ALK Diagnosis

What are the symptoms?

In this video, consultant respiratory physicians Dr Jennifer Yung and Dr Seamus Grundy discuss the importance of having a high 'index of suspicion' when it comes to diagnosing ALK+ lung cancer. The topics covered include:

The symptoms that can be seen in ALK+ lung cancer patients, including metastatic disease
The difficulty in diagnosing ALK+ lung cancer, and the importance of having a high index of suspicion
Important diagnostic tools, including chest x-rays

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.

The non-specific nature of symptoms makes it particularly difficult to diagnose lung cancer in never-smokers. Some of the symptoms that can be experienced are:

What are the symptoms of metastatic disease?

If the cancer has metastasised 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 patient, Kim. It is of course important to remember that every patient and every case is different, so experiences and the actions taken will vary.

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 the patient meets their oncologist.

Duncan's story: my experience with healthcare professionals

In this video, ALK patient Duncan shares his experience during diagnosis, and where it would have helped to have further explanation from his healthcare team. Duncan explains that it would have helped him to have:

Further detail about the purpose of the biopsy
A more positive and detailed explanation of ALK treatments
An understanding of the clinical meaning of ‘palliative care’

How is ALK tested?

Testing for an ALK fusion 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 fusion.

Step 1: Confirming a lung cancer diagnosis

A lung cancer diagnosis is confirmed via histopathology.

Step 2: Testing for an ALK fusion

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 these tests.

How testing is evolving

Previously, FISH (fluorescent in situ hybridisation) was considered to be the gold-standard test for assessing ALK fusion. FISH is a technique which uses fluorescently-labelled DNA probes to detect the presence of specific sequences on a chromosome. You can read more about FISH testing here: National Genomic Education Programme: FISH

FISH is costly and labour-intensive, as only one gene can be assessed at a time, while next-generation sequencing (genomic sequencing) can test for multiple mutations at a time. As a result, immunohistochemistry and next-generation sequencing are now used much more frequently than FISH.

ctDNA testing is also evolving in lung cancer. 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 fusions to be identified more quickly. The pilot is still ongoing (as of December 2024) but it is hoped that this process will become standard.

What are the challenges when testing for an ALK fusion?

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 delivered in England?

What is genomics?

In this video, medical oncologist Dr Matthew Krebs 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

In 2018 NHS England established the Genomics Medicines Service, to allow clinicians to order tests relating to their patients’ genetic makeup. Genomics testing is now run from seven genomic laboratory hubs (GLHs) around England.

The national genomic test directory outlines which tests are commissioned by the NHS in England, and which patients will be eligible for a test. Access the directory here: National genomic test directory

Scotland, Wales and Northern Ireland each have their own arrangements for requesting genomic tests. Find out more about how to request genomic testing in the devolved nations here: Genomic testing in the devolved nations

The pathway for lung cancer testing at the GLH

The flowchart below shows the path that is followed at the North West NHS Genomic Laboratory Hub when a sample is referred for lung next-generation sequencing (NGS).

NGS can test for multiple mutations at the same time. Patients with lung cancer referred for genomic testing will be queued for both the lung cancer DNA panel, which targets EGFR, BRAF, MET, KRAS and ERBB2, and the RNA fusion panel which targets a number of genes including ALK, ROS1, RET and the NTRKs.

Samples then undergo DNA quality checks (QC) to make sure the DNA is suitable for testing. Samples that fail the DNA QC are redirected down the lung cancer salvage pathway, where a smaller panel uses targeted PCR-based tests which do not require the same high quality and quantity of DNA as next generation sequencing.

Clinicians may also refer patients for rapid EGFR or KRAS G12C testing if results are particularly urgent. These will go straight on to the targeted tests which can be turned around more quickly.

Testing for an ALK fusion takes place as part of the lung RNA fusion panel, rather than the DNA panel.

The pathway for lung cancer testing in the North West of England GLH

Information source: North West Genomics Laboratory Hub

Acronyms used in the flowchart above (click to open):

FFPE

Formalin-fixed paraffin-embedded tissue (the preserved slice of tissue sample).

ctDNA

Circulating tumour DNA (cancer DNA in the blood).

NGS

Next generation sequencing.

EGFR, BRAF, MET, KRAS, ERBB2 and NTRK

Other somatic mutations found in lung cancer.

qPCR and ddPCR

Quantitative PCR and droplet digital PCR. These are two types of PCR (polymerase chain reaction) techniques used to quantify DNA or RNA.

BRAF codon 600

Part of the BRAF gene, another gene which can mutate to cause cancer.

KRAS G12C

A specific mutation in the KRAS gene.

Download flowchart and acronym definitions (PDF)

The RNA fusion panel

When a sample is tested through the RNA fusion panel at the GLH, the below steps are taken.

1

RNA is extracted from the formalin-fixed paraffin-embedded tissue using an automated laboratory machine such as a QIAsymphony.

2

The RNA goes through library preparation using a ‘pan-cancer fusion enrichment’ – it is compared with genes known to be involved in oncogenic gene fusions, across different types of cancer. Genomic regions are identified and barcoded. Inert coloured dyes are used to help visualise progress.

3

The libraries are sequenced by a next-generation sequencing platform such as NovaSeq.

4

The data is processed by the bioinformatics team. The bioinformatics pipeline looks for sequences which combine two different gene transcripts. The result is a list of all potential fusions for each sample.

How do we stage ALK+ lung cancer?

Non-small cell lung cancer tumours are classified using the TNM system. This system comprises three components:

T (tumour): this relates to the extent of the primary tumour. Its main categories range from T1 to T4*, with subcategories (such as T1a, T1b etc). The system factors in the size of the tumour, as well as the areas it has invaded.
N (node): this describes whether or not cancer is present in the lymph nodes near the primary tumour. The cancer is listed between N1 and N3*, depending on which nodes are affected.
M (metastases): this is labelled according to how many extrathoracic (outside the chest) metastases are present, and the number of organs affected. The main categories range from M1a – M1c*, with M1c containing two additional sub-categories.

*There are also additional categories used when the T, N or M are not present or can’t be assessed (for example, T0 means that there is no evidence of a primary tumour).

Specific combinations of T, N and M are used to give the cancer a stage, from 1 – 4 (or I – IV).

(Source: IALSC Staging manual in thoracic oncology, 2024)

The International Association for the Study of Lung Cancer (IALSC) has recently released the 9th edition of its Lung TNM Definitions. For the full guidance, visit the website via the button below.

IASLC TNM Staging

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?

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

Talking to patients about prognosis

Talking about prognosis can be difficult for both the patients and the healthcare provider. However, it is an important conversation to have. A key factor is the difference in estimated survival for patients with an ALK fusion, compared with those patients who have lung cancer without a targetable fusion. 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, Dr Fabio Gomes discusses talking to patients about their prognosis. The topics covered include:

The importance of discussing prognosis with patients, while respecting their preferences about the timing and pace of this conversation
The challenges of timing a prognosis discussion around when test results become available

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: https://doi.org/10.5306/wjco.v12.i4.217.
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: https://doi.org/10.1016/j.jtho.2023.06.017.
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: https://doi.org/10.1136/thoraxjnl-2012-202348.
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: https://doi.org/10.1038/s44276-023-00006-w.
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: https://doi.org/10.1016/j.cllc.2022.09.010.
National Lung Cancer Audit State of the Nation, 2024. London: Royal College of Surgeons of England, 2024. Available at: https://www.lungcanceraudit.org.uk/wp-content/uploads/2024/05/NLCA-State-of-the-Nation-2024_16.05.24_V2.0.pdf. 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: https://doi.org/10.1016/j.jtho.2018.12.014.
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: https://doi.org/10.1007/s12094-018-1838-z.
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: https://doi.org/10.1038/bjc.2015.30.
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: https://doi.org/10.1007/s00428-016-2005-y.

Diagnosis – 4 HCPs