20.500.12556/DKUM-47685-9aa73fd2-27d0-729c-69f3-44035b5f9513 Značilnosti poteka bolezni pri žleznem raku pljuč glede na aktivirajoče mutacije gena za epidermalni rastni faktor The characteristics of the course of the disease in lung adenocarcinoma in relation to activating mutations of the gene for epidermal growth factor receptor Uvod Zdravljenje žleznega raka pljuč je zaradi novih odkritij na področju molekularne biologije in novih tarčnih zdravil vse bolj prilagojeno posameznemu bolniku. Najbolj raziskan je receptor za epidermalni rastni dejavnik (EGFR), pri katerem aktivirajoče mutacije omogočajo zdravljenje z novimi tarčnimi zdravili. Pri kliničnem delu smo opažali precejšnje razlike med bolniki z žleznim rakom pljuč glede na EGFR-status, zato smo želeli ugotovili, ali se pri teh bolnikih mesta zasevkov ob diagnozi in njihovo pojavljanje med boleznijo, način zdravljenja, čas do napredovanja bolezni in preživetje, razlikujejo. Naša hipoteza je bila, da imajo bolniki z aktivirajočimi EGFR-mutacijami že ob diagnozi drugačen vzorec razsoja. Po kliničnih izkušnjah in do tedaj skromnih objavljenih podatkih smo domnevali, da imajo ti bolniki več zasevkov v centralni živčni sistem (CŽS) in kosti. Metode Raziskava je bila populacijsko observacijska, delno retrospektivna in delno prospektivna. Med bolniki z nedrobnoceličnim rakom pljuč, pri katerih je bilo opravljeno testiranje na aktivirajoče mutacije EGFR v letih 2010 in 2011, smo izbrali bolnike z žleznim rakom pljuč ter pregledali njihovo medicinsko dokumentacijo in njihovo zdravljenje spremljali do oktobra 2013. Rezultati Med 629 bolniki z žleznim rakom pljuč je imelo 137 (21,8 %) bolnikov prisotne aktivirajoče EGFR-mutacije. Značilno več bolnikov z EGFR-mutacijami je bilo med ženskami in nekadilci, mejno značilno več pa je bilo bolnikov z razsejanim stadijem bolezni. Bolniki z EGFR-mutiranimi tumorji, ki so kadarkoli med boleznijo razvili oddaljene zasevke, so imeli v primerjavi z bolniki brez mutacij značilno več zasevkov v CŽS (34 % proti 25 %), kosti (49 % proti 31 %), plevro (38 % proti 24 %) in pljuča (64 % proti 46 %). Razliko smo zaznali že ob diagnozi, saj so imeli EGFR-mutirani bolniki več zasevkov v kosti (35 % proti 22 %) in pljuča (37 % proti 22 %). Za CŽS je bila razlika ob diagnozi mejno značilna (19 % za mutirane in 13 % za nemutirane), vendar klinično pomembna. Pri tistih bolnikih, pri katerih je prišlo do razsoja bolezni, se je čas do razvoja zasevkov v posamezne organe razlikoval glede na EGFR-status. Zasevki so se značilno kasneje razvili pri EGFR-mutiranih bolnikih kot pri nemutiranih v CŽS (25,8 proti 11,8 meseca), pljuča (25,9 proti 9,9 meseca) in plevro (20,6 proti 9,9 meseca). Celokupno srednje preživetje vseh bolnikov je bilo 16,0 mesecev, značilno daljše za EGFR-pozitivne (32,7 meseca) kot za EGFR-negativne bolnike (13,7 meseca). Zaključki Bolniki z EGFR-mutacijami so imeli že ob diagnozi značilno več zasevkov v kosteh in pljučih, za CŽS pa je bila vrednost mejno značilna. Med potekom bolezni se je pojavilo pri bolnikih z EGFR-mutacijami več novih zasevkov v plevro, pri razsoju v druge organe pa ni bilo razlike med mutiranimi ter nemutiranimi tumorji. Bolniki z EGFR-mutiranimi tumorji so kasneje razvili zasevke v CŽS, pljuča in plevro kot nemutirani bolniki, pri napredovanju v ostale organe pa nismo beležili razlik glede na EGFR-status. Celokupno srednje preživetje bolnikov z EGFR-mutacijami je bilo značilno daljše kot za bolnike brez mutacij, ne glede na stadij bolezni in mesto ter število zasevkov. Pri polovici bolnikov z EGFR-mutacijami, lahko pričakujemo zasevke v kosti. Za bolnike, ki nimajo opravljene PET/CT preiskave v sklopu diagnostičnih preiskav za zamejitev bolezni, je zato kljub znanemu razsejanemu stadiju bolezni smiselno narediti scintigrafijo skeleta že ob diagnozi. Čas do razsoja bolezni v CŽS in preživetje sta za bolnike z odkritimi zasevki ob diagnozi za EGFR-mutirane bolnike ob ustreznem zdravljenju bistveno daljša kot za nemutirane bolnike, zato je tudi pri teh bolnikih pomembna skrbna diagnostika za prognozo ter zdravljenje bolezni. Introduction Treatment of lung adenocarcinoma is nowadays increasingly tailored to the individual patient due to new discoveries in the field of molecular biology and new targeted drugs. Among the most studied is the receptor for epidermal growth factor (EGFR), wherein the activating mutations allow the treatment with the new targeted drugs. In clinical work, we observed significant differences between patients according to EGFR-status, therefore we wanted to determine whether in these patients sites of metastases at diagnosis and their occurrence during the course of the disease, type of treatment, time to disease progression and survival, vary. Our hypothesis was that patients with activating EGFR mutations hold a different pattern of metastatic spread already at the time of diagnosis. According to our clinical experience and previously scarce published data, we assumed that those patients have more metastases in the central nervous system (CNS) and bone. Methods Our research was a type of observational population study, partly retrospective partly prospective. Among patients with non-small cell lung cancer, tested for activating EGFR mutations in the years 2010 and 2011, we selected patients with lung adenocarcinoma and reviewed their medical records and monitored their treatment by October 2013. Results Among the 629 patients with lung adenocarcinoma 137 (21.8%) patients had activating EGFR mutations. More patients with EGFR mutations were women and non-smokers, there were also more patients with metastatic stage of the disease, though not statistically significant. Patients with EGFR mutated tumors as compared to patients without EGFR mutations developed significantly more distant metastases to CNS (34% vs. 25%), bone (49% vs. 31%), pleura (38% vs. 24%) and lung (64% vs. 46%) at any time during the course of the disease. The difference was observed already at the time of diagnosis, since EGFR mutated patients had more metastases in bone (35% vs. 22%) and lung (37% vs. 22%). The difference for CNS at diagnosis was threshold significant (19% for the mutated, and 13% for the non-mutated), but clinically relevant. In those patients who developed metastases, time to development of metastases to specific organs was different according to EGFR status. Metastases to CNS (25.8 vs. 11.8 months), lung (25.9 vs. 9.9 months) and pleura (20.6 vs. 9.9 months) developed significantly later in EGFR mutated patients than in non-mutated. Median overall survival of all patients was 16.0 months, significantly longer for EGFR-positive (32.7 months) than for EGFR negative patients (13.7 months). Conclusions Patients with EGFR mutations had significantly more metastases in the bones and lungs already at the time of diagnosis and marginally significantly more in the CNS. During the course of the disease, patients with EGFR mutations developed more new metastases to pleura, but there was no difference between EGFR mutated and non-mutated tumors in other organs. Patients with EGFR-mutated tumors developed metastases in the central nervous system, lungs and pleura later than wild-type patients, while no distinction based on EGFR status has been recorded for progression to other organs. Median overall survival of patients with EGFR mutations was significantly longer than for patients without mutations, regardless of the stage of the disease, location and number of metastases. In half of the patients, we can expect metastases to bone. For patients who had not performed PET/CT as a part of diagnostic tests for the disease stage determination, therefore, in spite of the known disseminated stage, bone scintigraphy is justified already as a part of diagnostic procedures at diagnosis. As the time to CNS disease dissemination and survival for EGFR mutated patients is significantly longer if treated appropriately, careful diagnostic procedures for prognosis and treatment of disease is warranted in these patients. EGFR-mutacije žlezni rak pljuč zasevki vzorec razsoja preživetje EGFR mutations lung adenocarcinoma metastases metastatic pattern survival true false false Slovenski jezik Angleški jezik Doktorsko delo/naloga 2015-03-26 12:45:53 2015-04-16 11:29:04 2022-05-22 03:07:50 2021-05-07 03:27:11 2015 0 Maribor 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 512487736 URN:SI:UM:DK:ALZSN9TL DOK_Stanic_Karmen_2015.pdf DOK_Stanic_Karmen_2015.pdf 1 7A3DE10571162672BD2D3D41D912B1BC 4a826819667aa6c086e93c831e834ab2433608c5a850b11e48655fdaf4b3415f f6a933f6-7c07-11eb-bb7a-00155d0001ca https://dk.um.si/Dokument.php?lang=slv&id=70938 Medicinska fakulteta 0 0 0