Sistemsko zdravljenje razsejanih gastrointestinalnih stromalnih tumorjev prilagojeno genotipizaciji tumorja

Unk, Mojca (author), Jezeršek Novaković, Barbara (mentor)

Uvod: Gastrointestinalni stromalni tumorji (GIST) so najpogostejše mezenhimske neoplazme, ki prizadanejo prebavni trakt. Kljub vsemu predstavljajo manj kot en odstotek vseh malignomov prebavil in se uvrščajo med redke bolezni. Glavni dejavnik nastanka teh tumorjev, ne pa edini, so konstitutivne aktivirajoče mutacije protoonkogena KIT (KIT) in gena za receptor trombocitnega rastnega dejavnika A (PDGFRA). Te gonilne mutacije so prisotne pri 85–90% bolnikov z GIST in so medsebojno izključujoče. Prisotnost teh mutacij se je izkazala kot napovedni dejavnik odgovora na zdravljenje s tirozin kinaznimi inhibitorji (TKI) – imatinib, sunitinib, regorafenib, ripretinib, avapritinib, pri bolnikih z razsejanim GIST. Pred pričetkom sistemskega zdravljenja pri bolnikih z GIST je potrebno določiti gonilno mutacijo, da lahko napovemo odgovor na standardno zdravljenje s TKI. Pri 10–15% vseh GIST ne dokažemo aktivacijskih mutacij v KIT in PDGFRA – tedaj govorimo o KIT/PDGFRA divjega tipa (WT) GIST. Zanj je značilen slab odziv na TKI. Bolniki in metode: V raziskavo smo vključili 118 bolnikov z razsejanim KIT pozitivnim GIST, ki so v obdobju med januarjem 2002 in julijem 2020 pričeli z zdravljenjem na Onkološkem inštitutu v Ljubljani (OIL). S standardnima metodama reverzne transkripcije s polimerazno verižno reakcijo (RT-qPCR) in sekvenciranjem tumorske deoksiribonukleinske kisline (DNK) po Sangerju smo opredelili bolnike s KIT/PDGFRA/BRAF WT GIST. Le-te smo zatem dodatno opredelili s sekvenciranjem naslednje generacije (NGS). Pri bolnikih smo zabeležili klinično-patološke značilnosti, molekularne značilnosti tumorja, podatke o datumu napredovanja bolezni in/ali smrti (kjer je do teh dogodkov prišlo) in datum zadnje kontrole. Rezultati: V raziskavi smo pri 43,6% bolnikov s KIT/PDGFRA/BRAF WT GIST, določeno z RT-qPCR in sekvenciranjem DNK po Sangerju, z metodo NGS dokazali, da so v resnici nosilci patogenih mutacij KIT/PDGFRA, in ti bolniki so tudi odgovorili na zdravljenje s TKI. Odstotek resnično KIT/PDGFRA WT GIST v raziskavi se je tako zmanjšal z začetnih 13,7%, določeno z RT-qPCR in sekvenciranjem DNK po Sangerju, na 3,4% določeno z NGS. Njihov izid zdravljenja je bil večinoma slab. Zaključek: Zanesljivost rezultatov RT-qPCR in neposrednega sekvenciranja DNK po Sangerju za opredelitev bolnikov s KIT/PDGFRA/BRAF WT GIST ni zadostna. Priporočamo, da NGS postane pogoj za odločitev o sistemskem zdravljenju vsaj pri tistih bolnikih, ki jih z RT-qPCR in sekvenciranjem DNK po Sangerju opredelimo kot KIT/PDGFRA/BRAF WT GIST.

• Language: Slovenian
• Keywords: gastrointestinalni stromalni tumor (GIST), imatinib, sekvenciranje naslednje generacije (NGS), tirozin kinazni zaviralci (TKI), divji tip (WT)
• Work type: Doctoral dissertation
• Organization: MF - Faculty of Medicine
• Year: 2024
• PID: 20.500.12556/RUL-153569
• Publication date in RUL: 16.01.2024

Secondary language

• Language: English
• Title: Systemic treatment of gastrointestinal stromal tumours based on tumour genotyping

Abstract

Introduction: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal neoplasms affecting the gastrointestinal tract. However, they represent less than 1% of all gastrointestinal malignancies and are classified as rare diseases. Constitutive activating mutations of the KIT proto-oncogene (KIT) and the platelet-derived growth factor receptor A (PDGFRA) gene are the predominant, but not the only, oncogenic drivers of the disease. These driver mutations are present in 85–90% of GIST and are mutually exclusive. The presence of these mutations has been shown to be a predictive factor for response to treatment with tyrosine kinase inhibitors (TKI) – imatinib, sunitinib, regorafenib, ripretinib, avapritinib – in patients with disseminated GIST. The driver mutation should be determined prior to starting of systemic therapy in patients with GIST in order to predict the response to standard TKI therapy. In 10–15% of all GIST, the activating mutations in KIT and PDGFRA are not present – those are the so-called KIT/PDGFRA wild-type (WT) GIST. They are characterized by a poor response to TKI. Patient and methods: In the present study, 118 patients with KIT-positive GIST who started treatment at the Institute of Oncology Ljubljana (OIL) between January 2002 and July 2020 were included. Initially, we identified KIT/PDGFRA/BRAF WT GIST patients by conventional reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Sanger tumor deoxyribonucleic acid (DNA) sequencing method. The KIT/PDGFRA/BRAF WT GIST patients were further characterized by next-generation sequencing (NGS). Clinicopathological features, molecular characteristics of their tumors, date of disease progression and/or death (when applicable) and date of last follow-up were notified. Results: In the present study, 43.6% of patients with KIT/PDGFRA/BRAF WT GIST, as determined by RT-qPCR and Sanger DNA sequencing, were actually shown to be carriers of pathogenic KIT/PDGFRA mutations by NGS and were found responsive to TKI treatment. The percentage of true KIT/PDGFRA WT GIST in this study decreased from an initial 13.7% determined by RT-qPCR and Sanger DNA sequencing to 3.4% determined by NGS. The treatment outcome of truly WT GIST patients was poor. Conclusion: The reliability of RT-qPCR and direct Sanger DNA sequencing methods for the determination of WT GIST is insufficient. We recommend that NGS should become a prerequisite for the decision on systemic therapy at least in KIT/PDGFRA/BRAF WT GIST, as determined by RT-qPCR and Sanger DNA sequencing.

• Keywords: gastrointestinal stromal tumors (GIST), imatinib, next generation sequencing (NGS), tyrosine kinase inhibitors (TKI), wild type (WT)