Unstable chromosomes within lung tumors increases the risk of cancer returning after surgery, scientists have found. They also used this new knowledge to detect relapse long before standard testing.
The findings come from a clinical trial named TRAcking Non-small Cell Lung Cancer Evolution Through Therapy (TRACERx), the first study to look at the evolution of cancer in real time and immense detail. Researchers followed patients all the way from diagnosis through to either disease relapse or cure after surgery, tracking and analysing how their cancer developed.
Professor Charles Swanton, lead researcher based at the Francis Crick Institute in London, said:
“The TRACERx study is Cancer Research UK’s single biggest investment in lung cancer, and for the first time we’ve revealed new insights into how tumors evolve and evade treatment, a leading cause of cancer death.
We believe that this invaluable data generated during TRACERx will be seized upon by research teams across the world, helping us to answer more questions about lung cancer biology. We’ve only scraped the surface in terms of what is possible by looking at tumor evolution in such detail."
Non-small Cell Lung Cancer Tumor Diversity
In one study, published in the New England Journal of Medicine, scientists analyzed tumors from 100 non-small cell lung cancer (NSCLC) patients. They found that unstable chromosomes are the driving force behind genetic diversity within tumors.
They also showed that patients with a high proportion of unstable chromosomes in their tumor were more than four times more likely to have their cancer return, or die from their disease, within two years. This is because genetically diverse tumors are more likely to evolve, spread and become drug resistant, making a patient’s cancer much harder to treat.
Dr Mariam Jamal-Hanjani, lead author based at the UCL Cancer Institute, said:
“Determining the relationship between diversity within tumors and patient survival is one of the primary goals of TRACERx, so to find evidence for this so early on in the study is really encouraging. We’ve also identified what causes lung cancer to advance, providing us with insight into the biological processes that shape the evolution of the disease."
Researchers conducted a second study, published in Nature, to investigate whether this genetic diversity could be tracked clinically.
Using blood samples from 96 of the 100 patients, they demonstrated that the patchwork of genetic faults present in non-small cell lung cancer, could be monitored using bits of DNA in the blood that have broken off from a tumor (circulating tumor DNA).
They then analyzed blood taken from 24 patients after surgery for NSCLC, and accurately identified more than 90 per cent of those destined to relapse - up to a year before clinical imaging could confirm the disease’s return.
This finding opens up numerous opportunities for new drug trials in lung cancer to try to prevent relapse. Monitoring benefit from chemotherapy after surgery is not currently possible as there are often no clinical signs of disease.
With this in mind, the team also compared circulating tumor DNA levels immediately before and after chemotherapy was given to patients following surgery.
When levels of tumor DNA in the blood were not reduced following chemotherapy, the disease returned, suggesting that at least part of the tumor had become resistant to treatment.
The results provide a new means to monitor treatment after surgery, and point to an avenue for new treatments to target parts of the tumor that are resistant to existing approaches.
Dr Christopher Abbosh, lead author on the circulating tumor DNA study, based at the UCL Cancer Institute, said:
“In the future patients could be offered personalised treatments that target parts of the cancer responsible for relapse following surgery. Using circulating tumor DNA we can identify patients to treat even if they have no clinical signs of disease, and also monitor how well therapies are working. This represents new hope for combating lung cancer relapse following surgery, which occurs in up to half of all patients."
TRACERx involves the collaboration of more than 225 researchers and clinicians based at 19 centers across the country and is also supported by the Francis Crick Institute, UCL Cancer Institute, University College London Hospitals Biomedical Research Centre, The Royal Society, Achilles Therapeutics, illumina, Natera and Rosetrees Trust.
Jamal-Hanjani, M., Wilson, G.A., McGranahan, N., et al. TRACERx - Tracking Non-small Cell Lung Cancer Evolution New England Journal of Medicine. DOI: 10.1056/NEJMoa1616288
Abbosh, C., Birkbak, N, J., Wilson, G, A., et al. Phylogenetic ctDNA analysis depicts early stage lung cancer evolution Nature. DOI: 10.1038/nature22364
Image: Cancer Research UK