Why do some targeted treatments for lung cancer lose their effectiveness? A study in npj Precision Oncology, with Professor Paul Hofman, Director of the RespirERA Institute, as first author, explores the genetic changes associated with treatment resistance. It highlights the value of reassessing the tumour when the disease progresses.
Tumours can change during treatment
Some lung cancers carry an alteration in the ALK gene that contributes to tumour development. Targeted therapies (medicines designed to act on a specific abnormality in cancer cells) can be used to treat these cancers.
However, tumour cells can change over time. New mutations (changes in their DNA) can emerge and make a medicine less effective. Other mechanisms can also allow cancer cells to continue growing despite treatment.
Understanding these resistance mechanisms is therefore important for guiding subsequent care.
A large-scale analysis of resistance mechanisms
The researchers examined genetic testing results from nearly 135,000 tissue or blood samples from patients with lung cancer. Of these samples, 3,344 carried an ALK alteration.
The study reveals a wide range of resistance mechanisms. Some changes directly affect ALK. Others involve genes that enable cancer cells to use alternative pathways to continue growing.
Several resistance mutations can also be present in the same sample. This diversity highlights the importance of considering how a tumour has evolved, alongside the characteristics identified at diagnosis, when assessing treatment options.
Reassessing the tumour when the disease progresses
When lung cancer progresses despite ALK-targeted treatment, repeat genetic testing can provide information about newly developed resistance mechanisms.
Testing can be performed using tumour tissue or a liquid biopsy (a test that looks for fragments of tumour DNA in the blood). These approaches can identify changes that may help inform the choice of subsequent treatment.
The authors highlight the value of analysing multiple genes. Looking only for changes in ALK could leave other resistance mechanisms undetected.
The aim is to obtain a more complete picture of how the cancer has evolved, helping doctors assess the available treatment options.
Clinical observations that need further confirmation
The researchers also examined treatments and disease outcomes in a group of patients for whom this information was available.
Their observations suggest that considering a tumour’s resistance profile may help inform subsequent treatment choices. However, these findings require cautious interpretation: this part of the study involved small groups of patients, and some of the observed differences were not conclusive.
This was a retrospective study (an analysis of data that had already been collected). It does not, on its own, establish the benefit of a particular treatment strategy. Larger studies following patients over time will be needed to confirm these observations and assess the approaches proposed.
Through this publication, Professor Paul Hofman contributes to a better understanding of resistance to ALK-targeted therapies. These findings provide a basis for investigating care strategies that take greater account of how each cancer evolves.
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