Lung Cancer
Lung cancer is where molecular profiling most visibly changed clinical practice. In non-small cell lung cancer, a substantial proportion of cases carry an alteration in a recognised oncogenic driver, and identifying which driver is present is a routine part of the diagnostic pathway rather than an optional extra.
Disease categories
Major disease categories
- Non-small cell lung cancer — adenocarcinoma
- Non-small cell lung cancer — squamous cell carcinoma
- Small cell lung cancer
- Mesothelioma and other thoracic malignancies
- Neuroendocrine tumours of the lung
Molecular
Molecular considerations
Driver alterations assessed in non-small cell lung cancer include EGFR, ALK, ROS1, BRAF, KRAS, MET, RET, NTRK and HER2. These are largely mutually exclusive, which is one reason comprehensive profiling is preferred to sequential single-gene testing. PD-L1 expression is assessed alongside driver status.
Markers commonly discussed in lung cancer
- EGFR
- ALK
- ROS1
- BRAF V600E
- KRAS G12C
- MET exon 14
- RET
- NTRK
- HER2
- PD-L1
- TMB
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 profiling covering sequence variants, fusions and copy-number change is widely discussed, because several of the key alterations are fusions that sequence-only assays may miss.
Germline
Germline considerations
Germline assessment is less routine than in some other cancers but is considered where age, family history or specific findings suggest it.
Molecular monitoring
ctDNA and liquid biopsy considerations
ctDNA is well established in lung cancer, particularly where tissue is insufficient for full profiling and for detecting resistance alterations at progression. A negative plasma result does not exclude an alteration and generally prompts tissue testing where feasible.
Single-cell & computation
Single-cell and algorithmic approaches
Lung cancer is where single-cell work has been most directly informative about resistance. Single-cell RNA sequencing has shown that resistant states frequently exist as a minority population before treatment rather than arising afterwards, which changes how a baseline sample should be read. Single-cell DNA sequencing can establish whether a resistance alteration detected at progression was present subclonally at diagnosis. On the algorithmic side, the recurring engineering problem is fusion detection — several of the clinically decisive alterations in this disease are fusions, and pipelines built around sequence variants systematically under-call them. Work here spans RNA-based fusion callers, subclonal reconstruction across serial plasma samples, and classifiers that separate histological transformation from acquired target alteration.
In practice
What a review of this disease typically surfaces
The commonest problem is a molecular report generated by an assay that could not detect fusions, read as though it had excluded them. A report silent on ALK, ROS1 or RET from a sequence-variant panel is not a negative result. The second recurring finding is a driver alteration recorded by gene alone — 'EGFR mutation' — where the specific variant determines everything that follows. At progression, cases often arrive without any reassessment, where histological transformation would not be visible on a plasma assay at all.
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 profiling been performed, and does it cover fusions as well as sequence variants?
- Is PD-L1 recorded with the assay and scoring method used?
- If a driver alteration is present, is the specific variant recorded rather than only the gene?
- Was tissue adequate for the testing performed?
Resistance
Resistance and recurrence questions
- Has a resistance alteration been sought at progression?
- Is there evidence of histological transformation, which molecular testing alone would not show?
- Has ctDNA been considered where re-biopsy is difficult?
Trials
Clinical trial considerations
Lung cancer has one of the most alteration-specific trial landscapes in oncology; the precise variant and prior therapy both matter for eligibility.
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.