Tumour morphology, genetics and activity determine the outcome of lung cancer

Disease and treatment 21. sep 2023 2 min Senior Clinical Research Fellow David Moore Written by Kristian Sjøgren

Lung adenocarcinoma is the most common type of primary lung cancer and can differ in many ways. The tumour can send DNA into the bloodstream or spread through air spaces between healthy cells in the lungs. New research reveals that the morphology of tumours, their genetics and their activity in the body are all crucial to the outcome of people with lung adenocarcinoma.

Lung adenocarcinoma is complex and can differ between people.

Sometimes lung adenocarcinoma circulates tumour DNA around the body and sometimes not. Lung adenocarcinoma may spread through air spaces between healthy cells in the lungs but not always.

Likewise, the appearance of tumours in the lungs can differ under a microscope, and these differences can be associated with lower or higher growth and thus better or worse outcome.

Now researchers have closely examined how the genetics, appearance and activity of the tumours collectively create an overall picture of lung adenocarcinoma and how this understanding of differences between tumours and cancer cells might be used to predict individual outcomes.

“Some tumour characteristics are very clearly associated with a certain type of disease trajectory, and others with another trajectory. For example, we can use circulating tumour DNA in the blood and knowledge of the ability of cancer cells to spread through air spaces between healthy cells in the lungs to accurately predict who is likely to have a good outcome from treatment and who will probably do worse,” explains a researcher involved in the study, David Moore, Senior Clinical Research Fellow, Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, United Kingdom.

The research has been published in Nature Medicine.

Tumours are complex

The researchers characterised the morphology of 248 tumours from people with lung adenocarcinoma in depth.

Pathologists have previously established that tumours have six principal growth patterns, and three are associated with poorer outcome: cribriform, high-grade solid and micropapillary tumours.

The researchers compared the growth patterns with genetic profiling of the tumours, how the tumours developed over time and the outcomes.

The researchers examined whether the tumours spread through air spaces (STAS) or sent circulating tumour DNA (ctDNA) into the bloodstream. Both STAS and ctDNA are associated with a higher risk of relapse.

Differences in how the tumours metastasise

The researchers found that chromosomal instability, in which the chromosomes in cancer cells do not divide correctly, were associated with the high-grade solid and cribriform growth patterns but not the micropapillary pattern.

According to David Moore, this indicates that the underlying biology of micropapillary tumours differs from high-grade solid and cribriform tumours.

The researchers also discovered that solid and cribriform tumours were associated with ctDNA, whereas micropapillary tumours were associated with STAS. CtDNA was also associated with more dead cancer cells (necrosis) in the microscopic examinations of the tumours removed during surgery.

The researchers also identified differences in how the tumours metastasise by categorising patients according to the growth pattern of their tumours and then examining the location of the metastasis.

STAS and ctDNA associated with poorer outcomes

This part of the study showed that STAS and thus micropapillary tumours are typically associated with metastasis in the lungs and thoracic cavity, whereas ctDNA and thereby high-grade solid and cribriform tumours also more often lead to metastasis elsewhere in the body.

Finally, the researchers found that the people whose tumours were negative for both STAS and ctDNA had the best outcomes, whereas those positive for both STAS and ctDNA had the worst outcomes.

· Being positive for both STAS and ctDNA was associated with an 81% risk of relapse.

· Being positive for either STAS or ctDNA was associated with an outcome between the two extremes.

· Among those only positive for STAS, 76% had a relapse limited to the lungs and thoracic cavity, whereas 33% of those with only ctDNA had a relapse in the lungs and thoracic cavity.

“This aligns with the growth pattern of the tumours being associated with the risk of metastasis and that STAS or ctDNA seems to determine the association and location,” says David Moore.

Developing a future clinical tool

According to David Moore, ctDNA is not currently routinely used in this setting in clinical practice, but examining tumour samples for STAS and necrosis is easy for pathologists.

“By examining STAS and necrosis, we can easily create a model that can predict good and poor outcome. We have also validated this in another cohort of people with lung adenocarcinoma,” he adds.

However, David Moore emphasises that the researchers do not think that ctDNA, STAS and necrosis are immediately ready to be used as clinical tools but that this could be explored in the future.

“But based on studies of tumour growth profiles and other factors examined under the microscope, we have determined that we can begin to predict how tumours may act and how this may affect outcome,” he concludes.

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