Circulating Tumor DNA Analysis and Functional Imaging Provide Complementary Approaches for Comprehensive Disease Monitoring in Metastatic Melanoma

Abstract

Purpose Circulating tumor DNA (ctDNA) allows noninvasive disease monitoring across a range of malignancies. In metastatic melanoma, the extent to which ctDNA reflects changes in metabolic disease burden assessed by 18F-labeled fluorodeoxyglucose positron emission tomography (FDG-PET) is unknown. We assessed the role of ctDNA analysis in combination with FDG-PET to monitor tumor burden and genomic heterogeneity throughout treatment. Patients and Methods We performed a comprehensive analysis of serial ctDNA and FDG-PET in 52 patients who received systemic therapy for metastatic melanoma. Next-generation sequencing and digital polymerase chain reaction were used to analyze plasma samples from the cohort. Results ctDNA levels were monitored across patients with mutant BRAF, NRAS, and BRAF/NRAS wild type disease. Mutant BRAF and NRAS ctDNA levels correlated closely with changes in metabolic disease burden throughout treatment. TERT promoter mutant ctDNA levels also paralleled changes in tumor burden, which provide an alternative marker for disease monitoring. Of note, subcutaneous and cerebral disease sites were not well represented in plasma. Early changes in ctDNA and metabolic disease burden were important indicators of treatment response. Patients with an early decrease in ctDNA post-treatment had improved progression-free survival compared with patients in whom ctDNA levels remained unchanged or increased over time (hazard ratio, 2.6; P = .05). ctDNA analysis contributed key molecular information through the identification of putative resistance mechanisms to targeted therapy. A detailed comparison of the genomic architecture of plasma and multiregional tumor biopsy specimens at autopsy revealed the ability of ctDNA to comprehensively capture genomic heterogeneity across multiple disease sites. Conclusion The findings highlight the powerful role of ctDNA in metastatic melanoma as a complementary modality to functional imaging that allows real-time monitoring of both tumor burden and genomic changes throughout therapy.

From validity to clinical utility: the influence of circulating tumorDNAon melanoma patient management in a real‐world setting

“…This study is, therefore, one of very few trials to prospectively assess treatment outcomes after administration of targeted therapy based exclusively on a ctDNA test result (Remon et al, 2017). Further investigation among larger groups of patients will be needed to demonstrate how frequently plasmabased assessments of targetable somatic mutations improve patient outcomes when such a mutation is not revealed via tumor-based molecular testing (Thierry et al, 2014;Wong et al, 2017).…”

“…Intrapatient trends observed among serial ctDNA measurements were shown to differentiate progressive disease from an immune-related tumor response (Lee et al, 2018a, b). In addition, patients with advanced melanoma receiving inhibitors of the mitogen-activated protein kinase (MAPK) pathway showed marked increases in ctDNA that preceded the radiographic appearance of progressive disease, suggesting genomic changes linked to acquired drug resistance (Gray et al, 2015;Wong et al, 2017). Among patients with high-risk resected melanoma, ctDNA levels have been shown to predict disease relapse (Lee et al, 2018a,b).…”

Life and death of circulating cell-free DNA

“…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. This finding suggested that ctDNA measurements might be more relevant to advanced stages of the disease and less relevant to precancerous lesions.…”

Circulating tumor DNA analysis in the era of precision oncology

“…Others also found a correlation between serial ctDNA analysis of BRAF and NRAS status and tumor response. PFS was longer in patients with an early decrease (1-4 weeks post-treatment) in ctDNA levels than in patients with unchanged or increased ctDNA levels post-treatment (HR = 2.6; p = 0.05) [98]. In the post-surgical setting, ctDNA analysis of BRAF and NRAS mutations predicted OS in 161 patients with high-risk stage II/III melanoma who underwent surgical resection followed by adjuvant bevacizumab for 1 year [99].…”