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Lung Cancer Studies From TRACERx Consortium Explore How Tumor Cells Evolve

NEW YORK – Blood and tumor samples might be able to differentiate lung cancer patients whose disease is likely to spread from those who won't progress, according to three new studies.

More than 218,000 people are diagnosed with lung cancer each year in the US, and less than a fifth of patients survive for more than five years. Researchers from the Tracking Non-Small Cell Lung Cancer Evolution through Therapy (TRACERx) consortium say this low survival rate might be attributed in part to lung cancer cells' ability to evolve rapidly and become treatment resistant.

The TRACERx project, which includes more than 750 patients from more than a dozen UK hospitals, aims to tease out how lung cancer cells evolve and spread, as well as how patients' immune systems respond to the cancer.

Three new papers from the consortium, all published in Nature Medicine today, together suggest that analysis of blood and tumor tissue samples from patients might be able to identify early that a patient's tumor is spreading and becoming treatment resistant.

"Our research has shown that lung cancer is an extremely complicated disease with a patchwork of different cells making up each individual tumor," Charles Swanton, chief clinician at Cancer Research UK and the PI of the TRACERx project, said in a statement. "We think that understanding this variation, how these different cells come about, and how this variation is detected by the immune system will be key to improving lung cancer survival."

In the first paper, TRACERx researchers led by the University of Manchester's Caroline Dive analyzed blood samples collected from lung cancer patients before they underwent surgery for the presence of circulating tumor cells. Such cells, they reported, were present in nearly half the 100 patients analyzed and these patients were more likely to experience disease recurrence.

When they compared early disseminated cells to the primary tumor and to later metastases from a 74-year-old man with stage 3A invasive adenocarcinoma, the researchers found that mutations within his CTCs overlapped to a greater degree with mutations found in the metastases than with mutations from the primary tumor. This suggested to them that these early CTCs could be responsible for the spread of the disease.

Meanwhile, researchers led by Swanton examined whole-exome and RNA sequencing data from lung biopsies taken from different tumor regions of 48 TRACERx patients. They found that chromosomal instability is a major driver of transcriptomic intratumor heterogeneity, which they noted has limited the utility of existing expression-based biomarkers.

Instead, the researchers developed a 23-gene prognostic signature they called the outcome risk-associated clonal lung expression (ORACLE) biomarker that they said avoids the issue of heterogeneity by relying on stable genetic features. They reported that patients with a low-risk ORACLE signature had a higher three-year overall survival rate, as compared to those with a high-risk signature. They further suggested ORACLE was associated with tumor aggressiveness and metastatic potential and could represent a more accurate prediction tool.

Additionally, University College London's Benny Chain and his colleagues analyzed tumor and normal tissue samples as well as blood samples from 72 TRACERx patients. In particular, they focused on the immune response to tumors to find that host T cells were prevalent among the tumor samples, suggesting that the host immune system was able to identify the tumors' presence. This, they noted, could be applied to gauge how well a particular treatment is working as well as to determine which T cells could be harnessed to boost treatment efficacy.

A previous study from the TRACERx team also underscored the relationship between the host immune system and lung cancer, finding that the host immune system imposes selective pressure on lung tumors to affect their evolution.

Swanton added in a statement that these new TRACERx studies are enabling the researchers to better understand the development and spread of lung cancer, and that their future work building on these studies might yield better ways to treat lung cancer.