ADN tumoral circulant : aspects analytiques et intérêt dans la prise en charge des patients ayant un mélanome métastatique : Circulating tumour DNA: analytical aspects and clinical applications for metastatic melanoma patients

International audienceThe management of metastatic melanoma has evolved since the onset of treatments with BRAF inhibitors. In order to predict which patients are likely to respond to these treatments, the therapeutic strategy is now conditioned by the search for the activating mutations of the BRAF gene. Tumor genotyping is routinely performed from DNA extracted from tissue or cellular specimens from the primary tumor, metastases, or neoplastic effusions. Due to their invasiveness, these specimens are rarely repeated during the management. In addition, the analysis of the tumor material requires a pretreatment of the sample (formalin fixation, paraffin inclusion, preparation of tissue sections) and may take up to several weeks, making emergency treatment with BRAF inhibitors impossible. Circulating tumor DNA (ctDNA), released by cancer cells in the blood stream, appears as an alternative to tissue sampling. The pre-analytical conditions are now well defined, and several technological approaches can be used to demonstrate the desired molecular alterations. ctDNA is less affected by tumor heterogeneity, can be collected in a minimally invasive manner and analyzed rapidly. Furthermore, ctDNA can be repeatedly analyzed during follow-up, which makes it possible to envisage its use as a specific tumor marker, in order to monitor the response to the treatment and to detect treatment failure.La prise en charge du mélanome cutané métastatique a considérablement évolué depuis l’apparition des traitements ciblés par inhibiteurs de BRAF. Afin de prédire quels patients sont susceptibles de répondre à ces traitements, la stratégie thérapeutique est désormais conditionnée par la recherche des mutations activatrices du gène BRAF. Le génotypage tumoral est effectué en routine à partir de l’ADN extrait de prélèvements tissulaires ou cellulaires provenant de la tumeur primitive, de métastases, ou d’épanchements néoplasiques. Du fait de leur caractère invasif ces prélèvements sont rarement répétés au cours de la prise en charge. De plus, l’analyse du matériel tumoral nécessite un prétraitement de l’échantillon (fixation au formol, inclusion en paraffine, préparation de coupes fines) et peut demander plusieurs semaines, rendant impossible tout traitement en urgence par inhibiteurs de BRAF. L’ADN tumoral circulant (ADNtc), libéré par la cellule cancéreuse dans la circulation sanguine, apparaît comme une alternative au prélèvement tissulaire. Les conditions pré-analytiques sont bien définies, et plusieurs approches technologiques peuvent être utilisées pour mettre en évidence les altérations moléculaires recherchées. L’ADNtc n’est pas soumis à l’hétérogénéité tumorale, peut être obtenu de façon peu invasive et analysé rapidement. De plus, l’ADNtc peut être analysé de façon répétée au cours du suivi, ce qui permet d’envisager son utilisation comme marqueur tumoral spécifique, afin de monitorer la réponse au traitement et détecter l’échappement thérapeutique

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

International audienceImmunotherapies 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

Profile of vemurafenib-induced severe skin toxicities

International audienceBACKGROUND: Vemurafenib, a BRAF inhibitor, is commonly associated with skin toxicity. The impact of severe forms is unknown.OBJECTIVE: To determine the rate of permanent vemurafenib discontinuation due to grade 3-4 skin toxicity, features of these toxicities, their recurrence rate after a switch to dabrafenib and their impact on overall survival.METHODS: Retrospective cohort study of 131 patients treated with vemurafenib for melanoma between November 2010 and December 2014. Data on skin toxicities, the need for vemurafenib adjustment and the impact of switching to dabrafenib were collected. Regarding survival analysis, a conditional landmark analysis was performed to correct lead-time bias.RESULTS: Among the 131 vemurafenib-treated patients, 26% developed grade 3-4 skin toxicity. Forty-four percent of them permanently discontinued their treatment, mainly due to rash and classic skin adverse reactions (Steven-Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms). Conversely, photosensitivity and carcinomas rarely required treatment adjustment. Grade 3-4 rashes were associated with clinical or biological abnormalities in 94% of patients. Among the 10 patients who subsequently switched to dabrafenib, skin toxicity recurred only in one patient. Overall survival was significantly prolonged in case of severe skin toxicity emerging within the first 4 (P = 0.014) and 8 weeks (P = 0.038) on vemurafenib, with only a trend at 12 weeks (P = 0.052). Median overall survival was also prolonged in case of severe rash.CONCLUSION: In this study, vemurafenib was continued in 56% of patients with grade 3-4 skin toxicity, which was associated with prolonged overall survival when emerging within the first 4 and 8 weeks of treatment. While developing severe skin adverse reactions permanently contraindicates vemurafenib use, other rashes should lead to retreatment attempts with dose reduction. In case of recurrence, dabrafenib seems to be an interesting option. For other skin toxicities, including photosensitivity and cutaneous carcinoma, treatment adjustment is usually not needed

BRAF mutations might be more common than supposed in vulvar melanomas

International audienceData on BRAF, NRAS and KIT mutations are scarce in patients with vulvo-vaginal melanomas and are associated with important therapeutic issues. We investigated their prevalence in a cohort of patients with female lower genital tract melanomas between 2003 and 2017. Of the 22 patients, 5 (22.7 %) harbored a BRAF mutation which was much higher than the rate of 5% reported in the literature. One patient, who was tested negative on the primary melanoma, had a NRAS mutation in a cutaneous metastasis. Our data provides a rationale for prospective and repeated mutations testing in female lower genital tract melanomas

Incidence and Mortality of Pemphigus in France

International audienceNo abstract availabl

Photodynamic therapy with methyl-aminolevulinic acid for paucilesional mycosis fungoides: A prospective open study and review of the literature

International audienceBackground: Publications reporting photodynamic therapy (PDT) in mycosis fungoides (MF) are rare, involve small samples, and are difficult to compare because of a lack of technical standardization. Objective: We sought to assess PDT effectiveness and tolerability in early-stage MF using a strict reproducible procedure. Methods: This was a prospective study conducted in Nantes University Hospital, France, including patients older than 18 years with histologically proven MF (stage IA or IB). Methyl-aminolevulinic acid-PDT sessions were repeated monthly for 6 months. Clinical and histologic responses were assessed 1 month after the last session. Patient satisfaction was assessed by telephone survey. Results: Twelve patients (with 29 lesions) were treated with PDT. An objective response in target lesions was obtained in 75% of patients. Response rates were similar between plaques and patches but higher in sun-protected compared with sun-exposed areas (trend without reaching significance). During PDT, new lesions appeared in 5 of 12 patients in untreated areas. Most patients were highly satisfied and preferred PDT to the topical chemotherapy previously used. Limitations: PDT procedure criteria selection was partially arbitrary. Conclusions: In early-stage MF, PDT is effective and appreciated (especially when compared with conventional topical chemotherapy). Unilesional and paucilesional forms and lesions in sun-protected areas are to be preferred