Metastasized or unresectable melanoma has been the first malignant tumor to be successfully treated with checkpoint inhibitors.,Nevertheless, about 40-50% of the patients do not respond to these treatments and severe side effects are observed in up to 60%.,Therefore, there is a high need to identify reliable biomarkers predicting response.,Tumor Mutation Burden (TMB) is a debated predictor for response to checkpoint inhibitors and early measurement of ctDNA can help to detect treatment failure to immunotherapy in selected melanoma patients.,However, it has not yet been clarified how TMB and ctDNA can be used to estimate response to combined CTLA-4 and PD-1 antibody therapy in metastatic melanoma.,In this prospective biomarker study, we included 35 melanoma patients with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) therapy.,In all patients, a tumor panel of 710 tumor-associated genes was applied (tumor vs. reference tissue comparison), followed by repetitive liquid biopsies.,Cell-free DNA was extracted and at least one driver mutation was monitored.,Treatment response was evaluated after about three months of therapy.,TMB was significantly higher in responders than in nonresponders and TMB > 23.1 Mut/Mb (TMB-high) was associated with a survival benefit compared to TMB ≤ 23.1 Mut/Mb (TMB-low or TMB-intermediate).,Furthermore, a > 50% decrease of cell-free DNA concentration or undetectable circulating tumor DNA (ctDNA), measured by tumor-specific variant copies/ml of plasma at first follow-up three weeks after treatment initiation were significantly associated with response to combined immunotherapy and improved overall survival, respectively.,It is noticeable that no patient with TMB ≤ 23.1 Mut/Mb and detectable or increasing ctDNA at first follow-up responded to immunotherapy.,High TMB, > 50% decrease of cell-free DNA concentration, and undetectable ctDNA at first follow-up seem to be associated with response and overall survival under combined immunotherapy.,The evaluation of ctDNA and cell-free DNA three weeks after treatment initiation may be suitable for early assessment of efficacy of immunotherapy.,The online version of this article (10.1186/s40425-019-0659-0) contains supplementary material, which is available to authorized users.
Malignant melanoma is a rare disease in Asia, and knowledge on its characteristics and clinical outcome in Asian patients is limited.,The purpose of this observational study was to determine the clinical presentation and outcome of patients with melanoma in China.,A database was prospectively established for the purpose of this analysis.,The elements of the database included basic demographic data of patients and prognosticators previously reported in literature, as well as follow-up data including clinical outcome after treatment.,Medical record of all patients with pathologically diagnosed malignant melanoma consulted in our center since 2006 were retrieved and reviewed.,No patient was excluded in this study.,Statistical analyses including survival and multivariate analyses of factors associated with survival were respectively performed by Kaplan-Meier method and Cox proportional hazard model.,A total of 522 consecutive and nonselected cases were evaluated.,There were 218 cases (41.8%) of acral lentiginous melanoma (ALM), 118 (22.6%) of mucosal melanoma (MCM), 103 (19.7%) of nodular melanoma (NM), 33 (6.3%) of superficial spreading melanoma (SSM), and others were Lentigo maligna melanoma or unclassifiable disease.,The proportion of patients with clinical stage I, II, III, and IV diseases were 6.1%, 55.9%, 25.1%, and 12.8%, respectively.,Among the 357 cases of cutaneous melanoma, 234 patients (65.5%) had ulceration.,The 5-year overall survival rate of all 522 patients was 41.6%, and the median survival time was 3.92 years (95% CI, 3.282 to 4.558).,Five-year survival rates of patients with stage I, II, III, and IV diseases were 94.1%, 44.0%, 38.4% and 4.6% respectively (P < 0.001).,Multivariate analysis revealed that clinical stage and the ulceration were two significant prognosticators for OS.,In addition, extent of surgery and use of adjuvant therapy were significant prognosticators for DFS in patients with non-metastatic disease after definitive treatment.,Pathological subtype was not a significant prognostic factor to predict wither OS or DFS.,Prognoses of patients with malignant melanoma diagnosed in China were suboptimal, and most patients were diagnosed with locally advanced disease (i.e., stage II or above).,ALM and MCM are the two most commonly diagnosed pathological subtypes.,Clinical staging and presence of ulceration was significantly associated with clinical outcome in terms of OS, while treatment strategy including extent of surgery and use of adjuvant therapy were significant predictors of DFS.