Cancer Dictionary · Thoracic

Non-Small Cell Lung Cancer

Non-small cell lung cancer is separated first by histology, then in advanced disease by driver alteration. A single actionable driver can point to an entirely different class of first treatment, and several of these drivers are common enough that broad profiling before first-line therapy is routinely discussed rather than reserved for later lines.

Also called NSCLC, Lung adenocarcinoma, Lung squamous cell carcinoma.

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The governing idea

Advanced non-squamous lung cancer is the setting where a molecular result most often changes the first treatment given, which is why the timing of testing matters as much as the testing itself.

01Before any molecular question

How it usually presents

Usually established before molecular questions arise: the histological subtype (adenocarcinoma, squamous cell carcinoma or another), the stage, and whether the disease is localised, locally advanced or metastatic. Molecular profiling answers a different question from staging, and does not replace it.

Usually already established

Histological subtype from a pathology report
Stage, from imaging and any nodal sampling
PD-L1 expression, in most advanced-disease pathways
Whether tissue remains from the diagnostic biopsy

Major disease categories

The divisions below are not labels. Each one changes what the treatment discussion is actually about.

Early stage, resectable

Surgery is usually the organising decision. Molecular and immune markers are increasingly discussed around treatment given before or after surgery.

Locally advanced, unresectable

Combined chemoradiation and consolidation strategies dominate the discussion, and driver status is still relevant to what comes next.

Advanced or metastatic, non-squamous

The setting where comprehensive profiling most often changes first-line treatment. Several distinct drivers are each individually uncommon but collectively frequent.

Advanced or metastatic, squamous

Driver alterations are less common than in adenocarcinoma but are not absent, particularly in never-smokers or mixed histology.

03What is discussed

Molecular considerations

The alterations most discussed in advanced non-squamous disease include EGFR mutations, ALK and ROS1 rearrangements, BRAF V600E, MET exon 14 skipping and MET amplification, RET fusions, NTRK fusions, KRAS mutations including G12C, ERBB2 (HER2) mutations and NRG1 fusions. PD-L1 expression is assessed separately by immunohistochemistry and is not a genomic finding. Because several of these are structural rearrangements rather than point mutations, a panel that reads only single nucleotide variants can miss them, which is why panel scope is worth asking about explicitly.

Biomarkers commonly discussed

EGFR

Mutations in the kinase domain define one of the largest targetable groups in lung cancer.

ALK

A rearrangement, not a point mutation. Needs a panel that reads fusions.

ROS1

Another fusion driver, uncommon but with a well-established targeted class.

KRAS

The most frequent driver in lung adenocarcinoma. G12C is the specific variant with dedicated agents.

BRAF

V600E is the variant with the most established targeted evidence.

MET

Two separate questions: exon 14 skipping, and amplification. They are not the same finding.

RET

A fusion driver with dedicated selective agents.

NTRK

Rare, but actionable across many cancer types rather than lung specifically.

ERBB2 (HER2)

Mutation rather than amplification is the finding most discussed in lung.

PD-L1

An immunohistochemistry score, not a gene test. Assessed alongside, not instead of, profiling.

TMB

Tumour mutational burden, discussed in the immunotherapy conversation.

This is not an exhaustive list, and which markers are relevant depends on the individual case. Not every marker listed is assessed in every patient.

04What is tested, and from what

Testing, inherited risk and blood-based monitoring

Genomic testing considerations

The practical question is usually not whether to profile but whether the result will arrive before the first treatment decision has to be made. Tissue from the diagnostic biopsy is the conventional source, but lung biopsies are often small, and tissue exhaustion is a common reason profiling fails. Plasma-based testing is widely used in advanced disease, either alongside tissue or when tissue is insufficient. A negative plasma result in a patient with low tumour DNA shedding does not exclude a driver, and tissue confirmation is the usual next step in that situation.

Germline considerations

Most lung cancer is somatic rather than inherited. Germline questions arise less often than in breast, ovarian or colorectal disease, but a strong family history or an unusual presentation can still prompt the discussion, and some findings on a tumour panel raise a germline question incidentally.

Cancer genetics and hereditary risk

ctDNA and liquid biopsy considerations

Plasma ctDNA is well established in advanced lung cancer for identifying drivers when tissue is limited, and is used at progression to look for acquired resistance alterations. Shedding varies with disease burden and site, so a “not detected” plasma result is read in the context of how much tumour DNA was likely to be present at all.

When molecular information matters

Testing that arrives after the decision it was meant to inform has already been made is a common and avoidable problem. This is the sequence in which molecular information tends to become relevant.

At diagnosis, early stageHistology and stage lead. Molecular and PD-L1 status inform what is given around surgery.
Before first-line treatment in advanced diseaseThis is the highest-value moment for comprehensive profiling. A driver found here can change the first treatment given rather than the second.
If tissue is insufficientPlasma testing is commonly used in parallel rather than sequentially, to avoid losing weeks.
At progression on a targeted agentRepeat profiling is discussed to look for an acquired resistance mechanism, which can be a second mutation in the same gene or a bypass pathway.
At progression on immunotherapy or chemotherapyReassessment is discussed if the original profiling was narrow or is now several lines old.

06Take these to your team

Questions worth raising

When a decision is being made

Questions worth raising with a treating team.

Has comprehensive profiling been ordered, and will the result be available before first-line treatment starts?
Does the panel used read fusions and copy number, or only single nucleotide variants and small insertions and deletions?
If tissue was insufficient, has plasma testing been done in parallel rather than after a failed tissue attempt?
Has PD-L1 been assessed separately from the genomic panel?
If a driver was found, is the specific variant one with established targeted evidence, or a variant of uncertain significance in an actionable gene?

At progression, recurrence or resistance

The molecular picture at diagnosis is not always the molecular picture later.

Has the tumour been re-profiled since progression, rather than acting on the original result?
Is the resistance mechanism a second-site mutation, an amplification, a bypass pathway, or a histological transformation?
Would a repeat tissue biopsy add information that plasma cannot, particularly where transformation is suspected?

07What shapes eligibility

Clinical trial considerations

Lung cancer has one of the densest trial landscapes in oncology, and eligibility is usually written in molecular terms: a specific driver, a specific resistance mutation, a specific prior therapy. Both the alteration and the exact sequence of previous treatments shape eligibility, so an accurate treatment history matters as much as the genomic result.

Ask about trial matching

Plain-language glossary for this entry (5 terms)

Term	What it means
Driver alteration	A genetic change that the cancer depends on to grow, and therefore a potential point of attack.
Fusion	Two genes joined abnormally, producing a hybrid protein. Detected differently from a point mutation.
Exon 14 skipping	A splicing change that leaves out part of the MET gene, producing a protein that is not switched off properly.
Tissue exhaustion	When a biopsy sample is used up by earlier tests, leaving too little for genomic profiling.
Histological transformation	When a cancer changes its cell type under treatment pressure, for example from adenocarcinoma to small cell.

Where OnKommon fits

These are the services most often relevant to this cancer. Which of them applies is a clinical question, not an automatic one.

Signature STb O+The 523-gene comprehensive panel, with TMB and MSI.See how it works Signature STt OProfiling from an existing FFPE tissue block.See how it works SentinelSerial monitoring during active treatment.See how it works DecipherReinterprets sequencing already done elsewhere, without repeating it.See how it works

This entry is educational. It describes what is commonly discussed in this cancer, not what should happen for any individual. Which of it applies depends on the specific diagnosis, stage, prior treatment and the person themselves. Nothing here is a recommendation, and no list of biomarkers here is exhaustive. Decisions belong with a treating team who know the whole case.

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