ALK Diagnosis

What are the symptoms?

In this video, consultant respiratory physicians Dr Jennifer Yung and Dr Seamus Grundy discuss the symptoms of ALK+ lung cancer. The topics covered include:

The symptoms of ALK+ lung cancer
The profile of ALK+ patients
Symptoms relating to metastatic ALK+ lung cancer
What patients should do if they’re worried about symptoms

The symptoms of ALK are very similar to symptoms of other lung cancers. Often lung cancer has no symptoms at all in its early stages.

Most of the symptoms of lung cancer are non-specific; that is, they are symptoms that can be caused by a number of different conditions. Some of the symptoms that can be experienced are:

The non-specific nature of symptoms makes it particularly difficult to diagnose lung cancer in never-smokers. This is because it is much more common for these symptoms to be caused by a condition other than cancer.

What are the symptoms of metastatic disease?

If the cancer has metastasised (spread) to other parts of the body, this may also cause symptoms (in addition to those listed in the section above). Areas that lung cancer can spread to, and examples of symptoms this might cause, include:

How is ALK diagnosed?

To give an example of the diagnostic process for lung cancer in general (which can then lead to the identification of an ALK lung cancer), we will follow the diagnosis journey of a fictional person, Kim. It’s important to remember that every person is different, so the journey below will not be the same for everyone. Your healthcare team will plan the tests and treatments that are right for you as an individual.

In summary, you will find below the most common sequence of events when a lung cancer is diagnosed. Note that that the ALK testing results may only become available when you meet your oncologist.

Duncan's story: diagnosis

In this video, Duncan shares his story about being diagnosed with ALK+ lung cancer five years ago. The topics covered include:

His own experience of being diagnosed with ALK+ lung cancer
His feelings throughout the initial diagnosis process, and upon learning his cancer was ALK+
Advice for anyone who is newly diagnosed

How is ALK tested?

Testing for an ALK mutation is a two-stage process. First, a tissue sample is examined in the laboratory to confirm a diagnosis of lung cancer. If the sample is eligible for ALK testing, it then undergoes genomic testing and/or immunohistochemistry testing to check for an ALK mutation.

Step 1: Confirming a lung cancer diagnosis

In most cases, a lung cancer diagnosis is confirmed via histopathology.

Step 2: Testing for an ALK mutation

There are several different ways in which we test for ALK: the tests which are done in the lab, and genomic (or molecular) testing.

Click the circles in the timeline below to learn more about how these tests are carried out in England.

What are the challenges when testing for an ALK mutation?

ALK testing is a multi-step process that involves multiple sites and people. This multi-step process can lead to delays in treatment.
Taking a lung cancer sample can be challenging as it is an invasive procedure. In many cases, the sample may be too small to analyse.

Why do the ALK tests sometimes fail?

There are several reasons why the ALK tests can fail:

The biggest issue is the small size of the tissue sample taken for testing. The sample is needed for multiple steps, such as processing, diagnosis and ALK testing, and there is sometimes not enough tissue for all the steps.
There can be technical failures in the lab, for example during fixation of tissue and staining.
In genomic testing, DNA needs to be extracted from the tissue sample. The quality of the DNA can sometimes be affected when the tissue is processed, which can cause the analysis to fail.
Certain types of tissue, such as tissue taken from bone biopsy, are not reliable for DNA analysis.

How is the genomic testing organised?

What is genomics?

In this video Dr Matthew Krebs, medical oncologist and clinical lead for cancer genomics in the North West of England, describes how genomic testing takes place in England. The topics covered include:

An introduction to genomics in cancer
How genomic testing is organised in England
The journey of a biopsy sample
The ctDNA (circulating tumour DNA) pilot

You can also read a summary of the information covered in this video in the text below.

The video above covers these key points:

An introduction to genomics in cancer

Genomics involves studying the genetic information within a patient's cancer.

How genomic testing is organised in England

In 2018 NHS England established the Genomics Medicines Service, to allow clinicians to order genomic tests relevant to cancer diagnosis and treatment. Genomics testing is now run from seven Genomic Laboratory Hubs (GLHs) around England.

The journey of a biopsy sample

Once a biopsy has been taken, it follows the following steps:

After preparing the sample, the pathologist examines a slice under a microscope to confirm a lung cancer diagnosis (read more about this stage in the previous section).
At the same time, a sample is sent to the Genomics Laboratory Hub.
In the hub, DNA and RNA (molecules that hold our genetic information) are extracted. The sample is put into a specialised sequencing machine which reads the genetic code.
Computers interpret the genetic code, then this data is analysed by scientists in the lab.
RNA tests are particularly important in testing for an ALK alteration along with other gene fusions (ROS1, RET and NTRK fusions).

ctDNA (circulating tumour DNA) pilot

ctDNA allows genomic information to be taken from a blood sample rather than a biopsy (the biopsy is still needed for a cancer diagnosis). This is achievable because in some patients DNA from cancer cells is released into the bloodstream.
NHS England began a pilot in November 2022 in which blood samples are taken from patients early on in their lung cancer diagnosis. This process allows gene mutations and fusions to be identified more quickly. The pilot is still ongoing (as of December 2024) but is hoped that this process will become a routine test.

What are the different cancer stages?

The stage of a cancer is a description of how advanced it is; how big the cancer is and how far it has spread. Staging a cancer helps healthcare teams advise patients on which treatments should be considered and the overall prognosis.

Patients with ALK+ lung cancer will be staged using the same TNM staging system used for all non-small cell lung cancer. TNM stands for tumour, node and metastasis:

Tumour (T) refers to the size of the primary tumour in the lung (the initial mass where the cancer started, and often the main largest mass).
Node (N) refers to whether or not there is any cancer in the lymph nodes near the primary tumour.
Metastasis (M) refers to whether or not the cancer has spread to any other more distant parts of the body (such as the bones or brain).

There are four cancer stages (1-4). These are often written in Roman numerals (for example, stage 4 may be written as ‘stage IV’).

At which stage are most lung cancers diagnosed?

The percentages of lung cancers diagnosed at each stage (in England) are shown in the chart (source: National Lung Cancer Audit State of the Nation, 2024).

It is important to note that this data relates to all lung cancers, rather than just to ALK. The percentage of people diagnosed at stage 4 who have ALK+ lung cancer tends to be higher than in the general population with lung cancer.

There are several reasons for this:

Incidence stats at different satges

Many ALK patients are younger than the average person who has lung cancer.
Many ALK patients are never- or light-smokers (which means these patients can also be excluded from screening programmes where available).
The most common symptom is a cough which can be attributed to other benign causes such as infections.

These reasons lead to a low ‘index of suspicion’, for both the individuals and healthcare professionals.

What is the prognosis?

The estimated survival for patients with ALK+ lung cancer is longer than for those with lung cancer without targetable mutations. One US study reported an average survival for ALK positive patients diagnosed with stage 4 disease of 6.8 years (Pacheco et al., 2019), whilst the median survival of lung cancer in general (in England) is 327 days (National Lung Cancer Audit State of the Nation, 2024).

In this video, consultant medical oncologist Dr Fabio Gomes explains the prognosis for ALK+ lung cancer. The topics covered include:

Influences on the prognosis of ALK+ lung cancer
The impact of ALK inhibitors
The impact of brain metastases
How the cancer becomes resistant to tyrosine kinase inhibitors (TKIs)
The prognosis for early-stage ALK+ lung cancer

References

Please be aware that the following links are current (as of December 2024), some may reside behind a paywall.

Chevallier, M. et al. (2021) ‘Oncogenic driver mutations in non-small cell lung cancer: Past, present and future.’, World journal of clinical oncology, 12(4), pp. 217–237. Available at: doi.org.
Gillespie, C.S. et al. (2023) ‘Genomic Alterations and the Incidence of Brain Metastases in Advanced and Metastatic NSCLC: A Systematic Review and Meta-Analysis’, Journal of Thoracic Oncology. Elsevier Inc., pp. 1703–1713. Available at: doi.org.
Iyen-Omofoman, B. et al. (2013) ‘Using socio-demographic and early clinical features in general practice to identify people with lung cancer earlier.’, Thorax, 68(5), pp. 451–9. Available at: doi.org.
Khan, S. et al. (2023) ‘Lung cancer in never smokers (LCINS): development of a UK national research strategy’, BJC Reports, 1(1), p. 21. Available at: doi.org.
Lin, H.M. et al. (2023) ‘Real-world ALK Testing Trends in Patients With Advanced Non–Small-Cell Lung Cancer in the United States’, Clinical Lung Cancer, 24(1), pp. e39–e49. Available at: doi.org.
National Lung Cancer Audit State of the Nation, 2024. London: Royal College of Surgeons of England, 2024. Available at: lungcanceraudit.org.uk. Accessed 27 November 2024.
Pacheco, J.M. et al. (2019) “Natural History and Factors Associated with Overall Survival in Stage IV ALK-Rearranged Non–Small Cell Lung Cancer,” Journal of Thoracic Oncology, 14(4), pp. 691–700. Available at: doi.org.
Pan, X. et al. (2018) ‘Frequent genomic alterations and better prognosis among young patients with non-small-cell lung cancer aged 40 years or younger’, Clinical and Translational Oncology, 20(9), pp. 1168–1174. Available at: doi.org.
Walter, F.M. et al. (2015) ‘Symptoms and other factors associated with time to diagnosis and stage of lung cancer: a prospective cohort study.’, British journal of cancer, 112 Suppl 1(Suppl 1), pp. S6-13. Available at: doi.org.
Williams, A.S. et al. (2016) ‘ALK+ lung adenocarcinoma in never smokers and long-term ex-smokers: prevalence and detection by immunohistochemistry and fluorescence in situ hybridization’, Virchows Archiv, 469(5), pp. 533–540. Available at: doi.org

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ALK Diagnosis

What are the symptoms?

What are the symptoms of metastatic disease?