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Postsurgical ctDNA Analysis Predicts Adjuvant Chemotherapy Benefit in NSCLC

NEW YORK – Longitudinal analysis of non-small cell lung cancer patients' circulating tumor DNA following surgery can predict disease recurrence risk and help guide adjuvant chemotherapy decisions, according to new research from researchers in China.

The study, led by a group of researchers from the Chinese Academy of Medical Sciences and Peking Union Medical College as well as precision oncology firm Geneseeq and published on Friday in Nature Communications, showed that ctDNA analysis after surgery could shed light on which patients benefit from adjuvant chemotherapy, and potentially help to avoid unnecessary treatment of certain patients. Additionally, the study showed that a ctDNA-positive finding during postsurgical surveillance could indicate that a patient is going to experience radiological recurrence a median of 88 days ahead of time.

"Our findings reveal longitudinal ctDNA analysis as a promising tool to detect [minimal residual disease] in NSCLC, and we show pioneering work of using postsurgical ctDNA status to guide [adjuvant chemotherapy] and … dynamically predict recurrence risk," Bin Qiu of the Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing and his colleagues wrote.

To conduct their prospective cohort study, the researchers used a next-generation sequencing panel developed by Geneseeq that covers 139 lung cancer-related genes as well as Automated Triple Groom Sequencing technology for somatic variant analysis. They defined ctDNA positivity as the presence of one or more plasma mutations that were matched to the tumor sample.

Of 103 NSCLC patients enrolled in the study who had their tumor and plasma samples sequenced, 91 harbored tumor-specific mutations in their ctDNA, making them candidates for further ctDNA surveillance. Seventy-one of these patients received adjuvant chemotherapy — a decision that was based on their clinical features at the time, not on ctDNA status.

Qiu and colleagues collected both peripheral blood samples and tumor tissue right before surgery. These samples informed the baseline, pre-surgery mutational profiling. Then, they collected postsurgical blood samples within 30 days of surgery as well as every three months thereafter. Alongside the longitudinal blood samples, they monitored patients for disease progression with CT-based imaging. All of the sequencing was performed in Geneseeq's central lab.

The researchers found that patients who were ctDNA-negative immediately following surgery had improved relapse-free survival versus those who were ctDNA-positive. Relative to disease factors such as histology and baseline TP53 mutation status, among other measurements, postsurgical ctDNA status had the strongest independent association with relapse-free survival. This was true regardless of whether patients received adjuvant chemotherapy, meaning that ctDNA positivity was a valuable biomarker of prognosis independent of chemo.

In terms of using ctDNA positivity to guide adjuvant chemo decisions, the researchers found that ctDNA-negative patients had about the same recurrence risk — which, of note, was a notably low risk — with or without adjuvant chemo. Meanwhile, ctDNA-positive patients who received adjuvant chemotherapy experienced relapse-free survival improvement.

These findings could have implications for de-escalating therapy in patients who are unlikely to benefit from it. As of now, the authors wrote, decisions to prescribe adjuvant chemo are mostly rooted in clinical factors, such as disease stage. Post-surgery chemo is recommended for most stage II or stage III patients, for example.

"Therefore, postsurgical ctDNA status could potentially stratify these clinically high-risk NSCLC patients into two groups, the ctDNA-positive patients who could more likely benefit from [adjuvant chemo] and the ctDNA-negative group where [adjuvant chemo] seems to be unnecessary, with a minimal improvement in reducing their relapse risk," the authors wrote.

Additionally, the researchers used their ctDNA analysis approach to monitor patients after surgery, with the goal of identifying oncoming recurrence. Here, they found that 79 percent of relapsed patients had at least one sample positive for ctDNA during the surveillance period, compared with only 41 percent who tested positive for ctDNA directly following surgery. Also, among patients whose cancers recurred, just over 82 percent had ctDNA at or before relapse, and the median time from ctDNA positivity to the relapse showing up on imaging tests was 88 days.

Finally, Qiu and colleagues found that using longitudinal ctDNA as a dynamic biomarker — that is, measuring changes in ctDNA — and pairing that with more typical time-to-relapse data to create a joint prediction model, was a more accurate model than using the go-to Cox model for disease recurrence risk.

Going forward, the researchers noted that randomized studies will be required to say for sure whether ctDNA can guide adjuvant chemo decisions after surgery. Although this study was prospective with regard to the blood collection and longitudinal cell-free DNA sequencing, analyses of patient outcomes remained retrospective.

Ultimately, according to Hua Bao, Geneseeq's director of research and development and one of the authors on the Nature Communications paper, what sets this paper apart from other MRD studies in NSCLC is the time frame. "We know there are so many papers published that say that … ctDNA mutation-positive patients have worse survival," he said in an interview. "But we have here a very early time point before adjuvant treatment."

This study, in other words, showed that ctDNA detected in patients' blood immediately after surgery is early enough to guide chemotherapy decisions.

"We can use that time point to guide whether patients should get adjuvant chemotherapy or not," Bao continued. "If they're ctDNA-positive, that would suggest that we should use adjuvant chemotherapy. If they're ctDNA-negative … it's not necessary to use adjuvant chemotherapy anymore."