profiling is now part-and-parcel of routine cancer care. For example, in colorectal (bowel) cancer, knowing the status of a genes called RAS and BRAF can help tailor which drugs can be added to chemotherapy to boost effectiveness and which should be avoided.

Additional testing can determine if drugs usually used to treat breast cancer can also help in a patient with bowel cancer, or of immunotherapy could help even in the absence of the standard markers. In biliary tract cancer, identifying a target early can change what happens after first-line chemotherapy. In pancreatic cancer, germline findings can clarify treatment and family implications at the same time.

Genomic profiling is often spoken about as if it is one thing. In reality, there are three distinct categories of testing, and each has a different purpose.

Tumour tissue biopsy testing (NGS / comprehensive genomic profiling)
This is performed on tissue from a biopsy or an operation. Many patients already have suitable tissue stored from their diagnostic procedure. Tissue testing can detect a broad range of changes, including mutations, amplifications, and certain gene rearrangements. The laboratory can see the tumour structure and can run complementary tests (such as immunohistochemistry) alongside sequencing when needed.

Liquid biopsy (ctDNA blood testing)
Liquid biopsy is a blood test that looks for fragments of tumour DNA circulating in the bloodstream (ctDNA). It can be useful when tumour tissue is hard to obtain, when we want faster results, or when we want to capture the fact that different metastases may behave differently. A key limitation is that a negative liquid biopsy does not always mean nothing is there. Sometimes there is simply not enough ctDNA in the blood at that moment. That is why we interpret liquid biopsy carefully and sometimes combine it with tissue testing.

Germline testing (inherited risk)
This is different. Germline testing looks for inherited genetic changes that increase the risk of certain cancers and, importantly, can influence treatment choices. Germline testing can be relevant even when tumour sequencing is unremarkable.

Timing matters because the usefulness of a genomic report depends on what decisions are coming next. For many patients, the most valuable moment is at the diagnosis of advanced or recurrent disease, because the range of possible systemic treatments is widest at that point.

A second key moment is at progression on treatment. When a cancer changes pace or breaks through therapy, new testing can reveal resistance patterns or new options, and liquid biopsy can sometimes capture that evolution efficiently.

In earlier-stage disease, genomic profiling may still be relevant, but the questions are different. In colon cancer, mismatch repair testing is routinely important. In pancreatic cancer, germline testing may be considered regardless of stage because it can affect treatment planning and family risk. Some newer approaches, such as ctDNA-based monitoring after surgery, are emerging and may be used in research settings or selected centres, but they need careful interpretation and should not create anxiety if they are not part of your pathway.

A common fear is that testing will delay treatment. In most cases, it does not need to. We can often start standard treatment while results are pending, then adjust intelligently once the report is back.

The goal here is to give you a sense of what matters, without turning you into your own molecular pathologist.

MSI-high / dMMR / high TMB

What it means in plain English: The tumour has a faulty DNA repair system and makes many abnormal proteins

What it can change: Immunotherapy is much more likely to work

KRAS / NRAS (RAS status)

What it means in plain English: Growth signalling is permanently switched on through the RAS pathway

What it can change: EGFR-targeted drugs are unlikely to help if RAS is mutated

BRAF (including V600E)

What it means in plain English: Another growth-control gene; certain mutations behave more aggressively

What it can change: Can guide specific targeted combinations and trial strategies

HER2 amplification

What it means in plain English: The tumour is using HER2 signalling to drive growth

What it can change: May open HER2-targeted treatment options in advanced disease

NTRK fusion (rare)

What it means in plain English: A specific gene fusion driving the cancer

What it can change: Highly targetable when present

Other trial markers

What it means in plain English: A range of rarer findings

What it can change: Can support trial matching

It’s important to note many colorectal cancers do not have an obvious target that changes initial treatment. That does not mean genomic profiling was pointless. It still clarifies the nature of the cancer, helps avoid ineffective options, and often becomes more valuable later, particularly when trial access is being considered.

Pancreatic cancer is often described as having fewer actionable targets than some other cancers. That is true in a narrow sense, but it misses the real value of testing. In pancreas, the biggest gains often come from identifying DNA repair defects and from germline findings.

Germline BRCA1/2 and related DNA repair genes (including PALB2)

Why it matters: Some cancers are vulnerable to DNA-damaging treatments

What it can change: Can influence chemotherapy choices and targeted maintenance strategies in selected cases

MSI-high / dMMR (rare)

Why it matters: Immune signature predicts sensitivity

What it can change: Immunotherapy may become relevant

NTRK fusion (rare)

Why it matters: Targetable driver alteration

What it can change: Opens targeted options when present

Other markers such as KRAS mutation

Why it matters: Includes uncommon fusions and pathway changes

What it can change: Useful for trial matching, and may soon enable access to RAS inhibitor drugs

A key practical point is that pancreatic cancer also has a stronger inherited component than many people realise. That is why germline testing is often part of modern pancreatic cancer care, not just for the patient, but also for relatives who may benefit from risk assessment and surveillance.

HPB cancers are not one disease. The genomic makeup of cholangiocarcinoma is very different from hepatocellular carcinoma (HCC), and that matters for how useful profiling can be.

Cholangiocarcinoma and gallbladder cancer are often high-yield for genomic profiling. Certain alterations are sufficiently common and sufficiently targetable that sequencing can genuinely change the pathway for a meaningful minority of patients.

FGFR2 rearrangements (especially intrahepatic cholangiocarcinoma)

Why it matters: A targetable growth pathway

What it can change: May open FGFR-targeted therapy options

IDH1 mutation

Why it matters: Metabolic pathway alteration

What it can change: May open IDH-targeted options

HER2 amplification

Why it matters: Growth signalling pathway

What it can change: May open HER2-targeted options

BRAF V600E

Why it matters: Targetable signalling pathway

What it can change: May guide targeted combinations

NTRK fusion (rare)

Why it matters: Targetable fusion

What it can change: Highly actionable when present

MSI-high / dMMR (uncommon)

Why it matters: Immune signature

What it can change: Immunotherapy relevance

Hepatocellular carcinoma (HCC) is different. Genomic profiling can still be valuable, particularly for clinical trials and in selected cases where diagnosis is complex, but at present it more often informs research pathways than routine targeted drug choices.

One of the most common sources of anxiety is receiving a report full of unfamiliar terms and worrying that the meaning is hidden somewhere in the fine print. The truth is that many reports contain multiple findings, but only a small number are clinically meaningful.
When I interpret a genomic profile, I look at several layers:

• Is the result technically reliable?
• Is the finding truly actionable, or is it speculative?
• Does it change treatment now, later, or only in a trial context?
• How does it fit your overall situation: stage, pace of disease, prior treatment, symptoms, organ function, scan findings, other treatment options?

Two patients can have the same mutation and need different decisions based on their overall picture. The goal is not to chase every theoretical option, but to choose what is most likely to help, in the right order, with the least unnecessary treatment-related side-effects.

Genomic profiling is one tool in a wider strategy. It becomes most powerful when integrated into a complete plan.

• Chemotherapy remains the backbone for many patients, but genomic testing can help refine the pathway and identify what should come next.
• Targeted therapy depends on identifying the right biomarker. In biliary tract cancers in particular, this can be a major opportunity.
• Immunotherapy is highly effective in some biomarker-defined groups and much less effective in others. Profiling helps us avoid wishful thinking and focus on realistic options.
• Radiotherapy / SABR can be integrated with systemic therapy in oligometastatic disease or oligoprogression. Genomics can’t yet tell us if radiotherapy will be helpful, but it can guide drug choices while SABR controls limited areas of spread.
• Surgery remains critical in potentially curable disease and in selected metastatic scenarios. Genomics can support decisions around sequencing and trial options.

This integrated approach is also why multidisciplinary discussion matters. Genomic information is most valuable when interpreted within an MDT that can act on it quickly.

Genomic profiling is powerful, but it is not magic. It’s worth addressing a few key points:

• It does not usually tell you what caused the cancer – it can tell us what may be driving the cancer’s growth in the here-and-now, but in many people, having this knowledge doesn’t have a big impact on the outcome, or generate new option.
• It does not reliably predict whether standard chemotherapy will work, although it can strongly guide targeted therapy and immunotherapy decisions in certain contexts.
• If the report finds nothing actionable, that does not mean you have no options. It often means the most effective plan remains standard therapy or that trials may be the best option.
• Liquid biopsy is not always enough. It is a useful tool, but sometimes tumour tissue is required for full clarity.
• Genomics rarely delays treatment if organised properly. In many cases we can begin treatment and incorporate results as they arrive.