Unstable chromosomes in lung tumors increase risk of cancer relapse, study reveals

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April 27, 2017

The New England Journal of Medicine and Nature has published the first findings from the Cancer Research UK-funded Tracking Cancer Evolution through Treatment (Rx), TRACERx, lung cancer study, which reveals the increase in the risk of cancer relapse when lung tumors have unstable chromosomes. Scientists have used this new information to identify relapse long before standard testing.

TRACERx is the first study to focus on the enormous detail and development of cancer in real-time, which allows researchers to follow from diagnosis to recurrence of the disease or restored health after surgical procedures, monitoring and examining the development of the cancer in patients.

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."

The New England Journal of Medicine has published another study today, where researchers analyzed tumors from 100 non-small cell lung cancer (NSCLC) patients and found that the driving force behind genetic diversity within tumors is unstable chromosomes.

The study revealed that the likelihood of cancer returning or the patient dying within 2 years are more than four times higher when the tumors show a high proportion of unstable chromosomes. Treating these patients is difficult as genetically diverse tumors are often expected to develop, increase, and become resistant to drugs.

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."

Equipped with this discovery, further research was conducted by the scientists to inspect clinical tracking of the genetic diversity. The study was published today in Nature.

In a sample of 100 patients, blood samples were taken from 96 patients and the scientists proved that the patchwork of genetic faults present in NSCLC could be examined using bits of DNA in the blood that have broken off from a tumor.

In another sample of 24 patients, who had completed surgery for NSCLC, blood samples precisely identified that in more than 90% of the patients there is a chance of relapse up to a year, even before the clinical imaging confirmed the relapse of the disease.

The study results unlock various opportunities for new drug discovery trials in preventing lung cancer relapse.

Since there were not many clinical signs of cancer, there are no ways to observe the benefits from chemotherapy after the surgery. Fragments of DNA that were broken off from the tumor were compared immediately before and after chemotherapy. No decrease in the levels of tumor DNA in the blood post chemotherapy occurred in patients whose cancer relapsed. This indicates that a part of the tumor was resistant to treatment.

The study outcome provided a new method to examine treatment post-surgery and suggests a way for newer treatments to aim at the parts of the tumor that are resistant to treatment.

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 personalized treatments that target parts of the cancer responsible for relapse following surgery.”

"Using circulating tumour 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."

Lung cancer causes more than one in five of all cancer deaths in the UK and survival has only improved fractionally in the last 40 years. 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.”
Professor Karen Vousden,
Cancer Research UK's chief scientist.

"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."

Sam Howard, Chief Executive of Rosetrees Trust, said: "Rosetrees Trust is delighted to have supported Professor Swanton and the TRACERx project from the outset. We always believed in the importance of this research, the team of outstanding researchers and its potential for human impact."

About TRACERx

TRACERx is the single biggest investment in lung cancer research by Cancer Research UK - 14 million pounds. Taking place over nine years, the project aims to transform our understanding of non-small cell lung cancer (NSCLC) and take a practical step towards precision medicine. The study will uncover mechanisms of cancer evolution by analysing the intratumour heterogeneity in lung tumours from approximately 850 patients and tracking its evolutionary trajectory from diagnosis through to relapse. Supported by Francis Crick Institute, UCL Cancer Institute, University College London Hospitals Biomedical Research Centre, The Royal Society, Achilles Therapeutics, illumina, Natera, and Rosetrees Trust and TRACERx collaborates with more than 225 researchers and clinicians based at 19 centers across the country.

About Cancer Research UK

Cancer Research UK is the leading cancer charity in the world. With the work of 4,000 scientists, doctors, and nurses and relying on donations, the organization is dedicated to save lives through research. Today, 2 out of 4 people survive their cancer for a minimum of 10 years and the organization aims to speed up to the survival of 3 out of 4 patients by 2034. Cancer Research UK's pioneering work, together with its partners and supporters, has saved millions of lives and has a vision to bring forward the day when all cancers are cured.

Sources:

https://www.eurekalert.org/pub_releases/2017-04/cru-tuc042417.php
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