Undetectable circulating tumor DNA (ctDNA) levels correlate with favorable outcome in metastatic melanoma patients treated with anti-PD1 therapy

• Published in: Journal of translational medicine Vol. 17; no. 1; p. 303
• Main Authors: Seremet, Teofila, Jansen, Yanina, Planken, Simon, Njimi, Hassan, Delaunoy, Mélanie, El Housni, Hakim, Awada, Gil, Schwarze, Julia Katharina, Keyaerts, Marleen, Everaert, Hendrik, Lienard, Danielle, Del Marmol, Véronique, Heimann, Pierre, Neyns, Bart
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 05.09.2019; BioMed Central; BMC
• Subjects: Antibodies; Biological markers; Biomarkers; Cancer metastasis; Cancer therapies; Central nervous system; Circulating tumor DNA; Deoxyribonucleic acid; Diagnosis; Disease control; DNA; Gene mutation; Genetic aspects; Health aspects; Immunotherapy; Ipilimumab; Liquid biopsy; Melanoma; Metastases; Metastasis; Metastatic melanoma; Monitoring; Monoclonal antibodies; Multivariate analysis; Mutation; Patients; PD-1 protein; Retirement benefits; Translational research; Tumors; Belgium; United States > US; Metastatic melanoma; Translational research; BRAF/NRAS mutations monitoring; Immunotherapy; Liquid biopsy; Circulating tumor DNA; Monitoring
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-019-2051-8

Treatment with anti-PD1 monoclonal antibodies improves the survival of metastatic melanoma patients but only a subgroup of patients benefits from durable disease control. Predictive biomarkers for durable benefit could improve the clinical management of patients. Plasma samples were collected from patients receiving anti-PD1 therapy for ctDNA quantitative assessment of BRAF and NRAS mutations. After a median follow-up of 84 weeks 457 samples from 85 patients were analyzed. Patients with undetectable ctDNA at baseline had a better PFS (Hazard ratio (HR) = 0.47, median 26 weeks versus 9 weeks, p = 0.01) and OS (HR = 0.37, median not reached versus 21.3 weeks, p = 0.005) than patients with detectable ctDNA. Additionally, the HR for death was lower after the ctDNA level became undetectable during follow-up (adjusted HR: 0.16 (95% CI 0.07-0.36), p-value < 0.001). ctDNA levels > 500 copies/ml at baseline or week 3 were associated with poor clinical outcome. Patients progressive exclusively in the central nervous system (CNS) had undetectable ctDNA at baseline and at subsequent assessments. In multivariate analysis adjusted for LDH, CRP, ECOG and number of metastatic sites, the ctDNA remained significant for PFS and OS. A positive correlation was observed between ctDNA levels and total metabolic tumor volume (TMTV), number of metastatic sites and total tumor burden. Assessment of ctDNA baseline and during therapy was predictive for tumor response and clinical outcome in metastatic melanoma patients and reflected the tumor burden. ctDNA evaluation provided reliable complementary information during anti-PD1 antibody therapy.