Targeted therapy & molecular testing

Targeted therapy has changed the way we treat many Cancers. Unlike chemotherapy, which acts on rapidly dividing cells more broadly, targeted treatments are designed to interfere with a specific protein, pathway, receptor or genetic alteration helping the Cancer grow. They are not suitable for every Cancer, and they are not automatically “better” or free of side effects — the benefit depends on whether the relevant target is actually present.

This is why testing matters. Modern Cancer care is not simply about naming the organ where a Cancer started. In selected Cancers, understanding its biology can tell us which treatment is more likely to work, which treatments are unlikely to help, and sometimes gives important information about prognosis.

Why do we test a Cancer before choosing targeted treatment?

A biomarker is a measurable feature of the Cancer that can guide treatment. Depending on the Cancer and its stage, this may be tested by:

• Immunohistochemistry (IHC) — measures proteins such as ER, PR, HER2 or PD-L1.
• In-situ hybridisation (ISH/FISH) — looks for selected gene amplification or rearrangement, such as HER2.
• PCR or other focused molecular tests — useful when a specific alteration is being looked for.
• Next-generation sequencing (NGS) — can test many genes at once, especially useful when several actionable alterations are possible.
• Liquid biopsy (circulating tumour DNA) — a blood-based option in selected advanced Cancers, particularly when tissue is limited or when looking for resistance mutations.

Not every patient needs a large genomic panel. Sometimes a small number of well-chosen tests gives all the information needed. In other situations — especially advanced non-small-cell lung Cancer — broad molecular testing can be critical before treatment is selected.

Commonly used biomarker tests, and how they can change treatment

This is an overview, not a complete testing list. The tests that matter depend on the exact diagnosis, stage, previous treatment, tissue available and the treatment options being considered.

Breast Cancer: a clear example of how biology changed prognosis

Breast Cancer is not one disease. ER/PR and HER2 testing are fundamental because they divide breast Cancer into biologically different groups with very different treatment pathways. HER2-positive breast Cancer was historically considered an aggressive subtype; the development of HER2-directed therapy has markedly improved outcomes in both early and metastatic disease. In early-stage disease, anti-HER2 treatment has substantially reduced recurrence and death when combined with modern multidisciplinary treatment. In hormone-receptor-positive advanced breast Cancer, PIK3CA and ESR1 alterations can influence endocrine-targeted choices after progression, while germline BRCA1/2 testing can identify patients who may benefit from PARP inhibitors and also has implications for inherited Cancer risk. HER2 reporting has also become more nuanced: lower levels of HER2 expression can now influence eligibility for antibody-drug conjugates in selected metastatic settings, so accurate HER2 scoring remains important even when a tumour is not classically HER2-positive. The important message is that “targeted therapy” in breast Cancer begins with basic pathology (ER, PR and HER2) and then becomes more detailed only when the clinical situation requires it.

Lung Cancer: why molecular testing should come before treatment selection

Advanced non-small-cell lung Cancer is one of the strongest examples of precision oncology. Current ASCO guidance recommends access to broad multigene testing, using tissue and/or blood, together with validated IHC testing including PD-L1. This testing can completely change the first treatment: instead of starting with standard chemotherapy or immunotherapy, a patient whose Cancer has a targetable driver may receive a matched targeted drug, which can achieve rapid tumour shrinkage, prolonged disease control and, for several molecular subgroups, survival measured in years. They can also have important activity in the brain, which matters because lung Cancer frequently spreads there.

PD-L1 and driver-mutation testing answer different questions. A high PD-L1 result does not replace molecular testing — for example, EGFR-mutant disease follows a driver-directed treatment pathway even if PD-L1 is high.

MSI / mismatch-repair deficiency: when a DNA-repair defect predicts immunotherapy benefit

Some Cancers lose the ability to repair small DNA-copying errors, called mismatch-repair deficiency (dMMR), which often leads to microsatellite instability-high (MSI-H) status. This is seen most commonly in colorectal and endometrial Cancer, but can occur in many solid tumours. dMMR/MSI-H tumours accumulate many abnormal genetic changes, making them more recognisable to the immune system — which can make immune-checkpoint inhibitors particularly effective. In some Cancers, MSI/dMMR also has hereditary implications, particularly through Lynch syndrome, so the result may lead to additional genetic evaluation when appropriate. MSI-H/dMMR became one of the first biomarkers to support treatment based on the molecular feature of the tumour rather than only on the organ where the Cancer started, a major shift in oncology.

Haemato-oncological malignancies: precision treatment has been transformative

Some of the most dramatic successes of targeted therapy came from blood Cancers. In chronic myeloid leukaemia, identifying the BCR::ABL1 fusion led to tyrosine-kinase inhibitors such as imatinib and newer agents — a disease that once commonly progressed despite therapy can now, for most patients diagnosed in chronic phase, be controlled long term with survival approaching that of the general population; modern series report 10-year overall survival above 90%. In acute promyelocytic leukaemia, the PML::RARA fusion is both diagnostic and a therapeutic target; ATRA and arsenic trioxide transformed APL into one of the most curable acute leukaemias, with cure rates above 90% in many contemporary standard-risk settings when treatment is started promptly and complications are managed well. Molecular findings such as FLT3 or IDH mutations in AML, BCR::ABL1 in Philadelphia-positive ALL, and BTK/BCL2 pathway dependence in CLL can now guide therapy. These advances have reduced reliance on non-selective chemotherapy for many patients and created highly effective oral or targeted treatment pathways.

What targeted therapy can, and cannot, do

• A target must be present, and it must be clinically actionable — finding a mutation does not automatically mean there is an effective approved drug for it.
• Targeted therapies have their own side effects, which vary by drug and may include rash, diarrhoea, blood-pressure changes, liver abnormalities, cardiac effects or lung inflammation.
• Resistance can develop — Cancer cells may acquire new mutations, which is why repeat biopsy or liquid biopsy can sometimes be useful when disease progresses.
• Targeted therapy is sometimes used alone and sometimes combined with chemotherapy, endocrine therapy, immunotherapy or another targeted drug, only where supported by evidence for that Cancer.

My approach: test with a purpose

I do not see molecular testing as a checklist, or as a reason to order the largest possible panel for every patient. I use it when the result can answer a clinically useful question: will it change the treatment I recommend now, can it help us avoid a treatment unlikely to work, does it provide information about prognosis, could it identify an inherited Cancer risk that matters to the family, or — if the Cancer has progressed — can repeat testing reveal a resistance mechanism or a new treatment option? The goal is not more testing. The goal is the right testing, at the right time, for the right reason, and then translating the result into a treatment plan that fits the whole person in front of me.

This page is for patient education and does not replace an individual oncology consultation. Biomarker testing and treatment recommendations vary with diagnosis, stage, prior therapy, tissue availability, regulatory approval and patient-specific factors. Medically reviewed by Dr Sneha Kommineni.