POGOSTOST IN KLINIČNI POMEN BRAF, NRAS in c-KIT MUTACIJ PRI BOLNIKIH Z NAPREDOVALIM MELANOMOM V SLOVENIJI

Ebert Moltara, Maja (author), Ocvirk, Janja (mentor)

Uvod Incidenca melanoma narašča, vendar ima le manjši del bolnikov napredovali melanom, ki nosi slabo prognozo. V zadnjem obdobju je zdravljenje napredovalega melanoma doživelo velik napredek. Nova dognanja v razumevanju biologije melanoma, njegovega nastanka in poteka so v zdravljenje napredovalega melanoma poleg kemoterapije, učinkovito vpeljala tudi tarčno zdravljenje in imunoterapijo. Zdravljenje se izvaja vedno bolj individualno prilagojeno značilnostim tumorskega tkiva in bolnika. Mutacije v genih za BRAF, NRAS in c-KIT so pogoste in ključno vplivajo na odločitev o vrsti zdravljenja, odgovorih na zdravljenje in zato tudi na preživetja bolnikov z napredovalim melanomom. Namen Z raziskavo smo želeli ugotoviti pogostost BRAF, NRAS in c-KIT mutacij v slovenski populaciji bolnikov z napredovalim melanomom ter oceniti njihov vpliv na potek bolezni in zdravljenje. Metode V našo raziskavo smo vključili 230 bolnikov, ki so bili obravnavani na Onkološkem Inštitutu Ljubljana med aprilom 2013 in julijem 2016 z namenom sistemskega zdravljenja napredovalega melanoma. Raziskavo smo izvajali retrospektivno. Podatke o bolnikih, značilnostih tumorskih tkiv in poteku zdravljenja smo pridobili iz arhiva medicinske dokumentacije Onkološkega Inštituta Ljubljana in jih dopolnili s podatki Registra raka Republike Slovenije. Molekularno analizo smo izvedli z mutacijsko specifično verižno reakcijo s polimerazo v realnem času. Na pridobljenih podatkih smo opravili deskriptivno analizo, analize korelacij ter analizo preživetja. Podatke smo analizirali z račnalniškim paketom SPSS, verzija 22.0. Rezultati Povprečna starost bolnikov je bila 55,4 (20–83) let. 141 (61,3%) je bilo moških, 89 (38,7%) žensk. 167 (72,6%) je imelo melanom kože, 11 (4,8%) melanom očesa, 7 (3,0%) melanom sluznic in 45 (19,6%) melanom neznanega izvora. Mutacijo v genu BRAF smo ugotovili v 129 (56,1%) vzorcih, NRAS v 31 (15,1%) in c-KIT v 3 (1,5%). Bolniki z mutacijo v genu za BRAF so bili mlajši, melanom pa je bil najpogosteje odkrit na trupu. Bolniki z mutacijo v genu za NRAS so bili starejši, melanom pa je bil najpogosteje odkrit na okončinah. Povprečno preživetje bolnikov celotne študijske skupine je bilo 11,4 mesecev. Najkrajša preživetja so imeli bolniki, ki niso prejeli sistemskega zdravljenja 3,7 mesecev, najdaljša pa tisti zdravljeni z imunoterapijo 22,0 mesecev. Mutacija v BRAF in NRAS genu ni pokazala vpliva na celokupno preživetje. V skupini bolnikov z BRAF mutacijo so imeli najkrajša preživetja tisti, ki niso bili zdravljeni z BRAF inhibitorji (V600K 2,7 meseca, V600E 4,5 mesecev). Bolniki z BRAF mutacijo, zdravljeni z BRAF inhibitorji, so imeli daljša preživetja (V600E 12,0 mesecev, V600K 15,7 mesecev). Zaključki Mutacije v BRAF genu so v slovenski populaciji bolnikov z napredovalim melanom pogoste. Vpeljava novih sistemskih zdravljenj (tarčnih zdravil in imunoterapija) vplivajo na učinkovitost zdravljenja in preživetje. Mutacije v genih BRAF, NRAS in c-KIT so ključni elementi pri odločitvi o najprimernejšemu zdravljenju za individualnega bolnika.

• Language: Slovenian
• Keywords: melanom, BRAF, NRAS, c-KIT
• Work type: Doctoral dissertation
• Organization: MF - Faculty of Medicine
• Year: 2018
• PID: 20.500.12556/RUL-102688
• COBISS.SI-ID: 297224448
• Publication date in RUL: 07.09.2018

Secondary language

• Language: English
• Title: Frequency and impact on clinical outcome of BRAF, NRAS and c-KIT mutation in patients with metastatic melanoma in Slovenia

Abstract

Introduction The incidence of melanoma is raising, but only a small proportion of patients have advanced melanoma with poor prognosis. During last several years, the treatment of advanced melanoma has evolved. Understanding the biology of melanoma, its development and spreading are the hallmark of new treatments (target and immune therapy) of advanced melanoma. Treatment strategy is individually tailored according to the patient's and cancer's characteristics. Mutations in BRAF, NRAS and c-KIT are frequent in advanced melanoma. They influence the treatment decision, the responses to treatment and therefore the survival. Purpose Our aim was to determine the frequency of BRAF, NRAS and c-KIT mutations in the Slovene population of patients with advanced melanomas and to evaluate their effect on the course of the disease, treatment response and survival. Methods In our research, we included 230 patients with advanced melanoma who were treated at the Institute of Oncology Ljubljana between April 2013 and July 2016. We collected the data retrospectively. Information about the patients’ data, tumor characteristics and treatments were obtained from the archives of medical documentation and supplemented with data from The Cancer Registry of Republic of Slovenia. Molecular analysis was performed with a real-time PCR method. We have analysed the data with descriptive, correlation and survival analysis. As a statistical program we have used SPSS program, version 22.0. Results The average age of patients was 55,4 (20–83) years. 141 (61,3%) were men, 89 (38,7%) women. 167 (72,6%) had skin melanoma, 11 (4,8%) ocular melanoma, 7 (3,0%) mucous membrane melanoma, and 45 (19,6%) had melanoma of unknown primary origin. Mutation in the BRAF gene was found in 129 (56,1%), NRAS in 31 (15,1%) and c-KIT in 3 (1,5%) samples. Patients with BRAF mutation tend to be younger and with the most frequent location of melanoma on the trunk. Patients with NRAS mutation tend to be older and with the most frequent location of melanoma at the extremities. The average survival was 11, 4 months, with the lowest survival in a group of patients who didn’t receive systemic treatment 3,7 months. The longest survival of 22,0 months was observed in a group of patients who have been treated with immunotherapy. Mutation in BRAF and NRAS gene didn’t have any influence on overall survival. Among patients with BRAF mutation, the worst survival was in a group of patient with V600K mutation without treatment with BRAF inhibitors 2,7 months. Patients with V600E mutation had median survival of 4,5 months, if they received no treatment with BRAF inhibitors and 12,0 months if they did. The group with the longest survival had V600K mutation and was treated with BRAF inhibitors 15,7 months. Conclusions Mutation in the BRAF gene is common in the Slovene population of patients with advanced melanoma. The introductions of new systemic treatments (target and immuno therapy) have influenced on melanoma progression and survival. Mutations in the BRAF, NRAS and c-KIT genes are key elements in decision making which treatment is the most appropriate for an individual patient.

• Keywords: melanoma, BRAF, NRAS, c-KIT