Circulating Tumor DNA Reflects Tumor Metabolism Rather Than Tumor Burden in Chemotherapy-Naive Patients with Advanced Non–Small Cell Lung Cancer: ¹⁸F-FDG PET/CT Study

Abstract

We aimed to evaluate the relationships between circulating tumor cells (CTCs) or plasma cell-free DNA (cfDNA) on one side and a comprehensive range of F-FDG PET/CT-derived parameters on the other side in chemotherapy-naive patients with advanced non-small cell lung cancer (NSCLC). From a group of 79 patients included in a trial evaluating the role of pretreatment circulating tumor markers as predictors of prognosis in chemotherapy-naive patients with advanced NSCLC, we recruited all those who underwent F-FDG PET/CT for clinical reasons at our institution before inclusion in the trial (and thus just before chemotherapy). For each patient, a peripheral blood sample was collected at baseline for the evaluation of CTCs and cfDNA. CTCs were isolated by size using a filtration-based device and then morphologically identified and enumerated; cfDNA was isolated from plasma and quantified by a quantitative polymerase chain reaction using human telomerase reverse transcriptase. The followingF-FDG PET/CT-derived parameters were computed: maximum diameter of the primary lesion (T), of the largest lymph node (N), and of the largest metastatic lesion (M); SUV; SUV; size-incorporated SUV; metabolic tumor volume; and total lesion glycolysis. All parameters were independently measured for T, N, and M. The associations among CTCs, cfDNA, and F-FDG PET/CT-derived parameters were evaluated by multivariate-analysis. Patients were divided into 2 groups according to the presence of either limited metastatic involvement (M1a or M1b due to extrathoracic lymph nodes only) or disseminated metastatic disease. The presence or absence of metabolically active bone lesions was also recorded for each patient, and patient subgroups were compared. Thirty-seven patients recruited in the trial matched our PET-based criteria (24 men; age, 64.5 ± 8.1 y). SUV for the largest metastatic lesion was the only variable independently associated with baseline cfDNA levels ( = 0.016). Higher levels of cfDNA were detected in the subgroup of patients with metabolically active bone lesions ( = 0.02), but no difference was highlighted when patients with more limited metastatic disease were compared with patients with disseminated metastatic disease. The correlation of cfDNA levels with tumor metabolism, but not with metabolic tumor volume at regional or distant levels, suggests that cfDNA may better reflect tumor biologic behavior or aggressiveness rather than tumor burden in metastatic NSCLC.

The interplay of circulating tumor DNA and chromatin modification, therapeutic resistance, and metastasis

“…For example, when considering intratumor heterogeneity, subclones carrying driver mutations are more prone to release DNA [20]. However, some researches [21] in non-small cell lung cancer (NSCLC) have indicated that the cfDNA level is correlated with tumor metabolism and reflects tumor biological behaviors rather than tumor burden, potentially because nontumor DNA is also increased during tumor progression due to interactions between tumor cells and adjacent healthy tissue cells [22].…”

“…In addition to the tumor volume [125,133,134], it is also associated with factors such as necrosis, ki67, pathological type, lymph node metastasis, hematogenous metastasis, allele frequency, EpCAM-positive CTC mutation [135] and others [136]. The condition of ctDNA not only reflects the tumor burden but also relates to tumor metabolism, which indicates the biological behavior of the tumor [21].…”

“…Compared with 18F-FDG PET/ CT, the cfDNA level is not a simple measure of tumor burden, but it correlates to a complex tumor metabolism and biology, which makes it a better biomarker to reflect the biological behavior or aggressiveness of the tumor. [21,146,147] In addition to 18F-FDG PET/CT, lactate dehydrogenase (LDH), which catalyzes the final step of glycolysis, has also been described by researchers. Serum LDH is also a possible marker for metastasis, prediction of therapeutic efficacy and prognosis.…”

Life and death of circulating cell-free DNA

“…44,45 Therefore, although the variability in ctDNA is typically attributed to the tumor burden, 46 it actually might reflect tumor metabolism. 47,48 For example, in patients with melanoma, ctDNA levels were correlated with metabolic disease volume, estimated with 18 F-labelled fluorodeoxyglucose positron emission tomography. 49,50 Therefore, the ctDNA level was a complex reflection of tumor biology, rather than simply associated with tumor burden or the number of dying cells.…”

Combining 18F-FDG PET/CT–Based Metabolically Active Tumor Volume and Circulating Cell-Free DNA Significantly Improves Outcome Prediction in Chemorefractory Metastatic Colorectal Cancer

“…Baseline wholebody metabolically active tumor volume (WB-MATV), representing the patient's active tumor load before treatment, was recently validated by our group as a strong prognostic imaging biomarker in a large cohort of chemorefractory mCRC patients (16). Interestingly, another PET parameter evaluating the glycolytic activity of the disease, SUV max , was recently reported to be correlated with cfDNA in advanced non-small cell lung cancer patients (17).…”