Early ctDNA assessment may help identify patients with locally advanced or oligometastatic non-small cell lung cancer who have markedly different survival outcomes after radiotherapy.

Early ctDNA assessment may help identify patients with locally advanced or oligometastatic non-small cell lung cancer who have markedly different survival outcomes after radiotherapy-based treatment, according to a study published in Clinical Cancer Research. The study, led by Ayesha Hashmi and colleagues, evaluated whether circulating tumor fraction estimate, known as ctFE, could serve as a noninvasive biomarker of risk in patients with locally advanced and oligometastatic NSCLC treated with radiotherapy. ctFE is a machine learning-derived composite metric of circulating tumor DNA burden, designed to quantify tumor-derived DNA signal from plasma. The investigators found that both pretreatment and early on-treatment ctFE strongly stratified overall survival and progression-free survival. Importantly, ctFE outperformed maximum variant allele frequency and simple ctDNA detectability, suggesting that a burden-based ctDNA metric may provide more clinically useful information than whether ctDNA is merely present or absent. Why This Study Matters Radiotherapy plays a central role in the management of unresectable locally advanced NSCLC and is increasingly used in oligometastatic NSCLC. However, patients treated with radiotherapy represent a biologically heterogeneous group. Some experience durable disease control, while others progress early despite aggressive local and systemic therapy. Current risk stratification relies heavily on clinical stage, imaging, tumor burden, performance status, and pathology. These factors are useful, but they may not fully capture the molecular burden of disease. Circulating tumor DNA offers a way to assess cancer biology noninvasively and repeatedly during treatment. This study is important because it focuses not only on baseline ctDNA, but also on early on-treatment ctDNA dynamics, measured during days 10–14 of radiotherapy-based treatment. This early time point could be clinically meaningful, because it may identify patients whose disease is not responding molecularly before conventional imaging shows progression. Study Design The discovery cohort came from a prospective phase II clinical trial, NCT03916419, which enrolled 26 patients with unresectable stage IIB to IIIC NSCLC. These patients received magnetic resonance-guided hypofractionated chemoradiotherapy followed by immunotherapy. Plasma ctDNA was profiled at two key time points: baseline before treatment and mid-treatment during days 10–14. The investigators derived ctFE and maximum variant allele frequency from these samples. A burden-based ctFE threshold was derived from baseline samples. The same threshold was then applied unchanged to mid-treatment samples. This is important because it allowed the authors to test whether the same molecular risk definition remained useful after treatment had already begun. The ctFE approach was then validated in two external real-world cohorts. One cohort included 94 patients with locally advanced NSCLC treated with chemoradiotherapy. The second included 309 patients with oligometastatic NSCLC treated with radiotherapy. ctFE Strongly Stratified Survival In the prospective trial cohort, pretreatment ctFE was strongly associated with survival outcomes. Baseline ctFE was prognostic for overall survival, with a hazard ratio of 5.93 and a P value of 0.005. It was also prognostic for progression-free survival, with a hazard ratio of 11.08 and a P value of <0.001. The association remained strong at the early on-treatment time point. Mid-treatment ctFE was associated with overall survival, with a hazard ratio of 7.08, and with progression-free survival, with a hazard ratio of 12.06. Both associations had P values of <0.001. These findings suggest that ctFE measured early during therapy may capture residual molecular disease burden or inadequate early molecular response, both of which could identify patients at high risk for progression and death. ctFE Outperformed Max VAF And ctDNA Detectability A key message from the study is that not all ctDNA metrics perform equally. The investigators reported that ctFE burden outperformed maximum variant allele frequency and ctFE detectability for risk stratification. This distinction is clinically important. A detectable versus undetectable ctDNA result may be too binary, especially in patients receiving radiotherapy, where tumor burden, shedding patterns, and treatment-induced changes can vary. Max VAF may also be limited because it depends on the highest individual variant signal. In contrast, ctFE is designed as a composite metric of ctDNA burden, potentially making it more stable and informative across different tumor and plasma contexts. This suggests that the future of ctDNA-guided treatment adaptation may depend not only on detecting ctDNA, but on using more refined quantitative metrics. Early Molecular Response Defined Three Prognostic Groups The investigators also evaluated early ctFE dynamics from baseline to mid-treatment. These dynamics defined three molecular response groups with marked separation in overall survival. Median overall survival was 60.8 months in the most favorable molecular response group, 13.0 months in the intermediate group, and only 2.9 months in the poorest-risk group. The survival separation was statistically significant, with a P value of <0.001. This is one of the most clinically striking findings of the study. It suggests that early ctDNA kinetics may identify patients whose disease is responding well at the molecular level, as well as those with persistent or worsening molecular burden despite treatment. Such information could eventually help guide treatment adaptation. Patients with favorable early ctFE dynamics may be candidates for standard consolidation approaches, while those with poor molecular response could be considered for intensified systemic therapy, clinical trials, or closer surveillance. Validation In Locally Advanced And Oligometastatic NSCLC The study also tested ctFE in two external validation cohorts. In both the locally advanced real-world cohort and the oligometastatic real-world cohort, ctFE remained associated with survival. This external validation is important because the discovery cohort was relatively small, with only 26 patients. By validating the biomarker in larger cohorts, including 94 locally advanced and 309 oligometastatic NSCLC patients, the authors strengthened the clinical relevance of ctFE across different radiotherapy-treated NSCLC settings. The inclusion of oligometastatic disease is especially notable. Oligometastatic NSCLC is increasingly treated with aggressive local therapy, but patient selection remains challenging. A blood-based marker that identifies patients more likely to benefit from radiotherapy-based approaches could help refine treatment decisions. Clinical Meaning The findings suggest that ctFE may be a practical biomarker for precision treatment adaptation in NSCLC treated with radiotherapy. For locally advanced disease, early ctFE could potentially help identify patients at high risk of progression despite chemoradiotherapy and immunotherapy. For oligometastatic disease, ctFE could help distinguish patients with limited molecular disease burden from those whose systemic disease biology may be more aggressive than imaging suggests. The study also supports the broader concept that ctDNA may be most useful when assessed dynamically. A single baseline result can provide prognostic information, but early changes during treatment may offer deeper insight into treatment response and residual risk. Importantly, the authors used a tumor-naïve ctDNA assay. This could make the approach more clinically practical, because it does not require personalized tumor-informed assay design before treatment begins. Key Takeaway Hashmi and colleagues showed that early ctFE, derived from a clinically available tumor-naïve ctDNA assay, can noninvasively stratify survival in patients with locally advanced and oligometastatic NSCLC treated with radiotherapy. Baseline ctFE was strongly prognostic for overall survival and progression-free survival, and the association remained significant during early treatment. Early ctFE dynamics further separated patients into molecular response groups with markedly different overall survival outcomes. The study supports ctFE as a promising biomarker for risk stratification and treatment adaptation in radiotherapy-treated NSCLC. Prospective validation will be important, but these findings point toward a future in which early ctDNA kinetics may help guide more personalized treatment decisions in locally advanced and oligometastatic lung cancer.

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