o:24058 Ispitivanje prediktivne vrednosti molekularnih biomarkera u proceni toka i ishoda bolesti kod pacijentkinja sa HER2 negativnim i nodus negativnim karcinomom dojke doktorska disertacija Testing the predictive value of molecular biomarkers in the assessment of the course and outcome of the disease in patients with HER2 negative and nodus negative breast cancer : doctoral dissertation sr Kliničke studije i praksa su pokazali da hormon receptor (HR) pozitivni / receptor za humani epidermalni faktor rasta tip 2 (HER2) negativni karcinomi dojke imaju različitu prognozu i da postoji potreba da se na osnovu dodatnih molekularnih biomarkera ova grupa tumora dodatno reklasifikuje. Pacijenti i metode: Procenjivana je prognostička vrednost urokinaznog aktivatora plazminogena (uPA), inhibitora aktivatora plazminogena tip 1 (PAI-1) i 4G/5G varijante PAI-1 gena u grupi pacijentkinja radikalno operisanih zbog karcinoma dojke, kod kojih tumori pokazuju pozitivan steroidni receptorski status (estrogen receptor (ER)/progesteron receptor (PR)), a kod kojih je primenjivana adjuvantna hormonska terapija. Studija je uključila 81 pacijentkinju sa nodus negativnim, ER i/ili PR pozitivnim receptorima i HER2 negativnim operabilnim karcinomima dojke, koji su primale adjuvantnu hormonsku terapiju. Vrednosti uPA i PAI-1 koncentracije u tumorskom tkivu određene su FEMTELLE® uPA/PAI-1 ELISA testom. Inserciono/delecioni 4G/5G polimorfizam na poziciji -675 gena PAI-1 detektovan je PCR-RFLP metodom (engl. Polimerase chain reaction – restriction fragment length polymorphism). Rezultati: Istraživanje je pokazalo da pacijentkinje sa vrednošću uPA u tumorskom tkivu iznad 3 ng/mg proteina imaju značajno smanjeno vreme bez pojave bolesti (engl. disease-free survival, DFS) i ukupno preživljavanje (engl. overall survival, OS) u poređenju sa pacijentkinjama kod kojih su vrednosti uPA manje ili jednake 3 ng/mg proteina. Pacijentkinje sa vrednostima PAI-1 proteina u tumorskom tkivu iznad 14 ng/mg imaju značajno smanjeno ukupno preživljavanje u poređenju sa pacijentkinjama sa vrednošću PAI-1 proteina ispod ili jednako 14 ng/mg. Pacijentkinje sa dominantnim alelom u PAI-1 genotipu (heterozigot ili dominantni homozigot, -675 4G/5G i -675 5G/5G) imaju značajno duže vreme bez znakova bolesti (DFS) i ukupno preživljavanje (OS) u poređenju sa pacijentkinjama sa recesivnim homozigotnim genotipom (-675 4G/4G). Zaključak: Vrednosti molekularnih biomarkera uPA i PAI-1 u tumorskom tkivu mogu imati uticaj na ishod bolesti kod pacijentkinja sa ER/PR pozitivnim, HER2 negativnim i nodus negativnim karcinomom dojke lečene adjuvantnom hormonskom terapijom. Podgrupa pacijentkinja sa recesivnim homozigotnim genotipom gena PAI-1 (-675 4G/4G) može imati lošiji ishod bolesti u poređenju sa heterozigotnim/dominantno homozigotnim genotipom (-675 4G/5G i -675 5G/5G). Clinical studies and practice have shown that the hormone receptor (HR) positive/ receptor for human epidermal growth factor type 2 (HER2) negative breast cancers have different prognosis and that there is a need to further reclassify this group of tumors based on additional molecular biomarkers. Patients and methods: The prognostic value of urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1), and 4G/5G variant of PAI-1 gene was evaluated in a group of patients radically operated for breast cancer in whom tumors showed a positive steroid receptor status (estrogen receptor (ER) / progesterone receptor (PR)) and who were treated with adjuvant hormone therapy. The study included 81 patients with nodus negative, ER and/or PR positive and HER2 negative operable breast cancers receiving adjuvant endocrine therapy. uPA and PAI-1 concentrations in tumor tissue were determined by FEMTELLE® uPA/PAI-1 ELISA. Insertion (5G) / deletion (4G) polymorphism at position -675 of the PAI-1 gene was detected by PCR-RFLP analysis. Results: The study showed that patients with uPA values in tumor tissue above 3 ng/mg of protein had significantly reduced disease-free survival (DFS) and overall survival (OS) compared to patients whose uPA values were less than or equal to 3 ng/mg of protein. Patients with PAI-1 protein values in tumor tissue above 14 ng/mg of protein have significantly reduced overall survival compared to patients with PAI-1 protein values below or equal to 14 ng/mg of protein. Patients with a dominant allele in the PAI-1 genotype (heterozygote and dominant homozygote, -675 4G/5G and -675 5G/5G) have significantly longer DFS and OS compared with patients with recessive homozygote genotype (-675 4G/4G). Conclusion: Values of molecular biomarkers uPA and PAI-1 in tumor tissue may have an impact on disease outcome in patients with ER/PR positive, HER2 negative, and nodus negative breast cancer treated with adjuvant endocrine therapy. A subgroup of patients with recessive homozygous genotype of PAI-1 gene (-675 4G/4G) may have worse disease outcome compared to patients with heterozygous/dominant homozygous genotype (-675 4G/5G and -675 5G/5G). Medicina - Epidemiologija / Medicine- Epidemiology Datum odbrane: 25.06.2021. rani karcinom dojke, molerkularni biomarkeri, uPA/PAI-1, gen PAI-1 early breast cancer, molecular biomarkers, uPA/PAI-1, PAI-1 gene 618.19-006.6-036(043.3) yes 45130761 91552101 8284 91552100 45130761 2021-09-28T08:36:03.053Z 45 no 46 mentor Marko, 1977-, 73171209 Jevrić 2021 63 mentor Darija, 1975-, 12892519 Kisić-Tepavčević 2021 63 mentor Snežana, 1964-, 11986535 Šušnjar 2021 63 član komisije Tatjana, 1966-, 12668519 Pekmezović 2021 63 član komisije Ivan, 1958-, 20969831 Marković 2021 63 član komisije Ljiljana, 13570407 Mijatović Teodorović 2021 73 str. 1455867 http://phaidrabg.bg.ac.rs/o:24058 no yes 4 2021-09-28T08:36:03.320Z 70 11 1066950 1066978 rani karcinom dojke, molerkularni biomarkeri, uPA/PAI-1, gen PAI-1 early breast cancer, molecular biomarkers, uPA/PAI-1, PAI-1 gene 618.19-006.6-036(043.3) 1738 11A32 2021