A phase III study comparing SB3 (a proposed trastuzumab biosimilar) and trastuzumab reference product in HER2-positive early breast cancer treated with neoadjuvant-adjuvant treatment: Final safety, immunogenicity and survival results.

BACKGROUND: The equivalent efficacy between SB3, a proposed trastuzumab biosimilar, and the trastuzumab reference product (TRZ) in terms of the breast pathologic complete response rate after neoadjuvant therapy in patients with early or locally advanced human epidermal growth factor receptor 2-positive breast cancer was demonstrated in the previous report. Here, we report the final safety, immunogenicity and survival results after neoadjuvant-adjuvant treatment. PATIENTS AND METHODS: Patients were randomised 1:1 to receive neoadjuvant SB3 or TRZ for 8 cycles concurrently with chemotherapy (4 cycles of docetaxel followed by 4 cycles of 5-fluorouracil/epirubicin/cyclophosphamide). Patients then underwent surgery, followed by 10 cycles of adjuvant SB3 or TRZ as randomised. End-points included safety, immunogenicity, event-free survival (EFS) and overall survival through the adjuvant period. RESULTS: Of 875 patients randomised, 764 (SB3, n = 380; TRZ, n = 384) completed the study. The median follow-up duration was 437 days in the SB3 group and 438 days in the TRZ group. The incidence of treatment-emergent adverse events was comparable between groups (SB3, 97.5%; TRZ, 96.1%) during the overall study period. Up to the end of study, the overall incidence of antidrug antibody was low in both treatment groups (3 patients each). EFS was comparable between groups with a hazard ratio (SB3/TRZ) of 0.94 (95% confidence interval, 0.59-1.51) and EFS rates at 12 months of 93.7% for SB3 and 93.4% for TRZ. CONCLUSIONS: Final safety, immunogenicity and survival results of this study further support the biosimilarity established between SB3 and TRZ. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02149524); EudraCT (2013-004172-35).

Hematopoietic cytokines as tumor markers in breast malignancies. A multivariate analysis with ROC curve in breast cancer patients.

PURPOSE: Plasma levels of selected hematopoietic cytokines: interleukin 3 ( IL-3), stem cell factor (SCF), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF) and macrophage colony-stimulating factor (M-CSF), and the tumor marker carcinoma antigen 15-3 (CA 15-3) in breast cancer (BC) patients were investigated and compared to control groups: benign breast tumor patients and healthy subjects. MATERIAL/METHODS: Cytokine levels were determined by ELISA, CA 15-3 - using the CMIA method. RESULTS: A significant differences in the concentration of cytokines (with the exception of IL-3) and CA15-3 between the groups of BC patients, benign breast tumor patients and the healthy controls have been demonstrated. M-CSF has demonstrated higher or equal to CA 15-3 values of diagnostic sensitivity, specificity and the predictive values of positive and negative test results. The M-CSF area under the ROC curve (AUC) was the largest from all the cytokines tested and marginally lower than the AUC of CA 15-3. CONCLUSION: These findings suggest the usefulness of M-CSF in diagnosing breast cancer, especially when discriminating between cancer and non-carcinoma lesions.

Increased serum level of membrane type 1-matrix metalloproteinase (MT1-MMP/MMP-14) in patients with breast cancer.

UNLABELLED: Different types of matrix metalloproteinases, including membrane type 1 matrix metalloproteinase (MT1-MMP/MMP-14) can be easily detected in biological fluids and therefore may be contemplated as putative tumor markers. Although increased activity of MT1-MMP/MMP-14 have already been found in breast cancer, little is known about its circulating levels. The aim of the present study was therefore to evaluate serum levels of active form of membrane type 1 matrix metalloproteinase (MT1-MMP/MMP-14). A novel type of activity enzyme-linked immunosorbent assay was used to detect serum levels of MT1-MMP/MMP-14 in 18 patients with invasive ductal breast cancer and 11 healthy controls. In the breast cancer group of patients MT1-MMP/MMP-14 mean (+/-SD) concentration was 16.91+/-5.87 ng/ml which was significantly higher (p<0.0001) than the mean values obtained for the control i.e. 8.55+/-1.66 ng/ml. CONCLUSIONS: Higher levels of soluble form of MT1-MMP/MMP-14 could play a role in invasiveness and metastasis of breast cancer. Whether or not it has a potential as biochemical marker remains to be determined.

Phase II randomized study of trabectedin given as two different every 3 weeks dose schedules (1.5 mg/m2 24 h or 1.3 mg/m2 3 h) to patients with relapsed, platinum-sensitive, advanced ovarian cancer.

BACKGROUND: This randomized, open-label, phase II clinical trial evaluated the optimal regimen of trabectedin administered every 3 weeks in patients with platinum-sensitive, relapsed, advanced ovarian cancer (AOC). PATIENTS AND METHODS: Patients previously treated with less than two or two previous chemotherapy lines were randomized to receive trabectedin 1.5 mg/m(2) 24 h (arm A, n = 54) or 1.3 mg/m(2) 3 h (arm B, n = 53). Objective response rate (ORR) per RECIST was the primary efficacy end point. Toxic effects were graded according to the National Cancer Institute-Common Toxicity Criteria v. 2.0. RESULTS: ORR was 38.9% [95% confidence interval (CI) 25.9% to 53.1%; arm A] and 35.8% (95% CI 23.1% to 50.2%; arm B) (intention-to-treat primary analysis). Median time to progression was 6.2 months (95% CI 5.3-8.6 months; arm A) and 6.8 months (95% CI 4.6-7.4 months; arm B). Frequent severe adverse events were nausea/vomiting (24%, arm A; 15%, arm B) and fatigue (15%, arm A; 10%, arm B). Common severe laboratory abnormalities were transient, noncumulative neutropenia (55%, arm A; 37%, arm B) and transaminase increases (alanine aminotransferase, 55%, arm A; 59%, arm B). CONCLUSIONS: Both every-3-weeks trabectedin regimes, 1.5 mg/m(2) 24 h and 1.3 mg/m(2) 3 h, were active and reasonably well tolerated in AOC platinum-sensitive patients. Trabectedin every-3-weeks has promising activity and deserves to be further evaluated in relapsed AOC.

Loss of heterozygosity on chromosomes 2p, 3p, 18q21.3 and 11p15.5 as a poor prognostic factor in stage II and III (FIGO) cervical cancer treated by radiotherapy.

Loss of heterozygosity (LOH) has been shown to be an important prognostic factor in a variety of malignant neoplasm's. Cervical cancer develops as result of multiple genetic alterations. The aim of this study was to analyze presence of LOH in cervical cancer and to identify the correlation between LOH and survival and relapse-free survival time in patients treated with radiotherapy. Studies were performed on tumor specimens and venous blood from 20 patients with cervical cancer (squamous cell carcinoma G2 and G3) in stage II and III (FIGO) treated with radiotherapy. DNA was isolated using organic extraction. Additional microcolumn purification was performed. The fluorescent multiplex polymerase chain reaction (PCR) was used to amplify 10 microsatellite loci included in commercially available human identification kits. Microsatellite marker BAT 26 was amplified in separate PCR reactions. 75% cervical cancers manifested LOH. LOH in BAT 26 analysis (chromosome 2) was present in all these specimens. 60% of the cases showed LOH at one or more of other examined loci (mostly on 3p, 18q21.3, and 11p15.5). Eight of nine cervical cancers in clinical stage III showed LOH. All cases of G3 squamous cell carcinoma of the cervix manifested LOH on 2p. Patients with LOH have worse prognosis for survival and relapse-free survival compared to patients without LOH.

Vinorelbine plus trastuzumab combination as first-line therapy for HER 2-positive metastatic breast cancer patients: an international phase II trial.

The aim of this international phase II trial was to determine the efficacy and safety profile of weekly vinorelbine plus trastuzumab as first-line chemotherapy for women with HER 2-overexpressing metastatic breast cancer. Sixty-nine patients with tumours overexpressing HER 2 received vinorelbine: 30 mg m-2 week-1 and trastuzumab: 4 mg kg-1 on day 1 as a loading dose followed by 2 mg kg-1 week-1 starting on day 8. Sixty-two patients were evaluable for response and 69 patients were evaluable for toxicity. The overall response rate was 62.9%. The median time to response was 8.4 weeks, the median duration of response was 17.5 months, the median progression-free survival was 9.9 months (95% CI, 5.6-12.1) and the one-year progression-free survival was 39.1%. The median survival for all patients was 23.7 months (95% CI, 18.4-32.6). This regimen was safe: grade 3-4 neutropenia were observed over 17.7% of courses in 83.8% of patients, with only two episodes of febrile neutropenia (0.1%) in two patients (2.9%). Only one patient discontinued treatment due to grade 3 symptomatic cardiac dysfunction that resolved with therapy. Vinorelbine plus trastuzumab is one of the most active treatment regimens for patients with HER 2-positive metastatic breast cancer and demonstrates a very favourable safety profile allowing prolonged treatment with long-term survival. This study has been presented in part at the following conferences: The San Antonio Breast Cancer Symposium, San Antonio, TX, USA, 2003; The American Society of Clinical Oncology, Orlando, FL, USA, 2005.

Variations of enzymatic activity and biotypes of the yeast like fungi strains isolated from cancer patients.

PURPOSE: Determination of the enzymatic activity and enzymatic biotypes variations of the yeast like fungi strains isolated from cancer patients with oral candidiasis during last 5 years. MATERIAL AND METHODS: We evaluated enzymatic activity of 92 Candida albicans strains isolated from oral ontocenosis from cancer patients with candidiasis symptoms in 1999 and 2003. The enzymatic activity of the strains tested was assessed by the API ZYM (bioMerieux) method. Biotypes of the strains were determined according to Williamson's or Kurnatowska's and Kurnatowski's classifications. RESULTS: In 1999 Candida albicans 17 of 19 tested isolates had hydrolytic activity hydrolases and 87% of strains were assigned according to Wiliamson's. Only 8.7% of strains were classified according to Kurnatowska's and Kurnatowski's, but 4.3% strains according to Krajewska-Kulak et al. In 2003, 18 of 19 strains had hydrolytic activity and 93.5% of strains were classified according to Wiliamson's, but 4.3% according to Kurnatowska's and Kurnatowski's and 2.2% according to Krajewska-Kulak et al. CONCLUSIONS: The results of present study indicate that most of tested strains were classified into Wiliamson's system. Our findings suggest that other Candida biotypes should be determined according to their different enzymatic activity and susceptibilities.

Expression of glucose transporter GLUT-1 and estrogen receptors ER-alpha and ER-beta in human breast cancer.

We attempted to describe a GLUT-1 expression in breast cancer and characterize correlation between GLUT-1 and ERs alpha and beta expression as well as correlate this with clinicopathologic features. Sixty-nine patients were involved in the study. GLUT-1, ER-alpha and ER-beta immunocytochemistry was performed using the streptavidin- biotin method. Thirty-seven (53.6%) out of total 69 were GLUT-1 positive. Of GLUT- 1 positive 45.3% were ER-alpha-positive, whereas 81.3% of ER-alpha-negative were GLUT-1 positive. Statistically significant correlation was observed between GLUT-1 and ER-alpha expression status but neither between GLUT-1 and ER-beta nor with clinicopathologic features. No statistically significant correlation was found between expression level (expressed as immunocytoreactive score) of GLUT-1, ER-alpha and ER-beta. Since most of ER-alpha-negative (81.3%) were GLUT-1 positive and significant correlation exists between the two receptors it is reasonable to assume that some functional relation might exists between the expression of two receptors.

Treatment for primary refractory Hodgkin's disease: a comparison of high-dose chemotherapy followed by ASCT with conventional therapy.

Our previously published study showed promising results of autologous stem cell transplantation (ASCT) in patients with primary resistant Hodgkin's disease (HD). Probabilities of overall survival (OS) and progression-free survival (PFS) at 3 years were 55 and 36%, respectively. The present study was undertaken to compare these results with conventionally treated patients and thus evaluate therapeutic options. Retrospective data on 76 adult patients who underwent ASCT were matched with 76 conventionally treated patients from 17 centers. Comparison of clinical characteristics in both groups showed that ASCT patients were younger (24 vs 31.5 years, P=0.001), more frequently presented with 'B' symptoms (P=0.03) and that more patients treated with chemotherapy (CT) had elevated LDH (P=0.03). In univariate analyses, bulky disease (P=0.0043) and complete resistance to standard CT (P=0.051) were found to be risk factors for OS. In a multivariate survival analysis only bulky disease was found to an independent prognostic factor (P=0.005). There was no difference in survival between the treatment groups with 5 years OS 33.7 (CI: 23-46) in the ASCT group and 35.6% (CI: 25-50) for the CT group (P=0.92). We conclude that ASCT is not superior to standard CT for treatment of patients with primary refractory HD.

Concentration of interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-10 (IL-10) in blood serum of breast cancer patients.

PURPOSE: Interleukins may stimulate cancer cells growth and contribute to locoregional relapse as well as metastasis. Permanent synthesis and release of these cytokines leads to augmentation of their serum concentration that might be utilized as a marker of immunity status and immune system activation in prognosis and monitoring of the course of cancer. MATERIAL AND METHODS: Therefore, in the present study we assessed the concentration of IL-6, IL-8 and IL-10 in blood serum of breast cancer patients to determine whether it correlates with the disease progression. RESULTS: We showed statistically higher serum concentrations of IL-6, IL-8 and IL-10 in breast cancer patients in comparison with healthy women, which also correlated with clinical stage of breast cancer. CONCLUSIONS: The present study indicates that elevated IL-6, IL-8, and IL-10 serum concentration, are strongly associated with breast cancer and correlate with clinical stage of disease. It was feasible that it can be used to diagnose women with breast cancer and to identify patients with a poor prognosis who may benefit from more aggressive management.

The hemostatic system and angiogenesis in malignancy.

Coagulopathy and angiogenesis are among the most consistent host responses associated with cancer. These two respective processes, hitherto viewed as distinct, may in fact be functionally inseparable as blood coagulation and fibrinolysis, in their own right, influence tumor angiogenesis and thereby contribute to malignant growth. In addition, tumor angiogenesis appears to be controlled through both standard and non-standard functions of such elements of the hemostatic system as tissue factor, thrombin, fibrin, plasminogen activators, plasminogen, and platelets. "Cryptic" domains can be released from hemostatic proteins through proteolytic cleavage, and act systemically as angiogenesis inhibitors (e.g., angiostatin, antiangiogenic antithrombin III aaATIII). Various components of the hemostatic system either promote or inhibit angiogenesis and likely act by changing the net angiogenic balance. However, their complex influences are far from being fully understood. Targeted pharmacological and/or genetic inhibition of pro-angiogenic activities of the hemostatic system and exploitation of endogenous angiogenesis inhibitors of the angiostatin and aaATIII variety are under study as prospective anti-cancer treatments.

Lactacystin inhibits cathepsin A activity in melanoma cell lines.

We describe the inhibitory effect of the proteasome inhibitor, lactacystin, on cathepsin A activity in murine melanoma cell lines. In vitro lactacystin metabolite, beta-lactone, at a concentration of 1 microM, significantly suppressed cathepsin A activity in B78 melanoma cell lysates by about 50%. Exposure of three murine melanoma cell lines with different metastatic potential to lactacystin at a concentration of 5 microM for 6 h caused a significant reduction in the carboxypeptidase activity of this enzyme, while the inhibitory activity remained unchanged for at least 12 h. Other proteasome-specific inhibitors, e.g. epoxomicin and N-benzyloxycarbonyl-Ile-Glu(O-tert-Bu)-Ala-leucinal (PSI) at a concentration of 1 microM did not affect cathepsin A activity in melanoma cell line lysates. These data support our previous proposal that lactacystin is not a specific inhibitor of the proteasome. Since cathepsin A is also a tumor-associated enzyme, further research is needed to clarify its role and the significance of its inhibition by lactacystin in tumor biology.

Localization of blood coagulation factors in situ in pancreatic carcinoma.

Blood coagulation is activated commonly in pancreatic carcinoma but the role of the tumor cell in this activation is undefined. Immunohistochemical procedures were applied to fixed sections of 22 cases of resected adenocarcinoma of the pancreas to determine the presence of components of coagulation and fibrinolysis pathways in situ. Tumor cell bodies stained for tissue factor: prothrombin: and factors VII, VIIIc, IX, X, XII, and subunit "a" of factor XIII. Fibrinogen existed throughout the tumor stroma, and tumor cells were surrounded by fibrin. Staining for tissue factor pathway inhibitor, and plasminogen activators was minimal and inconsistent. Plasminogen activator inhibitors -1, -2, and -3 were present in the tumor stroma, and on tumor cells and vascular endothelium. Extravascular coagulation activation exists associated with pancreatic carcinoma cells in situ that is apparently unopposed by naturally occurring inhibitors or the plasminogen activator-plasmin system. We postulate that such local coagulation activation may regulate growth of this malignancy. These findings provide a rationale for testing agents that modulate the blood coagulation/fibrinolytic system (that inhibit tumor growth in other settings) in pancreatic carcinoma.

A rare localization of Hodgkin's disease in the breast--a case report.

In this paper we present a rare localization of Hodgkin's disease--in the breast. An awareness of such unusual clinical presentation of Hodgkin's disease is important to prevent a delay in diagnosis and treatment.

[Metastases of malignant melanoma of unknown primary site: an important diagnostic and therapeutic problem]. / Przerzuty czerniaka zlosliwego o nieznanej lokalizacji ogniska pierwotnego--istotny problem diagnostyczny i terapeutyczny.

Malignant melanoma of an unknown primary site remains a diagnostic and therapeutic challenge in clinical practice. With this in mind, we have presented 12 patients with malignant melanoma of an unknown primary site, diagnosed and treated in the Regional Cancer Center in Bialystok. This clinical presentation accounted for 2% of all malignant melanocytic lesions treated in our center during ten year period from 1987 to 1997.

[Cardiotoxicity of anthracycline]. / Kardiotoksycznosc antracyklin.

The anthracyclines are among the most active and useful anticancer agents, but they are also the most common chemotherapeutics associated with the development of congestive heart failure. Twenty seven to sixty percent of patients with anthracycline-induced cardiomyopathy die of congestive cardiac failure. The paper presents the pathomechanisms of anthracycline-induced cardiotoxicity and perspectives on prevention of congestive heart failure resulting from anthracycline chemo-therapy.

Cathepsin A activity in primary and metastatic human melanocytic tumors.

Several lysosomal proteases including cathepsins B, D, H and L have been found to play a role in the metastasis of tumor cells. However, up to now no information on the role of cathepsin A, a lysosomal multifunctional peptidase, in the proliferative, invasive, and metastatic potential of malignant tumors has been available. In the present study we compared the activity of cathepsin A in lysates of 34 human melanocytic tumors: primary (n = 12) and metastatic (n = 5) malignant melanoma, dysplastic pigmented nevi (n = 6) and pigmented nevi without evidence of dysplastic melanocytes (n = 11). The carboxypeptidase activity of cathepsin A was assayed at pH 5.0 with its specific substrate Cbz-Phe-Ala. The amount of released C-terminal alanine was measured by the ninhydrin method. We found that lysates of primary malignant melanoma lesions exhibited significantly higher cathepsin A activity than lysates of dysplastic and normal pigmented nevi. The cathepsin A activity in lysates of metastatic lesions of malignant melanoma was significantly higher than in primary focus lysates. It seems that cathepsin A may play a role in malignant transformation and metastatic dissemination of malignant melanoma.