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Early TRACERx Results Illuminate Tumor Evolution, Show Promise of Natera ctDNA Analyses

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NEW YORK (GenomeWeb) – Researchers this week shared early data from the first 100 patients in the ongoing TRACERx (Tracking Cancer Evolution through Therapy) lung cancer study, illustrating how the effort is illuminating the clonal evolution of the disease in new ways, with implications for possible new targeted and immunotherapy.

The data, which were presented at the American Association for Cancer Research meeting in New Orleans, also included results from an initial analysis of a subset of 50 patients who have so far been tested using Natera's multiplex PCR technology in the study. According to the investigators, the platform's performance has been promising, but they still see significant room for improvement in their ability to track the breadth of subclonal branches of a cancer in blood.

Led by Charles Swanton at the Francis Crick Institute, TRACERx aims to systematically pursue and characterize the genomic paths cancers take in adapting and becoming resistant to therapy.

Researchers have been analyzing multiple biopsy samples, as well as circulating DNA, in the lung cancer patients recruited to the study, beginning with their primary disease diagnosis, through initial treatment, and to progression and metastasis if it occurs.

When Natera announced last summer that the study would be using its massively multiplexed PCR platform for the ctDNA analysis portion of this protocol, company officials said the results would be a "springboard" for its plans to develop and launch commercially available cfDNA-based diagnostics.

As the Liquid Biopsy market precipitates more and more rapidly, both PCR and next-gen sequencing have taken prominent positions in the commercial plans of companies. Natera's technology, first developed for non-invasive prenatal testing, occupies somewhat of a middle path.

The firm describes its proprietary PCR methodology as "massively multiplexed," because it allows up to tens of thousands of primers in a single reaction. This multiplexing is then followed by next-generation sequencing, with resulting data comparable to SNP microarray results, but with the precision and reproducibility of NGS, the company has said.

In previous presentations, Natera has shown that its technology can provide highly accurate detection of both copy-number variants and single-nucleotide variants in cancer patients' plasma, with sensitivities lower than 0.5 percent frequency for the detection of CNVs and as low as 0.01 percent for the detection of SNVs.

At AACR, Swanton shared early results from a first 100 patients recruited to TRACERx, half of whom have so far had their ctDNA analyzed by Natera in addition to their tissue biopsy samples.

Analyses of these first subjects have yielded significant insights, Swanton said, into the patterns of cancer evolution, including the lack of a direct link between the number of mutations in a tumor and number of subclonal branches in its evolution.

Researchers in the study have also been able to link specific mutations to different time points in a cancer's evolutionary tree, either in the trunk or in subsequent branches.

From this the group was able to see, for example, clear divisions between smoking- or environmental exposure-associated tumors — which tend to show frequent mutations in the trunk — in contrast with non-smoking cancers — in which the balance of mutations skews toward the branches.

The pattern of mutations in trunk versus branch also looks like it could be informative in regard to patients' benefit or lack of benefit from immunotherapy, Swanton said in his presentation.

Alongside these positive insights, he added, the results have also illustrated clearly that sequencing tissue samples still dramatically underestimates the subclonal evolution of a cancer. In incorporating liquid biopsy into the study, the investigators hoped to have an answer to this shortfall.

So far, Swanton said, the group has looked at ctDNA results from 50 patients, and has started to be able to answer one of its main questions for liquid biopsy, which was how effectively blood-borne markers, in this case SNVs, would actually be in tracking particular tumor evolutionary, or clonal branches.

The group's protocol using Natera's technology includes sequencing each patient's tumor tissue, and identifying 15 to 20 mutations that distinguish trunk and individual branch mutations. The group then creates primers for these mutations, and uses Natera's platform to detect circulating ctDNA molecules linked to clonal and subclonal cell populations.

Having performed 884 total assays from the first 50 patients in the cohort, Swanton said the team is beginning to get some insight into how effective the approach is.

Overall, they have been able to detect one or more SNVs in 34 of these 50 patients, with the highest failure rate in patients with the earliest stages of lung cancer.

"We have some way to go to optimize our sensitivity to detect subclones" Swanton said during his presentation, "but the results are certainly promising."

Jimmy Lin, who joined Natera as its new chief scientific officer for oncology last fall, told GenomeWeb this week that there are a few different reasons why a mutation might not be detectable in the blood when it is in tissue.

Because Natera's technology involves parallel analysis of multiple targets, he said the company is able to use multiple lines of evidence to conclude that if a mutation is not detected, it's probably because it was not present in the blood to begin with for one reason or another.

As the samples from TRACERx accrue, and the company profiles a larger number of subjects, Lin said the company expects that it will be detecting a greater proportion of SNVs across the cohort as a whole.

Though other studies have inferred that ctDNA represents a portrait of subclonal heterogeneity based on analysis of different variant frequencies, Lin highlighted that TRACERx is the first to match ctDNA with multiple biopsies to definitively link intratumoral heterogeneity and specific subclonal populations with circulating DNA molecules.

According to Solomon Moshkevich, Natera's vice president of product and strategy, the company expects this year to share additional data on its own liquid biopsy test development. This will include ctDNA versus tissue concordance results in other indications it has mentioned like breast and ovarian cancer, as well as data on detection of benign versus malignant disease.

Moshkevich and Lin declined to comment on the firm's commercial timeline.

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