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Background/aim: Detection of disseminated tumor cells (DTCs) after systemic treatment predicts poor prognosis in breast cancer patients. The aim of our study was to assess the expression of stem-cell marker SOX2 on DTCs and in the primary tumor of patients treated with neoadjuvant chemotherapy (NAT)., Materials and Methods: In 170 DTC-positive patients after NAT an additional slide of bone marrow aspirate was stained by double immunofluorescence to detect SOX2-positive DTCs. The SOX2 status of the primary tumor was assessed using the same antibody., Results: The SOX2-status of DTCs was determined in 62 patients and 20 of those (32%) had SOX2 positive DTCs. The SOX2 status of DTCs was not associated with any of the clinicopathological factors. A total of 36% of the patients with a SOX2-negative tumor showed SOX2-positive persistent DTCs., Conclusion: SOX2-positive DTCs can be detected in breast cancer patients after NAT, even in patients with SOX2-negative primary tumors. This suggests that these populations may have evolved independently of each other., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Only 30-50% of patients with sentinel lymph node (SLN) metastases present with further axillary lymph node metastases. Therefore, up to 70% of patients with positive SLN are overtreated by axillary dissection (AD) and may suffer from complications such as sensory disturbances or lymphedema. According to the current S3 guidelines, AD can be avoided in patients with a T1/T2 tumor if breast-conserving surgery with subsequent tangential irradiation is performed and no more than two SLNs are affected. Additionally, use of nomograms, that predict the probability of non-sentinel lymph node (NSLN) metastases, is recommended. Therefore, models for the prediction of NSLN metastases in our defined population were constructed and compared with the published nomograms., Patients and Methods: In a retrospective study, 2,146 primary breast cancer patients, who underwent SLN biopsy at the University Women's Hospital in Tuebingen, were evaluated by dividing the patient group in a training and validation collective (TC or VC). Using the SLN-positive TC patients, three models for the prediction of the likelihood of NSLN metastases were adapted and were then validated using the SLN-positive VC patients. In addition, the predictive power of nomograms from Memorial Sloan Kettering Cancer Center (MSKCC), Stanford, and the Cambridge model were compared with regard to our patient collective., Results: A total of 2,146 patients were included in the study. Of these, 470 patients had positive SLN, 295 consisted the training collective and 175 consisted the validation collective. In a regression model, three variants - with 11, 6 and 2 variables - were developed for the prediction of NSLN metastases in our defined population and compared to the most frequently used nomograms. Our variants with 11 and with 6 variables were proven to be a particularly suitable model and showed similarly good results as the published MSKCC nomogram., Conclusion: Our developed nomograms may be used as a prediction tool for NSLN metastases after positive SLN., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Borderline ovarian tumors (BOT) are malignant epithelial ovarian tumors with a very low incidence, therefore lacking sufficient clinical experience in diagnostics and treatment. This study characterized the histology, clinical features, diagnostics and therapy of BOT including patients treated at the Department of Gynecology and Obstetrics of the University Medicine Greifswald., Materials and Methods: In this retrospective, single-center study, patients with BOT treated between 1990 and 2010 were analyzed according to their histological and clinical reports., Results: A total of 54 patients were enrolled. The median age was 54.6 (range=23-83) years. Distribution of histological subtypes was: serous in 31 patients (57.4 %) and mucinous in 23 patients (42.6%). All patients underwent surgery. Eight patients (14.8%) were treated according to actual therapy recommendations during the initial surgery. Eight patients (14.8%) received adjuvant chemotherapy contrary to treatment recommendations. In the case of 36 patients (66.7%), a frozen section was taken intraoperatively, which matched the definitive histological result in 88.9%. During average follow-up of 70.3 months (range=0-231 months), two patients (3.7%) developed tumor recurrence after 9 and 29 months, respectively, two patients (3.7%) died of causes other than BOT., Conclusion: Our study critically demonstrated that until a few years ago, BOTs were not usually treated according to international therapy recommendations. Nevertheless, the rate of tumor recurrence was very low., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: By definition, tumor cells do not pass the epithelial basement membrane in pre-invasive lesions. However, recently, it was shown that hematogenous tumor cell dissemination already takes place in patients with ductal carcinoma in situ (DCIS), giving disseminated tumor cells (DTCs) in the bone marrow the opportunity to interact with the peripheral immune system. We, therefore, investigated the relationship between DTCs and the peripheral innate and adaptive immune system of DCIS patients, as immunosurveillance might also be impaired in pre-invasive lesions., Materials and Methods: We analyzed the peripheral immune status of 115 DCIS patients by flow cytometry. Results were correlated with presence of DTCs, that were detected in the bone marrow by immunocytochemistry (pan-cytokeratin antibody A45-B/B3) using the automated cellular imaging system (ACIS) according to the international society of hematotherapy and graft engineering (ISHAGE) evaluation criteria. Apoptotic DTCs were characterized by positive M30 staining and cytomorphological criteria., Results: In contrast to breast cancer, we found no significant correlation between appearance of DTCs and quantitative distribution of T-cell sub-populations, B and NK-cells neither in the bone marrow nor in the peripheral blood. Moreover, DTCs did not affect the expression of important immunomodulatory antigens for functional integrity of specific immune response such as, TCR-ζ, CD28 or CD95. Interestingly, 39% of DTCs were positive for M30 expression and showed cytomorphological signs of apoptosis., Conclusion: In contrast to breast cancer, DTCs of DCIS seem to be less immunogenic, which might result in a diverging way to evade immunosurveillance., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Aim: To delineate the role of pelvic and para-aortic node involvement in patients with optimally cytoreduced (R≤1 cm; R=residual tumor) stage IIIC ovarian cancer., Patients and Methods: Ninety-five consecutive optimally cytoreduced patients with primary stage IIIc ovarian cancer underwent stage-related surgery and adjuvant platinum-based chemotherapy, with a median follow-up of 53.5 months. All patients underwent systematic lymphadenectomy. On average, 24.7 pelvic and para-aortic lymph nodes were removed per patient (range=1-60 nodes); Patients were stratified into three groups to evaluate nodal involvement (ratio of affected to resected nodes): 0: no lymph node metastases; >0-0.5: >0 and fewer than 50% of involved nodes; >0.5-1: more than 50% of nodes involved. Clinical parameters were retrospectively evaluated., Results: Most often, serous histology, histological grade 3 and a node ratio >0-≤0.5 (61.1%) were detected. Complete cytoreduction (R=0 mm) had significant best prognostic impact compared to R>0 mm-1 cm (overall survival: p=0.047, progression-free survival: p<0.001). Nodal involvement was associated with serous histology and grade 3 tumor. Best overall survival was associated with a node ratio >0-≤0.5 (p=0.011). A solitary affection of the pelvic or rather para-aortic nodes was detected in 22.1% vs. 16.%, respectively; a combined affection of pelvic and paraaortic nodes were detected in 34.8%., Conclusion: The goal is optimal cytoreduction in advanced ovarian cancer. More extensive pelvic and para-aortic lymphadenectomy seems to play an important role in providing accurate staging in optimally-cytoreduced advanced ovarian cancer and the node ratio might give prognostic information. Current prospective studies should investigate if these data have therapeutic implications and may be considered in future staging., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Aim: To delineate the relevance of pelvic and para-aortic node involvement in early-stage ovarian cancer., Patients and Methods: Data on 75 consecutive patients with primary stage T1 and 2 ovarian cancer treated at the Department of Gynecology, University Tuebingen, Germany were retrospectively analyzed. All patients underwent stage-related surgery with pelvic and para-aortic lymphadenectomy and adjuvant platinum-based chemotherapy (except pT1aG1). Median follow up was 53.5 months. Clinico-pathological parameters and the distribution pattern of node metastases were evaluated. Statistical analyses were performed using PASW., Results: Lymph node metastases were detectable in T1 and T2 in 6 (8%) of 75 patients. Three patients (4%) had lymph node metastases in the pelvic nodes only, 2 patients (2.7%) in the para-aortic nodes only; 1 patient (1.3%) both in the pelvic and para-aortic nodes. On multivariate analysis, histological grade 1/ 2 and 3 tumors, serous and endometrioid histology were independent predictors for node metastases, respectively. The risk of relapse was significantly higher with detection of node metastases (p=0.004)., Conclusion: A systematic lymphadenectomy in early-stage ovarian cancer leads to an upstaging in a few patients after detection of node metastases even in pelvic or para-aortic nodes, especially in patients with grade 3 tumours and serous cancers. Pelvic and para-aortic lymphadenectomy may detect node involvement in early-stage ovarian cancer and might be helpful in correct staging., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Detection of circulating tumor cells (CTCs) in the peripheral blood of patients with primary breast cancer is associated with poor clinical outcome. Recent studies have found evidence for immunological influence on tumor cell dormancy. We therefore investigated the relationship between peripheral T-cells and CTCs, as immunological factors may contribute to the fate of CTCs., Materials and Methods: The peripheral blood immune status of 116 patients with primary breast cancer was analyzed by flow cytometry. Results were correlated with the presence of CTCs and clinicopathological parameters of these patients., Results: Appearance of CTCs was significantly associated with grade III tumors (p<0.05). Interestingly, CTC-positive patients presented with a significant increase of peripheral CD95(FAS)-positive T-helper cells. As immune response is regulated by CD95(APO-1/FAS)-CD95ligand interaction and tumor cells induce apoptosis via the CD95/CD95L (ligand) pathway, this might lead to tumor cell escape by apoptotic T-helper cells., Conclusion: Absence of T-cell help at the time of priming may result in a loss of long-term antigen-activation of CD8 lymphocytes and could lead to an ineffective anti-tumor cell response. This might contribute to systemic immunosuppression and open the door for tumor cell dormancy.

Background: Disseminated tumor cells (DTCs) in bone marrow (BM) occur in 30-40% of primary breast cancer patients. An impaired bone microenvironment may lead to reduced bone density and osteoporosis affecting the BM as a homing site for DTCs. The bone mineral density (BMD) and its correlation to DTC in BM was evaluated., Materials and Methods: One hundred and eighty-one women (70 premenopausal, 111 postmenopausal) underwent quantitative ultrasonometry before adjuvant chemotherapy. BM aspirates were analyzed by immunocytochemistry using the ACIS system (Chromavision) based on immunostaining., Results: DTCs were detected in 39% of the patients. Positive BM status correlated significantly with the nodal status. BMD was significantly reduced in the postmenopausal patients (p=0.003). Smaller tumors and higher BMD correlated significantly (p<0.014). Fifty percent of the patients with preclinical osteoporosis were BM positive, whereas 37% with normal or osteopenic BMD had DTCs., Conclusion: An impaired bone micro-environment as found in preclinical osteoporosis might be a homing site for DTCs.

Background: The detection of >5 circulating tumor cells (CTCs)/7.5 ml blood in patients being treated for metastatic breast cancer (MBC) has recently been shown to be predictive for therapy efficacy. The aim of this study was to investigate whether changing CTC levels during the course of chemotherapy treatment would also be useful in monitoring response to treatment., Patients and Methods: CTC levels were determined in 58 MBC patients at the beginning and after 3 cycles of chemotherapy. Changes in CTC level (either negative CTCs (<5 CTCs/7.5 ml blood) turning positive, vice versa, or a change of ±25%) were correlated to radiologic Response Evaluation Criteria In Solid Tumors (RECIST) criteria, as well as serum CA 15-3 measurements, and were evaluated for their capability to predict survival., Results: Changing CTC levels significantly correlated with response to therapy as measured by radiologic RECIST criteria (p<0.001), and serum CA 15-3 level changes (p=0.017). Patients with decreasing CTC levels survived significantly longer than patients with increasing CTC levels (17.67±5.90 months versus 4.53±0.54 months, p<0.001)., Conclusion: The observation of changes in CTC level during the course of chemotherapy is useful in monitoring therapy efficacy and is correlated with overall survival. Further prospective trials should investigate the clinical usefulness of determining changes in CTC level during chemotherapy of MBC.

Aim: Hysteroscopy is a routine procedure for the diagnosis of endometrial cancer (EC). Moreover, with implementation of sentinel lymph node technique, a second hysteroscopy is necessary for technetium injection before performing lymphadenectomy. As yet, no data are available showing whether the time interval between hysteroscopy and definitive surgery, or the number of preoperative hysteroscopies, have an influence on the intraperitoneal cytology results., Patients and Methods: Data from patients with EC undergoing surgery in the years 2005-2008 at the Department of Obstetrics and Gynecology, University of Tübingen, were analyzed retrospectively. Cytological results were correlated with the number of preoperative hysteroscopies and with the time interval between hysteroscopy and surgery., Results: In 2005-2008, a total of 196 patients with EC and known cytological results underwent surgery. Positive cytological results (C+) were obtained in 11 patients (5.6%). The rate of C+ in patients without hysteroscopy was 18.2% (n=4) and in patients after one and two hysteroscopies, 1.9% (n=2) and 7.1% (n=5), respectively (p=0.008). The rate of C+ in patients with early EC (FIGO I and II) increased after two hysteroscopies (3.1% vs. 1% after one hysteroscopy and 0% without hysteroscopy) but the difference did not reach statistical significance (p=0.513). The mean time interval between hysteroscopy and definitive surgery with cytological examination was 11.1+/-15.2 days (range 0-97 days, median=1). C+ in the group of patients with a time gap between hysteroscopy and surgery of 1 day there was in 1 case (p=0.161)., Conclusion: The finding of positive cytology results is independent from the time interval between preoperative hysteroscopy and definitive surgery. Furthermore, multiple hysteroscopies do not appear to significantly increase peritoneal tumor cell dissemination. Hysteroscopy is safe and indispensable in patients with EC.

Background: Persistence of disseminated tumor cells (DTCs) is observed in 10 to 15% of breast cancer patients and is associated with poor prognosis. These patients might benefit from secondary adjuvant targeted therapy. The aim of this study was to assess HER2 status of persistent DTCs to determine whether the use of HER2-targeted agents might be a therapeutic option in patients with tumor cell persistence., Patients and Methods: Bone marrow was obtained from 85 primary breast cancer patients intraoperatively and after completion of systemic treatment (median follow-up of 13 months; range: 6-30 months). Immunofluorescence double staining was used for identification of cytokeratin-positive, HER2-positive cells., Results: A total of 31 out of 85 (36%) patients had DTCs preoperatively. Out of 85 (16%) patients, 14 were DTC positive after completion of surgery and adjuvant cytotoxic therapy. Five of these patients had HER2-positive DTCs, however, the corresponding tumor was HER2 positive in only one case. The remaining nine patients with HER2-negative DTCs had HER2-negative primary tumors., Conclusion: HER2-positive DTCs can be detected in patients with HER2-negative tumors, even after adjuvant therapy. Such patients may benefit from (secondary) HER2-targeted therapy in an adjuvant setting.

Background: The influence of primary systemic therapy (PST) on the expression of relevant therapeutic markers is still under investigation., Patients and Methods: Corresponding "baseline" biopsies and post-chemotherapy surgical specimens from 87 patients treated with neoadjuvant anthracycline- or taxane-based chemotherapy were analysed for the expression of the oestrogen receptor (ER), the progesterone receptor (PR), the B-cell lymphoma protein 2 (Bcl-2), the v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (Her2/neu), the tumour protein p53 and the proliferation-related Ki-67 antigen., Results: The pathological response rate was 70%. Twenty-three tumours (26%) changed hormone receptor classification after chemotherapy (7, ER; 16 PR). A significant change was also observed for Her2/neu status. Eleven tumours which were positive prior to PST down-regulated Her2/neu after chemotherapy. The median Ki-67 index decreased from 30% before to 13% after treatment (p<0.01). Minor changes were observed in the expression of Bcl-2 and p53 (9%). Only the reduction of Ki-67 was associated with pathological response to PST., Conclusion: Her2/neu status as well as ER and PR status should be re-evaluated on post-chemotherapy surgical specimens since changes can be observed.

Background: Most patients with primary epithelial ovarian cancer (PEOC) treated with carboplatin/paclitaxel will relapse between one to two years. Our purpose was to define the optimal calculation method for the adenosine triphosphate-tumor chemosensitivity assay (ATP-TCA) applied to PEOC treated with platinum-containing chemotherapy and to analyze its predictive relevance., Materials and Methods: ATP-TCA results from 80 PEOC specimens were analyzed applying three different methods: 50% inhibition concentration, sensitivity index (IndexSUM), and area under curve by testing multiple cut-off levels. Correlation between in vitro results and clinical outcome was performed for 61 (76%) patients by univariative and multivariative analysis. Tumor recurrence 6 months after chemotherapy was classified as platinum-resistance., Results: The IndexSUM set at > 250 had the highest test sensitivity, specificity, positive and negative predictive value of 90%, 43%, 62% and 81%, respectively. Patients whose tumors were shown to be resistant by ATP-TCA had a higher risk for recurrence (RR) compared to those who tested as sensitive (p < 0.003, RR = 3.3, 95% CI = 1.2-9.4). This result was confirmed after adjustment for FIGO stage by logistic regression (p < 0.004, Odds ratio = 8.3, 95% CI = 1.9-35.5). In multivariate analysis ATP-TCA and the FIGO-stage were independent predictive factors of early recurrence., Conclusion: ATP-TCA results in combination with the use of IndexSUM > 250 are best able to predict platinum resistance.

Background: Several studies have supported the hypothesis that the concept of immuno-surveillance would not be effective in cancer patients. One reason for suppression of antitumor immunity may be attributed to immune impairment of T-lymphocytes, which extends beyond the tumor-microenvironment and might effect the peripheral blood. Therefore the aim of this study was to investigate the expression of immunoregulatory antigens in peripheral blood lymphocytes of primary breast cancer patients in comparison with healthy donors., Materials and Methods: The peripheral blood immune status of 61 patients with primary breast cancer was analysed by FACS-analysis. The different lymphocytic subpopulations were identified by intracellular/extracellular monoclonal antibodies in three-color flow cytometry. The distribution was compared to age-matched healthy female donors (n = 29)., Results: The expression of TCR zeta-chain, an important signal complex for T-cell activation and functional integrity of specific immune response, was significantly reduced in the cytotoxic specific T-cell population. Cytotoxic T-cells (CD3+/CD8+) also showed a down-regulation of CD28, the important ligand to the co-stimulatory molecule CD80 (B7.1) on antigen-presenting cells. Moreover, breast cancer patients had significantly more CD95 (FAS) expressing cytotoxic T-cells than their healthy counterparts (p < 0.05)., Conclusion: The significant up-regulation of CD95 and down-regulation of TCR zeta and CD28 in peripheral cytotoxic T-cells of breast cancer patients leads to the hypothesis of systemic immunosuppression, which could open the door for tumor cell dissemination via the blood stream and which is the subject of ongoing studies.

Low grade endometrial stromal sarcoma (LGESS) is a rare disease. LGESS usually expresses steroidal receptors and is regarded to be hormone-sensitive. Due to the rarity of the tumor, only few case series have been published so far. Here, we report the case of a 36-year-old woman who underwent an abdominal hysterectomy with bilateral salpingo-oophorectomy and adjuvant radiotherapy for a G1 LGESS in 1991. Twelve years later she presented to us with pelvic and peritoneal masses. The patient was treated with letrozole achieving a partial response which is lasting 39 months. Treatment is ongoing. Aromatase inhibitors represent an interesting treatment option for LGESS.

Background: Loading of dendritic cells (DCs) with tumor cell (TC) preparations is an attractive method for vaccine preparation because the entire antigen repertoire of a tumor is processed and presented by the DCs, thus allowing the simultaneous stimulation of T-helper cells and cytotoxic T-lymphocytes. However, optimal loading conditions have still to be defined., Materials and Methods: DCs were pulsed either with tumor lysates, apoptotic or necrotic preparations of a breast cancer cell line and subsequently used to stimulate autologous T-lymphocytes. Antigen loading was quantified using immunofluorescent-based methods., Results: Four hours co-incubation of apoptotic TCs or tumor lysates with DCs undergoing maturation resulted in effective DC-loading. However, the DCs pulsed with apoptotic TCs were best in stimulating interferon-gamma (INF-gamma) secretion as the effector function of autologous T-cells., Conclusion: Tumor lysates are in common use for DC-based vaccine manufacturing. However, our data indicate an advantage of apoptotic TC-preparations in regard to antigen loading effectiveness as well as the loaded DC's capacity to activate T-cells.

Background: Determination of Her-2/neu overexpression in breast cancer has previously been shown to be of prognostic significance. In this study, Her-2/neu expression in breast cancer was characterised by real-time PCR (RLT-PCR) based LightCycler-HER-2/neu DNA Quantification with immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH)., Material and Methods: Fifteen specimens of invasive breast cancer - whole tissue sections as well as microdissected tumour cells - were subjected to RLT-PCR. Additionally, IHC and FISH were performed., Results: Her-2/neu overexpression was detected by FISH and by real-time PCR in the same tumours. In contrast, IHC revealed discordant results., Conclusion: Determination of Her-2/neu amplification by real-time PCR is a sensitive and specific method with some advantages over FISH. This method is simple and reliable and has the potential of categorizing those tumours with borderline Her-2/neu overexpression as determined by IHC.

Background: The presence of cytokeratin (CK)-positive cells in the bone marrow (BM) of breast cancer patients is an independent prognostic marker for long-term survival. While the exact nature of these cells remains under investigation, their persistence after chemotherapy is linked to decreased survival, making them a potential therapeutic target. Targeted therapy using the her2 antibody has been shown to improve survival in breast cancer patients. We studied the her2 expression in the BM of 105 patients with CK-positive cells present and compared it with results from the primary tumor., Materials and Methods: BM cytospins were stained to detect CK-positive cells. In 105 patients with detectable CK-positive cells, additional staining with her2 antibody was performed. Using an automated imaging system, the her2 slides were evaluated based on the criteria of the International Society for Cellular Therapy. RESULTS were correlated with the her2 status of the primary tumor. Furthermore, the presence of her2 mRNA was examined in a subset of 27 patients using RT-PCR., Results: On 22/105 (21%) cytospins with CK-positive cells, her2-positive cells could be detected. The positivity rate for RT-PCR was 15%. Her2 overexpression on the primary tumor was 26/105 (25%). Correlation with the BM status was as follows: Hercep score 0 to 1+: 79 patients, 10 with positive BM for her2 (12%). Hercep scores 2+ to 3+: 26 patients, 12 with her2-positive bone marrows (46%) (p=0.001)., Conclusion: Her2-positive cells were detected in the BM of 15-21% of patients who were also CK-positive using immunocytochemistry and RT-PCR. Correlation exists between the presence of her2 on the primary tumor, the hercep score and the presence of her2- positive cells in the BM both with RT-PCR and immunocytochemistry. Despite this correlation, in 12.6% of patients with a her2-negative primary tumor, her2-positive cells could be detected in the BM.

Background: Serum HER2 testing allows the determination of the real-time HER2 status of breast cancer patients. The aim of this investigation was to study (i) whether changes of serum HER2 status occur during the clinical course of breast cancer and (ii) to evaluate the prognostic significance of serum HER2 status, at the time of first diagnosis of primary breast cancer and at the onset of metastatic disease, for survival after relapse (SAR)., Materials and Methods: HER2 serum levels were retrospectively measured in 152 breast cancer patients at the time of first diagnosis of breast cancer and at the onset of metastatic disease by enzyme immunoassay., Results: Twenty-seven out of 152 (18%) patients had elevated HER2 serum levels at the time of first diagnosis of breast cancer. In contrast, 56 out of 152 (37%) patients showed elevated serum HER2 levels when metastases were diagnosed. A change of serum HER2 status during clinical course was observed in 43 out of 152 (28%) patients. Serum HER2 status at the time of first diagnosis of breast cancer had no impact on survival after relapse (SAR) (p = 0.4). However, the median SAR for serum HER2-positive patients at the onset of metastatic disease was significantly shorter (8 months, 95% CI: 3-12) compared to patients serum HER2-negative at this time (18 months, 95% CI: 14-22) (p < 0.01)., Conclusion: Serum HER2 status can change during the course of disease. Therefore, the serum HER2 status should be re-evaluated at the time of diagnosis of metastatic disease to optimize treatment decisions.

Background: The presence of disseminated tumor cells in the bone marrow (BM) of breast cancer patients is associated with poor prognosis and may therefore be related to aggressive breast cancer as indicated by tumor biological and clinicopathological factors. The aim of this study was to identify those features of the primary tumor related to the presence of disseminated tumor cells in the BM., Patients and Methods: Clinical data from 508 primary breast cancer patients were analyzed. Tumor biological features of the primary tumor including HER2, p53, Ki-67, bcl-2 and hormone receptor status, as well as clinicopathological factors including histology, menopausal status, lymph node status, tumor size and grade, were studied for their association with BM involvement by univariate and multivariate analysis., Results: Two-hundred and two out of 508 (40%) primary breast cancer patients had disseminated tumor cells in the BM. p53 expression, hormone receptor status, HER2 and Ki-67 were significantly related to BM involvement. The multivariate analysis revealed that p53 expression (OR: 1.9, 95% CI: 1.2 - 3.0) followed by progesterone receptor status (OR: 1.5, 95% CI: 1.0 - 2.2) were the only independent determinants for BM involvement., Conclusion: The presence of disseminated tumor cells in the BM was not influenced by tumor load as reflected by tumor size and lymph node involvement, whereas tumor biological factors were independently correlated to BM involvement. The results substantiate the important role of tumor biological factors of the primary tumor for tumor cell dissemination.

Background: Serum HER2 testing allows the determination of real-time HER2 status during clinical course. The aim of this investigation was: (1) to study the prognostic significance of serum HER2 at the time of first diagnosis of metastatic breast cancer and (2) to evaluate its relationship to CA15-3 which is a surrogate marker for tumor load., Materials and Methods: Serum samples of 120 breast cancer patients were assayed for HER2 and CA15-3 at the onset of metastatic disease., Results: Forty-seven out of 120 (39%) metastatic breast cancer patients had elevated serum HER2 levels. The positivity rate of CA15-3 was 51%. The median survival after relapse (SAR) for HER2-positive patients was shorter (10 months, 95%-CI: 6-14 months) compared to the SAR of HER2-negative patients (19 months, 95%-CI:15-23 months) (p<0.01). The median survival of patients with increased CA15-3 was 13 months (95%-CI: 9-17 months) compared to 18 months (95%-CI: 15-21 months) for patients with normal CA15-3 concentrations (p<0.05). In the multivariate analysis serum HER2 was an independent prognostic marker for SAR even when adjusted for tumor load measured by CA15-3 levels., Conclusion: Serum HER2 is a strong independent prognostic factor for survival after relapse in metastatic breast cancer even when adjusted for tumor load. Therefore, the prognostic significance of serum HER2 may not only be related to the tumor load but also to the biological behavior of the tumor.

Purpose: The objective of this study was to evaluate the efficacy and tolerability of leuprorelin acetate in adjuvant treatment in comparison to standard chemotherapy with CMF in premenopausal, estrogen-receptor-positive or unknown, node-positive patients with early breast cancer., Patients and Methods: The patients were randomly assigned to receive either 2 years of hormone ablation with leuprorelin acetate 11.25 mg as a subcutaneous injection every three months or six courses of CMF (cyclophosphamide 500 mg/m2, methotrexate 40 mg/m2, fluorouracil 600 mg/m2, days 1 and 8, q 4 weeks). The primary study end-point was recurrence-free survival (RFS) after 2 years. Secondary end-points included overall survival, adverse events and hormonal suppression., Results: Between 1995 and 1999, a total of 589 patients with breast cancer were randomized to treatment with leuprorelin acetate or CMF. The data of 227 patients were available for this first interim analysis. One hundred and ten and 117 patients were assigned to leuprorelin acetate and chemotherapy, respectively. Both treatment arms were well balanced for baseline characteristics. So far, no difference between the groups has emerged with respect to recurrence-free or overall survivaL Suppression of serum estradiol levels and menstruation was less marked in the CMF-group compared to the leuprorelin arm. The most common adverse events were low-grade hot flushes, weight gain and increased sweating in the leuprorelin-treated patients and alopecia, nausea and vomiting in the CMF-group., Conclusion: According to these preliminary results, ovarian suppression with leuprorelin acetate was as effective as standard chemotherapy for premenopausal women with hormone-sensitive, node-positive early breast cancer.

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that may also function as an autocrine growth regulator. Thirty-one ovarian carcinomas were investigated for mRNA expression of VEGF and of a proliferation-dependent gene (histone H3) using slot-blot analysis. Tumor vascularity was assessed by immunohistochemistry and factor VIII. All tumors were demonstrated to express VEGF and histone H3, though to various degrees. There was a good correlation between VEGF mRNA values and histone H3 mRNA values (r = 0.71, p < 0.05). No correlation was found between tumor cell proliferation and tumor vascularity. There was no significant difference in relapse-free interval or overall survival between tumors with low and high VEGF expression. The close correlation of VEGF expression with tumor cell proliferation in this study raises the possibility of autocrine stimulation of ovarian carcinoma.