New biomarkers for targeted immunotherapy in endometrial cancer

Abstract

Karcinom endometrija (KE) najčešća je zloćudna novotvorina ženskog spolnog sustava i četvrti najčešći karcinom kod žena u zemljama razvijenog svijeta. U proteklom desetljeću incidencija KE bilježi porast od 2,4% i mortaliteta 1,9% godišnje. Ovaj neuspjeh u prevenciji i liječenju dijelom počiva na činjenici slabog razumijevanja heterogenosti i biološke raznolikosti ove zloćudne bolesti. The Cancer Genome Atlas Research Network nudi novu klasifikaciju KE kojom definira četiri podskupine karcinoma na temelju njihovih genetskih karakteristika. Integracija njihovih saznanja u postojeću klasifikaciju čini se nužna za stvaranje optimalne dijagnostičke i prognostičke klasifikacije. Ultramutirani tumori s velikim brojem somatskih mutacija unutar egzonuklearne domene DNA polimeraze epsilon (engl. polymerase epsilon exonuclease domain, POLE) i hipermutirani tumori s mikrosatelitnom nestabilnošću (engl. microsatellite instability, MSI), dvije su podskupine KE koji pokazuju visoku stopu ekspresija proteina programirane smrti 1 (engl. programmed death-1, PD-1) i njegova liganda (engl. programmed death ligand-1, PD-L1). Farmakološka inhibicija puta PD-1 / PD-L1 omogućava reaktivaciju imunološkog odgovora protiv tumora, odnosno smanjuje tumorom induciranu imunološku supresiju. Ova hipoteza je dala uspješne kliničke rezultate u drugim vrstama malignih bolesti kao što su nesitnostanični karcinomi pluća, melanom, karcinoma bubrega i mokraćnog mjehura. Nivolumab i pembrolizumab, oba monoklonska protutijela na PD-1 limfocitni receptor, dali su zadovoljavajuće preliminarne rezultate u imunoterapiji KE i znatno manju citotoksičnost od standardne adjuvantne terapije.Endometrial cancer (ED) is the most common malignancy of the female reproductive system and the fourth most common cancer in women in the developed world. In the past decade, the incidence of ED has increased by 2.4% and mortality by 1.9% per year. This failure in prevention and treatment rests in part on the fact of a poor understanding of the heterogeneity and biodiversity of this malignancy. The Cancer Genome Atlas Research Network provides a new classification of ED which defines four subgroups of cancers based on their genetic characteristics. The integration of their knowledge into the existing classification seems necessary to create an optimal diagnostic and prognostic classification. Ultramutated tumors with a large number of somatic mutations within the polymerase epsilon exonuclease domain (POLE) and hypermutated tumors with microsatellite instability (MSI) are two subgroups of the ED with significant expression of PD-1 (programmed death-1) and its ligand PD-L1 (programmed death ligand-1). Pharmacological inhibition of the PD-1 / PD-L1 pathway enables reactivation of the immune response against the tumor and therefore reduces tumorinduced immune suppression. This hypothesis has shown successful clinical outcomes in other types of malignancies such as non-small cell lung cancers, melanoma, kidney, and bladder cancers. Nivolumab and pembrolizumab, both monoclonal antibodies to the PD-1 lymphocyte receptor, give solid preliminary results in ED immunotherapy and significantly lower cytotoxicity than standard adjuvant therapy