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Background:ESMO COVID-19 and CAncer REgistry (ESMO-CoCARE) is an international collaborative registry-based, cohort study gathering real-world data from Europe, Asia/Oceania and Africa on the natural history, management and outcomes of patients with cancer infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).Patients and methods:ESMO-CoCARE captures information on patients with solid/haematological malignancies, diagnosed with coronavirus disease 2019 (COVID-19). Data collected since June 2020 include demographics, comorbidities, laboratory measurements, cancer characteristics, COVID-19 clinical features, management and outcome. Parameters influencing COVID-19 severity/recovery were investigated as well as factors associated with overall survival (OS) upon SARS-CoV-2 infection. Results:This analysis includes 1626 patients from 20 countries (87% from 24 European, 7% from 5 North African, 6% from 8 Asian/Oceanian centres), with COVID-19 diagnosis from January 2020 to May 2021. Median age was 64 years, with 52% of female, 57% of cancer stage III/IV and 65% receiving active cancer treatment. Nearly 64% patients required hospitalization due to COVID-19 diagnosis, with 11% receiving intensive care. In multivariable analysis, male sex, older age, Eastern Cooperative Oncology Group (ECOG) performance status ≥2, body mass index (BMI) 2, presence of comorbidities, symptomatic disease, as well as haematological malignancies, active/progressive cancer, neutrophil-to-lymphocyte ratio (NLR) ≥6 and OnCovid Inflammatory Score ≤40 were associated with COVID-19 severity (i.e. severe/moderate disease requiring hospitalization). About 98% of patients with mild COVID-19 recovered, as opposed to 71% with severe/moderate disease. Advanced cancer stage was an additional adverse prognostic factor for recovery. At data cut-off, and with median follow-up of 3 months, the COVID-19-related death rate was 24.5% (297/1212), with 380 deaths recorded in total. Almost all factors associated with COVID-19 severity, except for BMI and NLR, were also predictive of inferior OS, along with smoking and non-Asian ethnicity.Conclusions:Selected patient and cancer characteristics related to sex, ethnicity, poor fitness, comorbidities, inflammation and active malignancy predict for severe/moderate disease and adverse outcomes from COVID-19 in patients with cancer.

© 2018 Milica Nedeljković et al., published by De Gruyter Open 2018. Background: Triple negative breast cancer (TNBC) is characterized by aggressive clinical course and is unresponsive to anti-HER2 and endocrine therapy. TNBC is difficult to treat and is often lethal. Given the need to find new targets for therapy we explored clinicopathological significance of copy number gain of FGFR1 and c-MYC. Our aim was to determine the impact of FGFR1 and c-MYC copy number gain on clinical course and outcome of TNBC. Methods: FGFR1 and c-MYC gene copy number alterations were evaluated in 78 archive TNBC samples using TaqMan based quantitative real time PCR assays. Results: 50% of samples had increased c-MYC copy number. c-MYC copy number gain was associated with TNBC in contrast to ER positive cancers. Our results showed significant correlation between c-MYC copy number gain and high grade of TNBCs. This suggests that c-MYC copy number could be an useful prognostic marker for TNBC patients. c-MYC copy number gain was associated with high pTNM stage as well as lobular and medullary tumor subtypes. 43% of samples had increased FGFR1 copy number. No correlations between FGFR1 copy number gain and clinicopathological variables were observed. Conclusions: We identified c-MYC copy number gain as a prognostic marker for TNBC. Our results indicate that c- MYC may contribute to TNBC progression. We observed no significant association between c-MYC and/or FGFR1 copy number status and patient survival.

Background: Breast cancer is the most common form of cancer in women. It arises from multiple genetic changes in oncogenes and tumor suppressor genes. Among so far studied oncogenes relatively few, including epdermal growth factor receptor (EGfR), cyclinD1 (CCNDİ)and c-myc, have been found to play an important role in progression of this type of human malignancy. The aim of this study was to examine the prognostic potential of CCND1, c-myc and EGFR amplification and their possible cooperation in breast carcinogenesis. Methods: Copy number analyses of CCND1 and c-myc genes were done by TaqMan based quantitative real time PCR. Amplification status of EGFR was determined by differential Pcr. Results: Amplification of CCND1, c-myc and EGFR oncogene has been found in 20.4%, 26.5% and 26.5% of breast cancer cases, respectively. Analysis showed that amplification of CCND1 oncogene was significantly associated with the stage II of disease while amplification of EGFR gene was significantly associated with overexpression of HER-2/neu. Tumour stage and expression of HER-2/neu appeared to be significant predictors of patient's outcome. Stage I patients lived significantly longer then stage III patients (p=0.04) while patients with HER-2/neu overexpression had worse prognoses and lived significantly shorter (p=0.001). Finally, survival of patients who underwent hormone therapy only was significantly longer (p=0.001) then survival of the rest of patients. Conclusions: Amplification of CCND1 or EGFR oncogene is associated with the progression of breast cancer and bad prognosis. No co-ordination in amplification of CCND1, c-myc and EGFR oncogenes were established in this cohort of breast cancer patients. Uvod: Kancer dojke je najčešći tip maligniteta koji se javljaju kod žena. Tumori dojke nastaju kao rezultat akumulacije genetičkih promena kako u onkogenima tako i u tumor supresorskim genima. Među mnogim onkogenima čija je uloga u genezi tumora dojke ispitivana do danas, samo se neki smatraju značajnim za razviće ovih karcinoma. U tu se grupu svakako ubrajaju receptor za epidermalni factor rasta (EGFR), c-myc i ciklinD1 (CCND1). Cilj rada je bio utvrditi prognostički značaj amplifikacije CCND1, c-myc i EGFR onkogena u razviću tumora dojke kao i eventualne međusobne koalteracije ovih gena. Metode: Amplifikacioni status CCND1 i c-myc gena određen je kvantitativnim PCR-om u realnom vremenu, a amplifikacioni status EGFR onkogena je definisan diferencijalnim PCR-om. Rezultati: Amplifikacija CCND1 gena detektovana je kod 20.4%, a c-myc i EGFR onkogena kod 26.5% ispitanih uzoraka. Analize su pokazale da je amplifikacija CCND1 onkogena statistički značajno povezana sa stadijumom II tumora dojke kao i da amplifikacija EGFR-a značajno korelira sa povećanom ekspresijom HER2/neu. Analize kliničkih i histopatoloških parametara su jasno pokazale da stadijum tumora i nivo ekspresije HER2/neu gena predstavljaju značajne pokazatelje daljeg toka bolesti, odnosno sudbine pacijenta. Utvrđeno je da pacijentkinje sa tumorima dojke stadijuma I žive značajno duže od onih sa tumorom stadijuma III (p= 0.04) kao i da pacijentkinje sa HER2/neu pozitivnim statusom imaju goru prognozu i žive značajno krace (p=0.001). Na kraju, studija je pokazala da pacijentkinje podvrgnute samo hormonskoj terapiji imaju najbolju prognozu i žive značajno duže od ostalih (p=0.001). Zaključak: Amplifikacija CCND1 i EGFR onkogena je povezana sa lošom prognozom i progresijom karcinoma dojke. U ispitivanom tumorskom uzorku nisu detektovane nikakve koalteracije CCND1, c-myc i EGFR onkogena. Projekat ministarstva br. III 41031 i br. ON173049

Background: Radiation therapy is an indispensable part of various treatment modalities for breast cancer. Specifically, for non-inflammatory locally advanced breast cancer (LABC) patients, preoperative radiotherapy (pRT) is currently indicated as a second line therapy in the event of lack of response to neoadjuvant chemotherapy. Still approximately one third of patients fails to respond favourably to pRT. The aim of this study was to explore molecular mechanisms underlying differential response to radiotherapy (RT) to identify predictive biomarkers and potential targets for increasing radiosensitivity.Methods: The study was based on a cohort of 134 LABC patients, treated at the Institute of Oncology and Radiology of Serbia (IORS) with pRT, without previous or concomitant systemic therapy. Baseline transcriptional profiles were established using Agilent 60 K microarray platform in a subset of 23 formalin-fixed paraffin-embedded (FFPE) LABC tumour samples of which 11 radiotherapy naïve and 3 post-radiotherapy samples passed quality control and were used for downstream analysis. Biological networks and signalling pathways underlying differential response to RT were identified using Ingenuity Pathways Analysis software. Predictive value of candidate genes in the preoperative setting was further validated by qRT-PCR in an independent subset of 60 LABC samples of which 42 had sufficient quality for data analysis, and in postoperative setting using microarray data from 344 node-negative breast cancer patients (Erasmus cohort, GSE2034 and GSE5327) treated either with surgery only (20%) or surgery with RT (80%). Results: We identified 192 significantly differentially expressed genes (FDR < 0.10) between pRT-responsive and non-responsive tumours, related to regulation of cellular development, growth and proliferation, cell cycle control of chromosomal replication, glucose metabolism and NAD biosynthesis II route. APOA1, MAP3K4, and MMP14 genes were differentially expressed (FDR < 0.20) between pRT responders and non-responders in preoperative setting, while MAP3K4 was further validated as RT-specific predictive biomarker of distant metastasis free survival (HR = 2.54, [95%CI:1.42-4.55], p = 0.002) in the postoperative setting. Conclusions: This study pinpoints MAP3K4 as a putative biomarker of response to RT in both preoperative and postoperative settings and a potential target for radiosensitising combination therapy, warranting further pre-clinical studies and prospective clinical validation.

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).

Trostruko-negativni karcinom dojke (engl. triple-negative breast cancer –TNBC) predstavlja subtip karcinoma dojke koji zauzima 15-20% od svih karcinoma dojke, karakteriše se odsustvom receptora za ER i PR, kao i odsustvom povećane ekspresije Her-2 receptora. Kao posledica agresivnog tumorskog fenotipa, nemogućnosti sprovođenja ciljane antitumorske terapije zbog odsustva pomenutih receptora, kao i parcijalnog odgovora na hemioterapije koje se primenjuju za karcinom dojke, ovaj subtip ima lošu prognozu. Intenzivno se izučavaju molekulske mete za praćenje kliničkog toka bolesti i efekata antitumorke terapije. Epigenetičke promene igraju isto tako značajnu ulogu u nastanku kancera kao i promene koje se odvijaju u nivou gena. Cilj ovog rada je bio da se utvrdi da li metilacioni status promotora ispitivanih BRCA1, p16, O6MGMT, RASSF1 i CDH-1 gena kod bolesnica sa trostruko negativnim karcinomom dojke, kao prognostički najlošijom grupom karcinoma dojke sa agresivnim fenotipom, može da se poveže sa kliničkim tokom bolesti i da posluži kao eventualni pokazatelj prognoze bolesti. Materijal i metode: U rad je uključena 131 bolesnica sa karcinomom dojke koje su na početku lečenja bile podvrgnute hirurškom lečenju (61 sa trostruko negativnim karcinomom dojke, a drugu grupu čini 70 bolesnica koje spadaju u najbolju prognostičku grupu karcinoma dojke (ER+, PR+, Her2-). Bolesnice su praćene između 1 i 87 meseci (medijana 78 meseci). Hipermetilacioni status promotorskog regiona BRCA1, p16, O6MGMT, RASSSF1 i CDH-1 gena je određivan u tumorskom tkivu, obzirom da je metilacija tkivno i tumor specifična. DNK iz uzoraka sveže smrznutog tumorskog tkiva je izolovana metodom isoljavanja. Određivanje hipermetilacije promotora specifičnih gena je urađeno metilaciono-specifičnim PCR metodom. Rezultati: Poređenje hipermetilacije promotora BRCA1, p16, O6MGMT, RASSF1 i CDH-1 gena pokazalo je da se ove dve grupe statistički značajno razlikuju samo u odnosu na učestalost hipermetilacije promotora p16 gena – statistički značajno veći broj hipermeilacija promotora gena pronađen je u grupi trostruko negativnog karcinoma dojke, 33 (54.1%) vs. 20 (28.6%), p=0.00298. Iako nije pokazana statistički značajna razlika u učestalosti hipermetilacije promotora BRCA1 gena između ispitivanih grupa bolesnica, uočen je trend ka većem broju hipermetilacija u trostruko negativnom karcinomu dojke grupi bolesnica: 33 (54.1%) prema 27 (38.6%), χ2 test, p=0.0752... riple-negative breast cancer, present with frequency of about 15-20% of all breast cancers, is characterized with the lack of estrogen, progesterone and Her-2 receptors and aggressive form of disease. As the consequence of aggressive tumor phenotype, lack of targeted anticancer therapy due to the absence of biological markers, as well as poor response to conventional chemotherapy, triple-negative breast cancer is associated with poor prognosis. Molecular targets that can serve as prognostic as well as predictive markers are intensively studied. It has been proposed that epigenetic changes in the cancer development are as significant as genetic changes. Aim: This work was done in order to evaluate if methylation status of BRCA1, p16, MGMT, RASSF1 and CDH-1 genes in triple-negative brast cancer as prognostically the worst subtype of breast cancer, can be correlated with clinical course and can serve as prognostic markers of disease. Material and Methods: 131 breast cancer patients with surgery as primary treatment were included: 61with triple-negative breast cancer (TNBC) and 70 with estrogen, progesterone positive and Her2 negative (ER+, PR+, Her2- ) breast cancer that represents prognostically the best subtype of breast cancer. The pateints were followed up between 1 and 87 months (median 78 months). Status of promotor hypermethylation of BRCA1, p16, O6MGMT, RASSSF1 i CDH-1 genes was determined in the tumor tissue since methylation is tissue and tumor specific. DNA was isolated from fresh frozen tissues by salting out procedure. Status of promotor hypermethylation was determined by methylation-specific PCR. Results: There was statistically significant difference only in p16 hypermethylated breast cancer cases when TNBC was compared with ER+PR+Her2- group, 33 (54.1%) vs. 20 (28.6%), p=0.00298. Although the difference between the incidences of BRCA1 hypermethylation between the examined groups of patients did not reach statistical significance, we observed a tendency towards higher occurrence of BRCA1 hypermethylation in TNBC compared to ER+PR+Her2- cases: 33 (54.1%) vs. 27 (38.6%), p=0.0752. When the frequencies of co-methylated (combined hypermethylation of the examined genes) p16 and RASSF1A genes (p16+RASSF1A+) were compared between the breast cancer patients with TNBC and ER+PR+Her2- characteristics, we found that the number of patients with both hypermethylated genes was significantly higher in the TNBC than in ER+PR+Her2- group: 20 (32.8%) vs. 10 (14.3%), p=0.0225...

Sve pacijentkinje sa detektabilnom ekspresijom hormonskih receptora (HR) za karcinom dojke (KD) trebalo bi da se leče endokrinom terapijom (ET). Za premenopauzne pacijentkinje, tamoksifen i/ili ovarijalna supresija (OvS) su adekvatna terapija. Promene u fosfataza i tenzin homolog (PTEN) signalnom putu bi mogle da budu jedan od mogućih mehanizama rezistencije na antiestrogenu terapiju. Cilj ovog istraživanja je ispitivanje povezanosti ekspresije PTEN proteina sa prognostičkim faktorima [(histologija i gradus tumora, status receptora za estrogen (ER) i receptora za progesteron (PgR), status receptora za humani epidermalni faktor rasta (HER2)] i sa odgovorom na terapiju kod premenopauznih pacijentkinja sa HR pozitivnim ranim KD lečenih adjuvantnom ovarijalnom ablacijom (OA). Pacijenti i metode: Analizirali smo grupu premenopauznih pacijentkinja sa ranim (stadijum I/II) HR pozitivnim KD koji su lečeni radikalnom mastektomijom a zatim adjuvantnom terapijom u vidu OA. Sadržaji ER i PgR su određeni klasičnom biohemijskom metodom [engl. Classical biochemical dextrane-coated charcoal (DCC) method], HER2 status je određen hromogenom in situ hibridizacijom (CISH metoda) i PTEN status je određen imunohistohemijskom metodom (IHH). Rezultati: U ovu analizu je uključeno 66 premenopauznih pacijentkinja. Medijana praćenja je 17 godina (opseg 1-29 godina). U poređenju sa PTEN pozitivnim KD, PTEN negativni KD su bili značajno više povezani sa lobularnim histološkim tipovima tumora (p

terapiji lokalno odmaklog karcinoma dojke (LOKD) preoperativna radioterapija (PRT) je u današnje vreme indikovana nakon primarne (neoadjuvantne) hemioterapije (PHT) u slučaju da nije postignuta resektabilnost tumora. Pre uvodjenja neoadjuvantne hemioterapije, PRT se mnogo češće koristila kao jedini neoadjuvantni pristup za inicijalno inoperabilne tumore, u cilju smanjenja tumorskog volumena i omogućavanja radikalne hirurgije. Cilj ove analize je evaluacija tumorskog odgovora i dugoročnog ishoda bolesti kod pacijenata tretiranih samo PRT, bez uticaja sistemske terapije, i procena povezanosti bioloških markera sa odgovorom na PRT. Metod: U periodu od 1997-2000.godine 134 bolesnica sa neinflamatornim LOKD stadijuma IIIA i IIIB tretirano je preoperativnom RT. Tumorska doza je bila 45 Gy u 15 frakcija (3 Gy po frakciji) naizmenično svakog drugog dana na regiju dojke i regionalnih limfatika u toku 6 nedelja. Šest nedelja po završenoj RT, učinjena je radikalna mastektomija kod svih bolesnica i potom primenjena adjuvantna terapija (hemioterapija i/ili hormonska terapija) po tadašnjem protokolu. Ishod bolesti je procenjivan na osnovu ukupnog preživljavanja (OS) i preživljavanja bez znakova bolesti (DFS). Krive preživljavanja (OS i DFS) su procenjivane korišćenjem Kaplan-Meier metode i univarijantne statističke analize korišćenjem Log-Rank testa u cilju procene razlike izmedju analiziranih grupa. Status hormonskih receptora ER i PgR, HER-2 status i Ki-67 su analizirani imunohistohemijskim metodama na uzorku biopsiranog tumora i uzorku na mastektomiji. Merenje genske ekspresije vršeno je iz parafinskih uzoraka tumorskog tkiva Microarray analizom. Rezultati: Medijana praćenja iznosila je 74 meseca (ranga 4-216). Klinički odgovor tumora na PRT zabeležen je kod 77.6% bolesnica. Klinički kompletan odgovor tumora (cCR) postignut je kod 21.6% bolesnica, dok je patohistološki kompletan odgovor (pCR) u dojci registrovan kod 15% bolesnica. Od toga 10/134 (7.5%) je ostvario totalni pCR (bez invazivnog tumora u dojci i bez pozitivnih limfnih čvorova u aksili). Petogodišnje i l0-godišnje OS je bilo 55.1% i 37.8%, dok je 5-godišnje i 10-godišnje DFS bilo 39.2% i 27%. Bolesnice koje su postigle cCR su imale statistički duže OS u poredjenju sa onima sa cPR i cSD (Log-Rank test, p=0.038). Slično je i DFS bolesnica sa cCR bilo duže u odnosu na cPR i cSD, mada razlika nije bila statistčki značajna. Analizom bioloških markera pokazano je da pacijenti sa luminal A tumorima imaju bolje preživljavanje u odnosu na ostale podtipove, dok trostruko negativni tumori imaju najbolji odgovor na PRT (40% pCR i pNCR). Analiza genske ekspresije primarnog tumora je pokazala da su tri gena (APOA1, MAP3K4 i MMPM) značajno različito eksprimirana izmedju RT-rezistentnih i RT-responzivnih tumora. Zaključak: Naši rezultai su pokazali da lokalna kontrola pacijenata sa LOKD tretiranih preoperativnom RT i radikalnom mastektomijom je komparabilna sa rezultatima prikazanim u literaturi. Kompletan patohistološki odgovor (pCR) na PRT izdvaja grupu bolesnica koje naginju ka boljem OS i DFS. In the treatment of locally advanced breast cancer (LABC) preoperative radiotherapy (PRT) today is indicated after primary (neoadjuvant) chemotherapy (PCT) if resectability of tumor was not achieved. Before the introduction of PCT in treatment strategy, PRT was more frequently used as the sole neoadjuvant approach for initially inoperable tumors, in order to reduce tumor volume and reach radical surgery. The purpose of this analysis was to evaluate the tumor response and long-term outcome at patients treated with only PRT, without influence of systemic therapy, and to assess the relationship of biological markers with response to PRT. Method: Between 1997 and 2000, 134 patients with non-inflammatory LABC stage IIIA and IIIB were treated with PRT. The tumor dose was 45 Gy in 15 fractions (3 Gy per fraction) every second day to the breast and to regional lymph nodes over 6 weeks. Radical mastectomy was performed 6 weeks after PRT to all patients and adjuvant systemic therapy was administered as per protocol. The measure of disease outcome were overall survival (OS) and disease-free survival (DFS). Survival and DFS curves were estimated using the Kaplan-Meier method and univariate statistical analysis by Log rank test was used to assess the difference in time to event (OS/DFS) between the analyzed groups. The hormone receptor status of ER and PgR, HER-2 status and Ki-67 were assessed by immunohistochemistry on the biopsy and mastectomy specimens. Gene expression profiles were established using micro-array analysis in a formalin-fixed paraffin-embedded (FFPE) tumor samples. Results: Median follow-up was 74 months (range 4-216 months). An objective clinical tumor response after preoperative RT was observed in 77.6% of patients. Clinical complete tumor response (cCR) was achieved in 21.6% of patients. Pathological CR in the breast was achieved in 15% of patients. Among them 10/134 (7.5%) had total pCR (no invasive tumor in breast associated with no involved regional axillary lymph nodes. The 5 and 10-year OS were 55.1% and 37.8% respectively. The 5 and 10-year DFS were 39.2% and 27% respectively. Patients who achieved cCR had significantly longer OS in comparison with patients achieving cPR and cSD. Similarly, DFS of patients in cCR group was longer compered to patients with cPR and cSD, although it did not reach statistical significance. Analysis of biological markers has shown that patients with luminal A tumors had better OS than other subtypes, but triple-negative breast cancers (TNBC) had the best response to PRT (40% of pCR and pNCR). Gene expression analysis of primary tumor has shown that three genes (APOA1, MAP3K4 and MMPM) were significantly differentially expressed between RT-resistant and RT-responsive tumors. Conclusion: Our results showed that local control in LABC patients achieved by primary PRT, followed by radical mastectomy was comparable with the results reported in literature. Complete pathologic response to PRT identified a subgroup of patents with a trend toward better DFS and OS.

Androgeni receptor je u visokom procentu zastupljen u tkivu karcinoma dojke, gde se može naći i do 70%, ali je njegov značaj do sada nedovoljno ispitivan. Cilj: Želeli smo da ispitamo prognostičku ulogu androgenog receptora u ranom karcinomu dojke (KD). Metrijal i metode: Prognostičku ulogu androgenog receptora (AR) ispitali smo kroz metaanalizu publikovanih kliničkih studija koje su ispitivale uticaj ekspresije AR na preživljavanje bez bolesti (eng. disease free survival-DFS), kao i ukupno preživljavanje (eng. overall survival-OS) kod pacijentkinja sa ranim karcinomom dojke. Koristeći ključne reči na engleskom jeziku "karcinom dojke" i "androgen receptor" pretražili smo dostupne elektronske baze podataka (PubMed, Google school i Cohrane review) kako bismo identifikovali studije koje su odgovarale unapred zadatim kriterijumima. Kvalitativnu procenu studija koje su selektovane za kliničku meta-analizu vršili smo pomoću REMARK kriterijuma. U skopu meta-analize izračunali smo kombinovani indeks rizika (eng.hazard ratio-HR) sa 95% intervalom poverenja (eng. confidence interval-CI) koristeći AR negativne pacijentkinje kao referentnu vrednost. Drugi deo mata-analize se odnosi na podatke dobijene ekpresijom gena (eng. gene-expression) dostupnih kroz setove podataka mikroareja (eng. microarray) pacijentkinja sa KD i poznatim ishodom bolesti. Koristeći PAM50 molekularni klasifikator (eng. molecular classifier) odredili smo molekularne podtipove KD. Ispitivali smo korelaciju AR iRNK sa kliničko-patološkim varijablama, drugim individualnim genima i genskim zapisima (eng. gene signatures) i kliničkim ishodom... Androgen receptor (AR) expression has been observed in about 70% of breast cancer (BC) patients, but its prognostic role is not yet established. Aim: To evaluate prognostic role of androgen receptor in patients with early breast cancer. Methods: To assess the prognostic role of AR in breast cancer we performed a metaanalysis of studies that evaluated the impact of AR on disease free survival (DFS) and/or overall survival (OS) in patients with early stage BC. Eligible studies were identified by systematic review of electronic databases using the MeSH terms "breast neoplasm" and "androgen receptor". Evaluable studies were selected after a qualitative assessment based on the REMARK criteria. We report combined Hazard Ratios (HRs) with 95% confidence intervals (CI) using AR negative patients as a reference. In addition, we conducted an in-silico pooled analysis of publicly available microarray data sets, from patients with early stage BC with known gene expression profiling and clinical outcome. By using PAM50 molecular classifier we assigned patients to molecular subtypes. We explored correlations of AR mRNA levels with clinico-pathological variables, other individual genes and gene signatures and clinical outcome. Results: 22 out of 33 eligible studies for the clinical meta-analysis, including 10.004 patients, were considered as evaluable for the current study after the qualitative assessment...