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Personalised Medicine at a Glance: Lung Cancer

For patients, policy makers and other non-medical professionals

This text was prepared by ESMO for the European Alliance for Personalised Medicine in January 2015 and updated in February 2017

Despite reductions in smoking in many European countries, lung cancer remains the most frequent cause of cancer deaths among men and rivals tumours of the breast as the main cause of cancer mortality among women. But lung cancer is a not a single disease: it can arise in different types of lung cell, and, even within the same cell type, can be driven by different molecular abnormalities.

In tailoring treatment to a patient’s individual circumstances, the first step is to identify the cancer’s cell of origin. In 10-15% of cases, lung cancer is of the “small cell” subtype. The great majority, though, are non-small-cell lung cancers, shortened to NSCLC. The rest of this discussion deals with NSCLC. This kind of lung cancer is further categorised as either squamous cell carcinoma or adenocarcinoma, and this subdivision may have implications when deciding the most appropriate therapy.

Video resource: How personalised medicine will affect lung cancer patients

Lung cancers differ according to the type of cell in which they arise. In some of these subtypes, specific molecular targets have been identified. Certain specific gene alterations exclude other kinds of mutation, and it is important to understand which one is the major factor underlying uncontrolled tumour growth in a particular patient. If the genetic abnormality identified can be targeted by a drug, then we can hope for a beneficial therapeutic effect. Patients should be aware of the distinction between different types of lung cancer and look for a specific diagnosis. This will require study of tissue taken from the tumour by biopsy.

May 2013

With all cancers, the risk of over-treatment, which produces side-effects without benefiting the patient, must be balanced against the risk of under-treatment, which means that patients do not gain from the improved survival and quality of life that can result from effective interventions. For many years, the benefits achieved by chemotherapy in advanced lung cancer were relatively small. And the toxicity associated with treatment was substantial.

NSCLC biomakers

More recently, our increased ability to understand the molecular mechanisms responsible for the development and progression of NSCLC in particular groups of patients has led to targeted drug therapies which are both more effective and better tolerated.  It is now common for doctors to test lung cancer tissue for the presence of two molecular abnormalities before recommending personalised treatment. These two abnormalities are, firstly, mutations of the epidermal growth factor receptor (EGFR) and, secondly, rearrangements of the anaplastic lymphoma kinase (ALK) gene. Both abnormalities have been validated as biomarkers that predict good response to specific classes of drug.

Cells have receptors on their surface which act like docking stations for growth factors that circulate in the blood. Once a growth factor molecule has docked with a receptor, a signal is sent to the cell nucleus and the nucleus then divides. Normally, the concentration of growth factors and the receptors’ sensitivity to them are delicately balanced so that cells divide only when required for normal growth or to replace damaged tissue.

In around 10% of patients with NSCLC, receptors for epidermal growth factor are abnormally sensitive and cell division runs out of control. Cancers with this abnormality are likely to respond well to a class of oral drugs called the EGFR tyrosine kinase inhibitors. These block the transmission of growth signals from the activated receptor to the cell nucleus. The main examples are gefitinib, erlotinib and afatinib. Patients with lung cancers that do not have sensitising EGFR mutations are unlikely to respond to these agents.

Around 5% of patients with NSCLC have tumours which show abnormalities in the ALK gene which leads to production of an excessively active form of a growth-promoting enzyme. Cancers that are ALK-positive respond well to treatment with crizotinib, a tyrosine kinase inhibitor which blocks the transmission of growth signals to the cell nucleus.

Although 80-90% of lung cancers are caused by smoking, some occur in people who have never smoked. Lung cancers that are not associated with smoking are more frequent in women than in men. Lung cancers that have not been caused by smoking, those in women, and those that occur in people of East Asian origin are more likely to show the EGFR mutations mentioned above. Lung cancers in women and in non-smokers are also more likely to have cancer-promoting ALK gene rearrangements.  In both cases, diagnosis of these abnormalities requires sophisticated technology and should be undertaken only in specialised laboratories with rigorous procedures to assure quality control.

Multi-modality treatment

For the majority of patients with NSCLC, whose tumours do not show the EGFR or ALK abnormalities discussed, the search will continue for molecular markers that characterise their particular disease and for drugs that can be used to treat them.

Even in the absence of identified molecular abnormalities that lead to specific drug treatments, care of lung cancer patients can be personalised in many important ways. Central to this is accurate assessment of the size and location of the primary tumour and the extent to which the disease has spread. Sophisticated imaging techniques such as positron emission tomography (PET) and magnetic resonance imaging (MRI) are playing an increasingly valuable role in precisely locating secondary cancers (also known as metastases).

Small cancers confined to the lung can be treated surgically, often with additional radiotherapy. Disease that is locally advanced or that has spread to other parts of the body may require systemic treatment. Typically, this is based on chemotherapy drugs containing platinum such as cisplatin or carboplatin.

Chemotherapy may be combined with a biological agent – the antibody bevacizumab – that targets Vascular Endothelial Growth Factor (VEGF). As its name suggests, this factor promotes the growth of blood vessels, including those that supply blood to the tumour. Preventing this can cause the tumour to shrink.

Since lung cancer is so closely linked to smoking, which has many adverse effects on health, patients often have associated respiratory, heart and vascular disease. They may already have limited fitness and be restricted in their activities. These factors can mean that cytotoxic chemotherapy involving a combination of drugs (or bevacizumab) is not appropriate. Use of a single cytotoxic agent is a possible alternative. Choice of cancer treatment has to take such problems into account along, of course, with the preferences of the patient.  

A new kind of drug treatment: immune checkpoint inhibitors

Although targeted biological drugs and chemotherapy can cause many lung cancers to stop growing for a period of weeks or months, or even reduce them in size, most tumours eventually resume their growth. If this happens, we need effective second-line treatments.

Certain patients are now being helped by a new class of targeted antibody drugs called checkpoint inhibitors. A characteristic of many cancers is that they find ways of evading our body’s immune response. The new class of checkpoint inhibitors has been described as taking the brakes off the immune system, giving it greater opportunity to fight back against cancer.

The first such agent in lung cancer was nivolumab, which has now been followed by pembrolizumab. These drugs target a receptor called programmed cell death-1 (PD-1). Not all lung cancers express this target receptor to the same extent, and it is likely that tumours expressing PD-1 at a high level respond better to checkpoint inhibitors than tumours with little PD-1 expression.

Testing for this biomarker – as with many of the treatments discussed above – is therefore becoming another example of the importance of personalised medicine that decides the most appropriate treatment by taking into account the specific molecular characteristics of the cancer affecting an individual patient.

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