Genetic profile of lung cancer can predict disease’s next move

A comprehensive analysis by British researchers of the way lung cancer evolves over time gives medical scientists a new means of predicting how individual patients’ tumours will develop and deciding how best to treat them.

Cancer Research UK released the results on Wednesday of a £14mn study called TracerX involving 800 patients over a nine-year period. Lung cancer is the world’s most deadly cancer, killing about 35,000 people a year in the UK.

In seven papers published in the journals Nature and Nature Medicine, the researchers described how tracking mutations in the DNA of cancer cells enabled them to anticipate the cells’ future behaviour.

“We can observe how the tumour is likely to evolve over time, spread and respond to treatment,” said Professor Charles Swanton, Cancer Research UK’S chief clinician and leader of the landmark project based at London’s Francis Crick Institute.

Individual tumours turned out to contain more diverse populations of cancer cells carrying different mutations than the scientists had expected. Each genetic lineage undergoes Darwinian evolution allowing the tumour to resist attempts by the immune system to suppress it. The process also enables the tumour to become more resistant to drugs.

The most dangerous lung cancers were not usually the ones that are largest when diagnosed but smaller ones less than 1cm in diameter which contain a diverse population of rapidly mutating cells, the research found. “These tumours have a high potential to metastasise — spread to other sites,” said Swanton. “We call them ‘born to be bad’.”

The TracerX scientists found that they could track genetic changes without the need for surgery or biopsies, by analysing small quantities of DNA released into the bloodstream. The more “circulating tumour DNA” or ctDNA is present, the more likely the cancer will return after treatment.

“Analysis of ctDNA would give us a fuller picture of how the tumour is changing over the course of the patient’s disease using [liquid biopsy] blood tests,” said Iain Foulkes, Cancer Research UK research director. “It would allow doctors to treat people more proactively, taking swift action to change a treatment plan that’s not working.”

One of the studies made important discoveries about cachexia, the name given to the unexplained loss of weight, appetite and muscle that affects many people with advanced cancer. The researchers found distinct patterns of genes active in the tumours of cachexia patients and detected high activity of one particular gene called GDF15. They hope that a treatment targeting GDF15 will help clinicians manage or even prevent cachexia in susceptible patients.

“A biological understanding of this devastating condition has long eluded researchers,” said Mariam Jamal-Hanjani of University College London, who led the cachexia research. “We are particularly excited about trying to find alterations in the cancer or blood that can help identify which patients are at risk of developing cachexia in the future so that we can intervene before this happens.”

Cancer Research UK is extending TracerX into a second phase with £15mn additional funding over seven years, which will use the knowledge of tumour evolution to improve personalised cancer diagnosis and treatment. The scientists expect the findings also to guide the treatment of other cancers, including skin and kidney.