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Lung Cancer Treatment Response, Outcomes Linked to Liquid Biopsy Profiles

Cell-Free Circulating DNA

NEW YORK – A research team in China has started to tease out prognostically informative circulating tumor DNA (ctDNA) dynamics for non-small cell lung cancer (NSCLC) patients receiving chemoradiation treatment.

As they reported in Cancer Cell on Monday, the researchers — led by co-senior and co-corresponding authors Yi-Long Wu of the Southern Medical University's Guangdong Lung Cancer Institute and the Chinese Thoracic Oncology Group; Qing Zhou of the Guangdong Lung Cancer Institute; and Xin Yi of the Geneplus-Beijing Institute — relied on a next-generation sequencing approach known as MNavigator to profile ctDNA dynamics in 761 blood samples collected over time from 139 individuals with unresectable, locally advanced NSCLC.

Using this approach they teased out molecular residual disease (MRD) patterns coinciding with enhanced treatment responses and survival outcomes, and generated targeted panel sequences on tumor and germline peripheral blood lymphocyte samples from the participants.

"The overall sensitivity of longitudinal MRD was 97.8 percent, and only two patients with local progression were overlooked," the study's authors wrote, noting that "all 10 patients with brain-only metastasis showed detectable ctDNA signals."

The study included 115 patients treated with concurrent chemoradiation, 21 patients treated with definitive radiotherapy and chemotherapy in sequence, and three patients treated with definitive radiotherapy alone. A subset of 50 NSCLC patients received immune checkpoint inhibitor immunotherapy during a consolidative therapy step, while eight patients had consolidation therapy with tyrosine kinase inhibitors.

Not surprisingly, the team saw an overall dip in ctDNA concentrations in the NSCLC patients over the course of their treatments compared to samples collected prior to treatment, for example. But the specific ctDNA patterns detected also provided clues to both treatment response and survival outcomes.

In particular, the investigators described enhanced chemoradiation responses in 38 individuals who had undetected MRD in samples collected relatively early in the treatment process and in samples collected after radiotherapy — a pattern that held in patients who did or did not receive additional immune checkpoint inhibitor treatment.

Likewise, ctDNA profiles for around one-fifth of the patients profiled pointed to ongoing MRD in samples collected at three- to six-month intervals after treatment, the researchers reported, highlighting a group of "potentially cured" patients with progression-free survival rates that exceeded 88 percent at a two-year follow-up time point.

Finally, the team noted that genetic variants present in ctDNA prior to treatment helped to define mutation patterns needed to find MRD, particularly in patients without available matched tumor samples.

"[L]imited tissue sampling volume is a universal problem for unresectable NSCLC," the authors noted, adding that "pretreatment ctDNA-detected variants were an indispensable MRD-informed source" in the current study.

Even so, the authors cautioned that "there is still a long way to relying on the negative predictive value of MRD in guiding clinical decisions, owing to the insufficient sensitivity of the ctDNA-MRD assay." They noted that MRD-guided treatment for locally advanced NSCLC will be explored further through a Phase III APPROACH/CTONG2101 clinical trial.