Medical Oncologist
Non-Small-Cell Lung Cancer (NSCLC)
Accurate diagnosis · Staging · Molecular testing · Individualised treatment
Non-small-cell lung cancer (NSCLC) is not a single disease. It includes different histological types, most commonly adenocarcinoma and squamous cell carcinoma, which may have distinct biological and molecular characteristics.
The treatment strategy is initially determined by the stage of the disease—that is, how far and where it has spread—but this is no longer sufficient on its own. The histological diagnosis, the tumour’s molecular profile and biomarkers that may predict response to specific treatments all have a substantial bearing on the available options.
Management may therefore involve different combinations of surgery, radiotherapy, chemotherapy, immunotherapy and targeted therapies, according to the characteristics of the disease and the individual patient.
What needs to be known before treatment is selected?
The same diagnosis of ‘lung cancer’ may lead to very different treatment strategies. Before a major treatment decision is made, the tumour histology—as described in the pathology report from the biopsy—and the stage of the disease, meaning how extensive it is, must be known accurately. The results of adequate molecular testing and the necessary immunohistochemical biomarkers, such as PD-L1 and, depending on the treatment setting, HER2 and MET, are also required. Contemporary treatment of NSCLC is based on considering all these data together with the patient’s overall clinical condition, rather than on any single feature of the tumour.
Which type of non-small-cell lung cancer is it?
Non-small-cell lung cancer is not a single disease. It includes different histological types, most commonly adenocarcinoma and squamous cell carcinoma, as well as several less common forms. The distinction is made primarily through examination of the biopsy material by a pathologist.
Adenocarcinoma
The most common type of NSCLC. It may occur both in people who smoke and in those who have never smoked, and it often carries molecular alterations that can have a substantial influence on treatment.
Squamous Cell Carcinoma
It is more commonly associated with a history of smoking and has histological and molecular characteristics that differ from those of adenocarcinoma.
Other or Rarer Types
Less common forms of NSCLC exist, in which more specialised pathological assessment may be required to determine the tumour type accurately.
Which biomarkers should be assessed?
In NSCLC, treatment selection is not based on the histological diagnosis alone. The tumour also needs to be characterised biologically, as specific molecular alterations or the expression of certain proteins may determine which treatment is most likely to be effective. Where possible, broad molecular profiling is therefore preferred to sequential single-gene testing.
Molecular Testing
Next-generation sequencing (NGS) can assess many different mutations simultaneously. Depending on the stage and treatment setting, alterations involving EGFR, ALK, ROS1, BRAF, MET, RET, NTRK, KRAS and HER2 are particularly relevant, while newer and rarer targets, such as NRG1 fusions, are also becoming therapeutically relevant. These alterations do not all have the same significance at every stage of the disease, but identifying them may substantially change the choice or sequence of treatment.
Immunohistochemical Biomarkers
Alongside molecular testing, tumour proteins are assessed by immunohistochemistry. PD-L1 is an important biomarker when planning immunotherapy, while HER2 and MET expression may now also have therapeutic relevance. Current guidelines incorporate the assessment of PD-L1, HER2 and MET alongside broad molecular profiling of the tumour.
HER2 is a useful example of why different types of biomarker must be distinguished: an ERBB2/HER2 genetic alteration may be detected by molecular testing, while increased HER2 protein expression is assessed by immunohistochemistry. These are different findings with different therapeutic implications.
Tissue or Blood Testing?
Molecular testing may be performed on biopsy tissue and, in appropriate circumstances, through liquid biopsy by detecting circulating tumour DNA in the blood. The two approaches can be complementary. A positive blood result may provide useful information promptly, while a negative result does not necessarily exclude a molecular alteration and tissue testing may still be required.
Results Should Be Available Before a Treatment Decision Is Made
Particularly in advanced disease, the necessary molecular and immunohistochemical testing should be completed before the first treatment is selected. High PD-L1 expression alone, for example, is not sufficient to rule out the presence of an actionable driver alteration.
How Does Stage Influence Treatment Selection?
Stage indicates how far the disease has spread and is one of the most important factors in selecting treatment. In NSCLC, however, stage alone is not sufficient. Particularly in stages II and III, it is important to establish whether the tumour can be removed surgically, which lymph nodes are involved and the tumour’s molecular and immunohistochemical characteristics.
Early-Stage Disease
When the cancer is localised and can be completely removed, surgery is usually the main treatment. For patients who cannot undergo surgery, stereotactic radiotherapy may offer an alternative treatment with curative intent. Depending on the stage and tumour characteristics—which will be clarified in the pathology report—additional systemic treatment may also be required.
Resectable Stage II–III Disease
For many patients, treatment no longer necessarily begins with surgery. Chemotherapy combined with immunotherapy may be given before the operation, while in other cases systemic treatment is given after surgery. The presence of specific molecular alterations, such as EGFR or ALK, may also change the postoperative strategy and lead to targeted therapy.
Unresectable Stage III Disease
Stage III is not a single clinical situation. When the disease is not suitable for surgical resection, chemotherapy and radiotherapy usually form the basis of treatment, followed by systemic therapy according to the tumour’s characteristics. For example, in tumours with specific EGFR mutations, the treatment strategy after chemoradiotherapy differs from that used for NSCLC without such a molecular alteration.
Oligometastatic Disease
In some patients, the disease has spread beyond the lung but only to a limited number of sites. This is known as oligometastatic disease and is not always managed in the same way as widespread metastatic disease. In carefully selected patients, systemic treatment may be combined with local treatment of known sites, usually with stereotactic radiotherapy or, in some cases, surgery. The decision depends on the number and location of metastases, tumour biology, the response to systemic treatment and the patient’s overall condition, and requires multidisciplinary assessment.
Metastatic Disease
When the disease has spread to distant organs, systemic treatment has a central role. Options may include targeted therapy, immunotherapy, chemotherapy or combinations of these, and depend critically on the tumour’s molecular profile, PD-L1 expression and the patient’s overall condition.
How Is Treatment Selected in Metastatic Disease?
In metastatic disease, stage alone is not sufficient to select treatment. The first critical distinction is whether the tumour carries a molecular alteration for which a specific targeted treatment is available. For this reason, the necessary molecular and immunohistochemical testing should, where feasible, be completed before the first systemic treatment is started.
When an Actionable Molecular Alteration Is Present
In tumours with specific driver alterations—such as EGFR, ALK, ROS1, BRAF V600E, MET exon 14 skipping, RET, NTRK or HER2—treatment may be directed specifically at the corresponding alteration. In these circumstances, targeted therapy may be the preferred initial approach, irrespective of PD-L1 expression.
When No Driver Alteration Is Identified
When no molecular alteration directing treatment towards a specific targeted therapy is identified, the choice is based mainly on PD-L1 expression, tumour histology and the patient’s overall clinical condition. Depending on these features, immunotherapy may be used alone or in combination with chemotherapy, together with other contemporary treatment strategies.
PD-L1 Should Not Be Considered in Isolation
Even very high PD-L1 expression does not replace molecular testing. Some tumours with driver alterations may also express high levels of PD-L1, yet may be treated more effectively initially with targeted therapy. For example, current guidelines do not recommend first-line immunotherapy alone for patients with activating EGFR mutations, irrespective of the level of PD-L1 expression.
Treatment May Change Over the Course of the Disease
The treatment strategy is reassessed when the disease responds, remains stable or progresses. The site and pattern of recurrence, previous treatments, mechanisms of resistance and the patient’s general condition may influence the choice of the next treatment. In some cases, a new biopsy or repeat molecular testing may be required, particularly where this information could change the next treatment decision.
Frequently Asked Questions
Scientific Sources & Clinical Guidelines
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