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

// Guillaume Herbreteau 1, 2 , Audrey Vallee 1, 2 , Anne-Chantal Knol 2 , Sandrine Theoleyre 1, 2 , Gaelle Quereux 2, 3, 4 , Emilie Varey 2, 4 , Amir Khammari 2, 3, 4 , Brigitte Dreno 2, 3, 4 and Marc G. Denis 1, 2 1 Laboratoire de Biochimie et Plateforme de Genetique Moleculaire des Cancers, CHU Nantes, Nantes, France 2 Centre de Recherche en Cancerologie et Immunologie, CRCINA, INSERM U1232, Nantes, France 3 Service de Dermatologie, CHU Nantes, Nantes, France 4 Centre d’Investigation Clinique INSERM CIC1413, CHU Nantes, Nantes, France Correspondence to: Marc G. Denis, email: marc.denis@chu-nantes.fr Keywords: metastatic melanoma; anti-PD1; circulating tumor DNA; cell-free DNA; digital PCR Received: March 02, 2018      Accepted: April 28, 2018      Published: May 18, 2018 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.