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PURPOSE: Prognostic factors in metastatic breast cancer (MBC) differ from those of primary breast cancer. The aim of this study was to identify the clinical significance of combined estrogen and progesterone receptors (ER,PR) and human epidermal growth factor receptor-2 (HER2) status on MBC post relapse survival. METHODS: The survival of 109 MBC patients was analyzed according to clinical characteristics and ER/PR status (tested by ligand binding assay) and HER2 status (tested by chromogenic in situ hybridization/CISH). RESULTS: Proper parameters for follow up of MBC patients were patient age, duration of disease free interval (DFI), dominant site of metastasis, number of metastatic sites and ER, PR status. Follow up of MBC patients showed the statistically significant difference in post relapse survival between patients with extreme phenotypes ER+PR+ and ER-PR-. Addition of HER2 status confirmed negative effect of HER2 amplification on MBC post relapse survival resulting in worse prognosis of ER-PR-HER2+ patients. The corresponding triple receptor (ER,PR,HER2) combination repeated the same pattern. In combination with patient age it was shown that difference in post relapse survival between extreme phenotypes (ER+PR+HER2- and ER-PRHER2+) was age related i.e. patients older than 50 years, with ER-PR-HER2+ phenotype, had mortality rate 100% and median survival time 14 months. CONCLUSION: There is a strong indication for use of combined triple receptor status for follow-up of MBC patients. Based on our results, the worst phenotype was neither triple positive nor triple negative, but the one that most likely reflects the biological background of these biomarkers (ERPR- HER2+). Double and triple receptor status showed repeated pattern of influence on prognosis, but the finding that ER-PR-HER2+ phenotype in an age-restricted subgroup of patients means extremely poor prognosis and a highest mortality rate deserves further consideration regarding therapy efficiency.

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The aim of this study was to determine the relationship between amplification of HER2 (Human epidermal growth factor receptor 2) and Topo2a (topoisomerase 2a) and their influence on prognosis in metastatic breast cancer (MBC) patients. Amplification of both HER2 and Topo2a genes was determined by chromogenic in situ hybridization (CISH) in primary tumor tissue of 71 MBC patients. Starting point for follow-up was the time of diagnosis of metastatic disease. Although there was significant correlation between HER2 amplification and Topo2a alterations, Topo2a amplification was not strictly related to HER2 amplification. Follow-up of patients showed that there was no difference in MBC survival between HER2-nonamplified and HER2-amplified patients for subgroup as whole, but there was significant difference in MBC survival between patients with and without Topo2a amplification. HER2 amplification showed prognostic value in subgroups of patients, as well as Topo2a. Combination of these two genes with different status (nonamplified, amplified, coamplified) indicated that they might have additive effect. Also, it has been shown that Topo2a-amplified cases have poorer survival than Topo2a-nonamplified, when treated with CMF therapy. Topo2a amplification seems to be more promising biomarker of MBC survival, than HER2, and potential marker of resistance to CMF therapy.

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Transforming growth factor-beta1 (TGF-beta1) is a biomarker associated with the progression of breast cancer, characteristic by switching activity from tumor suppressor in early stages to tumor promoter at advanced disease. However, what cause this switch is still not clear. On the other hand, the relationship between steroid receptors (estrogen ER and progesterone PR) as the major discriminators of breast cancer phenotype and this paradoxical biomarker is not fully determined. In this pilot study on 52 breast cancer patients, quantitative plasma values of TGF-beta1 were determined by quantitative ELISA and steroid receptor content was measured in cytosol fraction of breast cancer tissue using dextran-coated (DCC) method. We tried to investigate the possibility that steroid receptor status of patients at different stages of disease could be the trigger that somehow causes variation of TGF-beta1 plasma levels. In nonmetastatic breast cancer patients, there was no statistically significant increase in the plasma levels of TGF-beta1, when patients are stratified by steroid receptor status (ER- vs. ER+, PR- vs. PR+). We found for the first time, that indeed in metastatic breast cancer statistically significant elevated levels of TGF-beta1 are related to negative steroid receptor status and moreover that, there is correlation between quantitative values of these parameters in this stage. This finding deserves further investigation because it could provide a new insight into more aggressive nature of steroid receptor negative tumors.

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PURPOSE: To assess the need and willing for education of oncology experts for the implementation of the European Educational Programme (EEP) "Learning to live with cancer", and to analyze how participants evaluated the first 3 seminars "Education of educators". MATERIALS AND METHODS: In March, April and May 2003, three 3-day seminars entitled "Education of educators" for implementing the EEP "Learning to live with cancer" were organized by a certified educator team of the Institute for Oncology and Radiology of Serbia, Belgrade. The attendees (n=70) answered a questionnaire specially constructed in order to assess their previous knowledge about the topics of the seminar, their satisfaction with the content of the seminar, their attitude towards implementation of what they learned in daily routine practice, and their willingness to continue such an education in the future. RESULTS: Education of patients and their families was not a part of daily routine practice of 79% of the attendees, and 88.6% of them thought that their patients would benefit from the implementation of the EEP. The knowledge acquired during the seminars was completely or partially new for 76% of the participants, and 96% of them thought that similar seminars should be organized on a regular basis--once a year. Readiness to participate actively in future seminars expressed 64% of the attendees, and all of them suggested topics they thought most interesting for their practice. CONCLUSION: The content of the three seminars satisfied the great majority of the attendees. Their positive attitude and willingness to implement what they have learned in their practice confirmed the need to apply the EEP in the holistic treatment of cancer patients.

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In order to address the heterogeneity of the pT1 breast cancer stages, we have been examining the natural and the clinical course of disease in relation to cathepsin D expression, as a molecular marker for the tumor progression that leads to metastasis. The original aim of our pilot study was to determine whether it was possible to distinguish high-risk from low-risk patients, on the basis of nonestrogen- vs. estrogen-regulated cathepsin D expression. Our results showed that estrogen-regulated cathepsin D expression could be useful as surrogate marker of node-positive status. Further, during the natural course of disease, none of 7 pT1N0 patients with tumors bearing nonestrogen-regulated cathepsin D expression developed metastasis. During the clinical course of disease, nonestrogen-regulated cathepsin D expression defined low-risk while estrogen-regulated cathepsin D expression defined high-risk pT1N+ subgroup of patients. Although there is no consensus with respect to metastasis-related prognostic value of cathepsin D expression, our pilot study implies its prognostic value in pT1 breast cancer patients and supports the hypothesis that cathepsin D may promote metastasis in this early stage of disease.

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PURPOSE: Breast carcinomas becoming tamoxifen-resistant after objective clinical response to antiestrogen therapy may remain responsive to other endocrine agents due to different mechanisms of action. The aim of our study was to analyze whether primarily tamoxifen-unresponsive/steroid receptor (SR) - positive breast carcinomas can respond to an aromatase inhibition. PATIENTS AND METHODS: Thirteen postmenopausal, SR-positive, metastatic breast cancer (MBC) patients were included: they had previously failed to respond to tamoxifen, either as primary systemic therapy for advanced disease, or as adjuvant treatment (5 and 8 patients, respectively). Patients were treated with 2.5 mg letrozole daily, from 2-25 months, mostly until disease progression. RESULTS: Partial response (PR) was obtained in one third of the patients (4/13); additionally, 3 patients showed disease stabilization (SD) longer than 6 months. The observed response duration lasted from 7 to 36+ months (median 9). Overall survival from the beginning of letrozole treatment was better in letrozole responders compared with nonresponders. It appeared as if there were two different subgroups of patients: one completely endocrine-unresponsive, and the other unresponsive to tamoxifen but responsive to letrozole (supposed to be primarily tamoxifen-resistant, but otherwise endocrine-responsive). HER-2 overexpression (immunohistochemically determined as 2+ and 3+) was found in 3 patients, which could not account for the different endocrine responsiveness. CONCLUSION: Our study confirmed that some SR-positive breast carcinomas, primarily tamoxifen-unresponsive, may respond to letrozole, thus being endocrine-responsive, while others did not respond, probably due to complete endocrine unresponsiveness. It is not likely that HER-2 was the biomarker that made the difference between these two subgroups.

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PURPOSE: To assess the influence of steroid receptors (SR) status on disease outcome of early breast cancer patients treated with adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF) chemotherapy. PATIENTS AND METHODS: Sixty-six node-negative patients with grade 3 invasive breast carcinoma and 95 patients with 1-3 involved axillary lymph nodes regardless of tumor grade received adjuvant CMF chemotherapy. The endpoints of this analysis were disease-free survival (DFS) and overall survival (OS). Statistical analysis included log rank test and Cox regression models. RESULTS: The median follow-up period was 81 months (range 6-208). Patients with progesterone receptor (PR) - negative tumors had better DFS compared to women with PR-positive tumors (log rank test, p=0.033). Estrogen receptor (ER) - negative and PR-negative patients in the node-negative subgroup had better DFS than ER-positive and PR-positive patients (for ER: log rank test, p=0.009, and for PR: log rank test, p=0.004). However, positive lymph nodes were the only significant predictor of disease progression among patients receiving CMF therapy (Likelihood Ratio test, p <0.001). Women under 40 bearing SR-positive breast cancer had a trend toward worse DFS (log rank test, p=0.054) compared to older SR-positive premenopausal women. CONCLUSION: We can not unequivocally reveal the influence of SR status on disease outcome in early breast cancer patients treated with adjuvant CMF, although SR-positive patients in the node-negative group were shown to have worse DFS in comparison to SR-negative ones. However, nodal status remained the only independent predictor of disease progression in these patients.

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Although overexpression of TGF-beta1 protein has been demonstrated in advanced breast cancer (BC) patients, as well as in other solid tumours, the molecular mechanism of this process remains obscure. This paper proposes that a genetic/epigenetic alteration might occur in the TGF-beta1 gene, within the region coding for the recognition site with TGFbeta receptor type II, leading to a disruption of the ligand-receptor interaction and triggering the TGF-beta1 cascade-related BC progression. To establish the operational framework for this hypothesis, in the present study, this recognition site was identified by the Informational Spectrum Method (ISM) to comprise two TGF-beta1 peptides (positions 47-66 aa and 83-112 aa) and one receptor peptide at positions 112-151 aa of the extracellular domain of the receptor (TbetaRIIM). The TbetaRIIM locus was further evaluated by ISM-derived deletion analysis of the TbetaRII sequences. To provide experimental support for the proposed model, a pilot study of plasma TGF-beta1 analysis was performed in advanced BC patients (n = 8). Two commercial ELISA assays, one with specific alphaTGF-beta1 MAb (MAb) and other with TbetaRIIM as the immobilized phase, revealed pronounced differences in the pattern of plasma TGF-beta1 elevation. In MAb-profile, the TGF-beta1 increase was detected in 7 of 8 patients, whereas analogous TbetaRIIM-profile revealed the elevation in 3 of 8 patients, taking a 50% of maximal elevation as the cut-off value. These findings are consistent with the proposed aberration of TGF-beta1 ligand within the TbetaRII recognition site. Summarizing, this model system is a good starting point for further genetic studies, particularly on genetic/epigenetic alterations of sequences involved in TGF-beta1 and TbetaRIIM interaction, with putative prognostic value for breast cancer.

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PURPOSE: Radiation treatment of breast cancer (BC) often results in post-therapy complications. The undesired sequelae could be avoided by the diagnostic screening of biomarkers for prediction of ionizing radiation (IR)-linked injury of healthy tissues. PATIENTS AND METHODS: The expression of antioxidative defence enzymes CuZn- and Mn-superoxide dismutase (CuZnSOD, MnSOD) and tumor suppressor protein p53 was measured in blood cells of 19 women with BC (age groups 30-45 and 46-60 years) and respective controls. The proteins were detected by specific immunostaining and quantified by laser-scanning densitometry. RESULTS: Constitutive expression of CuZnSOD was significantly elevated in the group of BC patients (up to 254 arbitrary units, AU/mL) relative to the control group (105-130 AU/mL). The constitutive expression of MnSOD was elevated (up to 94 AU/mL) in the group of BC patients relative to the controls (53-56 AU/mL). p53 was also constitutively more expressed in BC patients (35-42 AU/mL) than in controls (32-33 AU/mL). Both MnSOD and p53 were inducible by (60)Co gamma-ray IR (up to 170 AU/mL and 51 AU/mL, respectively) in the BC patient group. The levels of IR-induced p53 correlated inversely with MnSOD levels. CONCLUSION: The constitutive expression of all 3 proteins could be a useful biomarker for the presence of BC, but only MnSOD overexpression may be the predictive biomarker for selection of BC patients that would be less susceptible to IR-linked complications.

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Irradiation is the conventional treatment modality for cancer patients. However, besides its cytotoxic effects on malignant cells it might also affect the biology of surviving cells. Since overexpression of HER-2 receptors on malignant cells is a prerequisite for the therapeutic efficacy of Herceptin, it seems important to know whether previous irradiation changes their overexpression. The experiments performed in this work were aimed to determine whether X-ray irradiation of MDA-MB-361 and MDA-MB-453 breast carcinoma cell lines, besides its cytotoxic action, affects the overexpression of HER-2 protein. Determination of the cytotoxic effect of X-ray irradiation was done using trypan blue test. The breast carcinoma cell responsiveness to herceptin treatment in the presence of 10% fresh human serum (from healthy volunteer's) in the presence or absence of 25 microg/ml of herceptin, in vitro before and after cell-irradiation, was evaluated by MTT test. The degree of HER-2 overexpression was determined by immunocytochemistry, using DAKO HercepTest. Preliminary results obtained in this work showed that X-ray irradiation, besides its cytotoxic effect on malignant cells, could lead to overexpression of HER-2 receptors on (initially by immunocytochemistry, HER-2 negative) tumor cells, indicating change in biology of treated tumor cells. Further investigation in this direction will probably be helpful to elucidate this task in order to improve the selection of irradiated patients for Herceptin therapy.

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A pilot study was conducted to assess whether plasma levels of transforming growth factor-beta1 (TGF-beta1) might facilitate biological subgrouping of postmenopausal metastatic breast cancer patients, and, accordingly, its applicability in clinical oncology. This study included 29 postmenopausal metastatic breast cancer patients. Plasma TGF-beta1 levels were detected by enzyme-linked immunosorbent assay (ELISA). Estrogen and progesterone receptors were assayed by radioligand binding, in accordance with the recommendation of the EORTC. Concentrations of 17-beta estradiol were determined by using ELISA-microwell method (DIALAB). Overall survival was followed for 24 months for each individual patient. Stratification of the patients by ER/PR status showed that 14 patients with estrogen receptor-negative, progesterone receptor-negative carcinomas displayed a statistically significant increase in plasma TGF-beta1 levels when compared to plasma TGF-beta1 levels of 6 patients with ER-positive, PR-positive carcinomas (P=0.04). In this study, 7 out of 14 patients with negative receptors' status had no plasma TGF-beta1 values overlapping with patients having positive receptors' status. The TGF-beta1 cut-off value was defined as the highest plasma TGF-beta1 level of ER-positive, PR-positive patients: 3.28 ng/ml. This plasma TGF-beta1 cut-off value defined low-risk subgroup of 19 patients (< or = 3.28 ng/ml) and high-risk subgroup of 10 patients (> 3.28 ng/ml) (P=0.047). Plasma TGF-beta1-related survival was independent of the classical prognostic factors of metastatic breast cancer. Accordingly, a clinical significance of elevated plasma TGF-beta1 levels may be suggested.

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Two major trends are evident from ongoing conferences and panels of experts on early breast cancer adjuvant treatment. The first strongly suggests the application of wellestablished standards of adjuvant treatment in everyday clinical practice. The second encourages participation in international adjuvant clinical studies of breast cancer. Our growing knowledge of the role of endocrine adjuvant therapy in early breast cancer has emerged from the findings of large adjuvant studies. Meta-analyses of numerous randomised trials have accumulated evidence that has been analysed on many occasions by international panels of experts and has become a major source of consensus recommendations. Nevertheless, many open questions still exist, and new ones arise. This paper reviews the current standards for the adjuvant treatment of endocrine-dependent breast cancer, as well as some perspectives emerging from ongoing clinical studies.

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This study attempted to evaluate the first-generation prognostic factors in terms of relapse-free interval in 297 node-negative breast cancer patients treated with locoregional therapy alone. Predictors of outcome were, in order of strength: tumor size (RR 2.09), tumor grade (RR 2.03) and age (RR 0.97). Age was a single independent prognostic parameter in premenopausal patients younger than 45 (RR 0.82). Tumor size was also a single independent prognostic parameter in middle-aged patients (RR 2.05). In older patients, aged 60 and over, tumor grade (RR 11.6) and type (RR 0,52) in addition to tumor size (RR 7.00) were independent prognostic parameters. Our study of disease-free survival identified high risk-related subgroups: patients younger than 35, middle-aged post-menopausal patients bearing pT2 carcinoma with steroid receptor content lower than 5 fmol/mg, and patients older than 59 bearing pT2 carcinoma with grade 11 and unfavorable types-ductal, lobular.

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The biological significance of estrogen receptor-negative but progesterone receptor-positive breast carcinomas is not clear. In the present study the aggressiveness of breast carcinomas in relation to ER and PgR status has been investigated. The probability of disease-free survival in 297 node-negative breast carcinoma patients was monitored during a follow-up ranging from six to 96 months (median 45 months). Steroid hormone receptor content was assayed with the biochemical method recommended by the EORTC. The probability of disease-free survival was significantly worse for patients with ER-negative, PgR-positive carcinomas compared to the other three steroid hormone receptor phenotypes. Our results suggest that ER-negative, PgR-positive breast carcinomas are biologically different in terms of aggressiveness from the other steroid hormone receptor phenotypes.

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PURPOSE: The usefulness of steroid receptor content in breast cancer metastases for metastatic disease therapy planning was examined in this study. METHODS: Steroid receptors in primary tumors and corresponding metastases in the same breast cancer patients ( n=23) were determined by five-point DCC assay. We carried out an analysis of the therapeutic response and comparison of the progression-free interval of patients treated with endocrine/chemo-endocrine therapy for metastatic disease according to the positive/negative progesterone receptor status of primary tumors, or of breast cancer metastases. RESULTS AND CONCLUSIONS: It seems that the lack of positive progesterone receptors in metastasis (0/8) and conversion from PR+ primary to PR- metastasis (5/8) may be important in describing the non-responder phenotype. We obtained a similar progression-free interval in patients with progesterone receptor-positive/negative primary tumors, but a longer progression-free interval in the patients with progesterone receptor-positive metastases ( n=9) than with negative ones ( n=14), indicating the possibility of using steroid receptor content from metastases for metastatic disease therapy planning.

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This study includes 152 patients with histologically confirmed breast carcinoma. Steroid hormone receptors (SR), estrogen (ER) and progesteron (PR) receptors, and pS2 protein were assayed on the same cytosolic extract in accordance with the recommendation of EORTC. Our results showed menopausal- and histologic grade-related expression of pS2 protein. Unfavorable carcinoma subgroups, in relation to expression of pS2 protein were defined: postmenopausal carcinomas with histologic grade II, and pre-, as well as postmenopausal carcinomas with histologic grade III. There were overlappings of individual pS2 protein values between favorable and unfavorable carcinoma subgroups in relation to the expression of pS2 protein. Otherwise, no overlapping of pS2 protein values was obtained between ER-positive and ER-negative carcinomas within defined unfavorable menopausal - and histologic grade-related expression of pS2 protein subgroups. The highest pS2 protein level observed in ER-negative unfavorable subgroups (15 ng/mg) was considered as the cut-off value which defined estrogen-regulated expression of pS2 protein.

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The aim of our single-center, prospective, randomized, open study was to evaluate the antiemetic efficacy and tolerability of a regimen based on a single oral dose of ondansetron 8 mg in comparison with a metoclopramide-based regimen, for prevention of acute FAC (fluorouracil, doxorubicin and cyclophosphamide) chemotherapy-induced emesis. A total of 149 chemotherapy-naive, female outpatients, under 50 years of age and with no history of alcohol consumption, scheduled to receive their first cycle of FAC chemotherapy, were included. The patients received either oral ondansetron (8 mg) or metoclopramide (1.5 mg/kg, i.v.), both combined with dexamethasone (16 mg, i.v.) and alprazolam (0.5 mg t.i.d. orally). No antiemetic prophylaxis was given for delayed emesis. Complete control of acute vomiting was obtained in 69/74 (93%) of patients receiving ondansetron, and in 49/75 (65%) of those receiving metoclopramide (p=0.00003). Complete control of acute nausea was obtained in 58% of patients receiving ondansetron and in 36% of those receiving metoclopramide (p=0.007). Complete prevention of delayed vomiting/nausea was achieved in 73%/20% and 60%/16% of patients, respectively. Sedation was more frequent in the metoclopramide arm (p=0.04). As far as we know this is the first study that supports the efficacy of a regimen based on a single oral dose of ondansetron 8 mg in the prevention of acute FAC chemotherapy-induced emesis. The ondansetron regimen was highly effective in female patients and was superior to the metoclopramide based regimen.

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Epidermal growth factor receptor (EGF-R) is known as an indicator of endocrine independence of breast cancer. However, a small proportion of EGF-R expressing tumors was found to respond to endocrine treatments. On the other side, a cut-off point of EGF-R positivity is not yet defined. In the aim to find out whether there exists a cut-off value that sharply discriminate the endocrine sensitive and endocrine insensitive breast cancers, the quantitative EGF-R content was analyzed in a group of 42 female patients with metastatic disease, being routinely treated with chemo-, chemo-endocrine, or endocrine therapy alone. Steroid receptors (SR) and EGF-R were determined by biochemical methods in tissue samples of an unselected group of patients. Patients with metastatic disease, either at diagnosis, or developed after the treatment of operable or locally advanced breast cancer, were included in the present analysis. According to the treatments used, and their therapeutic response, all patients were divided in endocrine sensitive or resistant, and chemo-sensitive or resistant. The SR and EGF-R status and content was analyzed in relation to the sensitivity to both systemic treatments. The EGF-R content was significantly lower in responders to endocrine treatments, compared to non-responders, while there was no difference in EGF-R level, in relation to the sensitivity to chemotherapy. In addition, the EGF-R content was significantly higher in chemo-sensitive tumors, than in endocrine sensitive. On the contrary, ER content was significantly higher in endocrine sensitive, than in endocrine resistant, and in chemo sensitive patients, as well. Similar differences were found in PR content, but they were less pronounced. While the individual ER contents in endocrine sensitive and endocrine resistant tumors overlapped, the EGF-R ranges were different: no one endocrine sensitive tumor exceeded the EGF-R content of 26 fmol/mg, thus suggesting the EGF-R cut-off point of endocrine sensitivity. The clinical use of EGF-R, with the cut-off point of 26 fmol/mg, in addition to clinical criteria of endocrine sensitivity and SRs, would significantly improve the correct endocrine sensitivity prediction (from 52 to 78%). In conclusion, in a group of metastatic breast cancer patients, treated routinely by systemic therapies it was found, that the use of higher cut-off point for EGF-R positivity can improve the prediction of endocrine sensitivity. The prognostic relevance of this cut-off value remains to be analyzed.

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The aim of our study was to explore the possible relationship between patient satisfaction with antiemetic treatment and quality of life (QoL). The study sample consisted of 136 chemotherapy-naive patients with breast cancer, with Karnofsky index 90% to 100%, scheduled to receive their first cycle of, mainly adjuvant, 5-fluorouracil/doxorubicin/cyclophosphamide chemotherapy. Two antiemetic regimens were used for the prevention of acute emesis. No antiemetic prophylaxis was given for delayed emesis. QoL was assessed using the Rotterdam Symptom Checklist (RSCL). The RSCL was completed before chemotherapy (day 1) and on day 5. Statement of satisfaction was given on day 5. The change in RSCL scores between day 5 and day 1 was calculated and compared in three subgroups of patients: those very satisfied (n = 55), satisfied (n = 65), and unsatisfied with antiemetic treatment (n = 16). Patient statement of satisfaction was related to psychological distress (p = 0.002), physical symptom distress (p = 0.002), and activity level (p = 0.002). It was also related to the control of nausea (p < 0.01) and vomiting (p < 0.0001). We suggest that patient statement of satisfaction with antiemetic treatment could be an outcome measure for response assessment in antiemetic trials.

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