Found: Key Driver of Lung Cancer Evolution and Relapse

Pam Harrison

May 02, 2017

New findings on how lung cancer evolves offer hope for a test that can detect a recurrence long before it can be detected with imaging, say British researchers.

Reporting the first results from the Tracking Non-Small-Cell Lung Cancer Evolution through Therapy (TRACERx) study, they found that intratumor heterogeneity mediated through chromosome instability is associated with an increased risk for recurrence or death from non–small cell lung cancer (NSCLC). And this chromosome instability may serve as a prognostic marker for recurrence long before cancer is detected using standard imaging techniques, they add.

"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," commented senior author Charles Swanton, MD, PhD, from the Cancer Research UK, London Institute, and the University College London (UCL), United Kingdom.

"Determining the relationship between diversity within tumors and patient survival is one of the primary goals of TRACERx, so to find evidence for this [relationship] so early on in the study is really encouraging," added lead author Mariam Jamal-Hanjani, MD, PhD, UCL Cancer Institute.

"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," she stated.

Results Reported in NEJM

Findings from part of the study were published online April 26 in he New England Journal of Medicine.

For this part of the study, researchers harvested tumor samples from the first 100 patients with NSCLC enrolled in TRACERx.

All but one patient had stage IA through IIIA NSCLC, making them eligible for surgical treatment with intent to cure. None of the patients had received prior systemic therapy.

Using multiregion whole-exome sequencing, investigators sequenced 327 tumor regions. Of these, 323 were primary tumor regions, and four were from lymph-node metastases.

"We observed extensive intratumor heterogeneity, with a median of 30% of somatic mutations identified as subclonal and a median of 48% of copy-number alterations as subclonal," the researchers report.

They point out that intratumor heterogeneity is what fuels the evolution of these tumors to become resistant to systemic therapy. Genetically diverse tumors are thus more likely to evolve, metastasize, and become resistant to drugs.

Interestingly, squamous cell tumors harbored significantly more clonal mutations than adenocarcinomas (P = .003) — possibly reflecting a more extensive history of smoking, at 41 pack-years for those with squamous cell carcinomas vs 32 pack-years for those with adenocarcinomas, they note.

In preliminary analyses, TRACERx researchers also found that patients who carried a high proportion of subclonal copy-number alterations had almost a fivefold higher risk for recurrence or death than patients with a low proportion of subclonal copy-number alterations, at a hazard ratio of 4.9, a difference between the two groups that was highly statistically significant.

Indeed, "the median time until recurrence or death was 24.4 months in the higher risk group of patients compared with a median that was not reached in the lower risk group," they emphasize. This difference remained significant after adjusting for multiple confounders, they add.

Also Published in Nature

Further results, from a second study involving the same TRACERx cohort, were published online April 26 in Nature.

In this study, a team led by Christopher Abbosh, MD, PhD, from the UCL Cancer Institute, took blood samples from 96 of the 100 TRACERx patients to see whether the genetic diversity observed in NSCLC tumors might be clinically prognostic.

First, they demonstrated that genetic aberrations present in these tumors could be tracked via small pieces of DNA in the blood that had broken off from a tumor. These fragments are referred to as circulating DNA.

Blinded profiling of postoperative plasma from 24 patients revealed that they could accurately identify more than 90% of patients destined to relapse up to a year before clinical imaging could confirm recurrence.

The team also compared circulating tumor DNA levels immediately before and after patients had completed the requisite course of chemotherapy.

These analyses revealed that when circulating levels of tumor DNA were not reduced by chemotherapy, patients were at higher risk for recurrence, a finding that suggests that the tumors had become resistant to drug therapy.

"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," Dr Abbosh said in a statement.

"This represents new hope for combating lung cancer relapse following surgery, which occurs in up to half of all patients," he added.

The TRACERx study is supported by the Francis Crick Institute, the UCL Cancer Institute, the University College London Hospitals Biomedical Research Center, the Royal Society, Achilles Therapeutics, Illumina, Natera, and Rosetrees Trust. The authors of the articles have disclosed no relevant financial relationships.

N Engl J Med. Published online April 26, 2017. Full text

Nature. Published online April 26, 2017. Abstract

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