Prognostičko značenje ekspresije proteina Cox-2 u bolesnica s rakom dojke

Milas, Ivan (2005) Prognostičko značenje ekspresije proteina Cox-2 u bolesnica s rakom dojke. PhD thesis, Sveučilište u Zagrebu.

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Abstract

The present thesis analyses data on 150 female patients who started their breast cancer treatment at the Oncological Surgery Department, University Hospital for Tumors between 1995 and 1997. The patients are divided in three groups, according to the tumor differentiation, and each group includes 50 patients with well, moderately and poorly differentiated tumors, respectively. All patients were diagnosed with invasive ductal carcinoma. In time of diagnosis none of patients had distant metastases. The following clinical and patohistological factors were analyzed: age, clinical stage, tumor differentiation grade, tumor size, lymph node status, hormone receptor status, and method of treatment. Cox-2 protein expression was studied using immunohistochemical method, and the tumor cell DNA content was analyzed with flow cytometer. The disease course was followed up until the end of 2004. Fifty-nine (39.3%) of patients followed up during the period 1995-2004 developed metastases, of which 54 patients (91.5%) died and 5 (8.5%) survived until the end of the study period. The aim of the study was to determine expression of Cox-2 protein in primary breast tumors, and establish association between the Cox-2 expression in breast cancer cells and an outcome of therapy and its relation to other prognostic factors, to analyze relation between the Cox-2 expression and the flow cytometry results as an indicator of proliferating tumor, and different Cox-2 expressions in patients with moderately differentiated tumors related to the disease course. The study results show that the well differentiated tumors were statistically significantly smaller in size (P<0,001), metastases spread on a smaller number of lymph nodes (P=0,002), and the estrogen receptors were positive in more cases (P=0,02). No statistically significant difference was determined for metastasizing and survival relation to the tumor grade by either univariate or multivariate analyses. However, the tumor size and lymph node status have proven as prognostically significant in both univariate and multivariate analyses (P=0,049). Patients with negative estrogen receptors developed distant metastases faster (P=0,023), while in patients with negative progesterone receptors no statistically significant difference in development of metastases was recorded (P=0,054). Univariate analysis of hormone receptors and overall survival showed that, statistically, survival time of patients with negative estrogen (P=0,032) and progesterone receptors (P=0,027) is significantly shorter. The multivariate analysis of hormone receptors also showed statistically significant poor survival of patients with negative estrogen receptors as compared to the patients with positive receptors (P=0,049). Tumor analysis with flow cytometry showed that, statistically, the patients with lower tumor grade had significantly more diploid tumors (P<0,001) and tumors with lower proliferating S phase (P<0,001). Neither univariate nor multivariate analysis of metastasis development and survival showed statistically significant difference between the patients with diploid vs. aneuploid tumors or between the patients with lower vs. higher proliferation rate. Cox-2 protein positive tumor cells were presented by granular cytoplasm staining. In our study, 65 patients (43.3%) were Cox-2 positive. Analysis of Cox-2 protein expression and tumor grade revealed a statistically significant difference in Cox-2 expression in patients with different tumor grades (P=0,018), while no statistically significant difference was found by analyses of relations between Cox-2 expression and tumor size, and Cox-2 and lymph node status. The study shows that the Cox-2 positive tumors are prevalently aneuploid and the Cox-2 negative tumors are more frequently diploid (P=0,031). The study does not show interrelation between elevated Cox-2 expression and tumor proliferation rate (S phase) measured with the flow cytometer. The study also did not detect a difference in Cox-2 protein expression depending on tumor hormone receptor status. Analysis of association of Cox-2 expression with development of metastases and survival (univariate and multivariate analysis) showed no statistically significant difference between the Cox-2 negative and positive patients. The study indicates that Cox-2 protein expression in the breast cancer patients is increased. In most cases Cox-2 was increased in patients with moderately differentiated tumors. However, the study did not confirm a prognostic value of Cox-2 protein.

Abstract in Croatian

U ovom radu analizirani su podaci dobiveni od 150 bolesnica koje su započele liječenje zloćudnog tumora dojke na Odjelu Onkološke kirurgije Klinike za tumore u periodu od 1995. do 1997. godine. Bolesnice su svrstane u tri skupine, ovisno o diferenciranosti tumora, a svaka skupina sadržavala je po 50 bolesnica s dobro, srednje i slabo diferenciranim tumorima. Sve bolesnice su imale duktalni invazivni karcinom. U vrijeme dijagnoze nitko od bolesnica nije imao udaljenih metastaza. Kod bolesnica su analizirani slijedeći klinički i patohistološki čimbenici: dob, klinički stupanj bolesti, stupanj diferenciranosti tumora, veličina tumora, status limfnih čvorova, status hormonskih receptora te način liječenja bolesnica. Kod bolesnica je analiza izražajnosti Cox-2 proteina učinjena imunohistokemijskom metodom te analiza sadržaja stanične DNA na protočnom citometru. Praćenje tijeka bolesti napravljeno je do 31.12. 2004. godine. Od ukupnog broja bolesnica tijekom praćenja (1995-2004.) njih 59 (39,3%) dobilo je metastaze. Od 59 bolesnica koje su dobile metastaze nakon završenog praćenja 54 bolesnice su umrle (91.5%) dok ih je 5 (8,5%) živih. Cilj rada bio je utvrditi izražajnost Cox-2 proteina u primarnim tumorima dojke; utvrditi povezanosti izražajnosti Cox-2 u stanicama raka dojke s ishodom liječenja i njegovu povezanost s ostalim prognostičkim čimbenicima kod raka dojke; ispitati povezanost izražajnosti Cox-2 s rezultatima protočne citometrije kao pokazateljem proliferacijske aktivnosti tumora te razliku izražajnosti Cox-2 u bolesnica sa srednje diferenciranim tumorima u odnosu na tijek bolesti. Rezultat studije pokazuje da su bolesnice s bolje diferenciranim tumorima imale statistički značajno manje tumore (P<0,001), manji broj limfnih čvorova je bio zauzet metastazama (P=0,002) te češće pozitivne estrogenske receptore (P=0,02). Ni univarijantna ni multivarijantna analiza dobivanja metastaza i preživljenja ovisno o gradusu tumora nisu pokazale statistički značajne razlike. Veličina tumora i status limfnih čvorova pokazale su prognostičko značenje i univarijantnom i multivarijantnom analizom (P=0,049). Bolesnice s negativnim estrogenskim receptorima brže su razvijale udaljene metastaze (P=0,023), dok za bolesnice s negativnim progesteronskim receptorima nije zabilježena statistički značajna razlika u pojavljivanju metastaza (P=0,054). Univarijantna analiza hormonskih receptora i dužine preživljenja pokazala je i za bolesnice s negativnim estrogenskim (P=0,032) i progesteronskim receptorima (P=0,027) statistički značajnije kraće preživljenje. Također je i multivarijantna analiza vrijednosti hormonskih receptora pokazala statistički značajno lošije preživljenje u bolesnica s negativnim estrogenskih receptorima u odnosu na one s pozitivnim receptorima (P=0,049). Analiza tumora protočnom citometrijom pokazala je da su bolesnice s nižim gradusom tumora imale statistički značajno veći broj diploidnih tumora (P<0,001)i tumore s nižom proliferacijskom «S» fazom tumora (P<0,001). Ni univarijantna ni multivarijatna analiza pojave metastaza i preživljenja nisu pokazale statistički značajne razlike između žena s diploidnim i aneuploidnim tumorima te između žena s nižom i višom proliferacijom. Pozitivnost na Cox-2 protein u tumorskim stanicama očitovala se u granularnom citoplazmatskom bojenju. U našoj studiji Cox-2 bio je pozitivan u 65 bolesnica (43,3%). Analiza izražajnosti Cox-2 proteina i gradusa pokazala je statistički značajnu razliku izraženosti Cox-2 u bolesnica s različitim gradusima (P=0,018) dok analize izražajnosti Cox-2 i veličine tumora te Cox-2 i statusa limfnih čvorova nisu pokazale statistički značajne razlike. Studija je pokazala da su tumori pozitivni na Cox-2 protein u većem broju bili aneuploidni dok su tumori negativni na Cox-2 češće bili diploidni (P=0,031). Naša studija nije pokazala povezanost između povećane izražajnosti Cox-2 i proliferacijske aktivnosti tumora (S-faze tumora) mjerene na protočnom citometru . Također u studiji nije pronađena razlika u izražajnosti Cox-2 proteina ovisno o hormonskom statusu tumora. Analiza izražajnosti Cox-2 s pojavom metastaza i preživljenjem (univarijatna i multivarijantna analiza) nije pokazala statistički značajne razlike između bolesnica s negativnim i pozitivnim Cox-2 proteinom. Studija je pokazala povišenu izražajnost Cox-2 proteina u bolesnica s rakom dojke. Cox-2 najčešće je bio povišen u bolesnica sa srednje diferenciranim tumorima. Studija nije pokazala prognostičko značenje Cox-2 proteina.

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