NEW YORK – Investigators from the ongoing TRACERx trial published a new report this week highlighting findings from a subset of patients tested using Personalis' molecular/minimal residual disease (MRD) test, dubbed NeXT Personal, which is designed to catch DNA fragments shed from a cancerous tumor into a patient's blood.
Designed for long-term data collection, TRACERx has been assessing the genomic evolution of lung cancer and the impact of various molecular signals on prognosis and outcomes. When the trial first began testing patients for the presence of circulating tumor DNA (ctDNA), investigators used narrower assay technologies including Natera's Signatera platform. As the project has progressed, researchers have progressively embraced broader approaches, Personalis' test being the most recent.
NeXT Personal relies on initial whole-genome sequencing of a patient’s tumor tissue to identify a set of cancer-associated targets that can include up to around 1,800 genetic variants. These variants then comprise a personalized blood-based panel, which is used to search for the presence of tumor-derived DNA fragments circulating in the blood.
Prior studies, both within TRACERx and by other groups, have shown that adenocarcinoma patients with ctDNA present before and/or after curative-intent surgery have a higher risk of relapse than those who test negative. But this lung cancer subtype is also known to be challenging to detect in blood because it is less prone to shedding DNA into the blood.
Because patients with early-stage NSCLC have a high risk of relapse even when given curative-intent treatment, the potential to stratify patients — ramp up treatment for those at the highest risk and minimize the risk of overtreatment in those likely to have a good outcome — is of great interest to the oncology community.
In their paper, published Monday in Nature Medicine, authors from the UK-funded study reported on a cohort of 171 patients with stage I to stage III lung cancer, who were tested with NeXT Personal before receiving surgery.
The team reported that the test was able to detect cancer DNA in the blood of 100 percent of non-adenocarcinomas and 81 percent of adenocarcinomas, the more challenging tumor type to detect.
Broken down by disease stage, the test detected 57 percent of cases with stage I cancer and 79 percent of stage II cases. In prior studies using narrower panels, the TRACERx team was only able to detect a fraction of these earlier stage cancers — less than 20 percent of stage I cases and around 40 percent of stage II tumors.
Richard Chen, Personalis' chief medical officer, said that it was clear from the first interactions with the TRACERx team that investigators believed there was definitely room for improvement in terms of assay performance. "They could see that in the earlier data … that some of the patients that were testing negative were going on to recur over time. And that indicates that maybe there could be more sensitivity that could really help those patients," he said.
Investigators also explored whether the presence of pretreatment ctDNA correlated at all with patients' risk of relapse. Focusing on the adenocarcinomas in the cohort, the researchers calculated that early-stage patients who tested negative for ctDNA had a 100 percent five-year overall survival rate. In comparison, those who tested positive, even with the barest traces of tumor DNA in their blood, had a much higher risk of recurrence.
Chen highlighted this result as particularly encouraging for Personalis as it seeks to further commercialize its MRD platform, and potentially wrest market share from other commercial tests that offer less sensitivity.
Analyzing only samples with ctDNA levels lower than the limit of detection of previously tested assays, the researchers found MRD-positivity remained prognostic for poor overall survival. The authors wrote that this suggests that there is a subset of at-risk patients who can be definitively identified only by using an ultrasensitive ctDNA assay.
"We always want to be careful because these aren't exactly the same patients. They're drawn from the same study, but we're not doing a direct comparison with prior assays, but we think this is really compelling evidence that the ultrasensitive approach really makes a big difference … because we also looked at only those patients that were in the ultrasensitive range … and they still had a higher risk of recurrence," said Chen.
"It really suggests that if you use a less sensitive approach, you would have potentially misclassified these patients," he added.
The current publication did not report on NeXT Personal's performance in postsurgical disease detecting and monitoring, but this is something that the study has been following with plans to publish the new findings in a future paper.
According to Chen, the company expects these additional results to help support a submission for Medicare coverage of its test in lung cancer.
"We'll be looking at a set of patients that's quite a bit larger … and looking at monitoring and detecting recurrence longitudinally," he said.
Personalis is not alone in pushing sensitivity limits in MRD testing. Other companies that have turned to whole-genome approaches include Foresight Diagnostics and C2i Genomics. In a recent survey of GenomeWeb readers, respondents were almost equally split between viewing larger MRD test panels with more targets as likely to improve sensitivity versus thinking that it doesn't matter.
The study authors cautioned that the current TRACERx analysis was retrospective, and prospective follow-up will be necessary to determine if there is clinical utility in using the test in this patient population.