Acta Dermato-Venereologica 99-2CompleteContent | Page 18

206 INVESTIGATIVE REPORT Early Circulating Tumour DNA Variations Predict Tumour Response in Melanoma Patients Treated with Immunotherapy Laura KELLER 1–3 , Nicolas GUIBERT 1–4 , Anne CASANOVA 1,2 , Stephanie BRAYER 5 , Magali FARELLA 1,2 , Myriam DELAUNAY 1–4 , Julia GILHODES 6 , Elodie MARTIN 6 , Gisèle BALAGUÉ 7 , Gilles FAVRE 1–3 , Anne PRADINES 1,2 and Nicolas MEYER 2,3,5 1 Medical Biology Laboratory, 6 Biostatistics Department and 7 Medical Imaging Department, Claudius Regaud Institute, Toulouse University Cancer Institute (IUCT-O), 2 CRCT, Inserm, University of Toulouse III - Paul Sabatier, CNRS, 3 University of Toulouse III - Paul Sabatier, 4 Thoracic Oncology Department, Larrey Hospital, University Hospital of Toulouse, and 5 Dermatology Department, University Hospital of Toulouse, Toulouse University Cancer Institute (IUCT-O), Toulouse, France Antibodies targeting immune checkpoints were re- cently approved for metastatic melanoma. However, not all patients will respond to the treatment and some will experience grade III–IV immune-related adverse events. Therefore, early identification of non- responder patients would greatly aid clinical practice. Detection of circulating tumour DNA (ctDNA) is a non- invasive approach to monitor tumour response. Digital droplet PCR was used to quantify BRAF and NRAS mu- tations in the plasma of patients with metastatic mela- noma treated with immunotherapy. In 16 patients, ct- DNA variations mirrored tumour response (p  = 0.034) and ctDNA augmentation during follow-up detected tumour progression with 100% specificity. In 13 pa- tients, early ctDNA variation was associated with clini- cian decision at first evaluation (p  = 0.0046), and early ctDNA increase with shorter progression-free survival (median 21 vs. 145 days; p  = 0.001). Monitoring ctDNA variations early during immunotherapy may help clini- cians rapidly to discriminate non-responder patients, allow early adaptation of therapeutic strategies, and reduce exposure to ineffective, expensive treatment. Key words: ctDNA; melanoma; immunotherapy; biomarker; therapeutic response. Accepted Nov 1, 2018; E-published Nov 5, 2018 Acta Derm Venereol 2019; 99: 206–210. Corr: Dr Anne Pradines, Medical Biology Laboratory, Claudius Regaud In- stitute, Toulouse University Cancer Institute (IUCT-O), FR-31059 Toulou- se Cedex 9, and Pr. Nicolas Meyer, CRCT, Inserm, University of Toulouse III - Paul Sabatier, CNRS, FR-31000 Toulouse Cedex 9, France. E-mail: [email protected]; [email protected] I mmune checkpoint inhibitors (anti-CTLA-4, anti-PD1 or combination of both) have revolutionized the treat­ ment of metastatic melanoma (1) with striking results on overall survival (OS) in advanced-stage metastatic melanoma (the 3-year OS were, respectively, 34%, 52% and 58%) (2). However, this mode of treatment is effec- tive only in a subset of patients as 40–65% have shown minimal or no RECIST (Response Evaluation Criteria in Solid Tumours) response and 43% of responders develop acquired resistance by 3 years (2). In addition, up to 55% of patients may experience grade 3–4 immune-related adverse events (2–5). Today, none of predictive biomar- kers appear sufficiently robust and easily transferable doi: 10.2340/00015555-3080 Acta Derm Venereol 2019; 99: 206–210 SIGNIFICANCE Immunotherapy has yielded a dramatic improvement in the prognosis and survival of patients with unresectable melanoma. However, not all patients respond to treatment and some experience severe adverse events. The detec- tion of mutations in peripheral blood (i.e. ctDNA) is a new, non-invasive approach to monitor tumour response. Using a sensitive method, this study showed that early assess- ment of ctDNA variation during the course of therapy could predict the tumour response to treatment. These results may help clinicians to rapidly discriminate non-responders, allowing early adaptation of therapeutic strategies and re- ducing their exposure to ineffective and costly treatment. into clinical practice to guide treatment choices. Indeed, intratumoural lymphoid infiltrates and tumoural PD-L1 expression at baseline both have a lack of discriminative capacity between responders and non-responders (6, 7). The interpretation of PD-L1 immunostaining on pri- mary tumour biopsies is currently limited by spatiotem- poral intratumoural heterogeneity. As a consequence, the choice of treatment and evaluation of its efficacy is based on clinical–radiological criteria 12 weeks after induction, since contrary to chemotherapies, immunotherapy (IT) demonstrates a delayed response to treatment. Thus, development of new, early prognostic and predictive biomarkers to enable fine monitoring of tumour response is critical, as it may: (i) reduce exposure to potentially toxic and expensive treatments in non-responders; (ii) allow for early adaptation of therapeutic strategies in non-responders; and (iii) provide useful information for the management of adverse events in responders. Detection of mutations in circulating cell-free tumour DNA (i.e. ctDNA) is a useful, non-invasive and repea- table approach that can be used to assess the mutational status of tumours in different cancers (8). ctDNA has been correlated with baseline tumour burden (9–11) and with tumour-size evolution (12). Moreover, it overcomes tumour heterogeneity. Our team has recently shown the utility of detection of BRAFV600E and KRAS mutations in plasma to monitor non-small-cell lung cancer evolu- tion (13, 14) and to discriminate pseudo-progression cases (15). This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica.