How tumour testing shapes treatment: a plain guide to cancer genetic testing

Not long ago cancer was treated “by organ”: a tumour in the lung got one regimen, a tumour in the bowel another. Today doctors also look into the tumour’s “passport”, the genetic faults that make its cells divide out of control.

For many modern drugs this test is a must: without a confirmed mutation the drug simply will not work.

Why the genetic test comes before the drug

Targeted therapy works like a key and a lock. The drug has a precise target, for example a mutated EGFR receptor or a fault in the BRCA1/2 genes. If the tumour does not have that target, taking the drug is pointless. Osimertinib, for instance, is prescribed only for EGFR mutations, and olaparib for BRCA1/2 faults.

Prescribing such drugs blind means losing time and money while the disease moves on. So the order is now reversed: first find the target, then choose the drug.

Where the sample comes from

Material for testing comes from two sources, and each has its own specifics.

Tumour tissue (the main option). A small piece of tissue taken at biopsy or during surgery. In the laboratory it is embedded in paraffin and stored as a block. If you already have such a block, no repeat biopsy is needed: it is enough to collect it and hand it over for testing.

Blood (liquid biopsy). As tumour cells die, they leave fragments of their DNA in the blood. All the test needs is a blood draw from a vein, with no surgery.

Important: the sample has to meet strict requirements. At least 20% of its cells must be tumour cells, and the tissue must be fixed correctly. When there is little tissue (for example, after a lung core biopsy), laboratories ask for each core to go into its own cassette so that no material is lost.

The four main testing methods and how they differ

“Mutation testing” is not one test but several different technologies. Which one to use depends on what the doctor is looking for.

• IHC (immunohistochemistry) shows whether a specific protein is present in the cells and how much of it (for example, PD-L1 before immunotherapy, or HER2, which decides whether lapatinib and tucatinib are an option).
• FISH finds gene rearrangements and amplifications. It is often used to settle unclear IHC results, for example to confirm an ALK rearrangement, the target of crizotinib, alectinib and lorlatinib.
• PCR quickly and cheaply checks one or two of the most common mutations (for example, EGFR, KRAS, BRAF). The result decides whether gefitinib and erlotinib fit an EGFR mutation, sotorasib a KRAS G12C mutation or vemurafenib BRAF V600E.
• NGS (next-generation sequencing) reads dozens or hundreds of genes in one run. It fits when there are many possible targets or the usual tests found nothing.

PCR takes a few days; a broad NGS panel takes one to three weeks.

What tissue-agnostic drugs are

One of the key discoveries of modern oncology is drugs aimed not at an organ but at the genetic fault itself, wherever it turns up: in the breast, lung or bowel.

Such indications are called tissue-agnostic. For example, larotrectinib and repotrectinib are prescribed for NTRK gene fusions, and selpercatinib for RET fusions, regardless of where the tumour grew.

According to studies, at least one such universal marker is found in about 21% of patients. For people with rare tumours this is often the only chance of treatment that works.

Liquid biopsy: convenient, with an important caveat

A blood test is convenient: no anaesthesia is needed, and it can be repeated to follow how things change. But it has one important feature:

• If a mutation is found in the blood, the result can be trusted and treatment is started on it.
• If no mutation is found, that does not mean there is none.

Some tumours, especially in the brain or abdomen, release too little DNA into the blood. If its share in the plasma is below 1%, a negative result tells you nothing. In that case the doctor will send the tissue block for testing.

Tumour testing versus test-tube assays: fact and marketing

These two approaches are easy to confuse, and the difference between them is fundamental.

• Molecular profiling (genetic testing) is an international standard with proven benefit: it shows whether the tumour has targets for targeted drugs.
• Chemosensitivity assays (“growing cells in a test tube”): the patient’s cells are treated with different chemotherapy drugs in the lab to see what works. ASCO (the American Society of Clinical Oncology) does not recommend using these tests to choose treatment outside research: their benefit has not been proven.

The idea has a promising continuation in organoids, three-dimensional mini-copies of the tumour. But for now they are only being studied in clinical trials and are not used in routine practice.

What to discuss with your oncologist

To leave the appointment with a clear plan, ask your doctor:

• Are there genetic targets in my diagnosis for which drugs already exist?
• Is the existing paraffin block enough, or will a new tissue sample be needed?
• Which test is better in my case: a targeted one (PCR/IHC) or a broad panel (NGS)?
• How long will testing take, and how will that affect the start of treatment?
• If the blood test is negative, will we re-check the result on tissue?
• Are there free testing programmes from drug manufacturers for my diagnosis?