Liquid biopsies — blood tests that detect circulating tumor DNA (ctDNA) and other tumor material — may provide life-prolonging benefits for patients undergoing treatment for non–small cell lung cancer (NSCLC), a large international trial revealed.
Among patients for whom ctDNA alterations were detected, survival was shorter, but those who received targeted therapy that was based on the alterations survived longer than those who did not receive targeted therapies.
The findings, which highlight “potentially greater survival gains with liquid biopsy–matched therapy,” suggest that liquid biopsies could expand access to precision cancer care to the community healthcare setting and ultimately improve patient outcomes, according to researchers at Memorial Sloan Kettering Cancer Center (MSKCC) in New York City and GenesisCare in Sydney, Australia.
The study was published online in November in Nature Medicine.
Liquid biopsies are increasingly being used to monitor patients and guide therapy decisions, but the tests have been studied mostly in small cohorts with insufficient follow-up, the authors explain, and their impact on survival has been unclear.
To better understand the usefulness of ctDNA for patient outcomes, the researchers prospectively assessed survival in 1127 patients with metastatic NSCLC who received ctDNA sequencing using the ctDx Lung platform, a next-generation sequencing panel. In addition, 429 patients underwent tissue next-generation sequencing with a targeted assay.
Failure rates were lower (2% vs 13%) and turnaround times faster (11 vs 33 days) with ctDNA in comparison with tissue sequencing.
Overall, 722 patients (64%) had detectable levels of ctDNA. Of those, 255 (23%) had tumors with genomic alterations that were revealed by ctDNA sequencing and for which targeted therapies were available.
The presence of ctDNA was associated with shorter survival (hazard ratio [HR], 2.05), but among patients who received targeted therapy that was matched by ctDNA sequencing, mortality was reduced by 37% in comparison with mortality among 163 patients whose treatment was selected on the basis of tissue analysis (HR, 0.63).
Among the patients who underwent tissue sequencing with 30 days of ctDNA sequencing, 25% were found to have mutations in ctDNA that were absent after tumor sequencing (ctDNA-only group). These ctDNA-only alterations disproportionately featured subclonal drivers of resistance, such as RICTOR amplification and PIK3CA mutations, and were associated with shorter survival, the authors report. This finding suggests “that ctDNA-only alterations are related to tumor heterogeneity missed by spatially restricted tissue sequencing,” the researchers state. Although tumor sequencing remains valuable, these data suggest that “ctDNA-guided therapy may increase survival.”
The study was limited by its nonrandomized, real-world design. Nevertheless, the findings “align with historic randomized trials and propensity-matched analyses, suggesting that targeted therapy matched by either ctDNA or tissue is associated with survival benefit,” the authors write.
In addition, “the robust, independent prognostic utility of ctDNA suggests that liquid biopsies are a marker for increased micrometastatic or especially aggressive tumor biology and should supplement radiologic reports when assessing disease burden and chance of relapse following systemic therapy.”
The authors note that the availability of ctDNA sequencing may increase clinical trial enrollment in disadvantaged communities and could “provide an invaluable tool for monitoring disease relapse, emergence of secondary actionable drivers, and tumor evolution. By helping to overcome barriers to sequencing, liquid biopsies provide an opportunity to match patients to life-prolonging therapies on a previously unseen scale.”
The study was supported by a grant from the Antidote Health Foundation for Cure of Cancer, the National Institutes of Health, the Molecular Diagnostics Service in the Department of Pathology, and the Marie-Josee and Henry R. Kravis Center for Molecular Oncology. One author has a patent licensed by MDSeq.
Nat Med. 2022;28:2353-63. Abstract
Sharon Worcester, MA, is an award-winning medical journalist based in Birmingham, Alabama, writing for Medscape, MDedge and other affiliate sites. She currently covers oncology, but she has also written on a variety of other medical specialties and healthcare topics. She can be reached at [email protected] or on Twitter: @SW_MedReporter.
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