1. Quick Summary
Tumours carry many genetic alterations, most of which do not drive the cancer. Identifying the ones that do is the core problem.
Where a clear driver exists and a drug targets it, matched therapy has produced substantial benefit. Those cases are a minority of patients.
Broad sequencing programmes have shown that finding an alteration is much easier than finding one that changes outcome.
2. What It Means
Driver alterations contribute to cancer growth; passenger alterations accumulate without contributing. Distinguishing them requires functional evidence, not only recurrence across patients.
Tumours are heterogeneous. Different regions of the same tumour, and different metastases, can carry different alterations, so a single biopsy may not represent the whole.
Resistance is expected. Targeted treatments select for cells that bypass the blocked pathway, so responses are often followed by progression.
Biomarkers vary in what they predict. Some indicate drug sensitivity, others prognosis, and a marker that correlates with outcome is not necessarily the target of treatment.
3. Why It Happens
Most alterations found by sequencing are not actionable. They are real but no approved drug targets them, or targeting them does not affect the tumour.
Access to matched drugs is often through trials, and eligibility depends on the patient’s condition, prior treatments and location.
Clonal architecture matters. An alteration present in only a subset of cells may produce a partial or brief response.
Tissue site matters less than expected in some cases and more in others. The same alteration can behave differently depending on the tissue context.
Response evaluation is imperfect. Tumour shrinkage is the usual measure, but it does not always translate into longer survival, which is the outcome patients care about.
4. Real Examples
A small number of alterations — in certain kinases and in some DNA repair pathways — have clear matched therapies with documented benefit.
Liquid biopsies detect tumour DNA in blood, useful for monitoring and for detecting resistance mechanisms, though sensitivity is limited when tumour fraction is low.
Tumour-agnostic approvals recognise that some alterations predict response regardless of where the tumour arose, which is a meaningful regulatory shift.
Combination approaches target a driver and the resistance pathway simultaneously, which is where much current work is concentrated.
5. How It Affects Us
Sequencing costs have fallen enough that testing is common, which raises questions about consent, incidental findings and how uncertain results are communicated.
Expectations matter clinically. A patient who has been told sequencing will find a treatment may face a result that changes nothing.
Trial design is shifting toward smaller, biomarker-defined groups, which requires far more patients screened than enrolled.
Data sharing determines how fast rare alterations are understood, since individual centres see too few cases to draw conclusions.
6. Key Takeaways
- Finding an alteration is easy; finding one that changes outcome is rare.
- Clear successes exist but apply to a minority of patients and tumours.
- Tumour heterogeneity and resistance limit how durable responses are.
- Sequencing is most valuable where an established matched therapy exists.