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

Abstract

Background 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. Methods Plasma samples were collected from patients receiving anti-PD1 therapy for ctDNA quantitative assessment of BRAF V600 and NRAS Q61/G12/G13 mutations. Results 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. Conclusions 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.

Circulating Tumor DNA Testing Opens New Perspectives in Melanoma Management

“…Recently, Biocartis (Belgium) developed a new fully automated platform, designated Idylla, for detecting the major NRAS , BRAF , KRAS or EGFR mutations in either ctDNA or genomic DNA isolated from tissue. The test allows the detection of BRAF V600 mutations in plasma with up to three mutant copies per PCR reaction with an analytical sensitivity of 0.01% [ 18 ]. A 75% clinical sensitivity has been reported in stage IV melanoma patients [ 19 ].…”

“…The basal levels of ctDNA are also a relevant prognostic marker in patients treated with immunotherapy. Seremet assessed ctDNA levels in 85 advanced melanoma patients using either the Idylla assay or a ddPCR test [ 18 ]. They found that patients in which the ctDNA was not detectable at baseline had longer PFS (HR, 0.47) and OS (HR, 0.37) as compared with patients with detectable ctDNA.…”

miRNAs in the Diagnosis and Prognosis of Skin Cancer

“…When following therapy efficacy in melanoma, in addition to the classical circulating markers as LDH, S100 calcium-binding protein B (S100B), melanoma inhibitory activity (MIA) (Neagu et al, 2009), and, lately, ctDNA (Seremet et al, 2019), circulating miRNAs gained interest. As circulating miRNAs have structural stability, they can become robust non-invasive biomarkers when several technicalities can be standardized, such as the sample type (plasma versus serum) and pre-analytical and analytical workflows (Mumford et al, 2018).…”

The Tumor and Host Immune Signature, and the Gut Microbiota as Predictive Biomarkers for Immune Checkpoint Inhibitor Response in Melanoma Patients

“…However, these results are unlikely to provide a predictive biomarker of response due to the use of small patient groups, the different types of cancer investigated, and the variable treatment options. Conversely, Serement et al [ 53 ] performed a study on 85 melanoma patients receiving anti-PD-1 immunotherapy in which plasma cfDNA was analyzed for BRAF V600 and proto-oncogene NRAS Q61/G12/G13 mutations. Patients with undetected ctDNA at the baseline were reported to have a better clinical outcome: better PFS (median 26 weeks vs. 9 weeks, p = 0.01) and better OS (median not reached vs. 21.3 weeks, p = 0.005) compared to patients with a detectable ctDNA.…”

“…Moreover, >500 ctDNA copies detected before treatment or as early as the third week of therapy were related to a poor clinical outcome following anti-PD-1 therapy. Interestingly, the ctDNA level was not elevated in the serum of patients with a progression exclusively in the central nervous system [ 52 , 53 ]. These results show limitations of ctDNA prognosis application for brain metastases, mainly as a result of blood–brain barrier selectivity [ 54 ].…”