Circulating tumor DNA analysis and functional imaging provide complementary approaches for comprehensive disease monitoring in metastatic melanoma

Stephen Q. Wong, Jeanette M. Raleigh, Jason Callahan, Ismael A. Vergara, Sarah Ftouni, Athena Hatzimihalis, Andrew J. Colebatch, Jason Li, Timothy Semple, Kenneth Doig, Christopher Mintoff, Devbarna Sinha, Paul Yeh, Maria Joao Silva, Kathryn Alsop, Heather Thorne, David D. Bowtell, David E. Gyorki, Gisela Mir Arnau, Carleen CullinaneDamien Kee, Benjamin Brady, Fergal Kelleher, Mark A. Dawson, Anthony T. Papenfuss, Mark Shackleton, Rodney J. Hicks, Grant A. McArthur, Shahneen Sandhu, Sarah Jane Dawson

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45 Citations (Scopus)

Abstract

Purpose Circulating tumorDNA(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.Weassessed the role ofctDNAanalysis in combination with FDG-PET to monitor tumor burden and genomic heterogeneity throughout treatment. PatientsandMethodsWeperformed a comprehensiveanalysis of serialctDNAandFDG-PETin 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 inctDNApost-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.

Original languageEnglish
Pages (from-to)1-14
Number of pages14
JournalJCO Precision Oncology
Volume2017
Issue number1
DOIs
Publication statusPublished - 2017
Externally publishedYes

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