Estrogen and Progesterone Receptor Status in Primary Breast Cancer – A Study of 11,273 Patients from the Year 1990 to 2002

The aim of this study was to gain insight of the breast cancer hormone receptor status of our patients, its stratification according to age as well as its changes during the period of 13 years. 11,273 patients with primary breast cancer from several towns in Croatia were included in this study. Patients’ tumour specimens were collected from 1990 to 2002 and were analysed on estrogen (ER) and progesterone (PR) receptors in the Laboratory of the Department of Medical Oncology, University Hospital Centre Zagreb. More than half of our breast cancer patients had ER positive tumours (54.3%). We observed ER+ tumours increased with age continuously, with highest percentage in the age group of 70 to 79 years (68.1%). Similarly, proportion of PR+ tumours was higher in the older age groups, being the highest between 40 and 49 years (55.9%). During 13 years of the study, the increase in frequency and proportion of ER+ tumours was observed (from 52% in 1990 to 62% in 2002) and decrease of PR+ tumours (56% to 53%). We confirm previous findings that the risk of hormone dependent breast cancer increases with aging. Risk of ER+ breast cancer increased for 10% from 1990 to 2002 and PR+ tumours decreased for 3.5% in the same period

Primjena molekulskih ciljanih lijekova u bolesnika s proširenim rakom debelog crijeva

The introduction of targeted therapies has made substantial progress in advanced colorectal cancer treatment. Compared to chemotherapy, which is unselective – cytotoxic for both healthy and malignant cells and thus causes multiple adverse events, the targeted therapy is directed upon specific tumor cell markers. This leads to lower toxicity and improves therapy results. There are several groups of agents used in targeted therapy and two are in clinical use: monoclonal antibodies and small molecules – inhibitors of tyrosine kynase. Monoclonal antibody therapy is highly tumor specific with low toxicity. Two main functions of antibodies include recognizing and binding of antigens, and subsequently provoking immunological response of the patient. Small molecules act as inhibitors of tyrozine kynase intracellular domain, preventing phosphorilation and intracellular signal transduction. The tagreted therapy of colorectal cancer is directed upon EGFR (epidermal growth factor receptor) and its intracellular signal transduction as well as neoangiogenesis.Uvođenjem ciljanih terapija postignut je znatan napredak u liječenju uznapredovalog raka debelog crijeva. U usporedbi s kemoterapijom, koja je neselektivna – citotoksična i za zdrave i zloćudne stanice te ima višestruke štetne učinke, ciljana terapija usmjerena je prema specifičnim obilježjima tumorskih stanica. Time se postiže manja toksičnost i bolji rezultati liječenja. U ciljanoj terapiji primjenjuje se nekoliko skupina lijekova, a dvije su u kliničkoj uporabi: monoklonska protutijela i male molekule – inhibitori tirozin kinaze. Monoklonska protuutijela djeluju vrlo specifično na tumor, a toksičnost im je mala. Dvije glavne funkcije protutijela jesu prepoznavanje i vezanje antigena, a time i poticanje imunološkog odgovora u bolesnika. Male molekule djeluju kao inhibitori tirozin kinaze u unutarstaničnoj domeni te priječi fosforilaciju i unutarstanični prijenos signala. Ciljana terapija raka debeloga crijeva usmjerena je na receptor epidermalnog čimbenika rasta i unutarstanični prijenos signala te neoangiogenezu

Primjena molekulskih ciljanih lijekova u bolesnika s proširenim rakom debelog crijeva

The introduction of targeted therapies has made substantial progress in advanced colorectal cancer treatment. Compared to chemotherapy, which is unselective – cytotoxic for both healthy and malignant cells and thus causes multiple adverse events, the targeted therapy is directed upon specific tumor cell markers. This leads to lower toxicity and improves therapy results. There are several groups of agents used in targeted therapy and two are in clinical use: monoclonal antibodies and small molecules – inhibitors of tyrosine kynase. Monoclonal antibody therapy is highly tumor specific with low toxicity. Two main functions of antibodies include recognizing and binding of antigens, and subsequently provoking immunological response of the patient. Small molecules act as inhibitors of tyrozine kynase intracellular domain, preventing phosphorilation and intracellular signal transduction. The tagreted therapy of colorectal cancer is directed upon EGFR (epidermal growth factor receptor) and its intracellular signal transduction as well as neoangiogenesis.Uvođenjem ciljanih terapija postignut je znatan napredak u liječenju uznapredovalog raka debelog crijeva. U usporedbi s kemoterapijom, koja je neselektivna – citotoksična i za zdrave i zloćudne stanice te ima višestruke štetne učinke, ciljana terapija usmjerena je prema specifičnim obilježjima tumorskih stanica. Time se postiže manja toksičnost i bolji rezultati liječenja. U ciljanoj terapiji primjenjuje se nekoliko skupina lijekova, a dvije su u kliničkoj uporabi: monoklonska protutijela i male molekule – inhibitori tirozin kinaze. Monoklonska protuutijela djeluju vrlo specifično na tumor, a toksičnost im je mala. Dvije glavne funkcije protutijela jesu prepoznavanje i vezanje antigena, a time i poticanje imunološkog odgovora u bolesnika. Male molekule djeluju kao inhibitori tirozin kinaze u unutarstaničnoj domeni te priječi fosforilaciju i unutarstanični prijenos signala. Ciljana terapija raka debeloga crijeva usmjerena je na receptor epidermalnog čimbenika rasta i unutarstanični prijenos signala te neoangiogenezu

Hormonal resistance in breast- and prostate cancer

Breast and prostate cancers are the most common malignant disease in female and male world population, respectively. Both of these tumors are predominantly hormonal-dependent, what is rationale for the widely used endocrine treatment, with specific approach in each of them. Although endocrine treatment is obviously effective and responsible for prolonged progression-free survival and even survival, the problem is that breast and prostate cancers inevitably become "hormone-resistant". The paradigm of treatment has to be changed and today there are some ways to overcome these lack of endocrine responsivness. It is known better today whichmechanisms are involved in hormone-resistance, and they are numerous, so the designation of new drugs with key features necessary activity in hormone-resistant tumors. In breast cancer, there are selective estrogen modulators as a way to overcome this problem; there is also a combination of receptor-tyrosine kinase and hormonal treatment documented as active in such cases. On the other hand, abirateron-acetat and enzalutamide as a new androgen-receptor-signalling inhibitors proved that androgen signalling cascade is still active even in a castration-resistant prostate cancer

Targeted Drugs in Gastrointestinal Oncology

Posljednjih nekoliko godina napredak u našem razumijevanju biologije signalnih staničnih putova doveo je do uvođenja novih terapijskih postupaka, koji se često zajedničkim imenom nazivaju ciljana (biološka) terapija, usmjerenih prema specifičnim molekularnim čimbenicima uključenim u tumorski rast. Velik broj tih molekula nalazi se u kliničkim i pretkliničkim ispitivanjima. Djelujući znatno selektivnije protiv tumorskih stanica, molekularna ciljana terapija pruža mogućnost veće učinkovitosti i manje toksičnosti ako se uspoređuje sa standardnom kemoterapijom. U nekim slučajevima ta je terapija promijenila sam prirodni tijek tumorske bolesti kao što je to primjerice s gastrointestinalnim stromalnim tumorima. U ovom pregledu opisani su najvažniji lijekovi koji se danas rabe u gastrointestinalnoj onkologiji: monoklonska protutijela (bevacizumab, cetuksimab, panitumumab, aflibercept i trastuzumab) i tzv. „male molekule“ (imatinib, sunitinib, erlotinib, regorafenib, sorafenib i everolimus).Over the last few years advances in our understanding of the biology of cell signalling have led to the introduction of novel therapies, often collectively termed targeted drugs, rationally designed to target specific molecular factors implicated in tumour growth. A large number of these drugs are currently in clinical or preclinical trials. By acting more selectively against tumour cells, these molecular targeted agents offer the potential for improved efficacy and lower toxicity when compared with conventional chemotherapy. In some cases, these agents have profoundly changed the natural history of disease, e.g. imatinib in gastrointestinal stromal tumours. In this article, we describe the most important drugs currently used in gastrointestinal oncology: monoclonal antibodies (bevacizumab, cetuximab, panitumumab, aflibercept, trastuzumab) and small-molecule compounds (imatinib, sunitinib, erlotinib, regorafenib, sorafenib, everolimus)

New primary non-breast malignancies after breast cancer: ten years single institution follow-up

Background and Purpose: Breast cancer is the most common cancer in Croatian women. Due to improved diagnostic and treatment options women with breast cancer now live longer, which increases their risk of developing new primary malignancies. The aim of this study was to establish incidence of new primary non-breast malignancies after breast cancer diagnosis. Material and Methods: In the study cohort that included 215 consecutive patients treated for early breast cancer at University Hospital Center Zagreb, Croatia, 12 patients (5.58%) have developed new primary non-breast malignancy within nearly ten year follow-up. Results: Although the majority of studies found gynecological cancers to be the most common cancer site of new primary non-breast malignancies after breast cancer diagnosis, in our study most patients developed colorectal cancer. Conclusion: This is particularly interesting if you take into account that after breast cancer colorectal cancer is the second most common cancer in Croatian women. In order to stratify the risk for the development of new primary tumors it is necessary to further investigate the interaction of various factors that are thought to influence the evolvement of tumors

Prognostička vrijednost topoizomeraze 2-alfa i B-Myb u ranom raku dojke liječenom adjuvantnom kemoterapijom

Breast cancer is the most common malignancy in females. Despite its well-established prognostic factors, our prognostic ability at an individual patient level remains limited. In this study, the immunohistochemical expression of B-Myb and DNA topoisomerase 2-alpha (Topo2a) was analyzed in primary tumors to identify patients with a higher risk of disease recurrence after adjuvant chemotherapy for early invasive breast cancer. We analyzed a cohort of 215 early invasive breast cancer patients having undergone surgery from 2002 to 2003 at the Zagreb University Hospital Centre, including 153 patients treated with adjuvant chemotherapy. All of them were followed-up prospectively for at least ten years according to routine institutional practice. Statistically significant correlations were found between B-Myb and Topo2a expression levels and particular well-established prognostic factors. B-Myb expression was lower in estrogen receptor (ER)-positive tumors (p=0.0773), whereas larger tumors and those with positive lymphovascular invasion displayed a statistically significantly higher B-Myb expression (p=0.0409 and p=0.0196). Higher tumor grade indicated higher Topo2a values (p=0.0102 and p=0.0069). The subgroup with the expression of both proteins above the median value had an almost statistically significantly (p=0.0613) inferior prognosis compared to the rest of the cohort. Study results showed the B-Myb and Topo2a expression to have a prognostic value in breast cancer patients after adjuvant chemotherapy, which should be additionally explored in future studies in a larger patient cohort.Rak dojke je najčešći zloćudni tumor u žena. Unatoč dobro definiranim “tradicionalnim” prognostičkim čimbenicima naša mogućnost prognoze za svaku pojedinu bolesnicu je ograničena. U ovom istraživanju smo analizirali imunohistokemijsku izraženost B-Myb-a i DNA topoizomeraze 2-alfa (Topo2a) u primarnim tumorima kako bi se identificirale bolesnice s većim rizikom povrata bolesti nakon adjuvantne kemoterapije za rani invazivni rak dojke. Analizirana je kohorta od 215 bolesnica s ranim invazivnim karcinomima dojke koje su operirane u Kliničkom bolničkom centru Zagreb od 2002. do 2003. godine, uključujući 153 bolesnice koje su liječene adjuvantnom kemoterapijom. Sve su praćene prospektivno najmanje deset godina prema rutinskoj kliničkoj praksi. Dokazali smo statistički značajne korelacije između razine izraženosti B-Myb i Topo2a te nekih „tradicionalnih” prognostičkih čimbenika. Izraženost B-Myb je bila niža u ER pozitivnim tumorima (p=0,0773), ali su veći tumori, kao i oni s pozitivnom limfovaskularnom invazijom imali statistički značajno veću izraženost proteina B-Myb (p=0,0409 i p =0,0196). Također, pokazali smo da veći gradus tumora ukazuje na višu vrijednost Topo2a (p=0,0102 i p=0,0069). Pokazali smo da podskupina bolesnica s izraženošću oba proteina iznad srednje vrijednosti ima lošiji ishod bolesti u odnosu na ostatak skupine, ali rezultat je blizu granice statističke značajnosti (p=0,0613). Naše istraživanje je pokazalo prognostičku vrijednost kombinacije prekomjerne imunohistokemijske izraženosti B-Myb i Topo2a u bolesnica s rakom dojke nakon adjuvantne kemoterapije, što zaslužuje daljnja istraživanja na većim skupinama bolesnica