Genomika raka prostate: klinička primjena i izazovi

The studying of prostate cancer genomics is important for understanding prostate cancer biology, it can provide clinically relevant stratification into subtypes, the development of new prognostic and predictive markers in the context of precision medicine, and the development of new targeted therapies. Recent studies have provided detailed insight into genomics, epigenomics and proteomics of prostate cancer, both primary and metastatic castration-resistant (mCRPC). Many mutations have been discovered, both those that occur early in the carcinogenesis and progression as well as those responsible for the resistance to therapy occurring later under the influence of treatment. A large number of characteristic mutated signaling pathways has been identified, e.g. the mutations in DNA repair pathway were found in 23% of mCRPC, which suggests potential response to PARP inhibitors. Multifocality and intralesional genomic heterogeneity of prostate cancer make the clinical application of genomics complicated. Although a great progress was made in understanding prostate cancer genomic, and clinical studies related to its routine application are ongoing, prostate cancer genomics still needs to find its standard wide routine application in patients with prostate cancer.Istraživanje genomike raka prostate je važno za razumijevanje biologije raka prostate, može omogućiti klinički relevantnu stratifikaciju u podtipove, razvoj novih prognostičkih i prediktivnih biljega u kontekstu precizne medicine i razvoj novih ciljanih terapija. Novija istraživanja omogućila su detaljan uvid u genomiku, epigenomiku i proteomiku raka prostate, i primarnog i metastatskog otpornog na kastraciju (mCRPC). Tako je otkriven velik broj karakterističnih mutacija, kako onih koje se događaju rano u nastanku i progresiji raka prostate, tako i onih koje nastaju kasnije pod utjecajem terapije i odgovorne su za rezistenciju na liječenje. Identificirani su signalni putovi karakteristično pogođeni mutacijama, npr. u 23% mCRPC nađene su mutacije u genima za popravak oštećenja DNA što ukazuje na moguć odgovor na liječenje PARP inhibitorima. Ono što komplicira kliničku primjenu genomike je multifokalnost te intralezijska i interlezijska genomska heterogenost raka prostate. Iako je ostvaren veliki napredak u razumijevanju genomike raka prostate i provode se klinička istraživanja vezana uz njenu rutinsku primjenu, genomika još treba naći svoju standardnu široku rutinsku primjenu u bolesnika s rakom prostate

Izazovi manipuliranja imunološkim sustavom u svrhu liječenja raka prostate

First cancer vaccine that was approved for routine therapy was sipuleucel-T for treatment of patients with metastatic castration resistant prostate cancer. However, other immunotherapy drugs evaluated in prostate cancer, particularly immune checkpoint inhibitors, have failed to show therapeutic effect. There are several potential explanations for lack of response of prostate cancer to these drugs. These explanations, which are related to specific genetic (e.g. low mutational burden) and immunological (e.g. immunosuppressive tumor immune microenvironment) background of prostate cancer are discussed in this review. Also, new therapeutic strategies to overcome prostate cancer immunotherapy resistance and to select subgroups of patients that could benefit from immunotherapy are outlined.Prva vakcina za rak koja je odobrena za rutinsko liječenje bio je sipuleucel-T za liječenje bolesnika s metastatskim kastracijski rezistentnim rakom prostate. Međutim, drugi imunoterapijski lijekovi koji su bili istraživani u bolesnika s rakom prostate, posebno inhibitori imunološke kontrolne točke, nisu pokazali terapijski učinak. Nekoliko je mogućih objašnjenja za nedostatak terapijskog odgovora na ove lijekove kod raka prostate. Ta objašnjenja koja su vezana uz specifična genetička (npr. nisko mutacijsko opterećenje) i imunološka (npr. imunosupresivni tumorski imunološki mikrookoliš) obilježja raka prostate opisana su u ovom preglednom radu. Također, prikazane su nove terapijske strategije s ciljem prevladavanja otpornosti raka prostate na imunoterapiju i za odabir podskupina bolesnika u kojih se može očekivati korist od imunoterapije

Medularni karcinom štitnjače - pregled značajki i novosti u sustavnom liječenju

Medullary thyroid carcinoma (MTC) is a rare malignancy that originates from parafollicular (C cells) of the thyroid and accounts for 2-4% of all thyroid malignancies. MTC may be sporadic or inherited, the latter as part of the MEN 2 syndromes. Germline mutations in the RET proto-oncogene (REarranged during Transfection) are driver mutations in hereditary MTC, whereas somatic RET mutations and, less frequently, RAS mutations, have been described in tumor tissues of sporadic MTC. Genetic screening for germline mutations in RET proto-oncogene identifies gene carriers of germline mutations. That enables primary prevention (the avoidance of disease onset by total prophylactic thyroidectomy), or at least secondary prevention (early detection) of the disease. Radical surgery with complete tumor resection is still pivotal in attaining cure for MTC. Despite recent advances, the treatment of advanced, metastatic, and progressive MTC remains challenging. Metastatic MTC can have an indolent clinical course; therefore, it is necessary to assess which patient to cure and when to initiate the treatment. Multidisciplinary boards of various specialists involved in the diagnostics and therapy of the patients with MTC in highly specialized centers with a high volume of patients provide optimal patient management. Multikinase inhibitors (MKI) vandetanib and cabozantinib were approved for the treatment of progressive or symptomatic metastatic/unresectable MTC. Although these treatments have been shown to improve progression-free survival (PFS) with higher overall response rates (ORR) compared with placebo, no MKI has been shown to increase the overall survival (OS) yet, except in the subgroup of patients with RETM918T-mutations on cabozantinib therapy. As these drugs are nonselective, significant off-target toxicities may occur. Recently, next-generation small-molecule tyrosine kinase inhibitors (TKIs) have been developed. These highly selective RET-inhibitors are specifically designed for highly potent and selective targeting of oncogenic RET alterations, making them promising drugs for the treatment of advanced MTC. The selective RET-inhibitor selpercatinib has been very recently registered for the treatment of RET-mutated thyroid cancer.Medularni karcinomi štitnjače (MKŠ) rijetke su zloćudne bolesti podrijetla parafolikularnih (C-stanica) štitnjače i čine oko 2-4% svih zloćudnih tumora štitnjače. MKŠ može biti sporadičan ili nasljedan, potonji kao dio MEN 2 sindroma. N asljedne mutacije protoonkogena RET (od engl. REarranged during Transfection) pokretačke su mutacije kod nasljednih MKŠ, dok su somatske RET mutacije, ili, rjeđe, RAS mutacije, opisane u tumorskom tkivu kod sporadičnih MKŠ. Genetski probir na nasljedne mutacije protoonkogena RET identificira nosioce nasljednih genetskih mutacija. To omogućuje primarnu (sprječavanje razvoja bolesti provođenjem profilaktičke totalne tireoidektomije) ili barem sekundarnu prevenciju bolesti (rano otkrivanje MKŠ-a). Radikalna operacija s kompletnom resekcijom tumora još je uvijek ključna u postizanju izlječenja kod MKŠ. Naime, unatoč nedavnim dostignućima, liječenje uznapredovalog, metastatskog i progresivnog MKŠ-a i dalje predstavlja izazov. Metastatski MKŠ može biti indolentnog kliničkog tijeka, stoga je potrebno procijeniti kojeg bolesnika liječiti i kada liječenje započeti. Multidisciplinarni timovi različitih specijalista uključenih u dijagnostiku i liječenje bolesnika s MKŠ-om u visoko specijaliziranim centrima s velikim brojem bolesnika omogućuju njihovo optimalno zbrinjavanje. Multikinazni inhibitori (MKI) vandetanib i kabozantinib, odobreni su za liječenje progresivnog ili simptomatskog metastatskog/ neresektabilnog MKŠ. Premda je ovo liječenje pokazalo dobit u preživljenju bez progresije bolesti (PFS, od engl. Progression Free Survival) uz veću ukupnu stopu odgovora (ORR, od engl. Overall Response Rate) naspram placeba, MKI nisu polučili dobit u ukupnom preživljenju (OS, od engl. Overall Survival), osim kod podskupine bolesnika s RETM918T-mutacijama na terapiji kabozantinibom. Multikinazni inhibitori su neselektivni, stoga je moguća značajna toksičnost terapije. Nedavno su razvijene nove generacije tirozin-kinaznih inhibitora (TKI). Ovi visoko selektivni RET-inhibitori specifično su dizajnirani za visoko učinkovito i selektivno ciljanje onkogenih RET alteracija, što ih čini obećavajućim lijekovima u liječenju uznapredovalog MKŠ. Selektivni RET-inhibitor selperkatinib vrlo je nedavno registriran za liječenje RET-mutiranih karcinoma štitnjače

Zadnja postignuća u radioterapiji raka prostate

Radiotherapy is the attractive treatment option for prostate cancer and has a clear role in all stages of the disease. Over the last decade, advances in technology, imaging capabilities, and improved radiobiological understanding have deeply transformed radiotherapy for prostate cancer, allowing dose escalation and wide adoption of hypofractionation. Furthermore, the integration of magnetic resonance imaging (MRI) and improved physical precision of dose delivery have given an impetus to additionally target intraprostatic tumor lesions, previously agnostic to conventional radiotherapy target definition concept. The emerging data from randomized clinical trials and observation research show that ultra-hypofractionation is a safe approach while further follow-up is needed to assess its efficacy compared to standard fractionation. There is an ongoing uncertainty surrounding true alpha/beta ratio for prostate cancer since hypofractionation has so far failed to yield theoretically envisioned superior biochemical control outcomes. Finally, recently published randomized trial settled ongoing controversy regarding the role of elective pelvic lymph node radiotherapy in patients with high-risk prostate cancer, showing clear benefit when pelvic nodes were treated to 50 Gy. The role of partial gland dose escalation/tumor boosting is evolving, and more data is needed to adopt this approach in routine clinical care. Going forward, molecular imaging will be crucial to assess biology of the disease, predict a response potentially, and optimally personalize radiotherapy treatment decisions. In this narrative review, we critically analyzed the published literature and provided practical summary of recent prostate radiotherapy advances for busy clinicians.Radioterapija je neizostavan oblik liječenja raka prostate i ima ulogu u svim fazama bolesti. Zadnjeg desetljeća napreci u tehnologiji i radiobiologiji su preobrazili radioterapiju raka prostate te omogućili eskalaciju doze i hipofrakcioniranje. Nadalje, integracija magnetske rezonance i povećana fizikalna preciznost isporuke radioterapije omogućila je ciljanje intraprostatičkih tumora. Mnoge studije pokazuju da je ultra hipofrakcioniranje obećavajući koncept liječenja, iako postoje mnoge nejasnoće o pravom alfa-beta omjeru raka prostate te posljedičnom stvarnom terapijskom benefitu hipofrakcioniranja. Recentno objavljena studija ukazala je na korist elektivne radioterapije zdjeličnih limfnih čvorova u bolesnika sa visokorizičnim rakom prostate. Nadalje, u tijeku su studije koje će ocijeniti valjanost daljnje intraprostatičke eskalacije doze. Moderno molekularno oslikavanje donosi veliku promjenu u načinu kako shvaćamo i liječimo rak prostate. U ovom preglednom članku kritički smo analizirali literaturu i dali smjernice za svakodnevnu radioterapijsku kliničku praksu

Uloga moderne anti-androgene terapije u liječenju lokaliziranog raka prostate

Anti-androgen therapy continues to be a basic pilar of treatment for both localized and metastatic prostate cancer. The advent of new generation of androgen receptor targeted agents (ARTA) transformed the care of patients with advanced disease. After such a success, the steps were taken to incorporate a new generation of ARTAs into the treatment landscape of localized prostate cancer. High-risk prostate cancer represents the most aggressive form of localized disease with significant metastatic potential and poor outcome. Here, the impact of novel therapies will likely be profound and transforming. This clinical space has already been a showcase for multidisciplinary treatment where the combination of local therapies with systemic treatment gradually improved patient outcomes and the chances of cure. The most recent step in redefining the treatment of localized disease is the adoption of novel ARTAs moving forward the multidisciplinary platform. In this narrative review, we discuss current clinical evidence supporting the use of novel ARTAs in patients with localized high-risk prostate cancer and cover recent developments in biomarker-driven strategies for treatment individualization in this clinical context.Anti-androgena terapija je temelj liječenja lokaliziranog i uznapredovalog raka prostate. Dolazak nove generacije lijekova koji inhibiraju androgenu osovinu preobrazila je liječenje bolesnika sa uznapredovalim rakom prostate. Temeljem uspjeha u uznapredovaloj bolesti, u tijeku su napori da se nova generacija anti-androgenih lijekova inkorporira u liječenje lokalizirane bolesti. Visokorizičan rak prostate predstavlja najagresivniji oblik lokalizirane bolesti sa značajnim metastatskim potencijalom. Za očekivati je da će u ovom stadiju utjecaj novih terapija biti preobražavajući. Lokalizirani visokorizični rak prostate se liječi multidisciplinarno. Tu su kombinacije lokalnog liječenja i sustavne terapije postepeno popravljale ishode liječenja i omogućavale priliku za izliječenje. Zadnji napor predstavlja usvajanje novih anti-androgenih terapija. U ovom preglednom članku razmatramo kliničke dokaze za upotrebu nove generacije anti-adrogene terapije u bolesnika sa lokaliziranim visokorizičnim rakom prostate i dajemo pregled zadnjih strategija za personalizaciju liječenja