Quantitative monitoring of circulating tumor DNA predicts response of cutaneous metastatic melanoma to anti-PD1 immunotherapy

Abstract

Immunotherapies have changed the medical management of metastatic melanoma. However, the early detection of patients who do not respond to these treatments is a key issue. We evaluated the quantitative monitoring of circulating tumor DNA (ctDNA) as an early predictor of response to anti-PD1. Patients treated with anti-PD1 for metastatic mutated melanoma were selected. The somatic alteration detected on the tumor tissue was quantified on plasma DNA by digital PCR (dPCR) at treatment initiation, after 2 and 4 weeks of treatment, and then every 4 weeks until progression. The absence of biological response (defined as a significant decrease in the amount of ctDNA relative to the baseline level) after 2 weeks of treatment was associated with a lack of clinical benefit under anti-PD1. In the presence of a biological response at week 2, detection of subsequent biological progression (significant increase in the amount of ctDNA relative to its nadir) was 100% predictive of progressive disease, on average 75 days prior to radiological detection. Patients with a persistent biological response beyond week 16 did not experience any progressive disease and exhibited sustained responses. In conclusion, we show that quantitative monitoring of ctDNA, using criteria accounting for dPCR measurement imprecision, allows the early and specific detection of patients who do not respond to anti-PD1 therapy.

PD-L1 Expression on Circulating Tumor Cells May Be Predictive of Response to Pembrolizumab in Advanced Melanoma: Results from a Pilot Study

“…CTCs were not detectable in about a third of patients, which could be related to disease biology or technical limitations. For comparison, circulating tumor DNA is detectable in around 43%–76% of patients with advanced melanoma , suggesting that circulating markers are below detection in some patients with melanoma despite disseminated disease. There was no standardization of imaging modalities used to assess response to treatment.…”

Liquid Biopsies in Cancer Diagnosis, Monitoring, and Prognosis

“…Allele-specific PCR was the first approach used in ctDNA detection [16] and a quantitative PCR (qPCR) variation of this technique is currently adopted by the cobas® EGFR test [8]. Considering that the fraction of ctDNA in total cfDNA is usually very low, often less than 0.01% [21], more sensitive technologies have been developed and successfully used for ctDNA analysis, such as digital PCR (dPCR) [22], droplet digital PCR (ddPCR) [23] and Beads, Emulsion, Amplification, Magnetics (BEAMing) [24]. Although very sensitive, quick and relatively inexpensive, PCRbased assays are limited by low multiplexing capacity, allowing for analysis of a restricted number of loci in parallel [13].…”

High‐throughput isolation of circulating tumor DNA: a comparison of automated platforms

“…With the discovery of cell‐free DNA (cfDNA), first described in 1948 by Mandel and Metais (), and subsequently circulating tumor DNA (ctDNA; Stroun et al ., ), a novel biomarker in cancer research became available. Since then, many studies have shown its great potential for detecting minimal residual disease and evaluating treatment response (Bidard et al ., ; Dawson et al ., ; Diaz and Bardelli, ; Diehl et al ., ; Forshew et al ., ; Herbreteau et al ., ; Murtaza et al ., ; Pugh, ; Shinozaki et al ., ). However, to enable high‐throughput ctDNA analyses a fast, accurate, and efficient cfDNA isolation method is highly needed.Currently, the majority of ctDNA studies use Qiagen's QIAamp (QA) platform for cfDNA isolation (Oxnard et al ., ; Sefrioui et al ., ; Zill et al ., ).…”