Unstable Chromosomes Increase Risk of Non-Small Cell Lung Cancer Relapse

Unstable chromosomes drive genetic diversity in lung tumors and increase the risk of cancer relapse, according to a study published in the New England Journal of Medicine. These findings provide new insight into relapse prevention for lung cancer.

The results are from the Cancer Research UK-funded TRACERx lung cancer study, which is the first to look at the evolution of cancer in both detail and real time.

For the study, investigators followed patients from diagnosis to either disease relapse or cure after surgery, whichever came first. They then tracked and analyzed how the cancer developed.

“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,” said lead researcher Charles Swanton, of the Francis Crick Institute in London. “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.”

In one study, the investigators analyzed tumors from 100 patients with non-small cell lung cancer (NSCLC). The findings showed that unstable chromosomes drive genetic diversity in these tumors.

Furthermore, patients who had a higher number of unstable chromosomes within their tumors were more than 4 times more likely to relapse or die from the cancer within 2 years. According to the authors, this is because genetically diverse tumors are more likely to evolve, metastasize, and develop resistance to treatment.

“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,” said lead author Dr Mariam Jamal-Hanjani. “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.”

Based on these findings, the investigators conducted a second study that was published in Nature to examine whether they could clinically track the genetic diversity.

The investigators obtained blood samples from 96 of 100 patients, and found that the patchwork of the genetic faults in NSCLC could be monitored using circulating tumor DNA.

Next, they analyzed the blood of 24 patients with NSCLC after they had undergone surgery. The investigators were able to accurately identify more than 90% of patients who would relapse up to a year before clinical imaging could confirm the disease was back.

Because physicians are unable to monitor the benefit of chemotherapy after surgery, the investigators sought to compare circulating tumor DNA levels immediately before and after chemotherapy post-surgery.

Following chemotherapy, the levels of tumor DNA were not reduced, and as a result, the disease returned. This suggests that at least part of the tumor had built up resistance to treatment.

“In the future, patients could be offered personalized treatments that target parts of the cancer responsible for relapse following surgery,” said lead author Dr Christopher Abbosh. “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.”

In the UK, lung cancer accounts for more than 1 in 5 of all cancer deaths. In the last 40 years, survival only improved fractionally.

“Understanding these highly complex processes is enormously challenging and the contribution made by both of these studies is an important step in the right direction,” said Professor Karen Vousden, chief scientist at Cancer Research UK. “These findings could also help us to identify how lung cancers respond to therapy, building a bigger picture of the disease and potentially pointing the way to developing new treatments and, crucially, saving more lives.”