losartan-potassium and Breast-Neoplasms

Erythropoiesis-stimulating agents (ESAs) have been reported to increase the risk of death in cancer patients. In this study, we selected breast cancer, which is currently the most prevalent cancer worldwide, for a meta-analysis to re-examine the advantages and disadvantages of using ESAs. All relevant studies were searched by PubMed, Embase, Web of science, and Cochrane Library. Endpoints including mortality, incidence of thrombo-vascular events, hemoglobin, and transfusion requirements were meta-analyzed based on random-effects model or fixed-effect model. 10 studies were finally included, with a total sample size of 6785 patients. The risk of mortality was higher in patients using ESA than in controls (RR 1.07, 95% CI 1.01-1.13, P = 0.03); subgroup analysis found that the mortality rate was higher in patients treating with ESA for > 6 months (RR 1.27, 95% CI 1.05-1.55, P = 0.01) and epoetin α (RR 1.07, 95% CI 1.01-1.14, P = 0.03). The incidence of thrombo-vascular adverse events was higher in patients using ESA than in controls (RR 1.53, 95% CI 1.27-1.86, P < 0.0001). The ESA group was more effective in improving anemia in cancer patients (MD 1.20, 95% CI 0.77-1.63, P < 0.00001). The blood transfusion needs of patients in the ESA group were significantly lower (RR 0.52, 95%CI 0.44-0.60, P < 0.00001). There was no statistically significant difference between the two groups in disease progression-related conditions (HR 1.03, 95%CI 0.95-1.12, P = 0.52). ESAs increase the risk of mortality and the incidence of thrombo-vascular adverse events in breast cancer patients, while reducing their anemia symptoms and transfusion requirements. Registration PROSPERO CRD42022330450.

Topics: Anemia; Breast Neoplasms; Erythropoiesis; Erythropoietin; Female; Hematinics; Humans

Recombinant human erythropoietin (rhEPO) is used in breast and ovarian cancer patients to alleviate cancer- and chemotherapy-related anemia. Some clinical trials have reported that rhEPO may adversely impact survival and increase the risk of thrombovascular events in patients with breast cancer but not with ovarian cancer. The latter may potentially benefit the most from rhEPO treatment due to the nephrotoxic and myelosuppresive effects of standard platinum-based chemotherapy used in ovarian cancer disease. However, over the last decade the preclinical data have revealed that EPO is not only the principal growth factor and the hormone which regulates erythropoiesis, but also a cytokine with a pleiotropic activity which also can affect cancer cells. EPO can stimulate survival, ability to form metastases and drug resistance not only in continuous breast- and ovarian cancer cell lines but also in breast cancer stem-like cells. EPO receptor (EPOR) can also be constitutively active in both these cancers and, in breast cancer cells, may act in an interaction with estrogen receptor (ER) and epidermal growth factor receptor-2 (HER-2). EPOR, by an EPO-independent mechanism, promotes proliferation of breast cancer cells in cooperation with estrogen receptor, resulting in decreased effectiveness of tamoxifen treatment. In another interaction, as a result of the molecular antagonism between EPOR and HER2, rhEPO protects breast cancer cells against trastuzumab. Both clinical and preclinical evidence strongly suggest the urgent need to reevaluate the traditional use of rhEPO in the oncology setting.

Topics: Antineoplastic Agents; Breast Neoplasms; Drug Resistance; Erythropoietin; Female; Humans; Ovarian Neoplasms; Receptors, Erythropoietin; Recombinant Proteins; Signal Transduction; Vascular Diseases

Topics: Adrenal Cortex Hormones; Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Breast Neoplasms; Clinical Trials as Topic; Erythropoietin; Female; Humans; Models, Biological; Multiple Myeloma; Myeloproliferative Disorders; Neoplasms; Recombinant Proteins; Risk; Thrombophilia; Thrombosis; Venous Thromboembolism

Topics: Anemia, Hypochromic; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Small Cell; Clinical Protocols; Darbepoetin alfa; Data Interpretation, Statistical; Erythropoietin; Female; Filgrastim; Follow-Up Studies; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Granulocytes; Hematinics; Hematologic Neoplasms; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulins, Intravenous; Lung Neoplasms; Lymphoma; Lymphoma, Non-Hodgkin; Male; Multicenter Studies as Topic; Neoplasms; Neutropenia; Platelet Aggregation Inhibitors; Polycythemia Vera; Polyethylene Glycols; Randomized Controlled Trials as Topic; Recombinant Proteins; Research Design; Survival Analysis; Thrombocythemia, Essential; Treatment Outcome

The treatment of cancer-induced anemia with erythropoietin-stimulating agents (ESAs) is reviewed.. Before the introduction of ESAs, the only treatment option for cancer-related anemia was red blood cell (RBC) transfusion. The use of ESAs in multiple disease states has been well established and is now considered first-line treatment for many forms of anemia. Chang et al. evaluated the effect of epoetin alfa (40,000 units administered subcutaneously every week) and standard-of-care therapy on quality of life (QOL), transfusion requirements, and hemoglobin levels in 354 patients with breast cancer who had a baseline hemoglobin concentration of <15 g/dL. The authors concluded that early initiation of treatment with epoetin alfa in patients with breast cancer is effective in maintaining hemoglobin levels, reducing transfusions, and improving QOL. Leyland-Jones et al. conducted a study evaluating the effects of early intervention with epoetin alfa (40,000 units administered subcutaneously every week) on survival and QOL of mainly nonanemic patients with metastatic breast cancer. In contrast to Chang et al., this study was discontinued because of lower overall survival rates within the epoetin alfa group. In 2008, the Food and Drug Administration issued a black-box warning for both epoetin alfa and darbepoetin alfa. The warning acknowledges that ESAs have shortened overall survival and time to disease progression in patients with advanced breast cancer who are given these agents to achieve a target hemoglobin concentration of > or =12 g/dL.. When used in patients with cancer-induced anemia, ESAs should only be given at the lowest dose possible to prevent RBC transfusions. During treatment, hemoglobin levels should be monitored closely and ESA doses need to be adjusted accordingly.

Topics: Anemia; Blood Transfusion; Breast Neoplasms; Darbepoetin alfa; Drug Labeling; Drug Monitoring; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Survival Rate

Cancer anemia causes fatigue and correlates with poor treatment outcome. Erythropoietin has been introduced in an attempt to correct these defects. However, five recent clinical trials reported a negative impact of erythropoietin on survival and/or tumor control, indicating that experimental evaluation of a possible direct effect of erythropoietin on cancer cells is required. Cancer recurrence is thought to rely on the proliferation of cancer initiating cells (CICs). In breast cancer, CICs can be identified by phenotypic markers and their fate is controlled by the Notch pathway.. In this study, we investigated the effect of erythropoietin on CICs in breast cancer cell lines. Levels of erythropoietin receptor (EpoR), CD24, CD44, Jagged-1 expression, and activation of Notch-1 were assessed by flow cytometry. Self-renewing capacity of CICs was investigated in sphere formation assays.. EpoR expression was found on the surface of CICs. Recombinant human Epo (rhEpo) increased the numbers of CICs and self-renewing capacity in a Notch-dependent fashion by induction of Jagged-1. Inhibitors of the Notch pathway and PI3-kinase blocked both effects.. Erythropoietin functionally affects CICs directly. Our observation may explain the negative impact of recombinant Epo on local control and survival of cancer patients with EpoR-positive tumors.

Topics: Adenocarcinoma; Amyloid Precursor Protein Secretases; Breast Neoplasms; Cell Adhesion; Cell Division; Chromones; Erythropoietin; Female; Humans; Hyaluronan Receptors; Morpholines; Neoplasm Proteins; Neoplastic Stem Cells; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Receptor, Notch1; Receptors, Erythropoietin; Recombinant Fusion Proteins; Recombinant Proteins; Sialic Acid Binding Ig-like Lectin 2; Spheroids, Cellular; Transfection; Tumor Cells, Cultured

Many patients with breast cancer suffer from anaemia, as a consequence of the disease itself or its treatment. Anaemia has a negative impact on treatment outcome and overall survival, and affects the quality of life (QoL) of patients with cancer. Previously, cancer-related anaemia was treated with blood transfusion, but this is inconvenient, offers only temporary improvement in haemoglobin (Hb) level and is associated with several risks. Consequently, blood transfusion is usually reserved for patients with severe anaemia (Hb levels <8 g/dl). Recombinant human erythropoietin (epoetin) is an effective and convenient treatment for cancer-related anaemia without the risks associated with red blood cell transfusion. Epoetin therapy effectively increases Hb levels, thereby reducing the need for emergency blood transfusion and improving the QoL of patients with anaemia and breast cancer. Epoetin beta is also effective for the prevention of anaemia and reduction of transfusion requirements in patients with a high risk of developing anaemia during chemotherapy. With the increased use of dose-intensified chemotherapy in an attempt to improve response rates, administration of epoetin to prevent anaemia could potentially benefit many patients with breast cancer.

Topics: Adult; Age Distribution; Aged; Anemia, Hypochromic; Breast Neoplasms; Combined Modality Therapy; Comorbidity; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Humans; Incidence; Middle Aged; Neoplasm Staging; Prognosis; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Assessment; Severity of Illness Index; Sex Distribution; Survival Rate; Treatment Outcome

The estrogen receptor plays an important role in the development of hormone-dependent breast cancer. Experimental and clinical studies showed that hypoxia was involved in tumor progression and in the resistance to anticancer agents. The scope of this review is to summarize recent observations on these two signaling pathways and to show their importance and possible interaction in the development of hormone-dependent breast cancer.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Cell Hypoxia; Disease Progression; DNA-Binding Proteins; Drug Resistance, Neoplasm; Erythropoietin; Estradiol; Female; Genetic Therapy; Hemoglobins; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Neoplasms, Hormone-Dependent; Nuclear Proteins; Prognosis; Receptors, Estrogen; Signal Transduction; Transcription Factors; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases; Vascular Endothelial Growth Factor A; Von Hippel-Lindau Tumor Suppressor Protein

Treatment with recombinant human erythropoietin (epoetin alfa) has been shown to enhance quality of life and cognitive function. The mechanism of action for these changes appears to involve more than the alleviation of cancer treatment-induced anemia. Rather, there is increasing evidence that epoetin alfa treatment may modulate a series of cascading events that involve hypoxia-induced activation of vascular endothelial growth factor and an induction in the expression of vascular endothelial growth factor receptors via a hypoxia-inducible factor-1-mediated transcription among several other hypoxia-related events. The use of epoetin alfa to interfere with this hypoxia-induced cascade could provide significant benefits for cancer patients by enhancing survival through a direct modulation of tumor angiogenesis and effectiveness of cancer therapy. The enhanced quality of life seen with erythropoietin treatment may also involve a modulation of hypoxia-induced decrement in cognitive functioning. It appears that epoetin alfa is a useful addition to the treatment of breast cancer.

Topics: Angiogenesis Inhibitors; Apoptosis; Breast Neoplasms; Cell Hypoxia; Central Nervous System; Cognition; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Neoplasms; Neovascularization, Pathologic; Recombinant Proteins

Chemotherapy-associated cognitive dysfunction occurs in a subset of patients treated with adjuvant chemotherapy. Recent data suggest that development of chemotherapy-related anemia predisposes patients to cognitive dysfunction. Endogenous erythropoietin (EPO) is well recognized for its central role in erythropoiesis, and recombinant human EPO (epoetin alfa) is established as a safe and effective treatment for chemotherapy-related anemia. Treatment with epoetin alfa also improved health-related quality of life in anemic cancer patients undergoing chemotherapy, and several controlled studies have documented increases in quality-of-life scores correlated with increases in hemoglobin. Erythropoietin also plays a role in neuroprotection, presumably by activation of antiapoptotic genes. Erythropoietin and its receptor are expressed in neural cells of the human brain, and their expression is upregulated after hypoxic or ischemic injury. In animal models, systemic administration of epoetin alfa protects against such neural injury. Ongoing and future studies will determine whether epoetin alfa can provide neuroprotection with respect to the development of cognitive dysfunction in patients undergoing adjuvant chemotherapy treatment for breast cancer.

Topics: Anemia; Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cognition Disorders; Disease Models, Animal; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Quality of Life; Rats; Recombinant Proteins

Several recently published studies describe moderate to severe cognitive dysfunction in breast cancer survivors who were treated with adjuvant chemotherapy 1-5 years before undergoing extensive neuropsychological testing. While these studies are hypothesis-generating and preliminary given their small size and retrospective nature, they consistently suggest that between approximately 15% and 25% of chemotherapy-treated breast cancer patients will have evidence of cognitive dysfunction some years after chemotherapy, compared to about 10% of breast cancer survivors who did not receive chemotherapy. Recent preclinical data strongly suggest that erythropoetin is a potent, endogenous neuroprotective agent that prevents neuronal apoptosis from a variety of insults including hypoxia, trauma, subarachnoidal hemorrhage, and encephalitis. Erythropoietin also appears to enhance learning in a mouse spatial learning maze model. We have conducted a pilot study of epoetin alfa versus placebo in early-stage breast cancer patients who received standard adjuvant anthracycline-based chemotherapy to determine the feasibility of administering standardized neurocognitive assessment tests in the oncology practice setting in order to understand whether the Executive Interview 25 test can detect the subtle cognitive impairment in verbal fluency, attention, and short-term memory observed with chemotherapy, and to assess whether epoetin alfa-treated patients have less evidence of cognitive dysfunction during and 6 months after chemotherapy compared with control-treated patients. We report here the preliminary results of this pilot clinical trial.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Asthenia; Breast Neoplasms; Chemotherapy, Adjuvant; Cognition Disorders; Controlled Clinical Trials as Topic; Disease Models, Animal; Epoetin Alfa; Erythropoietin; Female; Humans; Mastectomy; Mice; Mood Disorders; Patient Satisfaction; Pilot Projects; Prognosis; Quality of Life; Recombinant Proteins; Severity of Illness Index; Treatment Outcome

A Consensus Conference on the use of recombinant human erythropoietin (rHuEPO, epoetin alfa) in gynecologic tumors was held in Rome in March 1999, and an associated consensus paper has been published in Italian. The current paper updates several discussions that took place at the 1999 meeting concerning epoetin alfa treatment in breast, ovarian, and cervical cancers; the role of epoetin alfa in mobilizing progenitor hematopoietic cells; administration of epoetin alfa in combination with granulocyte colony-stimulating factor; and the effect of hemoglobin levels on outcome of radiation or chemoradiation treatment.

Topics: Anemia; Antineoplastic Agents; Blood Transfusion; Breast Neoplasms; Epoetin Alfa; Erythropoietin; Female; Genital Neoplasms, Female; Granulocyte Colony-Stimulating Factor; Hematinics; Hematopoietic Stem Cell Mobilization; Hemoglobins; Humans; Ovarian Neoplasms; Quality of Life; Radiotherapy, Adjuvant; Recombinant Proteins; Uterine Cervical Neoplasms

Breast cancer patients undergoing therapeutic regimens of high-dose chemotherapy (HDCT) with circulating progenitor cell support often develop anemia. As a general consideration in the transplantation setting, red blood cell transfusions are normally required in patients who have passed the myeloablative phase after HDCT. In the initial 30-day period immediately following HDCT, the number of red blood cell units that are transfused will usually depend on a number of factors, including whether the transplantation was allogeneic or autologous. Observations and results from clinical studies have shown that the establishment of normal erythropoiesis varies depending on the source of the transplanted cells, resulting in different transfusion requirements. Several studies support the use of recombinant human erythropoietin (rHuEPO, epoetin alfa) after HDCT to ameliorate anemia and reduce transfusion requirements. Studies have also shown that administration of epoetin alfa prior to the myeloablative phase is an effective method for reducing red blood cell transfusion requirements in breast cancer patients receiving HDCT. Epoetin alfa in combination with other cytokines has been shown to positively affect the mobilization phase of hematopoietic progenitor cells for autografting. Furthermore, treatment with epoetin alfa could prove useful in bone marrow transplant recipients who experience delayed anemia. Recent studies that have addressed these topics in breast cancer indicate that, when used in the appropriate setting, epoetin alfa may play a role as a tool to decrease the need for red blood cell transfusion in patients undergoing HDCT plus autologous circulating progenitor cell support.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Bone Marrow Transplantation; Breast Neoplasms; Epoetin Alfa; Erythropoietin; Hematinics; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Recombinant Proteins

This article reviews complementary and alternative therapies for advanced prostate cancer. This is not a comprehensive survey of nontraditional therapies for prostate cancer. Rather, this review focuses on alternative and complementary therapies with published studies to evaluate efficacy and safety. Three areas are addressed: alternative forms of hormonal therapy, management of side effects of hormonal therapy, and management of skeletal complications.

Topics: Acupuncture; Adenocarcinoma; Androgen Antagonists; Androgens; Anemia; Anticarcinogenic Agents; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Breast Neoplasms; Clinical Trials, Phase II as Topic; Complementary Therapies; Depression; Diphosphonates; Drugs, Chinese Herbal; Erythropoietin; Female; Flushing; Humans; Hypericum; Male; Multicenter Studies as Topic; Neoplasms, Hormone-Dependent; Osteoporosis; Phytotherapy; Pilot Projects; Plant Extracts; Prospective Studies; Prostatic Hyperplasia; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Serenoa

Anemia is a common complication of myelosuppressive chemotherapy that results in a decreased functional capacity and quality of life (QOL) for cancer patients. Severe anemia is treated with red blood cell transfusions, but mild-to-moderate anemia in patients receiving chemotherapy has traditionally been managed conservatively on the basis of the perception that it was clinically unimportant. This practice has been reflected in the relative inattention to standardized and complete reporting of all degrees of chemotherapy-induced anemia. We undertook a comprehensive review of published chemotherapy trials of the most common single agents and combination chemotherapy regimens, including the new generation of chemotherapeutic agents, used in the treatment of the major nonmyeloid malignancies in adults to characterize and to document the incidence and severity of chemotherapy-induced anemia. Despite identified limitations in the grading and reporting of treatment-related anemia, the results confirm a relatively high incidence of mild-to-moderate anemia. Recent advances in assessing the relationships of anemia, fatigue, and QOL in cancer patients are providing new insights into these closely related factors. Clinical data are emerging that suggest that mild-to-moderate chemotherapy-induced anemia results in a perceptible reduction in a patient's energy level and QOL. Future research may lead to new classifications of chemotherapy-induced anemia that can guide therapeutic interventions on the basis of outcomes and hemoglobin levels. Perceptions by oncologists and patients that lesser degrees of anemia must be endured without treatment may be overcome as greater emphasis is placed on the QOL of the oncology patient and as research provides further insights into the relationships between hemoglobin levels, patient well-being, and symptoms.

Topics: Adult; Aged; Anemia; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Colorectal Neoplasms; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Female; Head and Neck Neoplasms; Hematinics; Humans; Incidence; Lung Neoplasms; Lymphoma; Middle Aged; Neoplasms; Ovarian Neoplasms; Recombinant Proteins; Severity of Illness Index; Treatment Outcome

Tansplantability, growth, morphology, and function of xenotransplanted human tumors, such as carcinomas of the lung, liver, breast, choriocarcinoma, and blastomas of the liver, lung, kidney, and uterus, are described. From the tumor take rate, it is clear that xenotransplantation cannot be used for the study of every human tumor: slow-growing tumors are difficult to analyze, and functioning adenomas and low-grade malignant carcinomas are at present almost impossible to study by this approach. From the authors' transplantation experience, tumor antigenicity to nude mice with no T-cell function, either tumor specific or species specific, was suspected. Therefore, the growth in nude mice may not equate to that in the human body. The stroma of the transplanted tumor, which is most likely of mouse origin, might also alter the growth rate, as it did the histology of some tumors. Another possible hindrance that has not been described in the text is the mouse endogenous virus. Serially transplanted human tumors are often infected with C particles, which could well influence the tumor growth and character. In spite of the presence of some factors unfavorable for the study of human tumors through xenotransplantation, it has, nevertheless, been clearly shown that the nude mouse/human tumor system is a very useful tool for functional analysis of tumors in relation to growth, differentiation, and morphology, such as eutopic or ectopic production of various hormones, AFP, normal serum proteins, colony-stimulating factor, erythropoietin, and so on. This system can be employed to elucidate the production of many other biologically active and inactive substances by a variety of tumors and their effects on the host in the future and should provide better understanding of human cancers. Attempts to induce differentiation and to change the biologic behavior of xenotransplanted human malignant tumors have failed so far, except for induced dormancy of breast carcinoma under unfavorable hormonal conditions. This line of investigation may have particular import on cancer research, particularly in relation to the biology and treatment of human cancers.

Topics: alpha-Fetoproteins; Animals; Blood Proteins; Breast Neoplasms; Carcinoma; Carcinoma, Adenoid Cystic; Cell Division; Choriocarcinoma; Erythropoietin; Female; Graft Survival; Hormones, Ectopic; Humans; Kidney Neoplasms; Liver Neoplasms; Liver Neoplasms, Experimental; Lung Neoplasms; Male; Mesenchymoma; Mice; Mice, Nude; Middle Aged; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms; Neoplasms, Experimental; Neoplasms, Hormone-Dependent; Pregnancy; Transplantation, Heterologous

WSG-ARA plus trial evaluated the effect of adjuvant darbepoetin alfa (DA) on outcome in node positive primary breast cancer (BC).. One thousand two hundred thirty-four patients were randomized to chemotherapy either with DA (DA+; n = 615) or without DA (DA-; n = 619). DA (500 µg q3w) was started at hemoglobin (Hb) levels <13.0 g/dl (<12 g/dl after DA label amendment) and stopped at Hb levels ≥14.0 g/dl (12 g/dl after label amendment). Primary efficacy end point was event-free survival (EFS); secondary end points were toxicity, quality of life (QoL) and overall survival (OS).. Venous thrombosis (DA+: 3.0%, DA-: 1.0%; P = 0.013) was significantly higher for DA+, but not pulmonary embolism (0.3% in both arms). Median Hb levels were stable in DA+ (12.6 g/dl) and decreased in DA- (11.7 g/dl). Hb levels >15 g/dl were reported in 0.8% of cycles. QoL parameters did not significantly differ between arms. At 39 months, DA had no significant impact on EFS (DA+: 89.3%, DA-: 87.5%; Plog-rank = 0.55) or OS (DA+: 95.5%, DA-: 95.4%; Plog-rank = 0.77).. DA treatment did not impact EFS or OS in routine adjuvant BC treatment.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Darbepoetin alfa; Disease-Free Survival; Erythropoietin; Female; Hematinics; Humans; Lymphatic Metastasis; Middle Aged; Proportional Hazards Models; Treatment Outcome

The AGO-ETC trial compared 5-year relapse-free survival of intense dose-dense (IDD) sequential chemotherapy with epirubicin (E), paclitaxel (T), and cyclophosphamide (C) (IDD-ETC) every 2 weeks vs conventional scheduled epirubicin/cyclophosphamide followed by paclitaxel (EC→T) (every 3 weeks) as adjuvant treatment in high-risk breast cancer patients. The objective of this study was to evaluate the safety and efficacy of epoetin alfa in a second randomization of the intense dose-dense arm.. One thousand two hundred eighty-four patients were enrolled; 658 patients were randomly assigned to the IDD-ETC treatment group. Within the IDD-ETC group, 324 patients were further randomly assigned to the epoetin alfa group, and 319 were randomly assigned to the non-erythropoiesis-stimulating agent (ESA) control group. Primary efficacy endpoints included change in hemoglobin level from baseline to Cycle 9 and the percentage of subjects requiring red blood cell transfusion. Relapse-free survival, overall survival, and intramammary relapse were secondary endpoints estimated with Kaplan-Meier and Cox regression methods. Except for the primary hypothesis, all statistical tests were two-sided.. Epoetin alfa avoided the decrease in hemoglobin level (no decrease in the epoetin alfa group vs -2.20g/dL change for the control group; P < .001) and statistically significantly reduced the percentage of subjects requiring red blood cell transfusion (12.8% vs 28.1%; P < .0001). The incidence of thrombotic events was 7% in the epoetin alfa arm vs 3% in the control arm. After a median follow-up of 62 months, epoetin alfa treatment did not affect overall survival, relapse-free survival, or intramammary relapse.. Epoetin alfa resulted in improved hemoglobin levels and decreased transfusions without an impact on relapse-free or overall survival. However, epoetin alfa had an adverse effect, resulting in increased thrombosis.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Blood Transfusion; Breast Neoplasms; Chemotherapy, Adjuvant; Cyclophosphamide; Disease-Free Survival; Drug Administration Schedule; Epirubicin; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Hematinics; Hemoglobins; Humans; Kaplan-Meier Estimate; Middle Aged; Paclitaxel; Proportional Hazards Models; Quality of Life; Recombinant Proteins; Risk Assessment; Treatment Outcome

The objective of this study was to compare the effect of dose-intensified neoadjuvant chemotherapy with that of standard epirubicin plus cyclophosphamide followed by paclitaxel in combination with or without darbepoetin on survival in primary breast cancer.. A total of 733 patients received either four cycles of neoadjuvant epirubicin 90 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 3 weeks followed by four cycles of paclitaxel 175 mg/m(2) every 3 weeks (EC→T), or three cycles of epirubicin 150 mg/m(2) every 2 weeks followed by three cycles of paclitaxel 225 mg/m(2) every 2 weeks followed by three cycles of combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (E(dd)→T(dd)→CMF). The patients were randomly assigned to receive darbepoetin or none. The primary objective was to demonstrate a superior disease-free survival (DFS) of E(dd)→T(dd)→CMF compared with EC→T.. Estimated 3-year DFS was 75.8% with EC→T versus 78.8% with E(dd)→T(dd)→CMF [hazard ratio (HR) 1.14; P = 0.37] and overall survival (OS) 88.4% versus 91.5% (HR 1.26; P = 0.237). Three-year DFS was 74.3% with darbepoetin versus 80.0% without (HR 1.31; P = 0.061) and OS 88.0% versus 91.8% (HR 1.33; P = 0.139). Patients with a pathologically documented complete response [pathological complete response (pCR)] had a significantly better DFS compared with those without achieving a pCR (estimated 3-year DFS: 89.2% versus 74.9%; HR 2.27; P = 0.001).. Neoadjuvant dose-intensified chemotherapy compared with standard chemotherapy did not improve DFS, whereas the addition of darbepoetin might have detrimental effects on DFS.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Cyclophosphamide; Darbepoetin alfa; Disease-Free Survival; Dose-Response Relationship, Drug; Epirubicin; Erythropoietin; Female; Fluorouracil; Humans; Methotrexate; Middle Aged; Multivariate Analysis; Neoadjuvant Therapy; Paclitaxel; Patient Compliance; Preoperative Care; Treatment Outcome; Young Adult

Preoperative chemotherapy is a recommended treatment of both primary operable and locally advanced breast cancer. Strategies to improve efficacy include the use of anthracyclines, taxanes, and intensified dose with bone marrow support.. Patients received neoadjuvant epirubicin 90 mg/m(2) plus cyclophosphamide 600 mg/m(2) followed by paclitaxel 175 mg/m(2) (EC→T), each 3-weekly for four cycles (n = 370), or epirubicin 150 mg/m(2) followed by paclitaxel 225 mg/m(2) with pegfilgrastim followed by CMF (cyclophosphamide 500 mg/m(2), methotrexate 40 mg/m(2), fluorouracil 600 mg/m(2)) on days 1 and 8 (E(dd)→T(dd)→CMF), each 2-weekly and for three cycles (n = 363). Patients were randomly allocated to either simultaneous darbepoetin alfa (DA) (n = 356) or none (n = 377).. Pathological complete response (pCR) rate (breast) was higher with E(dd)→T(dd)→CMF, 18.7% versus 13.2% with EC→T; P = 0.043, ypT0/Tis; ypN0 was reported in 20.9% versus 14.3% respectively; P = 0.019. Patients with grade 3 tumors and negative hormone receptor status had a significantly higher pCR rate. Mean hemoglobin values maintained higher with DA (13.6 versus 12.6 g/dl). E(dd)→T(dd)→CMF regimen showed more grade 3-4 mucositis, sensory neuropathy, and neurological complaints. Thromboembolic events were more frequent on DA (3% versus 6%; P = 0.055).. Dose-dense and -intensified neoadjuvant chemotherapy with E(dd)→T(dd)→CMF was potentially superior to EC→T in terms of pCR. Primary use of DA did not affect pCR.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Cyclophosphamide; Darbepoetin alfa; Dose-Response Relationship, Drug; Epirubicin; Erythropoietin; Female; Filgrastim; Fluorouracil; Granulocyte Colony-Stimulating Factor; Hemoglobins; Humans; Methotrexate; Middle Aged; Neoadjuvant Therapy; Paclitaxel; Patient Compliance; Polyethylene Glycols; Preoperative Care; Recombinant Proteins; Young Adult

To evaluate the effects of epoetin alfa on patient-reported outcomes (PROs) in patients with breast cancer receiving myelotoxic chemotherapy.. Women with hemoglobin concentrations ≤ 12.0 g/dl and an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0-3 were randomized 1:1 to receive epoetin alfa (10,000 IU 3 times weekly) or best standard care (BSC) during chemotherapy. The primary endpoint was the change from baseline in the total anemia subscale assessed by the Functional Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire after 12 weeks of treatment. The fatigue and nonfatigue subscales from the FACT-An, the Cancer Linear Analog Scale (CLAS), hemoglobin changes, ECOG PS score, tumor response, overall survival, and safety also were evaluated.. Of 223 patients randomized, 216 constituted the modified intent-to-treat population. Percentage changes in the total anemia subscale of the FACT-An were significantly different between epoetin alfa treatment (14.2%) and BSC (-0.5%; p = .002), favoring epoetin alfa; so were changes in the FACT-An fatigue subscale (epoetin alfa, 17.5%; BSC, -0.9%; p = .003) and nonfatigue subscale (epoetin alfa, 8.8%; BSC, 0.2%; p = .008). Similar results were observed with the CLAS. Hemoglobin concentrations > 12 g/dl were more common with epoetin alfa (62.0%) than with BSC (27.6%). Tumor response, ECOG PS score, 12-month survival rate, and the incidence of serious treatment-emergent adverse events were similar between groups.. Early intervention with epoetin alfa was well tolerated and improved anemia-related PROs in patients with breast cancer receiving myelotoxic chemotherapy.

Topics: Adult; Aged; Anemia; Antineoplastic Agents; Blood Transfusion; Breast Neoplasms; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Middle Aged; Prospective Studies; Recombinant Proteins

This prospective study quantifies the response of hemoglobin and other blood factors to Epoetin alpha (EPO) administration in the course of pre-operative chemotherapy in breast cancer. Blood count time series were analyzed in 38 primary breast cancer patients with/without EPO during the course of pre-operative chemotherapy with epirubicin and paclitaxel. EPO injections improved blood counts in 'anemic' patients (< or =12.0 g/dl) receiving chemotherapy, but had little effect when administered to patients with higher hemoglobin concentrations. On the average, without chemotherapy, hemoglobin concentrations drifted toward about 11.1 g/dl without EPO but could be maintained at near 12.0 g/dl with EPO. In conclusion, there is potential for improved anemia management using EPO during pre-operative chemotherapy, which not only benefits quality of life but could also influence long-term survival in breast cancer through improved tumor oxygenation.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Combined Modality Therapy; Epirubicin; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Middle Aged; Neoadjuvant Therapy; Paclitaxel; Recombinant Proteins

PURPOSE, PATIENTS AND METHODS: This retrospective analysis of the BRAVE study evaluated the impact of baseline risk factors and antithrombotic therapy on the risk of thrombovascular events (TVEs) in patients receiving epoetin compared to patients not receiving epoetin.. Baseline risk factors have a significant impact on TVE risk under epoetin therapy. More than 2 risk factors increased the risk of TVEs in patients receiving epoetin (hazard ratio [HR] 2.89, confidence interval [CI] 1.04-8.02, p value [p]=0.04). In patients on epoetin without antithrombotic therapy, the risk for TVEs was higher (HR 4.11, CI 1.37-12.4, p=0.01) compared to those who received antithrombotics (HR 1.37, CI 0.59-3.18, p=0.45).. Our analysis has identified several risk factors which may impact the risk of TVEs under epoetin therapy. These data suggest that antithrombotic therapy may have the potential to reduce the risk of TVEs under epoetin therapy. These findings are hypothesis-generating and need to be confirmed in a prospective, randomised study.

Topics: Adult; Aged; Aged, 80 and over; Breast Neoplasms; Epidemiologic Methods; Erythropoietin; Female; Fibrinolytic Agents; Hematinics; Hemoglobins; Humans; Middle Aged; Neoplasm Metastasis; Prognosis; Recombinant Proteins; Thrombophlebitis; Thrombosis

The Breast Cancer-Anemia and the Value of Erythropoietin (BRAVE) study evaluated whether epoetin beta would improve survival in patients with metastatic breast cancer (MBC).. BRAVE was an open-label, randomized, multicenter study in patients with MBC treated with anthracycline- and/or taxane-based chemotherapy. Patients (hemoglobin [Hb] < 12.9 g/dL) were randomly assigned (1:1) to epoetin beta 30,000 U subcutaneously once weekly or control for 24 weeks. The primary efficacy variable was overall survival. Secondary efficacy outcomes included progression-free survival, transfusion- and severe anemia-free survival, Hb response, safety, and quality of life (QoL).. After 18 months of follow-up, 62 (27%) of 231 patients survived with epoetin beta therapy and 63 (27%) of 232 with control. No difference was detected in overall survival (hazard ratio [HR] = 1.07; 95% CI, 0.87 to 1.33, P = .522) or progression-free survival (HR = 1.07; 95% CI, 0.89 to 1.30, P = .448). There was a statistically significant benefit on transfusion- and severe anemia-free survival compared with control (HR = 0.59; P = .0097). Median Hb level increased with epoetin beta (11.7 g/dL at baseline to 13.3 g/dL at 24 weeks) but did not change with control (11.5 v 11.4 g/dL). Patients receiving epoetin beta experienced more thromboembolic events (TEEs) compared with controls (13% v 6%; P = .012) with no difference in serious TEEs (4% v 3%). Epoetin beta did not significantly improve QoL in this study where patients had a high baseline Hb value.. In patients with MBC receiving chemotherapy and initial Hb less than 12.9 g/dL, epoetin beta increased Hb. No difference was detected in overall survival. Because of its superiority design, this study cannot, however, exclude clinically important differences in survival with absolute certainty.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Breast Neoplasms; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Erythropoietin; Female; Hemoglobins; Humans; Injections, Subcutaneous; Lymphatic Metastasis; Middle Aged; Quality of Life; Recombinant Proteins; Survival Rate; Taxoids

This study was aimed at investigating the effectiveness and safety of once-weekly epoetin beta for anaemic cancer patients receiving chemotherapy.. A total of 104 patients with a haemoglobin level of /=2.0 g/dL; the haemoglobin response rate. Quality of life (QOL) was assessed using the Functional Assessment of Cancer Therapy-Anaemia (FACT-An) questionnaire.. The haemoglobin response rate was 66.3% among the 98 patients (breast cancer: n = 25; malignant lymphoma: n = 21; ovarian cancer: n = 20; lung cancer: n = 15; other cancers: n = 17) assessable for a haemoglobin response. Thirty-nine patients (39.8%) required a dose escalation to 54 000 IU. At the end of the study, QOL assessable patients (n = 96) showed a mean improvement in the FACT-An total fatigue subscale score (FSS) of 0.3 points from baseline. Patients with a haemoglobin response had a mean change in the total FSS of +3.2, compared with -3.4 for patients without a haemoglobin response. No serious adverse event of epoetin beta was observed.. Epoetin beta administered at an initial dose of 36 000 IU once-weekly was well tolerated, with increased haemoglobin levels and improved QOL in anaemic cancer patients receiving myelosuppressive chemotherapy.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Administration Schedule; Erythrocyte Transfusion; Erythropoietin; Female; Hemoglobins; Humans; Lung Neoplasms; Lymphoma; Male; Middle Aged; Ovarian Neoplasms; Patient Compliance; Quality of Life; Recombinant Proteins

It is believed widely that chemotherapy-induced cognitive impairment occurs in a subgroup of patients with breast cancer. However, recent reports have provided no evidence that chemotherapy affects cognition. In this study, the authors questioned whether cognitive compromise in patients with breast cancer is attributable to chemotherapy. In addition, the effects of therapy-induced menopause and of the erythropoiesis-stimulating factor darbepoetin alpha on cognitive performance were assessed.. A battery of neuropsychological tests was used to assess cognitive performance in 101 patients with breast cancer before neoadjuvant chemotherapy (T1) and toward the end of neoadjuvant chemotherapy (T2) with combined epirubicin, paclitaxel, and cyclophosphamide with concomitant darbepoetin alpha. Repeated-measures multiple analyses of variance and a reliable-change approach were used for statistical analyses.. At T1, the group means ranged below the test norms in 5 of 12 cognitive tests. At T2, multiple analyses of variance (MANOVA) indicated a significant overall improvement in the test results (P<.001). After correcting for practice effects, cognitive decline predominated in 27% of patients, whereas improvement predominated in 28% of patients. Cognitive performance was not related significantly to self-reported cognitive problems, anxiety and depression, menopause, or darbepoetin alpha administration.. Even before chemotherapy, a subgroup of patients with breast cancer showed cognitive compromise that was unrelated to anxiety or depression. During chemotherapy, cognitive function remained stable in most patients, improved in a subgroup, and deteriorated in another subgroup. The deterioration may have been caused by side effects of chemotherapy, but it also may have been related to currently unidentified factors that cause prechemotherapy cognitive compromise. Therapy-induced menopause and darbepoetin alpha did not appear to influence cognition.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cognition; Cognition Disorders; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Humans; Longitudinal Studies; Menopause; Middle Aged; Neoadjuvant Therapy; Neuropsychological Tests; Prospective Studies

To determine whether weekly epoetin alfa could improve hemoglobin (HgB) levels, reduce RBC transfusions, and improve quality of life (QOL) in patients with advanced cancer and with anemia after receiving myelosuppressive chemotherapy.. This double-blind, placebo-controlled study randomly assigned patients to placebo or epoetin alfa (Ortho Biotech, Bridgewater, NJ) 40,000 U subcutaneous weekly for 16 weeks. QOL, HgB, and RBC transfusions were measured pretreatment and monthly.. The study accrued 344 patients; 330 were assessable for efficacy and 305 were assessable for QOL. Placebo-treated patients had a mean increase in HgB of 0.9 g/dL (range, -3.8 to +5.3) compared with 2.8 g/dL (range, -2.2 to +7.5) for epoetin-treated patients (P < .0001). During the study, 31.7% of placebo-treated patients achieved a > or = 2 g/dL HgB increase compared with 72.7% of epoetin-treated patients (P < .0001). The incidence of RBC transfusion for placebo and epoetin treatment arms was 39.6% and 25.3% (P = .005), respectively. The placebo group received 256 units of RBCs compared with 127 units in the epoetin group (P < .0001). The incidence of toxicity in the groups was similar. Changes in the average QOL scores from baseline to the end of the study were similar in the two groups (P = not significant). The HgB responders (irrespective of treatment arm) had a mean change in Functional Assessment of Cancer Therapy (FACT) fatigue score from a baseline of +5.1 compared with -2.1 for the nonresponders (P = .006).. Epoetin alfa significantly improved HgB and reduced transfusions in this patient population. These results support the use of weekly epoetin alfa as an ameliorative agent for cancer-related anemia.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Breast Neoplasms; Double-Blind Method; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Hemoglobins; Humans; Injections, Subcutaneous; Lung Neoplasms; Male; Middle Aged; Neoplasms; Placebos; Quality of Life; Recombinant Proteins; Treatment Outcome

Epoetin alfa administered at 40,000 U once weekly (qw) to anemic cancer patients receiving chemotherapy increases hemoglobin levels, improves quality of life (QOL), and reduces transfusions. The benefit of epoetin alfa in maintaining hemoglobin levels in cancer patients with hemoglobin less than 12 g/dL has not been evaluated.. Breast cancer patients (N = 354) receiving chemotherapy were randomly assigned in 1:1 ratio to epoetin alfa (40,000 U qw) or standard of care (SOC). QOL was assessed at baseline and week 12. Hemoglobin responses, transfusion requirements, and prognostic factors for responses were measured.. At week 12, Functional Assessment of Cancer Therapy-Anemia (FACT-An; mean, 2.16 +/- 12.84 for epoetin alfa v -4.43 +/- 13.42 for SOC) and FACT-An fatigue (mean, 1.85 +/- 10.52 for epoetin alfa v -3.55 +/- 11.14 for SOC) change scores were significantly higher in the epoetin alfa group (P < .0001). Hemoglobin responses defined as mean hemoglobin > or = 12 g/dL or a > or = 2 g/dL increase compared with baseline were significantly higher in the epoetin alfa group versus SOC: 52.0% v 5.1% and 65.7% v 6.3%, respectively (P < .0001 for both comparisons). Percentage transfused was significantly lower in the epoetin alfa group compared with SOC (8.6% v 22.9%). More than 90% of patients did not require a dose increase and 28.7% had a dose reduction.. Epoetin alfa administered at 40,000 U qw is effective in improving QOL, maintaining hemoglobin level, and reducing transfusion requirements in breast cancer patients. The high effectiveness observed could be attributed in part to early treatment with epoetin alfa.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Breast Neoplasms; Epoetin Alfa; Erythropoietin; Fatigue; Female; Hematinics; Hemoglobins; Humans; Injections, Subcutaneous; Middle Aged; Quality of Life; Recombinant Proteins; Treatment Outcome

Impaired cognition, fatigue, and diminished quality of life (QOL) are commonly associated with breast cancer chemotherapy. This randomized, double-blind, placebo-controlled pilot trial assessed the feasibility of quantifying the effects of epoetin alfa on cognitive function and mood, and evaluated its effects on fatigue and QOL in patients with breast cancer treated with anthracycline-based adjuvant or neoadjuvant chemotherapy. Patients were randomized to receive epoetin alfa 40,000 U subcutaneously once weekly or placebo at the beginning of 4 cycles of chemotherapy administered over 12 weeks. Cognitive function was assessed by Executive Interview (EXIT25) and Clock Drawing Tasks; mood by Profile of Mood States; anemia-related symptoms, including fatigue, by the Functional Assessment of Cancer Therapy-Anemia (FACT-An) subscale; and QOL by Linear Analog Scale Assessment. Ninety-four patients were evaluable for efficacy and safety. Mean change in EXIT25 scores from baseline to cycle 4 in the epoetin alfa group was 1.3 +/- 3.3; the mean change was 0.3 +/- 2.4 in the placebo group (a negative change indicates improved executive function). There was no difference between groups in mean change in EXIT25 score from baseline to 6-month follow-up assessment. Mean hemoglobin levels were higher in the epoetin alfa group compared with the placebo group after 4 cycles of chemotherapy. Epoetin alfa recipients had less of a decrease in FACT-An subscale scores from baseline to cycle 4 and improvement in FACT-An subscale scores at 6-month follow-up assessment compared with placebo. Epoetin alfa therapy was well tolerated. These data suggest that epoetin alfa may have attenuated the cognitive impairment and fatigue that occurred during adjuvant breast cancer chemotherapy.

Topics: Adult; Affect; Aged; Breast Neoplasms; Chemotherapy, Adjuvant; Cognition Disorders; Double-Blind Method; Epoetin Alfa; Erythropoietin; Fatigue; Female; Hematinics; Humans; Injections, Subcutaneous; Middle Aged; Neoadjuvant Therapy; Placebos; Quality of Life; Recombinant Proteins; Treatment Outcome

Anemia, fatigue, and diminished quality of life (QOL) often are associated with chemotherapy. In a previous study of patients with early-stage breast cancer and a mean baseline hemoglobin (Hb) level of 12.1 g/dL, Hb decreased by 2.0 g/dL after 4 cycles of adjuvant chemotherapy. The current open-label, nonrandomized, multicenter, prospective, community-based study evaluated the effects of 12-24 weeks of epoetin alfa (40,000 U subcutaneously once weekly initiated at the start of standard adjuvant chemotherapy) in patients with stage I-III breast cancer and baseline Hb levels > or =10 g/dL to < or =14 g/dL on Hb level, transfusions, and QOL.. Of 1792 patients enrolled, 1785 were evaluable for safety and 1632 for efficacy. Mean age was 53 years +/- 10.7 and mean baseline Hb level was 12.3 g/dL +/- 1.0. From baseline levels, epoetin alfa significantly increased Hb (1.3 g/dL +/- 1.5; P < 0.05) and improved QOL according to the Linear Analog Scale Assessment (LASA) of energy (5.1 mm +/- 27.7), LASA activity (5.1 mm +/- 28.2), LASA overall QOL (4.3 mm +/- 26.7), and Functional Assessment of Cancer Therapy-Anemia (1.7 points +/- 14.0; P < 0.05 in each case). Patients with baseline mild anemia (Hb level >10 g/dL to < or =12 g/dL) also had significant improvements from baseline levels in all 3 LASA parameters (P < 0.05). Epoetin alfa was well tolerated; clinically relevant thrombovascular events were reported in 4.3% of patients.. In this study, epoetin alfa significantly improved Hb and QOL in mildly anemic patients with early-stage breast cancer receiving adjuvant chemotherapy. However, based on recent studies showing an increased risk of thrombovascular events in patients with cancer treated with erythropoietic agents beyond correction of anemia, treatment with epoetin alfa is not indicated or recommended in patients with cancer and Hb levels > 12 g/dL.. Controlled studies are warranted to confirm the safety and efficacy of epoetin alfa therapy in patients with mild anemia receiving chemotherapy.

Topics: Adult; Anemia; Breast Neoplasms; Chemotherapy, Adjuvant; Epoetin Alfa; Erythropoietin; Fatigue; Female; Hematinics; Hemoglobins; Humans; Injections, Subcutaneous; Middle Aged; Prospective Studies; Quality of Life; Recombinant Proteins; Severity of Illness Index; Treatment Outcome

To evaluate the effect on survival and quality of life of maintaining hemoglobin (Hb) in the range of 12 to 14 g/dL with epoetin alfa versus placebo in women with metastatic breast cancer (MBC) receiving first-line chemotherapy.. Eligible patients were randomly assigned to receive epoetin alfa 40,000 U once weekly or placebo for 12 months. Study drug was initiated if baseline Hb was < or = 13 g/dL or when Hb decreased to < or = 13g/dL during the study. The primary end point was 12-month overall survival (OS).. The study drug administration was stopped early in accordance with a recommendation from the Independent Data Monitoring Committee because of higher mortality in the group treated with epoetin alfa. Enrollment had been completed, with 939 patients enrolled (epoetin alfa, n = 469; placebo, n = 470). Most patients had Hb more than 12 g/dL at baseline (median Hb, 12.8 g/dL) or during the study. From the final analysis, 12-month OS was 70% for epoetin alfa recipients and 76% for placebo recipients (P = .01). Optimal tumor response and time to disease progression were similar between groups. The reason for the difference in mortality between groups could not be determined from additional subsequent analyses involving both study data and chart review.. In this trial, the use of epoetin alfa to maintain high Hb targets in women with MBC, most of whom did not have anemia at the start of treatment, was associated with decreased survival. Additional research is required to clarify the potential impact of erythropoietic agents on survival when the Hb target range is 10 to 12 g/dL.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Breast Neoplasms; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Injections, Subcutaneous; Middle Aged; Neoplasm Metastasis; Placebos; Quality of Life; Recombinant Proteins; Survival Analysis

We recruited 50 patients with T2-4 N0-2 M0 primary breast cancer into a phase I/II study to define the maximum tolerated dose (MTD), efficacy and tolerability of preoperative gemcitabine (1250 mg/m fixed dose) plus epirubicin (doses escalated from 90 mg/m) for 5 cycles followed by 4 cycles of docetaxel (scheduled fixed dose 100 mg/m) given on day 1 every 2 weeks (q2w) with pegfilgrastim support. The MTD for epirubicin was 100 mg/m, but the docetaxel dose had to be reduced to 80 mg/m. Dose-limiting toxicities included fatigue, stomatitis, diarrhea and dyspnea (all grade 3) during gemcitabine plus epirubicin, and fatigue (grade 3) and allergic reaction (grade 4) during docetaxel treatment, respectively. A pathologic complete response could be achieved in 13 patients (pT0+pTis, 26%), and in the breast and axilla in 12 patients [(pT0 or pTis)+pN0, 24%). Breast-conserving surgery (BCS) was possible in 35 patients (70%). Main grade 3/4 adverse events at MTD were fatigue (57/0%), leukopenia (27/8%), and liver (14/0%) and lung toxicity (14/0%). In conclusion, gemcitabine plus epirubicin 1250/100 mg/m q2w followed sequentially by docetaxel 80 mg/m q2w is highly effective as pre-operative chemotherapy with manageable toxicity. However, response and BCS rates could not be increased by administering gemcitabine plus epirubicin and docetaxel in a dose-dense fashion.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Darbepoetin alfa; Deoxycytidine; Docetaxel; Dose-Response Relationship, Drug; Epirubicin; Erythropoietin; Female; Filgrastim; Gemcitabine; Granulocyte Colony-Stimulating Factor; Humans; Ki-67 Antigen; Middle Aged; Neutropenia; Polyethylene Glycols; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Recombinant Proteins; Taxoids; Treatment Outcome

At present, oncologists prescribe chemotherapy according to standard dose schedules, and as a result many patients develop serious, dose-limiting toxic effects such as anaemia. We aimed to develop a prediction model for anaemia in patients with breast cancer who were receiving adjuvant chemotherapy.. We reviewed medical records of 331 patients who had received adjuvant chemotherapy for breast cancer. Patients were divided randomly into a derivation sample (n=221) and internal-validation sample (n=110). An external sample of 119 patients enrolled onto the control group of a randomised trial of epoetin alfa was used to validate the model further. Multivariable logistic regression was applied to develop the initial model. We then developed a risk-scoring system, ranging from 0 (low risk) to 50 (high risk), based on the final regression variables. A receiver operating characteristic (ROC) curve analysis was done to measure the accuracy of the scoring system when applied to both validation samples.. The risk of anaemia increased as the pretreatment haemoglobin concentration decreased and was reduced with successive chemotherapy cycles. Risk was also predicted by a platelet count of 200x10(9) cells/L or less before chemotherapy, age 65 years or older, type of adjuvant chemotherapy, and use of prophylactic antibiotics. ROC analysis had acceptable areas under the curve of 0.88 for the internal-validation sample and 0.84 for the external validation sample. A risk score of > or = 24 to < 25 before chemotherapy was identified as the optimum cut-off for maximum sensitivity (83.5%) and specificity (92.3%) of the prediction model.. The application and continued refinement of this prediction model will help oncologists to identify patients at risk of developing anaemia during chemotherapy for breast cancer, and might enhance patient-centred care by the application of anaemia treatment in a proactive and appropriate way.

Topics: Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Epoetin Alfa; Erythropoietin; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematinics; Humans; Logistic Models; Medical Records; Middle Aged; Predictive Value of Tests; Recombinant Proteins; Risk Factors; ROC Curve

Dose-dense, every-2-week adjuvant chemotherapy using doxorubicin/cyclophosphamide (AC; 60/600 mg/m2 every 2 weeks x four cycles) followed by paclitaxel (175 mg/m2 every 2 weeks x four cycles), requiring filgrastim on days 3 through 10 of each cycle has been shown to improve survival compared with every-3-week treatment schedules but is associated with greater risk of RBC transfusion (13%). The role of long-acting hematopoietic growth factors in facilitating every-2-week chemotherapy and minimizing hematologic toxicity has not been established.. Women with stage I to III breast cancer received dose-dense AC --> paclitaxel as neoadjuvant or adjuvant chemotherapy. Patients received pegfilgrastim 6 mg subcutaneous (SQ) on day 2 of each cycle. Darbepoetin alfa was initiated at 200 microg SQ every 2 weeks for hemoglobin < or = 12 g/dL, and administered thereafter, according to a preplanned algorithm. The primary end points were to evaluate the percentage of patients with febrile neutropenia and the percentage of patients requiring RBC transfusion.. Among 135 women treated on this single arm study, there were two cases of febrile neutropenia (incidence 1.5%). No patients received RBC transfusion. Darbepoetin alfa therapy was initiated in 92% of patients. The modest leukocytosis seen during paclitaxel cycles was attributable, in part, to corticosteroid premedication. Other toxicity and dose-delivery were similar to dose-dense AC --> paclitaxel in Cancer and Leukemia Group B 9741.. Pegfilgrastim and darbepoetin alfa are effective and safe in facilitating every-2-week AC --> paclitaxel, minimizing rates of febrile neutropenia and RBC transfusion.

Topics: Adult; Aged; Algorithms; Anemia; Antineoplastic Combined Chemotherapy Protocols; Boston; Breast Neoplasms; Chemotherapy, Adjuvant; Cyclophosphamide; Darbepoetin alfa; Doxorubicin; Erythrocyte Transfusion; Erythropoietin; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Middle Aged; Neutropenia; Paclitaxel; Polyethylene Glycols; Recombinant Proteins; Treatment Outcome

Current chemotherapy regimens for breast cancer result in high incidences of anemia, which can be treated with erythropoietic agents. The relative efficacy of darbepoetin alfa and epoetin alfa was explored in this phase II, open-label, randomized, multicenter trial in anemic patients with breast cancer receiving chemotherapy.. Patients were randomized at a 1:1 ratio to receive darbepoetin alfa 200 microg every 2 weeks (n = 72) or epoetin alfa 40,000 U weekly (n = 69) for < or = 16 weeks. Clinical and hematologic endpoints and validation of a novel patient satisfaction questionnaire for anemia treatment were evaluated for all patients randomized to receive > or = 1 dose of study drug.. Baseline characteristics were generally similar between treatment groups. Mean changes in hemoglobin (Hb) level from baseline were similar at 1.9 g/dL for darbepoetin alfa and 1.7 g/dL for epoetin alfa. Hematopoietic responses (> or = 2 g/dL increase in Hb level from baseline or Hb level > or = 12 g/dL) were also similar between groups (88% for darbepoetin alfa and 81% for epoetin alfa). The proportions of patients who received a transfusion during treatment were 6% (95% CI, 0-11%) for darbepoetin alfa and 16% (95% CI, 7%-25%) for epoetin alfa. Most patients (67 patients receiving darbepoetin alfa [93%]; 61 patients receiving epoetin alfa [90%]) exhibited a clinically meaningful target Hb level > or = 11 g/dL. No differences in safety were observed.. These results suggest that, in patients with breast cancer, darbepoetin alfa 200 microg every 2 weeks and epoetin alfa 40,000 U weekly result in comparable clinical outcomes for the treatment of chemotherapy-induced anemia.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Darbepoetin alfa; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Humans; Middle Aged; Patient Satisfaction; Recombinant Proteins; Treatment Outcome

Recombinant human erythropoietin (r-HuEPO) corrects cancer-related anemia and, thereby, improves quality of life. The purpose of the present study was to measure the impact of erythropoietin on hemoglobin and mood state in patients with metastatic breast cancer and mild anemia (Hgb < 12.0 g/dL). Women were randomized to receive usual care (G1) or usual care plus r-HuEPO (G2). Usual care included transfusions as necessary and fatigue education. R-HuEPO was begun at 40,000U subcutaneously per week. At 4 weeks, the dose was increased to 60,000U if Hgb had not increased > or = 1.0 g/dL. The drug was discontinued at 8 weeks if hemoglobin improvement was < 1.0 g/dL. The study was terminated early (n = 27, G1 = 13, G2 = 14) when 4/14 (28.5%) subjects in G2 developed thrombotic events (deep vein thrombosis [DVT] in 1; DVT plus pulmonary embolism [PE] in 1; DVT plus PE 1 month after drug discontinuation in 1; and brachial vein thrombosis with infected Mediport in 1). In all four patients, Hgb levels were normal at the time of the event. No patient in G1 developed a thrombotic event. There were no significant differences in demographic characteristics or current chemotherapy regimen in G1 vs. G2. The decision to terminate the trial was made after considerable deliberation. The increased incidence of thrombotic events in the r-HuEPO (G2) arm of this study exceeds that in prior studies in this population and prior r-HuEPO trials. This may relate to the administration of r-HuEPO in this high-risk population, but the small sample size and possible predisposing risk factors preclude definitive conclusions.

Topics: Anemia; Breast Neoplasms; Erythropoietin; Fatigue; Female; Humans; Middle Aged; Palliative Care; Quality of Life; Recombinant Proteins; Thrombosis; Treatment Outcome; Withholding Treatment

Topics: Anemia; Breast Neoplasms; Erythropoietin; Female; Hemoglobins; Humans; Treatment Outcome

An important clinical question is the relative efficacy of the most common dosages of darbepoetin alfa (Aranesp; Amgen Inc.; Thousand Oaks, CA) 200 microg every 2 weeks (Q2W) and epoetin alfa (Procrit; Ortho Biotech Products, LP; Raritan, NJ) 40,000 U weekly (QW) for the treatment of chemotherapy-induced anemia. We designed three concurrent randomized, open-label, multicenter, identical trials (with the exception of tumor type criteria of breast, gynecologic, or lung cancer) of darbepoetin alfa and epoetin alfa in patients with chemotherapy-induced anemia to validate the Patient Satisfaction Questionnaire for Anemia (PSQ-An) treatment tool and to compare the efficacies and safety profiles of these two agents. In each trial, patients were randomized 1:1 to receive either darbepoetin alfa at a dose of 200 microg Q2W or epoetin alfa at a dose of 40,000 U QW for up to 16 weeks. The PSQ-An was assessed for validity, feasibility, and reliability. Secondary clinical endpoints were analyzed using the primary analysis set. Both individual trial analyses and a protocol-specified combined analysis of data from all three trials were conducted. Overall, 312 patients (157 darbepoetin alfa; 155 epoetin alfa) were randomized and received study drug. Baseline characteristics were similar in both treatment groups in each trial and overall. The PSQ-An was valid, feasible, and reliable. In general, no difference between treatment groups was observed for hemoglobin- and transfusion-based endpoints in each individual trial or in the combined analysis. From exploratory analyses, achievement and maintenance of a hemoglobin target range (11-13 g/dl) were similar in both groups. No differences in safety were observed. With the PSQ-An, formal comparisons of the impact of anemia therapies on patients and caregivers can be made in future prospective studies. Further, darbepoetin alfa (200 microg Q2W) and epoetin alfa (40,000 U QW) appear to achieve comparable clinical and hematologic outcomes.

Topics: Anemia; Antineoplastic Agents; Breast Neoplasms; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Female; Genital Neoplasms, Female; Hematinics; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Prospective Studies; Quality of Life; Recombinant Proteins; Reproducibility of Results; Surveys and Questionnaires

In a multinational trial of anaemic patients with cancer receiving nonplatinum-containing chemotherapy, epoetin-alfa effectively increased haemoglobin levels, reduced red blood cell transfusion requirements, and improved QOL. Although the study was not designed or powered to evaluate survival, a survival trend was noted favouring epoetin-alfa compared with placebo (median survival 17 vs 11 months [p = 0.126]).. To determine the incremental cost utility of epoetin-alfa versus placebo in anaemic patients with stage IV breast cancer from a UK National Health Service perspective.. Patient data regarding transfusions, epoetin-alfa usage, chemotherapy treatment cycles, and adverse events were recorded, with survival follow-up for 12-36 months post-study. Stage IV breast cancer therapy costs were collected by surveying UK oncologists, and utilities for associated health states were from published sources. Costs were in British pounds and year 2000 values. Costs and benefits were jointly determined for the stage IV breast cancer subgroup (n = 55). Incremental cost-utility ratios (ICURs) were calculated assuming a 6% annual discount rate for costs and a 1.5% annual discount rate for benefits. Bootstrap simulations (10,000 iterations) were conducted to account for uncertainty, and sensitivity analyses were conducted to establish robustness.. The ICUR for epoetin-alfa treatment was pounds 8,851 per QALY, with a 99% probability of a positive net benefit in QALYs (net benefit = 0.4805 years of perfect life) and a 94% probability of being acceptable using a threshold ICUR of pounds 30,000/QALY. The main cost drivers distinguishing epoetin-alfa from placebo were the costs of drug and patient care due to increased survival.. The available data suggest a high probability of favourable cost-utility outcomes with epoetin-alfa treatment for anaemia in patients with stage IV breast cancer receiving nonplatinum-containing chemotherapy. Additional studies are warranted.

Topics: Adult; Anemia; Antineoplastic Agents; Breast Neoplasms; Cost-Benefit Analysis; Double-Blind Method; Drug Administration Schedule; Endpoint Determination; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Injections, Subcutaneous; Neoplasm Staging; Quality of Life; Recombinant Proteins; Survival Analysis; Time Factors; Treatment Outcome

This study evaluated the effects of low-dose IL-2 plus G-CSF/EPO on post-PBSC transplantation (PBSCT) immune-hematopoietic reconstitution and NK activity in patients with breast (BrCa) and ovarian cancer (OvCa). To this end, two consecutive series of patients were prospectively assigned to distinct post-PBSCT cytokine regimens (from day +1 to day +12) which consisted of G-CSF (5 microg/kg/day) plus EPO (150 IU/kg/every other day) in 17 patients (13 BrCa and 4 OvCa) or G-CSF/EPO plus IL-2 (2 x 10(5) IU/m(2)/day) in 15 patients (10 BrCa and 5 OvCa). Hematopoietic recovery and post-transplantation clinical courses were comparable in G-CSF/EPO- and in G-CSF/EPO plus IL-2-treated patients, without significant side-effects attributable to IL-2 administration. In the early and late post-transplant period a significantly higher PMN count was observed in G-CSF/EPO plus IL-2-treated patients (P = 0.034 and P = 0.040 on day +20 and +100, respectively). No significant differences were found between the two groups of patients in the kinetics of most lymphocyte subsets except naive CD45RA(+) T cells which had a delayed recovery in G-CSF/EPO plus IL-2 patients (P = 0.021 on day +100). No significant difference was observed between NK activity in the two different groups, albeit a significantly higher NK count was observed in G-CSF/EPO plus IL-2 series on day +20 (P = 0.020). These results demonstrate that low-dose IL-2 can be safely administered in combination with G-CSF/EPO early after PBSCT and that it exerts favorable effects on post-PBSCT myeloid reconstitution, but not on immune recovery.

Topics: Adult; Breast Neoplasms; Drug Therapy, Combination; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Growth Substances; Hematopoiesis; Hematopoietic System; Humans; Immune System; Interleukin-2; Killer Cells, Natural; Middle Aged; Ovarian Neoplasms; Peripheral Blood Stem Cell Transplantation; Prospective Studies; Transplantation, Autologous

The objectives of this study were to assess the safety and efficacy of darbepoetin alfa (Aranesp) administered every 2 weeks in anemic patients with solid tumors receiving chemotherapy. This was an open-label, randomized, active-controlled, multicenter dose-finding study evaluating a range of every-2-week darbepoetin alfa doses. The active control arm received epoetin alfa (Epogen, Procrit) at 40,000 U weekly with a dose increase to 60,000 U weekly for subjects with an inadequate response. The lowest clinically effective doses of darbepoetin alfa in this study were 3.0 and 5.0 microg/kg every 2 weeks, with no additional benefit observed at higher doses. The percentage of patients who achieved a hematopoietic response in the 3.0- and 5.0-microg/kg groups was 66% (95% confidence interval [CI] = 46%-86%) and 84% (95% CI = 67%-100%), respectively, compared with 63% (95% CI = 46%-81%) in the epoetin alfa group. Darbepoetin alfa administered at a dose of 3.0 microg/kg every 2 weeks is safe and effective for treating anemia in patients with solid tumors on chemotherapy, and is comparable to epoetin alfa. A dose increase to 5.0 microg/kg of darbepoetin alfa administered every 2 weeks may be appropriate in patients with an inadequate initial response.

Topics: Anemia; Breast Neoplasms; Darbepoetin alfa; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Gastrointestinal Neoplasms; Genital Neoplasms, Female; Genital Neoplasms, Male; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Recombinant Proteins; Treatment Outcome

Several recently published studies describe moderate to severe cognitive dysfunction in breast cancer survivors who were treated with adjuvant chemotherapy 1-5 years before undergoing extensive neuropsychological testing. While these studies are hypothesis-generating and preliminary given their small size and retrospective nature, they consistently suggest that between approximately 15% and 25% of chemotherapy-treated breast cancer patients will have evidence of cognitive dysfunction some years after chemotherapy, compared to about 10% of breast cancer survivors who did not receive chemotherapy. Recent preclinical data strongly suggest that erythropoetin is a potent, endogenous neuroprotective agent that prevents neuronal apoptosis from a variety of insults including hypoxia, trauma, subarachnoidal hemorrhage, and encephalitis. Erythropoietin also appears to enhance learning in a mouse spatial learning maze model. We have conducted a pilot study of epoetin alfa versus placebo in early-stage breast cancer patients who received standard adjuvant anthracycline-based chemotherapy to determine the feasibility of administering standardized neurocognitive assessment tests in the oncology practice setting in order to understand whether the Executive Interview 25 test can detect the subtle cognitive impairment in verbal fluency, attention, and short-term memory observed with chemotherapy, and to assess whether epoetin alfa-treated patients have less evidence of cognitive dysfunction during and 6 months after chemotherapy compared with control-treated patients. We report here the preliminary results of this pilot clinical trial.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Asthenia; Breast Neoplasms; Chemotherapy, Adjuvant; Cognition Disorders; Controlled Clinical Trials as Topic; Disease Models, Animal; Epoetin Alfa; Erythropoietin; Female; Humans; Mastectomy; Mice; Mood Disorders; Patient Satisfaction; Pilot Projects; Prognosis; Quality of Life; Recombinant Proteins; Severity of Illness Index; Treatment Outcome

Erythropoietin is an effective treatment for anemia in patients with various types of cancers, but few studies have evaluated the benefit of treatment in advanced breast cancer. In this multicenter study, we investigated the influence of two different doses of epoetin-beta on the level of hemoglobin, the need for blood transfusion, quality of life and safety aspects in patients with metastatic breast cancer. A total of 180 patients were randomized to receive either 1000 IE or 5000 IE epoetin-beta subcutaneously three times per week for 24 weeks. An increase of 20 g/L was defined as a positive hemoglobin response. Blood transfusions were given, if clinically indicated. Additional laboratory values and adverse events were recorded. Quality of life was measured with the aid of the EORTC QLQ-C30 questionnaire. Hemoglobin levels increased significantly in both groups. In the high-dose group, the initial mean Hb value was 98 g/L (64-110), which increased to 121 g/L (83-165) by week 24. In the low-dose group, the mean Hb value was 99 g/L (77-110.5) and by week 24 it was 116 g/L (81-144). The majority of patients who responded to treatment did so during the first four weeks. After 4 weeks, 7 patients in the low-dose group and 24 patients in the high-dose group had increased their Hb values by more than 20 g/L. The need for transfusion was low and did not differ between the groups. Quality of life was significantly enhanced in both groups, and there was no difference in the global quality of life between the two study arms. Epoetin-beta is a well-tolerated, safe and effective treatment of anemia in patients with metastatic breast cancer. There were significant improvements in Hb levels and quality of life in both groups.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Blood Transfusion; Breast Neoplasms; Erythropoietin; Female; Hemoglobins; Humans; Middle Aged; Neoplasm Metastasis; Quality of Life; Recombinant Proteins

Peripheral blood progenitor cells (PBPC) can be mobilized by chemotherapy, cytokines, or the combination of both. Recently, data from two non-randomized studies were published, showing an advantage for a combination of rhG-CSF plus rhEpo compared to rhG-CSF alone in mobilization of PBPC. To address this question we initiated a prospective, randomized trial in patients with breast cancer. Thirty (28 female, two male) of 32 randomized patients were evaluable. After primary surgery, therapy consisted of two cycles of VIP-E chemotherapy followed by high-dose (HD) chemotherapy with VIC. Mobilization and harvest of PBPC followed cycle 2. Group A received 5 microg rhG-CSF/kg body weight (bw) plus 150 IU rhEpo/kg bw. Group B was treated with 5 microg rhG-CSF/kg bw from dl until end of harvest. In the peripheral blood CD34+ cells as well as colony-forming units (CFU) started to rise on d8 with a peak on d10, followed by a decrease. No significant differences were observed between the groups. Furthermore, there was no significant difference with regard to MNC, CD34+ cells BFU-E and CFU-GM in apheresis products. Transplantation of > 1 x 10(6) CD34+ cells/kg bw after HD chemotherapy resulted in normal hematological recovery of all patients. No differences were observed in time to neutrophil or platelet recovery and need for blood product support. In this study addition of rhEpo to our standard mobilization chemotherapy did not result in improved mobilization of PBPC or in clinical benefits after HD chemotherapy.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cisplatin; Cyclophosphamide; Epirubicin; Erythropoietin; Etoposide; Female; Fluorouracil; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Ifosfamide; Male; Methotrexate; Middle Aged; Prospective Studies; Recombinant Proteins; Transplantation Conditioning; Transplantation, Autologous

The role of erythropoietin (EPO) plus granulocyte-colony stimulating factor (G-CSF) combination in hemopoietic recovery was studied in patients with high-risk breast carcinoma and compared to a control group of previously treated identical patients who were not given EPO plus G-CSF. Eleven consecutive patients admitted to this study had Stage III or IV breast cancer. They received 6 cycles of intensive chemotherapy (epirubicin 150 mg/m2 and cyclophosphamide 1300 mg/m2). The 1st cycle served for mobilization of peripheral blood progenitor cells (PBPC). At its end leukaphereses collections of PBPC were performed to be used as hematologic support (PBPCT) in the 5 remaining cycles. The administration of EPO plus G-CSF was started when leukocyte (WBC) count in peripheral blood dropped below 1 x 10(9)/l and hemoglobin (Hb) level fell below 100 g/l. The treatment was stopped when leukocyte count rose to 5 x 10(9)/l and Hb to 130 g/l. EPO plus G-CSF combination after PBPCT produced significant effects in terms of hemopoietic recovery, clinical benefit and supportive care requirements when compared with 12 historic control patients: Periods of leukopenia were shorter which resulted in reduced risk of infectious complications. The grades of leukopenia in the study and control groups were as follows: grade 4 (36 vs. 18%), grade 3 (57 vs. 30%), grade 2 (7 vs. 13%) respectively. Significantly shorter was the time of PLT recovery < 50 x 10(9)/l (p < 0.001). The grades of thrombocytopenia were: grade 4 (29 vs. 11%), grade 3 (21 vs. 12%), grade 2 (25 vs. 36%) respectively. The number of necessary transfusions was significantly reduced as well as the length of hospital stay (p < 0.001). In conclusion, our results obtained in this study confirm that combination of EPO plus G-CSF not only increases the rate of hemopoietic recovery, reduces the number of necessary red blood cell and platelet transfusions but, at the same time, simplifies the clinical management and is more tolerable for the patients.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Breast Neoplasms; Cyclophosphamide; Drug Therapy, Combination; Epirubicin; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hematopoiesis; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Leukapheresis; Leukocyte Count; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Patient Selection; Recombinant Proteins

The cost of managing anemia with prophylactic epoetin alfa therapy versus blood transfusions in breast cancer patients receiving combination chemotherapy was studied. A retrospective study of anemia in breast cancer patients treated with four cycles of cyclophosphamide and doxorubicin with fluorouracil (CAF) or without fluorouracil (CA) was conducted. For each cycle of chemotherapy, patients were assessed for fatigue, subsequent blood transfusions administered, and potential response to and adverse effects of blood transfusions. Transfusions were given at the prescriber's discretion rather than in accordance with standard guidelines. The lowest hemoglobin concentration and hematocrit of each patient per cycle were reported. Data on these patients, along with data from published studies of prophylactic use of epoetin alfa, were used in a decision analysis of the costs associated with using epoetin alfa versus red blood cell transfusions to manage anemia. The charts of 50 patients were reviewed. In the study group, the percentage of patients with anemia and the frequency of fatigue rose with each chemotherapy cycle. In general, blood transfusions were not used. The cost of using epoetin alfa prophylactically for all four cycles was estimated at $6483 per patient for the literature-based group versus $169 for the study group. The cost of managing anemia in breast cancer patients was substantially lower when blood transfusions were used than when epoetin alfa was given prophylactically throughout four cycles of therapy with CAF or CA; the absence of standard guidelines for transfusion might have exaggerated the difference in costs.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Decision Trees; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Fatigue; Female; Hematinics; Humans; MEDLINE; Recombinant Proteins; Retrospective Studies

Serum erythropoietin (EPO), hematocrit and hemoglobin levels were determined in 17 female patients with stage II breast cancer before, during and at the conclusion of non-nephrotoxic chemotherapy. Serum EPO levels were determined using the ELISA technique. No irradiation was given to any patient. The hemoglobin and hematocrit levels remained stable. However, a statistically significant increase in EPO was noted (p<0.05). The possible factors involved in this increase are reviewed, however the exact mechanism remains to be elucidated.

Topics: Adenocarcinoma; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Fluorouracil; Hematocrit; Hemoglobins; Humans; Methotrexate; Neoplasm Staging; Prognosis; Sensitivity and Specificity

To evaluate the relationship between the hematocrit (HCT), serum erythropoietin (EPO) and insulin-like growth factor-1 (ILGF-1) levels in breast cancer patients receiving non-nephrotoxic chemotherapy.. Seventeen patients with stage II breast cancer were included. All received 6 cycles of non-nephrotoxic chemotherapy (cyclophosphamide, 5-fluorouracil and doxorubicin or methotrexate with or without tamoxifen). Insulin-like growth factor-1 and EPO levels were determined before and at the end of therapy. Serum EPO levels were determined by Enzyme linked- immunosorbant assay (ELISA) while those of ILGF- I by radioimmunoassay (RIA).. A significant drop in mean HCT from 37.41%+/-0.77% to 35.18%+/-0.70%, associated with a significant decline in ILGF-1 levels from 92.1+/-15.48 ng/ml to 52.75+/-10.5 ng/ml at the end of the treatment was noted. This association became significant when patients receiving tamoxifen were excluded (r=0.69, p=0.02). The mean serum EPO levels increased significantly from 13.64+/-0.55 U/l to 19.44+/-3.18 U/l and correlated negatively with ILGF-1 level (r=-0.46, p=0.05). There was no significant relation between the serum EPO levels and HCT (r=-0.26, p=0.32).. The current data show that ILGF-1 may play an important role in erythropoiesis and it correlates better than EPO with HCT in breast cancer patients receiving non-nephrotoxic chemotherapy.

Topics: Adenocarcinoma; Adult; Aged; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Confidence Intervals; Cyclophosphamide; Doxorubicin; Erythropoietin; Female; Fluorouracil; Hematocrit; Humans; Insulin-Like Growth Factor I; Methotrexate; Middle Aged; Neoplasm Staging; Prognosis; Sensitivity and Specificity

The present report describes the non-haematological toxicity and the influence of growth factor administration on haematological toxicity and haematopoietic recovery observed after high-dose carboplatin (1200 mg m(-2)), etoposide (900 mg m(-2)) and melphalan (100 mg m(-2)) (CEM) followed by peripheral blood progenitor cell transplantation (PBPCT) in 40 patients with high-risk cancer during their first-line treatment. PBPCs were collected during the previous outpatient induction chemotherapy programme by leukaphereses. CEM administration with PBPCT was associated with low non-haematological toxicity and the only significant toxicity consisted of a reversible grade III/IV increase in liver enzymes in 32% of the patients. Haematopoietic recovery was very fast in all patients and the administration of granulocyte colony-stimulating factor (G-CSF) plus erythropoietin (EPO) or granulocyte-macrophage colony-stimulating factor (GM-CSF) plus EPO after PBPCT significantly reduced haematological toxicity, abrogated antibiotic administration during neutropenia and significantly reduced hospital stay and patient's hospital charge compared with patients treated with PBPCT only. None of the patients died early of CEM plus PBPCT-related complications. Low non-haematological toxicity and accelerated haematopoietic recovery renders CEM with PBPC/growth factor support an acceptable therapeutic approach in an adjuvant or neoadjuvant setting.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carboplatin; Chemotherapy, Adjuvant; Erythropoietin; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Hematopoietic System; Humans; Length of Stay; Melphalan; Middle Aged; Neoplasm Staging; Ovarian Neoplasms; Recombinant Proteins; Survival Rate

Although erythropoietin (EPO) is known to be useful in treating chemotherapy-induced anemia, few data are available on its potential preventive role. The aim of this study was to evaluate the ability of EPO in preventing the development of clinically significant anemia in patients treated with chemotherapy.. Sixty-two early-stage breast cancer patients undergoing accelerated adjuvant chemotherapy were randomized to receive EPO 150 U/kg three times a week or no additional treatment. Chemotherapy consisted of six cycles of cyclophosphamide 600 mg/m2, epirubicin 60 mg/m2, and fluorouracil 600 mg/m2 (CEF) intravenously on day 1, every 2 weeks with the support of granulocyte colony-stimulating factor (G-CSF), 5 microg/kg subcutaneously from day 4 to day 11.. Throughout the six cycles of chemotherapy, EPO-treated patients maintained stable values of hemoglobin, whereas control patients developed a progressive anemia. At the end of chemotherapy, the mean (+/- SD) hemoglobin decrease in the control group was 3.05 g/dL (+/- 1.0; 95% confidence interval [CI], 2.6 to 3.5), whereas in the EPO group it was 0.8 (+/- 1.4; 95% CI, 0.3 to 1.4). Clinically significant anemia (hemoglobin < or = 10 g/dL) occurred in 16 patients (52%; 95% CI, 33 to 69) in the control arm and in no patient (0%; 95% CI, 0 to 14) in the EPO arm (P = .00001).. EPO prevents anemia in patients undergoing chemotherapy. Further trials are required to identify subsets of patients in which the preventive use of this drug could be cost-effective.

Topics: Adult; Aged; Anemia, Hypochromic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Administration Schedule; Erythropoietin; Female; Humans; Iron; Middle Aged; Treatment Outcome

Hematologic effects of granulocyte colony-stimulating factor (G-CSF) and erythropoietin (EPO) combination after printing intensive chemotherapy in the treatment of female breast carcinoma are presented. In a previous group treated with G-CSF alone, 36% of patients became anemic and had to be transfused for correction of their anemia. To the present study 11 consecutive patients with different stages of breast carcinoma were admitted. All were given priming intensive chemotherapy (epirubicin 150 mg/m2 and cyclophosphamide 1300 mg/m2 followed by subcutaneous application of G-CSF at a dose of 5 micrograms/kg/day and EPO 250 IU/kg/day. In cases where leucocyte counts dropped below 1 x 10(9)/l and hemoglobin levels fell to 85 g/l administration of growth factors was started. The therapy stopped when normal leucocyte count reached 4 x 10(9)/l for G-CSF and hemoglobin level rose to 115 g/l for EPO. Our results show significant difference between MNC/T1 (min.), CD34+ cells/microliters (min.), CFU-GM/ml (min.), BFU-E/ml (min.) and MNC/microliters (max.), CD34+ cells/microliters (max.), CFU-GM/ml (max.), BFU-E/ml (max.) p < 0.01, with mean peak values of 16.9-fold for circulating MNC/microliters, 7.8-fold for CD34+ cells/microliters 23.4-fold for CFU-GM/ml and 28.7-fold increase for BFU-E/ml. Side effects were minimal, no infectious complications occurred, body temperature did not rise over 38 degrees C and no corrections of anemia were needed. It is concluded that the administration of G-CSF plus EPO combination following intensive chemotherapy reduces hematologic toxicity and induces large amount of hemopoietic progenitors suitable for autologous transplantation in women with breast carcinoma.

Topics: Adult; Anemia; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cells; Hemoglobins; Humans; Middle Aged

In order to investigate the effects of erythropoietin (EPO) plus granulocyte colony-stimulating factor (G-CSF) administration after peripheral blood progenitor cell transplantation (PBPCT) we performed a phase I/II study in patients with high-risk cancer. 15 consecutive patients were treated wit recombinant human G-CSF (rhG-CSF) at the dose of 5 micrograms/kg subcutaneously (s.c.) every 24 h until day + 12 and with recombinant human EPO (rhEPO) at the dose of 150 IU/kg s.c. every 48 h until day + 11 following PBPCT. Their haemopoietic recovery was compared to that obtained in eight historic and control patients who did not receive any cytokines after PBPCT. No side-effects were observed during EPO plus G-CSF treatment and the treatment was not discontinued in any of the patients before completion of the treatment plan. The administration of EPO plus G-CSF after PBPCT produced a significant increase in the rate of white blood cell (WBC) (P = 0.0005), polymorphonuclear leucocyte (PMN) (P = 0.0005) and platelet (PLT) (P = 0.0105) recovery compared to the control group. The acceleration in haemopoietic recovery observed in the EPO plus G-CSF-treated patients produced a significant reduction of the days with WBC < 1 x 10(9)/l (P = 0.0009), PMN < 0.2 x 10(9)/l (P = 0.0030) and PMN < 0.5 x 10(9)/l (P = 0.0006). EPO plus G-CSF-treated patients required a significantly lower number of single donor PLT transfusions (P = 0.0142) and did not experience neutropenic fever, but historic control patients experienced fever > 38 degrees C for a median period of 4 d (0-12) with a medial period of parenteral antibiotic administration of 7.5 d (0-17). The length of the hospital stay was significantly shorter in the study group than in the historic control group (P = 0.0264). In conclusion, we can confirm that EPO plus G-CSF treatment is feasible and potentiates the haemopoietic recovery after PBPCT, thus simplifying the clinical management of cancer patients who undergo high-dose chemotherapy.

Topics: Adult; Breast Neoplasms; Combined Modality Therapy; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Middle Aged; Ovarian Neoplasms

Endogenous cytokines are thought to mediate numerous biologic processes and may account for some adverse effects experienced following the administration of recombinant proteins. This study describes the pattern of endogenous cytokine exposure following high-dose chemotherapy. Blood concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), macrophage colony-stimulating factor (M-CSF), and erythropoietin (EPO) were measured by enzyme-linked immunosorbent assay (ELISA) methods in 68 patients receiving the same ablative chemotherapy regimen (cyclophosphamide, cisplatin, carmustine). Patients were grouped according to cellular support (autologous bone marrow [BM] CSF-primed peripheral blood progenitor cells [PBPCs]) and prescribed growth factor (recombinant human granulocyte or granulocyte-macrophage colony-stimulating factor [rHuG-CSF or rHuGM-CSF]). Leukocyte reconstitution was most accelerated in the groups treated with PBPCs and rHuG-CSF. IL-6, M-CSF, and TNF-alpha concentrations were higher in the groups treated with rHuGM-CSF and without PBPCs. Maximal endogenous cytokine concentrations occurred approximately 12 days after BM reinfusion. High concentrations of EPO occurred in patients experiencing significant hypotension despite routine transfusions for hematocrit < 42%. High M-CSF and IL-6 levels were associated with increased platelet transfusion requirements. Concentrations of all four cytokines were significantly higher in patients experiencing renal or hepatic toxicity, with elevations occurring in a predictable sequence and M-CSF elevations occurring first. This report shows that endogenous cytokine concentrations may be influenced by either cellular or CSF support and are associated with differences in platelet reconstitution and organ toxicity.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Breast Neoplasms; Carmustine; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Cytokines; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-6; Kinetics; Macrophage Colony-Stimulating Factor; Melanoma; Neoplasm Staging; Recombinant Proteins; Transplantation, Autologous; Tumor Necrosis Factor-alpha

To determine the efficacy and safety of subcutaneous administration of recombinant human erythropoietin (r-HuEPO) at a dose of 200 units/kg/day to cancer patients undergoing radiotherapy.. This is a randomized, open-labeled, Phase II study. Only patients receiving radiotherapy +/- chemotherapy are included. Eligibility is restricted to patients with lung cancer, carcinoma of the uterine cervix, prostatic adenocarcinoma, or adenocarcinoma of the breast. Patients in the control and treatment arms receive radiotherapy with similar policies, and their doses of radiotherapy and treatment volumes are determined by the site and stage of the disease. Patients in the "treatment arm" receive 200 units/kg/day of r-HuEPO, subcutaneously, five times a week with iron (Fe SO4, 325 mg. p.o., t.i.d.) supplements. Complete blood counts are obtained weekly. Quality of life is assessed weekly by the patients themselves by a few simple entries on an analog scale.. Twenty-six patients have been entered in the study so far. Twelve patients were placed in the control arm and 14 in the treatment arm. Pre-randomization demographic and laboratory mean values in both arms were comparable, with none of 16 parameters compared reaching statistical significance. Our results can be summarized as follows: (a) Mean hemoglobin, hematocrit, and red blood cell values increased gradually in the treatment arm patients. Week-by-week comparison showed that mean values for these three parameters were significantly higher in the treatment arm than in the control arm. For example, the p values for the differences in hemoglobin mean values for weeks 1-6 were 0.015, 0.002, 0.003, 0.0002, 0.0006, and 0.007, respectively. Similar trends were observed for red blood cells and the hematocrit values. (b) No significant toxicity has been encountered. (c) No significant differences in the mean values of white blood cells and platelet counts were seen between the two arms. The values of these two parameters declined over the course of radiotherapy. (d) The mean weekly increase in hemoglobin levels in the treatment arm was 0.43 gm/dl.. (a) The safety and efficacy of r-HuEPO, with 200 units/kg/day of subcutaneous administration, have been confirmed in our study group. (b) However, the rate of increase in hemoglobin levels is not very rapid with the doses used. (c) Dose escalation studies are needed for determination of the feasibility of improving hemoglobin levels by about 1 gm/dl/week. (d) The question whether improvement in hemoglobin with r-HuEPO therapy can improve outcome by improving tumor oxygenation needs to be studied in carcinoma of the uterine cervix and squamous cell carcinoma of the head and neck.

Topics: Adenocarcinoma; Anemia; Breast Neoplasms; Combined Modality Therapy; Erythropoietin; Female; Humans; Injections, Subcutaneous; Lung Neoplasms; Male; Middle Aged; Prospective Studies; Prostatic Neoplasms; Recombinant Proteins

Cancer-related anemia (CRA) negatively influences cancer patients' survival, disease progression, treatment efficacy, and quality of life (QOL). Current treatments such as iron therapy, red cell transfusion, and erythropoietin-stimulating agents (ESAs) may cause severe adverse effects. Therefore, the development of long-lasting and curative therapies is urgently required.. In this study, a cell and gene therapy strategy was developed for in vivo delivery of EPO cDNA by way of genetic engineering of human Wharton's jelly mesenchymal stem cells (hWJMSCs) to produce and secrete human EPO protein for extended periods after transplantation into the mice model of CRA.. To evaluate CRA's treatment in cancer-free and cancerous conditions, first, a recombinant breast cancer cell line 4T1 which expressed herpes simplex virus type 1 thymidine kinase (HSV1-TK) by a lentiviral vector encoding HSV1-TK was developed and injected into mice. After three weeks, all mice developed metastatic breast cancer associated with acute anemia. Then, ganciclovir (GCV) was administered for ten days in half of the mice to clear cancer cells. Meanwhile, another lentiviral vector encoding EPO to transduce hWJMSCs was developed. Following implantation of rhWJMSCs-EPO in the second group of mice, peripheral blood samples were collected once a week for ten weeks from both groups.. Analysis of peripheral blood samples showed that plasma EPO, hemoglobin (Hb), and hematocrit (Hct) concentrations significantly increased and remained at therapeutic for >10 weeks in both treatment groups.. Data indicated that rhWJMSCs-EPO increased the circulating level of EPO, Hb, and Hct in both mouse subject groups and improved the anemia of cancer in both cancer-free and cancerous mice.

Topics: Anemia; Animals; Breast Neoplasms; Disease Models, Animal; DNA, Complementary; Erythropoietin; Female; Ganciclovir; Hemoglobins; Herpesvirus 1, Human; Humans; Iron; Mesenchymal Stem Cells; Mice; Quality of Life; Recombinant Proteins; Thymidine Kinase

Anemia of cancer (AoC) with its multifactorial etiology and complex pathology is a poor prognostic indicator for cancer patients. One of the main causes of AoC is cancer-associated inflammation that activates mechanisms, commonly observed in anemia of inflammation, whereby functional iron deficiency and iron-restricted erythropoiesis are induced by increased hepcidin levels in response to raised levels of interleukin-6. So far only a few AoC mouse models have been described, and most of them did not fully recapitulate the interplay of anemia, increased hepcidin levels and functional iron deficiency in human patients. To test if the selection and the complexity of AoC mouse models dictates the pathology or if AoC in mice per se develops independently of iron deficiency, we characterized AoC in Trp53floxWapCre mice that spontaneously develop breast cancer. These mice developed AoC associated with high levels of interleukin-6 and iron deficiency. However, hepcidin levels were not increased and hypoferremia coincided with anemia rather than causing it. Instead, an early shift in the commitment of common myeloid progenitors from the erythroid to the myeloid lineage resulted in increased myelopoiesis and in the excessive production of neutrophils that accumulate in necrotic tumor regions. This process could not be prevented by either iron or erythropoietin treatment. Trp53floxWapCre mice are the first mouse model in which erythropoietin-resistant anemia is described and may serve as a disease model to test therapeutic approaches for a subpopulation of human cancer patients with normal or corrected iron levels who do not respond to erythropoietin.

Topics: Anemia; Animals; Breast Neoplasms; Erythropoiesis; Erythropoietin; Female; Hepcidins; Humans; Inflammation; Interleukin-6; Iron; Iron Deficiencies; Mice

Early and adequate correction of the anemic syndrome (AS) of cancer patients can prevent deterioration in the quality of life and be considered as a reserve for increasing the effectiveness of treatment for breast cancer (BC). The aim of the study was to assess the status of iron using modern methods of ferrokinetics in breast cancer patients on the background of adjuvant chemotherapy for early diagnosis and adequate treatment of AS. The object of the study included 21 breast cancer patients with a relatively favorable prognosis, with luminal types A and B (Her 2 / neu positive or negative), three times negative type. The examination was carried out in the postoperative period, against the background of adjuvant chemotherapy. The main metabolites of ferrokinetics were studied: hepcidin 25 (GP25); ferritin (FR); soluble transferrin receptors (rRTP); transferin (TRF); iron (Fe); erythropoietin (EPO); CRP and IL-6 indicators. AC correction was performed (ferinject, epotin-alpha, B12). 10 (47.6%) patients with breast cancer had AS. Most of them were diagnosed with IDA with microcytic, hypochromic characteristics of erythrocytes, low concentration of FR, Fe, GP25, IL-6, CRP, and high levels of TRP and rRTP. Functional iron deficiency (FDF) was established in some patients. In contrast to patients with IDA, they had a high concentration of FR, CRP and significant production of GP25, IL-6. The EPO level was not optimal for the majority of patients with AS. In isolated cases, during treatment with recombinant erythropoietins, a deficiency of vitamin B12 (cyanocobalamin) was revealed. The rational use of iron preparations, vitamins, and recombinant forms of EPO made it possible to restore Fe metabolism, stabilize the hemoglobin level, and also improve the condition of most breast cancer patients. The obtained data on IL-6, GP25, CRP indicate a certain relationship between them in the development of anemia with VDF in breast cancer patients and the need for further study of the characteristics of iron metabolism in cancer patients.

Topics: Anemia; Anemia, Iron-Deficiency; Breast Neoplasms; Chemotherapy, Adjuvant; Erythropoietin; Female; Ferritins; Hemoglobins; Hepcidins; Humans; Interleukin-6; Iron; Quality of Life

Recombinant human erythropoietin (Epo) is an effective and convenient treatment for cancer-related anaemia. In our study for the first time, we evaluated the effect of simultaneous use of Epo and Bruton's tyrosine kinase (BTK) inhibitor LFM-A13 on the viability and tumour development of breast cancer cells. The results demonstrated that Epo significantly intensifies the anticancer activity of LFM-A13 in MCF-7 and MDA-MB-231. The featured therapeutic scheme efficiently blocked the tumour development in zebrafish experimental cancer model. Epo and LFM-A13 administered together resulted in effective cell killing, accompanied by attenuation of the BTK signalling pathways, loss of mitochondrial membrane potential (MMP), accumulation of apoptotic breast cancer cells with externalised PS, a slight increase in phase G0/G1 and a reduction in cyclin D1 expression. Simultaneous use of Epo with LFM-A13 inhibited early stages of tumour progression. This therapeutic scheme may be rationale for further possible research.

Topics: Adult; Aged; Aged, 80 and over; Amides; Antineoplastic Agents; Breast Neoplasms; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Erythropoietin; Female; Humans; Middle Aged; Molecular Structure; Nitriles; Structure-Activity Relationship; Tumor Cells, Cultured

Cancer is frequently associated with tumor-related anemia, and many chemotherapeutic agents impair hematopoiesis, leading to impaired quality of life for affected patients. The use of erythropoiesis-stimulating agents has come under scrutiny after prospective clinical trials using recombinant erythropoietin to correct anemia reported increased incidence of thromboembolic events and cancer-related deaths. Furthermore, previous preclinical reports indicated expansion of the pool of breast cancer-initiating cells when erythropoietin was combined with ionizing radiation.. Using four established breast cancer cell lines, we test the effects of recombinant human erythropoietin and the number of breast cancer-initiating cells in vitro and in vivo and study if recombinant human erythropoietin promotes the phenotype conversion of non-tumorigenic breast cancer cells into breast cancer-initiating cells. In a prospective study, we evaluate whether elevated endogenous serum erythropoietin levels correlate with increased numbers of tumor-initiating cells in a cohort of breast cancer patients who were scheduled to undergo radiation treatment.. Our results indicate that recombinant erythropoietin increased the number of tumor-initiating cells in established breast cancer lines in vitro. Irradiation of breast cancer xenografts caused a phenotype conversion of non-stem breast cancer cells into induced breast cancer-initiating cells. This effect coincided with re-expression of the pluripotency factors c-Myc, Sox2, and Oct4 and was enhanced by recombinant erythropoietin. Hemoglobin levels were inversely correlated with serum erythropoietin levels, and the latter were correlated with disease stage. However, tumor sections revealed a negative correlation between serum erythropoietin levels and the number of ALDH1A3-positive cells, a marker for breast cancer-initiating cells.. We conclude that physiologically slow-rising serum erythropoietin levels in response to tumor-related or chemotherapy-induced anemia, as opposed to large doses of recombinant erythropoietin, do not increase the pool of breast cancer-initiating cells.

Topics: Adult; Aged; Aged, 80 and over; Aldehyde Oxidoreductases; Anemia; Animals; Antineoplastic Agents; Breast; Breast Neoplasms; Cell Line, Tumor; Erythropoietin; Female; Hemoglobins; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Middle Aged; Neoplastic Stem Cells; Prospective Studies; Recombinant Proteins; Xenograft Model Antitumor Assays

A study of the clinical analysis of blood and major metabolites of ferrokinetics in 107 breast cancer patients before treatment was conducted. In 31 (28.9%) patients revealed anemic syndrome (AS). A feature of the AS is pronounced microcytosis, erythrocyte hypochromia and low hemoglobin content in reticulocytes. Most often (n = 22; 71%) there was iron deficiency (IDA), which was characterized by a low concentration of iron (F), ferritin (FR), hepcidin 25 (GP25), interleukin-6 (IL-6) and high - soluble transferrin receptors (rTFR), transferrin (TRF). In 9 (29%) patients with AS, on the basis of a high concentration of FR, GP25, IL-6, the anemia of chronic disease (AHZ) with functional iron deficiency (FDI) was established. In 23 (74.2%) patients with AS, the was a deficiency of erythropoietin (EPO), the lowest rates were found in the group of patients with a common tumor process and FDI, with less in patients with IDA.

Topics: Anemia; Anemia, Iron-Deficiency; Breast Neoplasms; Erythropoietin; Female; Ferritins; Hemoglobins; Hepcidins; Humans; Interleukin-6; Iron; Iron Deficiencies; Receptors, Transferrin; Transferrin

Breast cancer is a leading cause of cancer-related deaths. Anemia is common in breast cancer patients and can be treated with blood transfusions or with recombinant erythropoietin (EPO) to stimulate red blood cell production. Clinical studies have indicated decreased survival in some groups of cancer patients treated with EPO. Numerous tumor cells express the EPO receptor (EPOR), posing a risk that EPO treatment would enhance tumor growth, but the mechanisms involved in breast tumor progression are poorly understood.Here, we have examined the functional role of the EPO-EPOR axis in pre-clinical models of breast cancer. EPO induced the activation of PI3K/AKT and MAPK pathways in human breast cancer cell lines. EPOR knockdown abrogated human tumor cell growth, induced apoptosis through Bim, reduced invasiveness, and caused downregulation of MYC expression. EPO-induced MYC expression is mediated through the PI3K/AKT and MAPK pathways, and overexpression of MYC partially rescued loss of cell proliferation caused by EPOR downregulation. In a xenotransplantation model, designed to simulate recombinant EPO therapy in breast cancer patients, knockdown of EPOR markedly reduced tumor growth.Thus, our experiments in vitro and in vivo demonstrate that functional EPOR signaling is essential for the tumor-promoting effects of EPO and underline the importance of the EPO-EPOR axis in breast tumor progression.

Topics: Animals; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Disease Progression; Erythropoietin; Female; Heterografts; Humans; Mice; Mice, Nude; Receptors, Erythropoietin; Signal Transduction

The US Food and Drug Administration (FDA) has approved epoetin and darbepoetin for chemotherapy-induced anemia (CIA). Approved epoetin and darbepoetin dosing schedules were three times per week and weekly, respectively, although off-label, less frequent scheduling was common. In 2004, 2007, and 2008, a US Food and Drug Administration Advisory Committees warned of risks associated with erythropoiesis-stimulating agents. During this period, lawsuits alleging illegal darbepoetin marketing practices have concluded, resulting in $1.1 billion in fines and settlements and one criminal conviction. No prior study, to our knowledge, has reported on the use of darbepoetin versus epoetin for CIA.. We evaluated the dosing, utilization, and costs of erythropoiesis-stimulating agents among 3,761 South Carolina Medicaid patients with CIA.. Epoetin and darbepoetin utilization rates were 22% and 28% in 2003, 10% and 33% in 2007, and 3% and 7% in 2010, respectively. Mean per-patient per-administration epoetin and darbepoetin doses were 40,983 IU and 191 µg, respectively, in 2003 and 47,753 IU and 369 µg, respectively, in 2010. Mean monthly patient costs for epoetin and darbepoetin were $1,030 and $981, respectively, in 2003 and $932 and $1,352, respectively, in 2010. Epoetin use decreased steadily between 2002 and 2010; darbepoetin use increased steadily between 2003 and 2007 and then decreased steadily thereafter. Per-patient dosing of darbepoetin, but not epoetin, increased steadily between 2003 and 2010, and monthly per-patient epoetin costs decreased 3% while the per-patients costs of darbepoetin increased 30% between 2003 and 2010.. To our knowledge, our findings are the first data reporting on epoetin versus darbepoetin use for CIA and support recently concluded lawsuits involving allegations of illegal marketing practices of the manufacturer of darbepoetin.

Topics: Adolescent; Adult; Anemia; Antineoplastic Agents; Breast Neoplasms; Colorectal Neoplasms; Darbepoetin alfa; Drug Utilization; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Logistic Models; Lung Neoplasms; Male; Medicaid; Middle Aged; Recombinant Proteins; South Carolina; United States; Young Adult

We have previously reported hepcidin and ferritin increases in the plasma of breast cancer patients, but not in patients with benign breast disease. We hypothesized that these differences in systemic iron homeostasis may reflect alterations in different iron-related proteins also play a key biochemical and regulatory role in breast cancer. Thus, here we explored the expression of a bundle of molecules involved in both iron homeostasis and tumorigenesis in tissue samples. Enzyme-linked immunosorbent assay (ELISA) or reverse-phase protein array (RPPA), were used to measure the expression of 20 proteins linked to iron processes in 24 non-cancerous, and 56 cancerous, breast tumors. We found that cancerous tissues had higher level of hepcidin than benign lesions (p = 0.012). The univariate analysis of RPPA data highlighted the following seven proteins differentially expressed between non-cancerous and cancerous breast tissue: signal transducer and transcriptional activator 5 (STAT5), signal transducer and activator of transcription 3 (STAT3), bone morphogenetic protein 6 (BMP6), cluster of differentiation 74 (CD74), transferrin receptor (TFRC), inhibin alpha (INHA), and STAT5_pY694. These findings were confirmed for STAT5, STAT3, BMP6, CD74 and INHA when adjusting for age. The multivariate statistical analysis indicated an iron-related 10-protein panel effective in separating non-cancerous from cancerous lesions including STAT5, STAT5_pY694, myeloid differentiation factor 88 (MYD88), CD74, iron exporter ferroportin (FPN), high mobility group box 1 (HMGB1), STAT3_pS727, TFRC, ferritin heavy chain (FTH), and ferritin light chain (FTL). Our results showed an association between some iron-related proteins and the type of tumor tissue, which may provide insight in strategies for using iron chelators to treat breast cancer.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Blood Proteins; Breast Neoplasms; Diagnosis, Differential; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Ferritins; Hepcidins; Humans; Interleukin-6; Iron; Middle Aged; Protein Array Analysis; Proteins; Receptors, Transferrin; Young Adult

Anemia is associated with chemotherapy treatment in cancer patients. Erythropoietin (EPO) has been used to treat anemia of cancer patients, because it stimulates erythropoiesis. However, treatment of breast cancer patients with EPO has been associated with poor prognosis and decrease of survival. Epithelial to mesenchymal transition (EMT) is a process by which epithelial cells are transdifferentiated to a mesenchymal state. It has been implicated in tumor progression, because epithelial cells acquire the capacity to execute the multiple steps of invasion/metastasis process. However, the role of EPO on EMT process in human mammary epithelial cells has not been studied. In the present study, we demonstrate that EPO promotes a decrease of E-cadherin expression, an increase of N-cadherin, vimentin, and Snail2 expression, activation of FAK and Src kinases and an increase of MMP-2 and MMP-9 secretions. Moreover, EPO induces an increase of NFκB DNA binding activity, an increase of binding of p50 and p65 NFκB subunits to Snail1 promoter, migration, and invasion in mammary non-tumorigenic epithelial cells MCF10A. In summary, these findings demonstrate, for the first time, that EPO induces an EMT-like process in mammary non-tumorigenic epithelial cells. J. Cell. Biochem. 118: 2983-2992, 2017. © 2017 Wiley Periodicals, Inc.

Topics: Breast Neoplasms; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Erythropoietin; Female; Humans; Mammary Glands, Human; Neoplasm Proteins

Patients with cancer often exhibit signs of anemia as the result of the disease. Thus, cancer chemotherapies often include erythropoietin (EPO) in the regime to improve the survival rate of these patients. The aim of the present study was to determine the effect of EPO on doxorubicin-treated breast cancer cells. The cytotoxicity of doxorubicin alone or in combination with EPO against the MCF-7 and MDA-MB‑231 human breast cancer cells were determined using an MTT cell viability assay, neutral red (NR) uptake assay and lactate dehydrogenase (LDH) assay. The estimated half maximal inhibitory concentration values for doxorubicin and the combination of doxorubicin with EPO were between 0.140 and 0.260 µg/ml for all cells treated for 72 h. Treatment with doxorubicin in combination with EPO led to no notable difference in cytotoxicity, compared with treatment with doxorubicin alone. The antiproliferative effect of doxorubicin at a concentration of 1 µg/ml on the MDA‑MB‑231 cells was demonstrated by the decrease in viable cells from 3.6x10(5) at 24 h to 2.1x10(5) at 72 h of treatment. In order to confirm apoptosis in the doxorubicin-treated cells, the activities of caspases-3/7 and ‑9 were determined using a TBE assay. The results indicated that the activities of caspases-3/7 and ‑9 were significantly elevated in the doxorubicin-treated MDA-MB-231 cells by 571 and 645%, respectively, and in the MCF 7 cells by 471 and 345%, respectively, compared with the control cells. EPO did not modify the effect of doxorubicin on these cell lines. The results of the present study suggested that EPO was safe for use in combination with doxorubicin in the treatment of patients with breast cancer and concurrent anemia.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Proliferation; Cell Survival; Doxorubicin; Erythropoietin; Female; Humans; MCF-7 Cells; Recombinant Proteins

Topics: Anemia; Breast Neoplasms; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Neoplasms; Quality of Life; Recombinant Proteins; Standard of Care

This study aimed to explore the effects of recombinant human erythropoietin (rhEPO) on the growth of human breast cancer MDA-MB-231 cells in nude mice, and investigate its functions in regulating tumor growth, angiogenesis and apoptosis. A tumor-bearing nude mice model was established by subcutaneous injection of human breast cancer MDA-MB-231 cells. Two weeks later, the mice were randomly divided into four groups (n=6 for each group): negative control group, rhEPO group, EPO antibody group and EPO+EPO antibody group. Drugs were administered to the corresponding mice once every 3 days for five times. The size and weight of tumors were measured after the mice were sacrificed by cervical dislocation. The expression levels of EPO/EPOR, TNF-α, IL-10, and Bcl-2 in the tumor tissues were determined using RT-PCR and Western blot. The microvessel density (MVD) and expression of VEGF in the tumors were detected using immunohistochemistry. TUNEL assay was used to determine apoptosis in tumors. Results show that rhEPO significantly promoted the growth of MDA-MB-231 cells in nude mice (P<0.05). Compared with the negative control group, the expression levels of EPO, EPOR, TNF-α, IL-10, and VEGF, as well as the MVD values, were significantly elevated in the rhEPO group. However, the apoptotic index was significantly reduced (P<0.05). The ability of rhEPO to promote tumor growth may be associated with its functions in promoting microvessel formation and inhibiting tumor cell apoptosis.

Topics: Animals; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Disease Progression; Erythropoietin; Female; Humans; Mice, Inbred BALB C; Mice, Nude; Microvessels; Neovascularization, Pathologic; Recombinant Proteins; Vascular Endothelial Growth Factor A

While recombinant human erythropoietin (rhEpo) has been widely used to treat anemia in cancer patients, concerns about its adverse effects on patient survival have emerged. A lack of correlation between expression of the canonical EpoR and rhEpo's effects on cancer cells prompted us to consider the existence of an alternative Epo receptor. Here, we identified EphB4 as an Epo receptor that triggers downstream signaling via STAT3 and promotes rhEpo-induced tumor growth and progression. In human ovarian and breast cancer samples, expression of EphB4 rather than the canonical EpoR correlated with decreased disease-specific survival in rhEpo-treated patients. These results identify EphB4 as a critical mediator of erythropoietin-induced tumor progression and further provide clinically significant dimension to the biology of erythropoietin.

Topics: Adult; Aged; Aged, 80 and over; Animals; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Disease Progression; Erythropoietin; Female; Gene Expression Regulation, Neoplastic; Humans; Kaplan-Meier Estimate; MCF-7 Cells; Mice, Inbred C57BL; Mice, Nude; Middle Aged; Ovarian Neoplasms; Protein Binding; Receptor, EphB4; Receptors, Erythropoietin; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; STAT3 Transcription Factor; Young Adult

Hepcidin-25 production is stimulated by systemic inflammation, and it interferes with iron utilization, leading to anemia. This study aimed to investigate the relationships between the plasma levels of hepcidin, interleukin-6 (IL-6), erythropoietin (EPO) and erythroferrone (ERFE) in patients with benign breast disease or cancer.. Plasma samples from a cohort of 131 patients (47 with benign breast disease and 84 with breast cancer) were subjected to the evaluation of hepcidin, IL-6, EPO and ERFE using SELDI-TOF-MS or immunoassays.. An elevated hepcidin was observed in malignant breast tumors compared to benign ones. No correlation was observed between hepcidin and IL-6, EPO or ERFE.. Since the study included a cohort of patients (87%) with breast cancers smaller than 2 cm, these results may support our previous evidence about the potential role of hepcidin in breast cancer disease.

Topics: Adult; Aged; Aged, 80 and over; Breast Neoplasms; Case-Control Studies; Erythropoietin; Female; Hepcidins; Humans; Interleukin-6; Middle Aged; Peptide Hormones

Recent studies suggest that erythropoietin (EPO) has pleiotropic effects in several cell types in addition to hematopoietic cells; however, the role of EPO-mediated cell signaling in nonhematopoietic cells, including in cancer cells, remains controversial. Here, we report our findings of autocrine/paracrine production of EPO by breast cancer cells and its functional significance. We detected a significant level of autocrine/paracrine EPO in the conditioned medium from the culture of SKBR3 breast cancer cells, particularly when the cells were cultured in hypoxia. Through knockdown of EPO and EPO receptor expression and experimental elevation of EPO receptor expression in SKBR3 breast cancer cells, we demonstrated novel roles of autocrine/paracrine EPO-mediated cell signaling in regulating migration and invasion potential and stemness-like properties of breast cancer cells.

Topics: Autocrine Communication; Breast Neoplasms; Cell Hypoxia; Cell Line, Tumor; Cell Movement; Erythropoietin; Female; Humans; Neoplasm Invasiveness; Neoplastic Stem Cells; Paracrine Communication; Receptors, Erythropoietin; RNA, Small Interfering

Erythropoietin (EPO) is a hormone that induces red blood cell production. In its recombinant form, EPO is the one of most prescribed drugs to treat anemia, including that arising in cancer patients. In randomized trials, EPO administration to cancer patients has been associated with decreased survival. Here, we investigated the impact of EPO modulation on tumorigenesis. Using genetically engineered mouse models of breast cancer, we found that EPO promoted tumorigenesis by activating JAK/STAT signaling in breast tumor-initiating cells (TICs) and promoted TIC self renewal. We determined that EPO was induced by hypoxia in breast cancer cell lines, but not in human mammary epithelial cells. Additionally, we demonstrated that high levels of endogenous EPO gene expression correlated with shortened relapse-free survival and that pharmacologic JAK2 inhibition was synergistic with chemotherapy for tumor growth inhibition in vivo. These data define an active role for endogenous EPO in breast cancer progression and breast TIC self-renewal and reveal a potential application of EPO pathway inhibition in breast cancer therapy.

Topics: Animals; Breast Neoplasms; Carcinogenesis; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Disease Progression; Disease-Free Survival; Endothelial Cells; Erythropoietin; Female; Gene Expression Regulation; Humans; Hypoxia; Mammary Neoplasms, Experimental; Mice; Neoplasm Transplantation; Neoplastic Stem Cells; Recurrence; Signal Transduction; Tetrazolium Salts; Thiazoles; Time Factors

The main function of Erythropoietin (EPO) and its receptor (EPOR) is the stimulation of erythropoiesis. Recombinant human EPO (rhEPO) is therefore used to treat anemia in cancer patients. However, clinical trials have indicated that rhEPO treatment might promote tumor progression and has a negative effect on patient survival. In addition, EPOR expression has been detected in several cancer forms. Using a newly produced anti-EPOR antibody that reliably detects the full-length isoform of the EPOR we show that breast cancer tissue and cells express the EPOR protein. rhEPO stimulation of cultured EPOR expressing breast cancer cells did not result in increased proliferation, overt activation of EPOR (receptor phosphorylation) or a consistent activation of canonical EPOR signaling pathway mediators such as JAK2, STAT3, STAT5, or AKT. However, EPOR knockdown experiments suggested functional EPO receptors in estrogen receptor positive (ERα(+)) breast cancer cells, as reduced EPOR expression resulted in decreased proliferation. This effect on proliferation was not seen in ERα negative cells. EPOR knockdown decreased ERα activity further supports a mechanism by which EPOR affects proliferation via ERα-mediated mechanisms. We show that EPOR protein is expressed in breast cancer cells, where it appears to promote proliferation by an EPO-independent mechanism in ERα expressing breast cancer cells.

Topics: Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Erythropoietin; Estrogen Receptor alpha; Female; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Microscopy, Confocal; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptors, Erythropoietin; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Erythropoietin; Female; Hematinics; Hemoglobins; Humans

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Erythropoietin; Female; Hematinics; Hemoglobins; Humans

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Recombinant Proteins

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Recombinant Proteins

Recombinant erythropoietin (EPO) analogs [erythropoiesis-stimulating agents (ESA)] are clinically used to treat anemia in patients with cancer receiving chemotherapy. After clinical trials reporting increased adverse events and/or reduced survival in ESA-treated patients, concerns have been raised about the potential role of ESAs in promoting tumor progression, possibly through tumor cell stimulation. However, evidence is lacking on the ability of EPO to directly affect cancer stem-like cells, which are thought to be responsible for tumor progression and relapse. We found that breast cancer stem-like cells (BCSC) isolated from patient tumors express the EPO receptor and respond to EPO treatment with increased proliferation and self-renewal. Importantly, EPO stimulation increased BCSC resistance to chemotherapeutic agents and activated cellular pathways responsible for survival and drug resistance. Specifically, the Akt and ERK pathways were activated in BCSC at early time points following EPO treatment, whereas Bcl-xL levels increased at later times. In vivo, EPO administration counteracted the effects of chemotherapeutic agents on BCSC-derived orthotopic tumor xenografts and promoted metastatic progression both in the presence and in the absence of chemotherapy treatment. Altogether, these results indicate that EPO acts directly on BCSC by activating specific survival pathways, resulting in BCSC protection from chemotherapy and enhanced tumor progression.

Topics: Anemia; Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Breast Neoplasms; Cell Movement; Cell Proliferation; Disease Progression; Erythropoietin; Female; Flow Cytometry; Fluorescent Antibody Technique; Humans; Immunoenzyme Techniques; Mice; Mice, Inbred NOD; Mice, SCID; Neoplastic Stem Cells; Signal Transduction; Tumor Cells, Cultured

The microRNA 125b is a double-faced gene expression regulator described both as a tumor suppressor gene (in solid tumors) and an oncogene (in hematologic malignancies). In human breast cancer, it is one of the most down-regulated miRNAs and is able to modulate ERBB2/3 expression. Here, we investigated its targets in breast cancer cell lines after miRNA-mimic transfection. We examined the interactions of the validated targets with ERBB2 oncogene and the correlation of miR-125b expression with clinical variables.. MiR-125b possible targets were identified after transfecting a miRNA-mimic in MCF7 cell line and analyzing gene expression modifications with Agilent microarrays and Sylamer bioinformatic tool. Erythropoietin (EPO) and its receptor (EPOR) were validated as targets of miR-125b by luciferase assay and their expression was assessed by RT-qPCR in 42 breast cancers and 13 normal samples. The molecular talk between EPOR and ERBB2 transcripts, through miR-125b, was explored transfecting MDA-MD-453 and MDA-MB-157 with ERBB2 RNA and using RT-qPCR.. We identified a panel of genes down-regulated after miR-125b transfection and putative targets of miR-125b. Among them, we validated erythropoietin (EPO) and its receptor (EPOR) - frequently overexpressed in breast cancer--as true targets of miR-125b. Moreover, we explored possible correlations with clinical variables and we found a down-regulation of miR-125b in metastatic breast cancers and a significant positive correlation between EPOR and ERBB2/HER2 levels, that are both targets of miR-125b and function as competing endogenous RNAs (ceRNAs).. Taken together our results show a mechanism for EPO/EPOR and ERBB2 co-regulation in breast cancer and confirm the importance of miR-125b in controlling clinically-relevant cancer features.

Topics: 3' Untranslated Regions; Binding Sites; Breast Neoplasms; Erythropoietin; Female; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; HEK293 Cells; Humans; MCF-7 Cells; MicroRNAs; Molecular Sequence Annotation; Neoplasm Metastasis; Receptor, ErbB-2; Receptors, Erythropoietin; RNA Interference

Tumor anemia is very common in patients with cancer. The causes are very diverse and the parameter value depends on several factors. If this however develops to be symptomatic it may adversely impact health related quality of life. Erythropoietin or blood transfusion provides options for treatment. However, these are not always uneventful. There could also be a lack of response to Erythropoietin. This case report describes the complexity of tumor anemia. It also includes a more detailed discussion on the Fatigue Syndrome, which is one of the most common symptoms of patients with cancer. In the context of palliative care there is often the question of alternatives for improving the quality of patients life. Some kinds of treatment may also cause the opposite effect. A multidimensional assessment should help to approach this difficult issue and to find ways for a meaningful treatment of the symptoms of anemia.

Topics: Adenocarcinoma; Aged; Anemia; Bone Neoplasms; Breast Neoplasms; Combined Modality Therapy; Darbepoetin alfa; Disease Progression; Erythrocyte Transfusion; Erythropoietin; Fatigue; Female; Hematinics; Humans; Medical Futility; Neoplasm Staging; Palliative Care; Quality of Life; Treatment Failure; Treatment Outcome

The CHOICE study was a prospective, multicentre, observational study designed to assess levels of adherence in current clinical practice to the European product label and EORTC guidelines for the treatment of chemotherapy-induced anaemia (CIA) with darbepoetin alfa (DA). Here we present data split by tumour types: breast, colorectal, ovarian and lung.. Haemoglobin (Hb) levels and red blood cell transfusion requirements were evaluated among patients with solid tumours in 11 European countries. The primary outcome measure was the proportion of patients with a target Hb level of ≥10-≤12 g/dL.. The full analysis set included 1887 patients (mean ± SD 62.4 ± 11.4 years); 1585 (84%) had a current disease stage of ≥3. Common chemotherapy regimens were non-platinum + non-taxane based (n = 696 [37%]) or platinum + non-taxane based (n = 660 [35%]). Breast cancer (n = 575): The mean ± SD Hb level at baseline was 9.9 ± 0.8 g/dL (n = 568). Target Hb level was reached by 187 (55%) patients. Colorectal cancer (n = 310): At baseline the mean ± SD Hb level was 9.8 ± 0.8 g/dL (n = 306). Target Hb level was reached by 107 patients (56%). Ovarian cancer (n = 301): The mean ± SD Hb level at baseline was 9.7 ± 0.8 g/dL (n = 294). Target Hb level was reached by 81 patients (44%). Lung cancer (n = 701): At baseline the mean ± SD Hb level was 9.8 ± 0.9 g/dL (n = 692). Target Hb level was reached by 142 patients (39%).. Five severe or life-threatening adverse drug reactions were seen (three patients with breast cancer, one patient with colorectal cancer and one patient with ovarian cancer).. Potential bias could not be excluded due to the study's observational nature.. This study demonstrates that the recommendations are adhered to in clinical practice, with the mean starting Hb level <10 g/dL irrespective of tumour type. Furthermore, DA is likely to be effective and well tolerated for the treatment of CIA in patients with breast, colorectal, ovarian or lung cancer.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Breast Neoplasms; Colorectal Neoplasms; Darbepoetin alfa; Erythropoietin; Europe; Female; Hematinics; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Ovarian Neoplasms; Prospective Studies

The CHOICE study was a prospective, multicentre, observational study designed to assess the level of adherence in current clinical practice to the European product label and the EORTC guidelines for the treatment of chemotherapy-induced anaemia with darbepoetin alfa (DA).. Hb levels and red blood cell (RBC) transfusion requirements were evaluated among 1900 patients with solid tumours in 11 European countries. The primary outcome measure was the proportion of patients with a target Hb level of ≥10-≤12 g/dL after 9 weeks' DA treatment.. The full analysis set (FAS) comprised 1887 patients (mean ± SD age 62.4 ± 11.4 years) divided into categories by baseline Hb < 9 g/dL (n = 281); 9-<10 g/dL (n = 770); 10-<11 g/dL (n = 695); ≥11 g/dL (n = 114). The proportion of patients who remained on the study at week 9 achieving the target Hb level was 37% (n = 60), 48% (n = 217), 54% (n = 210) and 38% (n = 23) in the subgroups with a baseline Hb level of <9 g/dL, 9-<10 g/dL, 10-<11 g/dL and ≥11 g/dL, respectively. In the <9 g/dL, 9-<10 g/dL, 10-<11 g/dL and ≥11 g/dL subgroups of the FAS, the number of patients maintaining Hb levels ≥10 g/dL after their first achievement of an Hb value of 10 g/dL was 95 (34%), 372 (48%), 476 (68%) and 87 (76%), respectively. The Kaplan-Meier percentages of patients who required an RBC transfusion from week 5 until end of treatment period were: 29%, 20%, 12% and 17% in the <9 g/dL, 9-<10 g/dL, 10-<11 g/dL and ≥11 g/dL subgroups, respectively. Kaplan-Meier percentages of patients reaching an Hb level of >13 g/dL were 10%, 9%, 21% and 29%, respectively. Potential bias could not be excluded due to the study's observational nature.. DA initiation and target Hb ranges adhered to current guidelines in the majority of patients. Furthermore, this study demonstrates faster achievement of the target range and reduced transfusion requirements are associated with initiation of DA at Hb levels of 9-<10 g/dL and 10-<11 g/dL rather than <9 g/dL.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Breast Neoplasms; Colorectal Neoplasms; Darbepoetin alfa; Erythropoietin; Europe; Female; Guideline Adherence; Hematinics; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasms; Ovarian Neoplasms; Practice Guidelines as Topic; Prospective Studies

Recent data suggest that erythropoietin (EPO) plays a substantial role in cancer development and clinical outcome by stimulating cell proliferation, invasion and angiogenesis. A functional polymorphism (rs1617640 G>T) in the promoter region of the EPO gene increases EPO protein expression. In the present study, we investigated the association of EPO rs1617640 G>T with susceptibility and clinical outcome of early-stage breast cancer. Genomic DNA of 539 female patients with histologically confirmed early-stage breast cancer and 804 controls was genotyped for EPO rs1617640 G>T. No association was found between EPO rs1617640 G>T and early-stage breast cancer susceptibility and clinical outcome (hazard ratio=1.24, 95% confidence interval=1.82-1.90, p=0.31). In conclusion, our findings suggest a lack of influence of EPO rs1617640 G>T on early-stage breast carcinogenesis and clinical outcome.

Topics: Breast Neoplasms; Cell Transformation, Neoplastic; Erythropoietin; Female; Genetic Predisposition to Disease; Humans; Polymorphism, Genetic; Promoter Regions, Genetic; Treatment Outcome

Resistance to trastuzumab is a major issue in the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Several potential resistance mechanisms have been investigated, but the results are controversial and no conclusion has been reached. Erythropoietin receptor (EPOR) may function in cell growth, and expressed in various cancer cells. Because the downstream signaling pathways for EPOR and HER2 partially overlapped, we hypothesized that EPOR may play a role in the inhibition effect of trastuzumab and resistance to trastuzumab. Here, we detected the expression of EPOR mRNA and protein in HER2-positive breast cancer cell lines and tissues. EPOR expressed in SKBR3, MDA-MB-453, and UACC-812 cell lines, but not in BT474. Of the 55 HER2-positive cancer tissues, EPOR was positive in 42 samples and highly expressed (H-score ≥ 25) in 24 by immunohistochemistry. The difference between EPOR expression and Ki67 index was significant (P = 0.033), and EPOR expression also positively correlated with higher pathological stage (Spearman correlation coefficient = 0.359; P = 0.007). Exogenous EPO antagonized trastuzumab-induced inhibition of cell proliferation in HER2/EPOR dual-positive breast cancer cells. We then exposed SKBR3 cells to trastuzumab for 4 months to obtain trastuzumab-resistant SKBR3 cell line, which demonstrated higher phosphorylated EPOR level, higher EPO expression and more extracellular secretion than non-resistant parental SKBR3 cells. Downregulation EPOR expression using short hairpin RNA resensitized trastuzumab-resistant cells to this drug, and SKBR3 cells with EPOR downregulation demonstrated attenuated trastuzumab resistance after the same resistance induction. EPOR downregulation plus trastuzumab produced a synergetic action in the inhibition of cell proliferation and invasion in SKBR3 and MDA-MB-453 cell lines. Therefore, EPOR expression may be involved in tumor progression and proliferation in HER2-positive breast cancer. EPO/EPOR contributes to the mechanism of trastuzumab resistance in SKBR3 cell lines, and EPOR downregulation can reverse the resistance to trastuzumab and increase the inhibition effect of this drug.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Base Sequence; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Drug Resistance, Neoplasm; Erythropoietin; Female; Gene Expression Regulation, Neoplastic; Humans; Middle Aged; Molecular Sequence Data; Receptor, ErbB-2; Receptors, Erythropoietin; RNA, Small Interfering; Trastuzumab; Tumor Cells, Cultured

Erythropoietin (EPO) was shown to reduce tumor survival in recent trials, however, its mechanisms of action are unclear. Efforts to measure tumor EPO receptor (EPOR) are limited by the promiscuity of EPOR antibodies, and concerns as to whether EPOR mRNA measurements are confounded by heterogeneity of tumor vasculature, a known EPOR source.. This study compared mRNA levels of EPOR and JAK2 in 11 breast tumor epithelial versus endothelial dissections.. In nine tumors EPOR mRNA was 2.6 (1.2-5.7)-fold lower in the epithelial fraction, however, this reduction was less than the reduction of endothelial markers. In two tumors, EPOR mRNA was 2.9 (1.7-4.0)-fold higher in the epithelial fraction. The inter-tumor variation in EPOR levels exceeded the intra-tumor variation between fractions. Similar results were obtained for JAK2.. Tumor vasculature is not the sole source of EPOR and JAK2, and tumors can be segregated by EPOR and JAK2 levels for correlative analysis with clinical outcomes.

Topics: Adenocarcinoma, Mucinous; Adult; Aged; Aged, 80 and over; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Lobular; Endothelium, Vascular; Epithelial Cells; Erythropoietin; Female; Humans; Janus Kinase 2; Lasers; Microdissection; Middle Aged; Receptors, Erythropoietin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stromal Cells

The authors evaluated the patterns of use and the risk of thromboembolic events (TEE) associated with erythropoietin-stimulating agents (ESAs) in older patients with metastatic breast cancer who were receiving chemotherapy.. The study was retrospective and used the SEER-Medicare linked database. Stage IV breast cancer patients diagnosed from 1995-2005, treated with chemotherapy, ≥66 years old, with full coverage of Medicare A and B were included. The World Health Organization's International Classification of Diseases (ICD-9) and the Healthcare Common Procedure Coding System (HCPCS) were used to identify the use of ESAs, chemotherapy, and complications of therapy. Analyses included descriptive statistics and logistic regression.. Of 2266 women, 980 (43.3%) received ESAs, and 1286 (56.7%) did not. Patients diagnosed after 1999 or who received treatment with taxanes, anthracyclines, or vinorelbine were more likely to receive ESAs. Patients receiving ESAs had higher rates of stroke (18.5% vs 15.1%, P = .031); deep-vein thrombosis (DVT; 21.3% vs 14.4%, P<.001), other/unspecified thromboembolic event (TEE; 19.8% vs 14.7%, P = .001), and any clot (31.3% vs 23.4%, P<.0001). In multivariate analysis, patients receiving ESAs had increased risk for DVT (odds ratio [OR], 1.36; 95% confidence interval [CI], 1.05-1.75), and any clot (OR, 1.26; 95% CI, 1.02-1.57). A dose-dependent effect was evident for stroke, DVT, other TEE, and any clot.. In this cohort of patients, the use of ESAs increased the risk of TEEs, with a dose-dependent effect for stroke, DVT, other TEE, and any clot. The data show that among patients treated with chemotherapy and ESAs for metastatic breast cancer, TEEs are a common event. Therefore, caution is recommended when using these agents.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Erythropoietin; Female; Humans; Medicare; Neoplasm Metastasis; Retrospective Studies; SEER Program; Stroke; Thrombosis; United States; Venous Thrombosis

Erythropoiesis-stimulating agents (ESA) are used clinically for treating cancer-related anemia. Recent clinical trials have reported increased adverse events and reduced survival in ESA-treated breast cancer patients receiving chemotherapy, potentially related to erythropoietin (EPO)-induced cancer progression. However, minimal preclinical data are available about the impact of EPO on metastatic cell behavior and/or the metastatic process, and this was the goal of our study.. Breast cancer cell lines were treated with recombinant human EPO (rHuEPO) and screened for expression of EPO receptors (EPOR). MDA-MB-231 and MDA-MB-435 cell lines were used for functional assays in vitro (two-dimensional/three-dimensional growth and survival) and in vivo (tumorigenicity and metastasis), in the presence or absence of EPO and/or cytotoxic agents.. A large variation in EPOR expression across cell lines was observed. In vitro, rHuEPO had a protective effect on radiation-treated MDA-MB-435 cells (P < 0.05); however, rHuEPO treatment alone or combined with chemotherapy or hypoxia did not influence cell survival. In vivo, rHuEPO increased lung metastases in immunocompromised mice injected with MDA-MB-231 or MDA-MB-435 cells and treated with chemotherapy relative to mice treated with chemotherapy alone (P < 0.05).. The lack of an in vitro effect of rHuEPO highlights the importance of in vivo studies to delineate the effects of EPO on the metastatic process. These studies may begin to uncover the underlying functional explanation for the observed EPO-related adverse events and decreased survival in ESA-treated metastatic breast cancer patients undergoing chemotherapy.

Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Drug Evaluation, Preclinical; Erythropoietin; Female; Humans; Mammary Neoplasms, Experimental; Mice; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; Recombinant Proteins

Membrane-initiated androgen actions have now been acknowledged, even though a specific binding site has not been biochemically characterized yet. Recent data indicate that testosterone-BSA, a non-permeable testosterone analog, can exert specific actions in breast cancer cell lines, including proper transcriptional effects, independent of the intracellular androgen sites. In the present work we explore the effects of testosterone-BSA in two specifically modified pathways, revealed by early trascriptome analysis, namely the non-genotropic androgen signaling and the HIF1alpha pathway. We provide evidence that p38 MAPK and PI3K/Akt/NFkappaB and/or Rho/Actin pathways are directly involved in testosterone-induced apoptosis, while the JNK/c-JUN pathway is involved in membrane site-initiated transcription. Furthermore we show that membrane-acting androgens modify the transcription of the erythropoietin receptor (EPOR), leading to erythropoietin-initiated actions. Interestingly, association of recombinant human erythropoietin (rHuEPO) together with testosterone-BSA protects cells from apoptosis, through discrete signaling events. The effect of testosterone-BSA is exerted through the classical erythropoietin promoter, while rHuEPO decreases the transcription of EPOR acting on a newly identified regulatory/promoter region, upstream of its known promoter. These results suggest a new interaction of membrane-acting androgen with EPOR and should be taken into account in the pharmaceutical manipulations of breast cancer patients.

Topics: Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Membrane; Erythropoietin; Female; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Promoter Regions, Genetic; Receptors, Erythropoietin; Recombinant Proteins; Signal Transduction; Testosterone

Erythropoietin (Epo), the major regulator of erythropoiesis, and its cognate receptor (EpoR) are also expressed in nonerythroid tissues, including tumors. Clinical studies have highlighted the potential adverse effects of erythropoiesis-stimulating agents when used to treat cancer-related anemia. We assessed the ability of EpoR to enhance tumor growth and invasiveness following Epo stimulation. A benign noninvasive rat mammary cell line, Rama 37, was used as a model system. Cell signaling and malignant cell behavior were compared between parental Rama 37 cells, which express few or no endogenous EpoRs, and a modified cell line stably transfected with human EpoR (Rama 37-28). The incubation of Rama 37-28 cells with pharmacologic levels of Epo led to the rapid and sustained increases in phosphorylation of signal transducers and activators of transcription 5, Akt, and extracellular signal-regulated kinase. The activation of these signaling pathways significantly increased invasion, migration, adhesion, and colony formation. The Epo-induced invasion capacity of Rama 37-28 cells was reduced by the small interfering RNA-mediated knockdown of EpoR mRNA levels and by inhibitors of the phosphoinositide 3-kinase/Akt and Ras/extracellular signal-regulated kinase signaling pathways with adhesion also reduced by Janus-activated kinase 2/signal transducers and activators of transcription 5 inhibition. These data show that Epo induces phenotypic changes in the behavior of breast cancer cell lines and establishes links between individual cell signaling pathways and the potential for cancer spread.

Topics: Animals; Breast Neoplasms; Carcinoma; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Enzyme Inhibitors; Erythropoietin; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Janus Kinase 2; Neoplasm Invasiveness; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; ras Proteins; Rats; Receptors, Erythropoietin; RNA Interference; Signal Transduction; STAT5 Transcription Factor; Transcriptional Activation; Up-Regulation

Adverse outcomes in breast cancer patients treated with recombinant human erythropoietin (rhEpo) have been linked to the expression of Epo-receptors (EpoR) in cancer cells, although limited data on the clinical significance of these observations are available.. Tissue samples from 107 patients with breast cancer who did not receive rhEpo and from 12 patients with benign lesions were retrospectively analysed for EpoR expression by RT-PCR and Western blot, and the results were correlated to clinical and demographic data.. While EpoR levels were not linked to anaemia or inflammation, they were positively associated with progesterone and oestrogen receptor status. Patients with increased EpoR-mRNA expression had a higher local cancer recurrence rate (p=0.021), however, no significant difference in overall survival was observed.. Since EpoR expression is associated with hormone receptor positivity and decreased locoregional disease control, this parameter characterises a specific cancer phenotype rather than being a negative predictor itself.

Topics: Adult; Aged; Aged, 80 and over; Blotting, Western; Breast Neoplasms; Erythropoietin; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Neoplasm Staging; Prognosis; Receptors, Erythropoietin; Receptors, Estrogen; Receptors, Progesterone; Recombinant Proteins; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction

We found that the receptor for erythropoietin (EpoR) is coexpressed with human epidermal growth factor receptor-2 (HER2) in a significant percentage of human breast tumor specimens and breast cancer cell lines. Exposure of HER2 and EpoR dual-positive breast cancer cells to recombinant human erythropoietin (rHuEPO) activated cell signaling. Concurrent treatment of the cells with rHuEPO and trastuzumab reduced the cells' response to trastuzumab both in vitro and in vivo. We identified Jak2-mediated activation of Src and inactivation of PTEN as underlying mechanisms through which rHuEPO antagonizes trastuzumab-induced therapeutic effects. Furthermore, we found that compared with administration of trastuzumab alone, concurrent administration of rHuEPO and trastuzumab correlated with shorter progression-free and overall survival in patients with HER2-positive metastatic breast cancer.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Antagonism; Drug Resistance, Neoplasm; Enzyme Activation; Erythropoietin; Female; Humans; Janus Kinase 2; Mice; Proto-Oncogene Proteins pp60(c-src); PTEN Phosphohydrolase; Receptor, ErbB-2; Receptors, Erythropoietin; Recombinant Proteins; Signal Transduction; Transplantation, Heterologous; Trastuzumab

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Cyclophosphamide; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Epirubicin; Erythropoietin; Female; Humans; Mastectomy; Multicenter Studies as Topic; Neoplasm Staging; Paclitaxel; Randomized Controlled Trials as Topic; Recombinant Proteins; Survival Analysis

Cognitive dysfunction is a potential side effect of chemotherapy, and erythropoietin might be protective. A previously reported study compared quality-of-life in women undergoing chemotherapy for breast cancer who were randomized to receive epoetin-alpha or standard care. Here, we report a non-randomized sub-study in which cognitive function of participants was evaluated at 12-30 months after chemotherapy.. The primary endpoint was the proportion of women with moderate-severe cognitive impairment, as measured by the High Sensitivity Cognitive Screen (HSCS). Subjects also completed the Revised Hopkins Verbal Learning Test (HVLT-R), the Functional Assessment of Cancer Therapy--Fatigue (FACT-F) and FACT-G self-report questionnaires for fatigue and quality-of-life, and the Hospital Anxiety and Depression Scale.. Of 278 patients receiving adjuvant treatment in the primary study, 87 participated in the sub-study: 45 had received epoetin-alpha and 42 standard care. Groups were well matched for age and type of chemotherapy. Eight patients (9%) had moderate-severe cognitive dysfunction by the HSCS: six of them in the epoietin-alpha group (not significant). There were no significant differences in the HVLT-R, or in fatigue, but patients who had received epoetin-alpha reported better quality-of-life.. This study failed to demonstrate a protective effect of epoetin-alpha against the development of delayed cognitive dysfunction after chemotherapy.

Topics: Antineoplastic Agents; Breast Neoplasms; Case-Control Studies; Cognition Disorders; Epoetin Alfa; Erythropoietin; Fatigue; Female; Hematinics; Humans; Matched-Pair Analysis; Middle Aged; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins

Despite the prevalence of anemia in cancer, recombinant erythropoietin (Epo) has declined in use because of recent Phase III trials showing more rapid cancer progression and reduced survival in subjects randomized to Epo. Since Epo receptor (EpoR), Jak2, and Hsp70 are well-characterized mediators of Epo signaling in erythroid cells, we hypothesized that Epo might be especially harmful in patients whose tumors express high levels of these effectors. Because of the insensitivity of immunohistochemistry for detecting low level EpoR protein, we developed assays to measure levels of EpoR, Jak2 and Hsp70 mRNA in formalin-fixed paraffin-embedded (FFPE) tumors. We tested 23 archival breast tumors as well as 136 archival head and neck cancers from ENHANCE, a Phase III trial of 351 patients randomized to Epo versus placebo concomitant with radiotherapy following complete resection, partial resection, or no resection of tumor. EpoR, Jak2, and Hsp70 mRNA levels varied >30-fold, >12-fold, and >13-fold across the breast cancers, and >30-fold, >40-fold, and >30-fold across the head and neck cancers, respectively. Locoregional progression-free survival (LPFS) did not differ among patients whose head and neck cancers expressed above- versus below-median levels of EpoR, Jak2 or Hsp70, except in the subgroup of patients with unresected tumors (n = 28), where above-median EpoR, above-median Jak2, and below-median Hsp70 mRNA levels were all associated with significantly poorer LPFS. Our results provide a framework for exploring the relationship between Epo, cancer progression, and survival using archival tumors from other Phase III clinical trials.

Topics: Breast Neoplasms; Cell Line, Tumor; Clinical Trials, Phase III as Topic; Disease-Free Survival; Erythropoietin; Female; Flow Cytometry; Head and Neck Neoplasms; HSP70 Heat-Shock Proteins; Humans; Immunohistochemistry; Janus Kinase 2; Phosphorylation; Receptors, Erythropoietin; Reverse Transcriptase Polymerase Chain Reaction; STAT5 Transcription Factor

The main function of erythropoietin (EPO) is to stimulate erythropoiesis. EPO receptors (EPOR) are expressed in other cell types, including tumor cells, suggesting that the EPO/EPOR pathway governs additional cellular processes besides erythropoiesis. Recombinant EPO (rhEPO) is frequently given to anemic cancer patients, although data on clinical outcome are conflicting. In an attempt to understand these clinical data, we analyzed EPO and EPOR expression in breast cancer and evaluated EPOR as a putative prognostic and predictive marker in breast cancer patients treated with tamoxifen.. EPO mRNA/protein and EPOR mRNA were quantified by PCR and ELISA, respectively. Tissue microarrays containing 500 breast tumors from premenopausal women randomized to tamoxifen or no adjuvant treatment were evaluated for EPOR expression by immunohistochemistry. Predictive and prognostic information was evaluated using Kaplan-Meier curves and log-rank tests to estimate recurrence-free survival (RFS).. EPO and EPOR were expressed in cultured cells, and breast tumor specimens expressed EPOR at varying levels. Tamoxifen treatment significantly increased RFS in patients with estrogen receptor-positive/progesterone receptor-positive (ER(+)/PR(+)) tumors with low EPOR expression (P = 0.001) but had no effect on RFS in patients with tumors with high EPOR expression (P = 0.98). In the untreated cohort, RFS was significantly improved for patients with ER(+) tumors with high EPOR expression.. EPOR is abundantly expressed in breast cancer specimens. The fact that high expression of EPOR is related to an impaired tamoxifen response in ER(+)/PR(+) tumors and to improved survival in untreated patients suggests that EPOR expression in breast cancer affects tumor behavior.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Breast Neoplasms; Cell Line, Tumor; Erythropoietin; Female; Humans; Kaplan-Meier Estimate; Prognosis; Receptors, Erythropoietin; RNA, Messenger; Tamoxifen; Tissue Array Analysis

Erythropoiesis-stimulating agents (erythropoietin and darbepoietin) have been approved to reduce the number of blood transfusions required during chemotherapy; however, concerns about the risks of venous thromboembolism and mortality exist.. We identified patients who were aged 65 years or older in the Surveillance, Epidemiology, and End Results-Medicare database; who were diagnosed with colon, non-small cell lung, or breast cancer or with diffuse large B-cell lymphoma from January 1, 1991, through December 31, 2002; and who received chemotherapy. The main outcome measures were claims for use of an erythropoiesis-stimulating agent, blood transfusion, venous thromboembolism (ie, deep vein thrombosis or pulmonary embolism), and overall survival. We used multivariable logistic regression models to analyze the association of erythropoiesis-stimulating agent use with clinical and demographic variables. We used time-dependent Cox proportional hazards models to analyze the association of time to receipt of first erythropoiesis-stimulating agent with venous thromboembolism and overall survival. All statistical tests were two-sided.. Among 56,210 patients treated with chemotherapy from 1991 through 2002, 15,346 (27%) received an erythropoiesis-stimulating agent. The proportion of patients receiving erythropoiesis-stimulating agents increased from 4.8% in 1991 to 45.9% in 2002 (P < .001). Use was associated with more recent diagnosis, younger age, urban residence, comorbidities, receipt of radiation therapy, female sex, and metastatic or recurrent cancer. The rate of blood transfusion per year during 1991-2002 remained constant at 22%. Venous thromboembolism developed in 1796 (14.3%) of the 12,522 patients who received erythropoiesis-stimulating agent and 3400 (9.8%) of the 34,820 patients who did not (hazard ratio = 1.93, 95% confidence interval = 1.79 to 2.07). Overall survival was similar in both groups.. Use of erythropoiesis-stimulating agent increased rapidly after its approval in 1991, but the blood transfusion rate did not change. Use of erythropoiesis-stimulating agents was associated with an increased risk of venous thromboembolism but not of mortality.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Anemia; Antineoplastic Agents; Blood Transfusion; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Colonic Neoplasms; Confounding Factors, Epidemiologic; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Humans; Lung Neoplasms; Lymphoma, Large B-Cell, Diffuse; Male; Medical Record Linkage; Medicare; Neoplasms; Practice Patterns, Physicians'; Recombinant Proteins; Retrospective Studies; Risk Factors; SEER Program; United States; Venous Thromboembolism

STAT3 contributes to increase of EPO expression which is also HIF-1 dependent. EPO receptor activates STAT3. Expressions of STAT3 and hypoxia induced proteins: HIF-1, EPO and EPOR show mutual correlations in primary ductal breast cancers, which suggest co-operation among these proteins. Moreover, EPO-EPOR signaling was reported to mediate cell survival by targeting Bcl-xL in competition with Bax-dependent apoptosis. Our present study was focused on immunohistochemical evaluation of STAT3, HIF-1alpha, EPO and EPOR in relation to apoptosis regulators, Bax and Bcl-xL in 39 metastases of ductal breast cancers to lymph nodes. The proteins were abundantly expressed by cancer cells. HIF-1alpha correlated with EPOR in all and in chemotherapy treated metastases (r=0.428, p=0.007 and r=0.462, p=0.040, respectively). HIF-1 associated significantly with EPO in chemotherapy spared metastases (r=0.549, p=0.015) and comparison between those proteins almost reached statistical significance in entire number of metastatic breast cancers (r=0.309, p=0.056). Metastases from T2 primary tumors had significantly higher expressions of HIF-1alpha, EPO and EPOR compared to T1 originating metastases (p=0.020, p=0.028, p=0.021, respectively). Bax correlated with EPO and EPOR in all studied nodal metastases (r=0.449, p=0.006 and r=0.421, p=0.011, respectively) and so did Bcl-xL with HIF-1alpha (r=0.440, p=0.007), EPO and EPOR (r=0.383, p=0.021, r=0.495, p=0.002, respectively). Metastatic breast cancers seem to be areas of intensive signaling by STAT3, HIF-1, EPO and EPOR. Strong Bax and Bcl-xL labeling reflects accelerated cell turnover in nodal metastases. By means of association with Bcl-xL, HIF-1alpha, EPO and EPOR could favor growth of nodal metastases and survival of breast cancers cells.

Topics: bcl-2-Associated X Protein; bcl-X Protein; Breast Neoplasms; Carcinoma, Ductal, Breast; Erythropoietin; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Lymphatic Metastasis; Receptors, Erythropoietin; STAT3 Transcription Factor

The expression of erythropoietin (Epo) and the Epo receptor (EpoR) has been detected in healthy tissue as well as in a variety of human cancers, including breast. Functional Epo/EpoR signaling in cancer cells, which contributes to disease initiation/progression, is not completely straightforward and is difficult to reconcile with the clinical practice of preventing/treating anemia in cancer patients with recombinant Epo. Preclinical and clinical investigations have provided contrasting results, ranging from a beneficial role that improves the patient's overall survival to a negative impact that promotes tumor growth progression. A careful gathering of Epo/EpoR biomolecular information enabled us to assemble an unexpected jigsaw puzzle which, via distinct JAK-dependent and JAK-independent mechanisms and different internalization/recycling as well as ubiquitination/degradation pathways, could explain most of the controversies of preclinical and clinical studies. However, until the mechanisms of the contrasting literature data are resolved, this new point of view may shed light on the Epo/EpoR paracrine/autocrine system and function, providing a basis for further studies in order to achieve the highest possible benefit for cancer patients.

Topics: Anemia; Autocrine Communication; Breast Neoplasms; Clinical Trials as Topic; Erythropoietin; Female; Hematinics; Humans; Janus Kinase 2; Paracrine Communication; Receptors, Erythropoietin; Recombinant Proteins; Signal Transduction

Fatigue is a common complication of adjuvant chemotherapy and compromises the quality of life of breast cancer survivors. We sought to correlate serial hemoglobin (Hb) levels with fatigue in a population of women on adjuvant chemotherapy, none of whom received erythropoietin-stimulating agents or red blood cell transfusions.. Seventy-five women participated in a study using quality-of-life questionnaires to assess changes in need for psychosocial support over time. Questionnaires were administered within 30 days of initiating adjuvant therapy and at 2, 6, and 12 months. Fatigue was assessed by the 36-Item Short-Form Health Survey (SF-36). Hemoglobin levels at each time point were captured retrospectively. Complete data are included for 40 of the 46 women who received adjuvant chemotherapy. Paired-samples t tests were conducted to compare mean SF-36 Energy/Fatigue scores between time points, and independent-samples t tests were conducted for comparisons against norms. Simple correlations (Pearson R) were conducted between SF-36 variables and Hb levels at each time point.. At 2 months, 23.4% of women had Hb<11 g/dL compared with 12.9% at 12 months. Compared with norms for women in the general population and breast cancer survivors, these women reported worse fatigue at baseline and at 2 and 6 months. A strong linear relationship was observed between Hb at 2 months and SF-36 Energy/Fatigue scores at 12 months (r=0.71; P=.002).. Participants with high fatigue at 12 months had Hb levels at 2 months 13% lower than those with low fatigue. This finding suggests that chemotherapy-induced decline in Hb might be a marker of physiologic reserve.

Topics: Adult; Aged; Antineoplastic Agents; Breast Neoplasms; Chemotherapy, Adjuvant; Erythropoietin; Fatigue; Female; Hemoglobins; Humans; Middle Aged; Quality of Life; Recombinant Proteins; Surveys and Questionnaires

Erythropoietin (Epo) is an important regulator of erythropoiesis, and controls proliferation and differentiation of both erythroid and non-erythroid tissues. Epo is actively synthesized by breast cells during lactation, and also plays a role in breast tissues promoting hypoxia-induced cancer initiation. Our aims are to perform an exploratory investigation on the Epo accumulation in breast secretions from healthy and cancer patients and its localization in breast cancer cells.. Epo was determined by ELISA, immunoprecipitation, western blot and immunocytochemical analyses in 130 Nipple Aspirate Fluids (NAF) from 102 NoCancer and 28 Breast Cancer (BC) patients, comparing results with those found in 10 milk, 45 serum samples and breast cancer cell lines.. Epo levels in NAFs were significantly higher than those in milk and serum. No difference in Epo electrophoretic mobility was found among NAF, milk and serum samples, and conditioned cell culture medium. Immunolocalization of intracellular Epo in ductal cells floating in BC NAFs was similar to those of cancer cell lines. No significant correlation between TNM classification and Epo in NAFs from BC patients was found. Significantly higher Epo concentration was found in NAF from BC patients compared to NoCancer.. We demonstrate that breast epithelial cells are a source of Epo in breast microenvironment, suggesting the presence of a paracrine/autocrine Epo function in NAFs, triggering off intracellular signaling cascade with subsequent BC initiation.

Topics: Adult; Aged; Blotting, Western; Breast; Breast Neoplasms; Cell Line, Tumor; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Erythropoietin; Female; Humans; Immunoprecipitation; Microscopy, Immunoelectron; Middle Aged; Milk, Human; Nipples

Porphyrias are rare diseases, and for these patients every administration of drugs may induce an acute attack of porphyria. The list of safe compounds allowed in these patients is available for clinicians from specific websites cited in the text.. However, data concerning anticancer therapy in patients with such diseases remain poor. Therefore any publications can help clinicians to deal with this very specific group of patients.. In our institution, three patients received docetaxel and hematologic growth factors (erythropoietin and GCSF) without unexpected toxicities. Aromatase inhibitors (anstrozole and letrozole) were also given in one patient without any related problem.. The present observation adds some useful data for the possible treatment of cancer in patients with porphyria.

Topics: Anastrozole; Antineoplastic Agents; Aromatase Inhibitors; Breast Neoplasms; Docetaxel; Epoetin Alfa; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hematinics; Humans; Letrozole; Middle Aged; Nitriles; Porphyria, Acute Intermittent; Porphyria, Variegate; Recombinant Proteins; Risk Assessment; Taxoids; Triazoles; Uterine Neoplasms

Topics: Breast Neoplasms; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Recombinant Proteins; Survival Rate

Topics: Breast Neoplasms; Clinical Trials as Topic; Delivery of Health Care; Erythropoietin; Health Policy; Humans; National Health Programs; Organizational Objectives; Recombinant Proteins; United States

To assess recent developments in the use of transfusions.. Data from hospital-based sources were condensed in a single spread sheet covering 1611 transfusions of a total of 881 patients together with data on 25,264 treatment sessions in 6137 patients within a time period between 1 August 2001 and 31 July 2004.. Our audit showed an increase in transfusions of 25% in 3 years. This was accompanied by an increased threshold for transfusions, as shown by a significant rise in mean haemoglobin trigger levels from 8.53 to 8.86 g/dl (P<0.001) as well as an increase in treatment sessions and patient numbers - especially for chemotherapy or combinations of chemotherapy and radiotherapy. The highest transfusion rates and also the greatest increments occurred in patients with carcinoma of the ovary, lung and pancreas. Within these groups, treatment regimens as well as treatment lines were additional predictive factors.. This audit gives a detailed view on rising trends in transfusion requirements and, in light of anticipated restrictions on resources, it identifies high-risk areas, where the use of alternatives, such as erythropoietin, could be considered.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Breast Neoplasms; Cost-Benefit Analysis; Database Management Systems; England; Erythropoietin; Female; Health Services Needs and Demand; Hemoglobins; Hospitals, University; Humans; Lung Neoplasms; Male; Medical Audit; Medical Oncology; Ovarian Neoplasms; Pancreatic Neoplasms; Radiation Oncology; Utilization Review

STAT3 upregulates expression of HIF-1 induced EPO. Receptor EPOR was reported to activate STAT3. Our study was aimed at demonstration of tissue immunoreactivities of those proteins and determination of their relationships in reference to clinicopathological variables of breast cancers. We detected STAT3, HIF-1alpha, EPO and EPOR in specimens of 76 human, female, ductal breast cancers by immunohistochemistry. STAT3 was detected in 38 of 76 cancers (50%). HIF-1alpha was found in 55 cases (72%). EPO positive tumors comprised 89% of all the cancers (68 cases). EPOR was also visualized in 55 cases (72%). Anti-HIF-1alpha and anti-STAT3 stained nuclei and cytoplasm of breast cancer cells in diffuse and finely granular fashion. Strong membranous expressions of EPO and EPOR were distributed in cytoplasmic and membranous granularity or diffuse staining. STAT3 correlated with HIF-1 in general (r=0.4012, p<0.0001) and in different patients' subgroups. STAT3 was significantly associated with EPO and EPOR in all the cancers (r=0.2370, p=0.039 and r=0.3336, p=0.003, respectively). Besides a correlation between STAT3 and EPOR in node negative ones, STAT3 wasn't related to EPO and EPOR in remaining subgroups. HIF-1alpha correlated with EPO and EPOR in most of analyzed groups. Immunoreactivity to EPO generally was associated with EPOR (r=0.3520, p=0.002). Statistically analyzed distributions of the proteins reflected functional dependences among STAT3, HIF-1alpha, EPO and EPOR in cellular signal conduction.

Topics: Breast Neoplasms; Carcinoma, Ductal, Breast; Erythropoietin; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Receptors, Erythropoietin; Signal Transduction; STAT3 Transcription Factor

Autocrine/paracrine erythropoietin (EPO) action, promoting cell survival and mediated by its receptor (EPOR) in various solid tumors, including breast carcinoma, questions about the prognostic and therapeutic interest of this system. The expression of EPO/EPOR is steroid dependent in some tissues; however, a clear relationship of EPO/EPOR and steroid receptors in breast cancer has not been established thus far. Recently, the field of steroid receptors has expanded, including rapid effects mediated by membrane-associated receptors, regulating cell survival or apoptosis. The aim of this study was to evaluate EPO/EPOR and membrane-associated steroid receptor expression in breast carcinoma, in view of their prognostic significance, compared with other established markers [estrogen receptor (ER)-progesterone receptor (PR) status and Her2 expression] and hypoxia-induced factor 1 nuclear localization in 61 breast cancer specimens followed for

Topics: Adult; Aged; Breast; Breast Neoplasms; Cell Nucleus; Cell Transformation, Neoplastic; Disease-Free Survival; Erythropoietin; Female; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Microscopy, Fluorescence; Middle Aged; Mitochondrial Proteins; Neoplasm Proteins; Prognosis; Receptor, ErbB-2; Receptors, Androgen; Receptors, Erythropoietin; Receptors, Estrogen; Receptors, Progesterone; Statistics as Topic

Although a significant negative prognostic factor, tumor hypoxia can be exploited for gene therapy. To maximize targeting within the tumor mass, we have developed synthetic gene promoters containing hypoxia-responsive elements (HREs) from the erythropoietin (Epo) gene as well as radiation-responsive CArG elements from the early growth response (Egr) 1 gene. Furthermore, to achieve high and sustained expression of the suicide gene herpes simplex virus thymidine kinase (HSVtk), our gene therapy vectors contain an expression amplification system, or 'molecular switch', based on Cre/loxP recombination. In human glioma and breast adenocarcinoma cells exposed to hypoxia and/or radiation, the HRE/CArG promoter rapidly activated Cre recombinase expression leading to selective and sustained HSVtk synthesis. Killing of transfected tumor cells was measured after incubation with the prodrug ganciclovir (GCV; converted by HSVtk into a cytotoxin). In vitro, higher and more selective GCV-mediated toxicity was achieved with the switch vectors, when compared with the same inducible promoters driving HSVtk expression directly. In tumor xenografts implanted in nude mice, the HRE/CArG-switch induced significant growth delay and tumor eradication. In conclusion, hypoxia- and radiation-activated 'molecular switch' vectors represent a promising strategy for both targeted and effective gene therapy of solid tumors.

Topics: Adenocarcinoma; Adenoviridae; Animals; Antiviral Agents; Brain Neoplasms; Breast Neoplasms; Cell Death; Cell Hypoxia; Combined Modality Therapy; Early Growth Response Protein 1; Erythropoietin; Ganciclovir; Gene Expression Regulation, Neoplastic; Genes, Switch; Genes, Transgenic, Suicide; Genetic Engineering; Genetic Therapy; Genetic Vectors; Glioma; Humans; Mice; Mice, Nude; Neoplasms; Oncolytic Virotherapy; Promoter Regions, Genetic; Simplexvirus; Thymidine Kinase; Tumor Cells, Cultured

We investigated the significance of erythropoietin receptor (EPOR) expression following treatment with recombinant human erythropoietin (rHuEPO; epoetin alpha) and the effect of recombinant epoetins (epoetin alpha, epoetin beta, and darbepoetin alpha) alone or in combination with anticancer therapy on tumor growth in two well-established preclinical models of breast carcinoma (MDA-MB-231 and MCF-7 cell lines). Expression and localization of EPOR under hypoxic and normoxic conditions in MDA-MB-231 and MCF-7 cells were evaluated by immunoblotting, flow cytometry, and immunohistochemistry. EPOR binding was evaluated using [125I]rHuEPO. Proliferation, migration, and signaling in MDA-MB-231 and MCF-7 cells following treatment with rHuEPO were evaluated. Tumor growth was assessed following administration of recombinant epoetins alone and in combination with paclitaxel (anticancer therapy) in orthotopically implanted MDA-MB-231 and MCF-7 breast carcinoma xenograft models in athymic mice. EPOR expression was detected in both tumor cell lines. EPOR localization was found to be exclusively cytosolic and no specific [125I]rHuEPO binding was observed. There was no stimulated migration, proliferation, or activation of mitogen-activated protein kinase and AKT following rHuEPO treatment. In mice, treatment with recombinant epoetins alone and in combination with paclitaxel resulted in equivalent tumor burdens compared with vehicle-treated controls. Results from our study suggest that although EPOR expression was observed in two well-established breast carcinoma cell lines, it was localized to a cytosolic distribution and did not transduce a signaling cascade in tumors that leads to tumor growth. The addition of recombinant epoetins to paclitaxel did not affect the outcome of paclitaxel therapy in breast carcinoma xenograft models. These results show that recombinant epoetins do not evoke a physiologic response on EPOR-bearing tumor cells as assessed by numerous variables, including growth, migration, and cytotoxic challenge in preclinical in vivo tumor models.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma; Cell Hypoxia; Cell Movement; Cell Proliferation; Erythropoietin; Female; Humans; Mice; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Paclitaxel; Proto-Oncogene Proteins c-akt; Receptors, Erythropoietin; Recombinant Proteins; Xenograft Model Antitumor Assays

Evidence for erythropoietin signaling has been shown in several nonhematopoietic tissues, including many tumor types. Clinically, recombinant erythropoietin treatment of malignancy-related anemia has yet to be definitively associated with any modulation of chemotherapy or radiotherapy efficacy. Preclinically, recombinant erythropoietin has been shown to increase tumor oxygenation, but the direct effects of recombinant erythropoietin on tumor cells that express erythropoietin receptor are not yet fully characterized. This study examined the effects of exogenous recombinant erythropoietin on rodent mammary adenocarcinoma cells (R3230) in vitro and in vivo, and determined the effects of systemic recombinant erythropoietin on tumor growth delay in Taxol treatment. We showed that systemic recombinant erythropoietin treatment of rats bearing R3230 mammary carcinomas induced an increase in phospho-Akt levels within tumor cells. This was associated with a decrease in the frequency of apoptotic cells in tumors from recombinant erythropoietin-treated animals, but did not noticeably affect tumor growth rate. In vitro studies revealed that not only does recombinant erythropoietin induce Akt phosphorylation, but it also stimulates phosphorylation of p44/42 mitogen-activated protein kinases, Erk1 and Erk2. Activation of erythropoietin-mediated signaling in R3230 cells was associated with dose-dependent inhibition of apoptosis in response to Taxol treatment and serum starvation, an effect that was blocked by the addition of a phosphatidylinositol-3-kinase inhibitor. Despite its cytoprotective effects in vitro, recombinant erythropoietin did not significantly affect tumor growth delay in Taxol treatment. This study shows direct recombinant erythropoietin-mediated activation of specific intracellular signaling pathways in mammary adenocarcinoma cells in vivo and in vitro. Modulation of tumor apoptosis pathways by recombinant erythropoietin may have negative consequences by decreasing the chemosensitivity and radiosensitivity of erythropoietin receptor-positive breast tumors, although it did not have any obvious effects on growth with or without chemotherapy in this model.

Topics: Adenocarcinoma; Animals; Apoptosis; Breast Neoplasms; Drug Resistance, Neoplasm; Erythropoietin; Extracellular Signal-Regulated MAP Kinases; Female; Paclitaxel; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Receptors, Erythropoietin; Recombinant Proteins; Tumor Cells, Cultured

Erythropoietin (EPO) therapy is widely used for the prevention and treatment of anemia resulting from cancer chemotherapy. Native EPO regulates erythropoiesis, at least in part, by protecting erythroid progenitor cells from apoptotic cell death. The recent discovery of the EPO receptor (EPOR) on cancer cells raises the concern that EPO therapy might stimulate tumor growth and/or protect cancer cells from drug-induced apoptosis. Therefore, the capacity of EPO to interfere with the effects of conventional chemotherapeutic drugs on proliferation, apoptosis, and the induction of senescence was investigated in MCF-7 and MDA-MB231 breast tumor cells, which express the EPOR as well as in F-MEL erythroleukemia cells.. Breast cancer cells and F-MEL leukemic cells were cultured in the presence or absence of EPO and then exposed to antitumor drugs. Cell proliferation was assessed by a standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye reduction assay 72 hours after drug exposure. Cytotoxicity was monitored by clonogenic survival. Apoptosis was evaluated either by the terminal deoxyribonucleotide transferase-mediated nick-end labeling assay or fluorescence-activated cell sorting analysis, and senescence was monitored by beta-galactosidase staining. EPO signaling was assessed by monitoring the phosphorylation/activation of specific signaling proteins.. EPO failed to stimulate the proliferation of MCF-7 or MDA-MB231 breast tumor cells or F-MEL leukemic cells. EPO treatment also failed to interfere with the antiproliferative and/or cytotoxic effects of Adriamycin, Taxol, and tamoxifen in breast tumor cells (or of cytarabine and daunorubicin in F-MEL cells). EPO failed to prevent apoptosis induced by Taxol or senescence induced by Adriamycin in MCF-7 cells. EPO stimulated the activation of extracellular signal-regulated kinase, p38, and c-Jun-NH(2)-kinase in MCF-7 cells but did not activate Akt or signal transducers and activators of transcription 5 (STAT5). EPO failed to activate any of these signaling pathways in MDA-MB231 cells. Cytarabine and daunorubicin interfered with EPO signaling in F-MEL cells.. These findings suggest that EPO is unlikely to directly counteract the effectiveness of cancer chemotherapeutic drugs. This may be a consequence of either ineffective signaling through the EPOR or drug-mediated suppression of EPO signaling.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Doxorubicin; Drug Antagonism; Drug Screening Assays, Antitumor; Erythropoietin; Humans; Leukemia, Erythroblastic, Acute; Paclitaxel; Signal Transduction; Structure-Activity Relationship; Tamoxifen; Tumor Cells, Cultured

Treating anemia associated with chemotherapy and many cancers is often necessary. However, patient satisfaction with anemia treatment is limited by the lack of validated instruments. We developed and validated a new treatment-specific patient satisfaction instrument: the Patient Satisfaction Questionnaire for Anemia Treatment (PSQ-An). Treatment burden and overall satisfaction scales were designed for ease of use in clinical practice.. 312 cancer patients (141 breast, 69 gynecological, and 102 non-small cell lung) were targeted to complete the PSQ-An at 4 week intervals. Data from weeks 5 and 9 were analyzed. Patients also completed the MOS SF-36 Global Health assessment and questions concerning resources devoted to anemia treatment. Item reduction used endorsement rates, floor/ceiling effects, and item-item correlations. Factor analysis identified meaningful subscales. Test-retest reliability was assessed. Construct validity was tested, using Pearson's correlations, by comparing subscale scores to Global Health, hemoglobin levels, and resources devoted to anemia treatment.. The overall response rate was 92.9% (264/284) at week 5. Most (84.2%) of the patients were female, and the mean (SD) age was 60.2 (+/- 11.8) years. Two distinct subscales were identified measuring treatment burden (7 items) and overall satisfaction (2 items). Test-retest reliability was examined (ICC: 0.45-0.67); both were internally consistent (alpha = 0.83). Both subscales exhibited convergent and divergent validity with independent measures of health. ANOVA results indicated that the PSQ-An Satisfaction subscale discriminated between 5 levels of MOS SF-36 Global Health (P = 0.006).. The PSQ-An is a validated, treatment-specific instrument for measuring satisfaction with anemia treatment for cancer patients. PSQ-An subscales reflect the burden of injection anemia treatment on cancer patients and their assessment of the overall treatment value.

Topics: Aged; Anemia, Hemolytic; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Factor Analysis, Statistical; Female; Genital Neoplasms, Female; Hematinics; Humans; Karnofsky Performance Status; Male; Middle Aged; Multicenter Studies as Topic; Outcome Assessment, Health Care; Patient Satisfaction; Psychometrics; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Surveys and Questionnaires

Anaemia is a common toxicity in cancer patients and epoetins (EPOs) are now an established treatment. The economic profile of EPO treatment was assessed in patients with breast cancer treated by adjuvant-chemotherapy.. Two strategies were compared: without treatment by EPO and with the possible use of treatment by EPO (epoetin alfa) when required. The clinical effectiveness criterion was time adjusted to quality of life and economic data included only direct medical costs.. One hundred ninety-two patients were included. In the group with the strategy containing the possible use of EPO, 45.5% of patients effectively received EPO. A significant difference in the haemoglobin level profile over time was observed which provided a significant overall benefit of 0.0052 (p<10(-4)) quality-adjusted life year (QALY) associated with an extra cost of 1,615 (p<10(-4)). In the base case analysis, the cost per added QALY was estimated as 310,577 with the strategy containing the possible use of EPO.. This robust result seems to be unacceptable, but the only relevant point of discussion might be the level of acceptable incremental cost-effectiveness ratio (ICER) for a patient.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Breast Neoplasms; Chemotherapy, Adjuvant; Cost-Benefit Analysis; Cyclophosphamide; Doxorubicin; Epirubicin; Epoetin Alfa; Erythropoietin; Female; Fluorouracil; France; Hematinics; Hemoglobins; Humans; Infusions, Intravenous; Middle Aged; Quality of Life; Quality-Adjusted Life Years; Recombinant Proteins; Retrospective Studies; Sensitivity and Specificity; Treatment Outcome

Anemia is a common complication of cancer patients. Recombinant human erythropoietin (rhEPO) can alleviate the symptoms of cancer-related anemia. However, the optimal use of rhEPO is still on investigation. This study was to find out the optimal use of rhEPO in anemic cancer patients undergoing chemotherapy.. From May, 2004 to Feb, 2005, 30 patients with cancer-related anemia receiving concurrent chemotherapy were enrolled. This open-labeled, non-randomized, and pilot study evaluated the response rate of induction rhEPO 120,000 U (40,000 U was subcutaneously injected on d1, 3, 5) followed by subcutaneous injection of maintenance dose of 40,000 U once a week for 3 weeks (d8, 15, 22). Hemoglobin (Hb) and hematocrit (Hct) were measured before treatment and fortnightly during the treatment.. Mean Hb maintained increasing during treatment. In week 2 (n=29) and week 4 (n=21), there were 27.59% and 61.90% patients, respectively, whose Hb value had increased more than 20 g/L from the baseline (79.56 g/L) and mean Hb were 90.26 g/L and 96.81 g/L respectively (P<0.05). And mean Hct at week 2 and week 4 were 27.01% and 30.17% respectively, which were higher than the baseline (24.29%)(P=0.062 and 0.001 respectively). All patients demonstrated fine tolerance.. Induction therapy followed by maintenance with rhEPO can improve the level of hemoglobin significantly and quickly in anemic cancer patients.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Injections, Subcutaneous; Lung Neoplasms; Male; Middle Aged; Pilot Projects; Recombinant Proteins

Results of CALGB 9741 demonstrated that administering standard doxorubicin/cyclophosphamide (AC)-paclitaxel therapy for adjuvant therapy of breast cancer in a dose-dense fashion with colony-stimulating factors increases efficacy, decreases severe neutropenia, but may increase the need for blood transfusions. A chart review was performed to evaluate the rates of anemia, neutropenia and skin toxicities with dose-dense and traditional AC-taxane chemotherapy.. A total of 112 patients received one of four treatments: non-dose-dense AC-paclitaxel (NDD Pac), dose-dense AC-paclitaxel (DD Pac), non dose-dense AC-docetaxel (NDD Doc), or dose-dense AC-docetaxel (DD Doc).. Transfusion rates were not increased in the dose-dense population; however, rates of grade 2-4 anemia (23% versus 0%, P=0.029), as well as erythropoietin use (58% versus 0%, P <0.0001), were significantly increased in the DD Pac group compared with the NDD Pac group. Grade 3 skin toxicities were significantly increased in the DD Doc group compared with the NDD Doc group (70% versus 11%, P <0.0001).. These results demonstrate that dose-dense AC-taxane therapy may increase rates of anemia and the need for erythropoietin, and decrease rates of neutropenia. The utility of DD Doc appears limited by skin toxicities and its use outside of a clinical study should not be recommended.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Breast Neoplasms; Chemotherapy, Adjuvant; Cyclophosphamide; Docetaxel; Dose-Response Relationship, Drug; Doxorubicin; Erythropoietin; Female; Humans; Incidence; Middle Aged; Neutropenia; Paclitaxel; Retrospective Studies; Skin Diseases; Taxoids

Topics: Anemia; Breast Neoplasms; Erythropoietin; Humans; Neoplasms; Prognosis; Recombinant Proteins; Risk Factors; Survival Analysis

Recent studies indicate that cancer cells express erythropoietin receptor (EpoR). In this study, we have shown that erythropoietin (Epo) activates the mitogen-activated protein kinase, extracellular signal-regulated kinase (ERK), and promotes migration in MCF-7 breast cancer cells. Epo-stimulated MCF-7 cell migration was blocked by the MEK inhibitor PD098059 and by dominant negative MEK-1, indicating an essential role for ERK. When MCF-7 cells were exposed to hypoxia (1.0% O(2)) for 3 h, the Epo mRNA level increased 2.4 +/- 0.5-fold, the basal level of ERK activation increased, and cell migration increased 2.0 +/- 0.1-fold. Soluble EpoR and Epo-neutralizing antibody significantly inhibited hypoxia-induced MCF-7 cell migration, suggesting a major role for autocrine EpoR cell signaling. MCF-7 cell migration under hypoxic conditions was also inhibited by PD098059. These experiments identify a novel pathway by which exogenously administered Epo, and Epo that is produced locally by cancer cells under hypoxic conditions, may stimulate cancer cell migration.

Topics: Breast Neoplasms; Cell Hypoxia; Cell Line, Tumor; Cell Movement; Erythropoietin; Female; Flavonoids; Humans; MAP Kinase Signaling System; Neutralization Tests; Protein Kinase Inhibitors; Receptors, Erythropoietin; Recombinant Proteins; RNA, Messenger; RNA, Neoplasm

Hematopoietic growth factors have played a major role in preventing infection and shortening the duration of neutropenia in patients receiving cancer chemotherapy. Little information is available on how these growth factors are used in patients with cancer outside the clinical trial setting. We performed descriptive and exploratory analyses on the patterns and correlates of the use of hematopoietic growth factors in community-dwelling elderly patients.. We identified 5,843 women from the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked data cohorts who were diagnosed with breast cancer at age 65 or older in 1992 to 1999 from the 11 SEER areas and received chemotherapy.. Overall, 17.3% of the elderly women with breast cancer chemotherapy received filgrastim and 6.8% received epoetin. The use of the growth factors increased significantly over time from 1992 to 1999 (P < .001 for trend). Compared with patients diagnosed in 1992 to 1994, patients diagnosed in 1998 to 1999 were more than five times and 65 times more likely to receive filgrastim and epoetin, respectively, after controlling for other factors such as age and comorbidity. There also was substantial geographic variation in the use of hematopoietic growth factors, ranging from 10.6% in Seattle to 22.9% in Atlanta. Significant predictors of growth factors included patient age, race, tumor stage, and comorbidity.. There were substantial temporal and geographic variations in the use of hematopoietic growth factors among patients receiving chemotherapy for breast cancer. The nationwide and population-based Medicare claims provide potential for examining the effectiveness, medical costs, and cost effectiveness of hematopoietic growth factors in the community.

Topics: Age Factors; Aged; Aged, 80 and over; Breast Neoplasms; Cohort Studies; Epoetin Alfa; Erythropoietin; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematinics; Hematopoietic Cell Growth Factors; Humans; Multivariate Analysis; Neoplasm Staging; Recombinant Proteins; SEER Program; Treatment Outcome; United States

Consorcial projects focused on 5 cancer types, breast-, colorectal-, head and neck- and pediatric cancers, and malignant melanoma. Breast cancer studies revealed unique splicing mechanisms concerning BRCA1. In sporadic breast cancers the involvement of DNA-repair genes was proved to be dependent on the histological type. Bone-metastatic tumors have been characterized by decreased NM23 and increased c-met and p53 expressions. C-erbB2 genotype of the primary tumor was not maintained frequently in bone metastases. Application of DNA-microarray and quantitative PCR technologies improved the prediction of therapeutic sensitivity of breast cancers. Colorectal cancer studies revealed regional inhomogenities (clusters) in various geographical regions of Hungary, which were distinct in the case of colonic and rectal cancers. To increase the sensitivity of fecal blood test of colorectal cancer screening, a new double-antibody test was developed and tested in a large cohort of patients. Genetic analysis revealed that hypermethylation is a significant factor in microsatellite instability which, and plays a role in silencing of APC and E-cadherin genes as well. The Hungarian pattern of TS polymorphism was also determined and was correlated not only with the efficacy of 5-FU treatment but with the progression of the disease as well. Population-based studies have been carried out in head and neck cancer patients (HNC) and smokers as well to reveal the genetic background of increasing tumor incidence. These studies revealed polymorphism in XRCC1/3 methylation enzyme gene which has preventive role. Other studies found frequent local immunosuppression in HNC patients. Studies indicated that the success of irradiation in this cancer type is dependent on the anti-vascular effects. Pediatric cancer studies determined the parameters of neuroblastoma screening based on VMA measurements. New splice variants of the WT1 gene involved in the monitoring of MRD of ALL patients was also described this year. We also obtained positive experimental data for the retinoic acid therapy of ALL. Melanoma studies extensively used DNA-microarray technology which identified 4 melanoma-specific and 2 melanoma progression-specific genes. In experimental human melanoma xenograft models we have identified 3 anti-metastatic agents: low molecular weight heparin, 2-methoxyestradiol and erythropoietin-alpha, where the later was characterized by specific effects on tumor vasculature.

Topics: 2-Methoxyestradiol; Adult; Animals; Antineoplastic Agents; Biomarkers, Tumor; Biomedical Research; Bone Neoplasms; Breast Neoplasms; Child; Colorectal Neoplasms; Disease Models, Animal; Disease Progression; DNA Methylation; Epoetin Alfa; Erythropoietin; Estradiol; Female; Gene Expression Regulation, Neoplastic; Gene Silencing; Genetic Markers; Head and Neck Neoplasms; Heparin, Low-Molecular-Weight; Humans; Hungary; Incidence; Male; Melanoma; Microsatellite Repeats; Oligonucleotide Array Sequence Analysis; Polymerase Chain Reaction; Polymorphism, Genetic; Predictive Value of Tests; Recombinant Proteins; Transplantation, Heterologous

Topics: Anemia; Breast Neoplasms; Erythropoietin; Female; Head and Neck Neoplasms; Humans; Neoplasms; Randomized Controlled Trials as Topic; Recombinant Proteins

Disordered perfusion and the resulting hypoxia are important features conferring tumor heterogeneity, which may contribute to relapse. Hypoxic tumor cells have been associated with resistance both to radiation and to cytotoxic drugs. Hypoxia may also serve as a selection pressure in tumors by promoting apoptosis of some cells and expanding variants with decreased apoptotic potential, and thus play a role in the development of a more aggressive phenotype. Erythropoietin (Epo), induced by hypoxia, controls erythropoiesis and plays a role in protection of neurons from hypoxic damage. We have recently demonstrated hypoxia-stimulated expression of Epo and Epo receptor (EpoR) in human breast and cervix cancers, suggesting a role for autocrine Epo signaling in the hypoxic adaptations of carcinomas. In the current study we provide evidence that increased autocrine Epo signaling induced by moderate levels of hypoxia inhibits hypoxia-induced apoptosis and promotes survival in MCF-7 human breast cancer cells. The anti-apoptotic effect of Epo correlates with upregulation of bcl-2 and bcl-XL, suggesting a mechanism similar to those described in hematopoietic cells. The resulting decreased apoptotic potential of hypoxic tumor cells may contribute to increased aggressiveness and therapy resistance of breast cancers.

Topics: Apoptosis; Blotting, Western; Breast Neoplasms; Carcinoma; Cell Hypoxia; Cell Survival; Drug Resistance, Neoplasm; Erythropoietin; Female; Humans; In Situ Nick-End Labeling; Oxygen; Phenotype; Receptors, Erythropoietin; Signal Transduction; Tumor Cells, Cultured

Topics: Anemia; Breast Neoplasms; Erythropoietin; Female; Humans; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Recombinant Proteins; Survival Rate

A major goal of experimental and clinical hematology is the identification of mechanisms and conditions supporting the expansion of transplantable hematopoietic stem cells. We assessed the expansion potential of CD34+CD71-CD45- cells derived from granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood under recently defined serum-free culture conditions. The CD34+CD71-CD45- cells in mobilized peripheral blood were found to contain the majority (92%+/-5.6) of primitive long-term culture initiating cells (LTCIC) and 53.5%+/-16.7 of the more committed colony-forming cells (CFC). Furthermore, this population represents 23.3%+/-4.1 of the total CD34+ cells and allows reduction of the cell density important for maintenance/expansion of primitive progenitor cells. CD34+ CD71- CD45- cells were cultured in defined serum-free media supplemented with 300 ng each of Flt-3 ligand and stem cell factor (SCF), 60 ng of interleukin (IL)-3, and 20 ng each of IL-6 and G-CSF. Mononuclear cells (MNC) and CFC were expanded 50-fold and 200-fold, respectively; primitive progenitor cells (LTC-IC) were maintained at input values after a total of 10 days of expansion. The addition of IL-15 to our cytokine cocktail expanded LTC-IC 2- to 3-fold and CFC to >500-fold. The data presented should allow clinical manipulation (purging) and expansion procedures with mobilized PBPC harvests without the loss of primitive progenitor cells and could be made applicable for large-scale clinical expansion.

Topics: ADP-ribosyl Cyclase; ADP-ribosyl Cyclase 1; Antigens, CD; Antigens, CD34; Antigens, Differentiation, B-Lymphocyte; Breast Neoplasms; Cells, Cultured; Culture Media, Serum-Free; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cells; Humans; Interleukin-15; Interleukin-3; Interleukin-6; Leukocyte Common Antigens; Lymphoma, Non-Hodgkin; Membrane Glycoproteins; Membrane Proteins; Methylcellulose; Receptors, Transferrin; Stem Cells

Topics: Anemia; Breast Neoplasms; Cell Division; Erythropoietin; Female; Humans; Male; Neoplasms; Neovascularization, Pathologic; Receptors, Erythropoietin; Recombinant Proteins

Erythropoietin (Epo), induced by hypoxia, controls the survival, proliferation, and differentiation of Epo receptor (EpoR)-bearing erythroid progenitors and plays a role in the protection of neurons from hypoxic damage. Hypoxia in malignant disease is associated with invasion, metastasis, resistance to therapy, and selection for cells with diminished apoptotic potential. The authors recently demonstrated the basal and hypoxia-stimulated expression of Epo and EpoR in human breast carcinoma cell lines and in breast carcinomas, suggesting a role for autocrine Epo signaling in the hypoxic adaptations of mammary neoplasms.. The authors characterized the expression of Epo and EpoR by immunohistochemistry in 184 invasive mammary carcinomas and 158 in situ mammary carcinomas and benign mammary epithelium. They analyzed the correlation of Epo and EpoR immunostaining with clinicopathologic tumor features and the patients' smoking history.. Benign mammary epithelial cells showed weak-to-moderate expression of Epo and EpoR. EpoR immunostaining was increased in carcinomas compared with benign epithelium both in nonsmokers and smokers, and Epo immunostaining was increased in carcinomas compared with benign epithelium in nonsmokers but not in smokers. Prominent Epo staining was seen in tumor cells adjacent to necrotic areas and at the infiltrating edge of tumors. EpoR staining, but not Epo staining, was significantly greater in tumors that showed high histologic grade, tumor necrosis, lymphovascular invasion, lymph node metastases, and loss of hormone receptor expression.. The current findings suggest that increased EpoR expression may play an important role in breast carcinogenesis. The induction of autocrine or paracrine Epo signaling may represent a novel mechanism by which hypoxia can promote breast carcinoma.

Topics: Breast Neoplasms; Carcinoma; Cell Transformation, Neoplastic; Erythropoietin; Female; Humans; Hypoxia; Immunohistochemistry; Receptors, Erythropoietin; Signal Transduction; Smoking

Novel approaches to cancer gene therapy currently exploit tumour hypoxia to achieve transcriptional targeting using oxygen-regulated enhancer elements called hypoxia response elements. The activity of such elements in hypoxic cells is directly dependent on upregulation of the hypoxia-inducible transcription factor-1 However tumours also contain areas of anoxia, which may be considered a more tumour-selective transcriptional stimulus than hypoxia for targeting gene therapy to tumours. Another element, from the rat virus-like retrotransposon, VL30 (termed the "secondary anoxia response element") has been reported to be more highly inducible in rat fibroblasts under anoxia than hypoxia. To investigate anoxia as a potential transcriptional target in human tumours, we have examined secondary anoxia response element inducibility in two human breast cancer cell lines, MCF-7 and T47D, under anoxia, hypoxia and normoxia. In both cell types, the trimerised secondary anoxia response element showed greater inducibility in anoxia than hypoxia (1% and 0.5% O(2)). The anoxic response of the secondary anoxia response element was shown to be dependent on hypoxia-inducible transcription factor-1 and the presence of a hypoxia-inducible transcription binding site consensus (5'-ACGTG-3'). Mutational analysis demonstrated that the base immediately 5' to this modulates the anoxic/hypoxic induction of the secondary anoxia response element, such that TACGTG>GACGTG>>CACGTG. A similar correlation was found for erythropoietin, phosphoglycerate kinase 1, and aldolase hypoxia response elements, which contain these respective 5' flanking bases.

Topics: Animals; Breast Neoplasms; Cell Hypoxia; CHO Cells; Cricetinae; DNA-Binding Proteins; Erythropoietin; Female; Genetic Therapy; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Nuclear Proteins; Oxygen; Rats; Response Elements; Retroelements; Transcription Factors; Tumor Cells, Cultured

Our objective was to assess, using clinical trial simulation, the feasibility of a fixed 200-microg dose of darbepoetin alfa (Aranesp) administered every 2 weeks in chemotherapy-induced anemia. A pharmacokinetic/pharmacodynamic model was developed using clinical data from 547 cancer patients who received darbepoetin alfa at various doses and schedules. Monte Carlo simulations were performed for weight-based (3 microg/kg every 2 weeks) and fixed-dose (200 microg every 2 weeks) regimens and were compared with observed clinical data. Mean hemoglobin changes from baseline to end of treatment were +1.61 g/dL, +1.83 g/dL, and +1.79 g/dL for observed data, the weight-based simulation, and the fixed-dose simulation, respectively. The rates of required transfusions (hemoglobin < or = 8 g/dL) were also similar between groups. For patients between 45 and 95 kg (over 90% of the population), the impact of a fixed dose on mean hemoglobin change was negligible. There was a slight weight effect at body weight extremes (< 45 kg and > 95 kg). Clinical outcomes from simulations of weight-based andfixed dosing of darbepoetin alfa were similar to those of observed weight-based data. Given the weight distribution of a typical cancer population, the majority would be expected to benefit equally from weight-based and fixed-dose darbepoetin alfa in the amelioration of chemotherapy-induced anemia.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Body Weight; Breast Neoplasms; Clinical Trials as Topic; Computer Simulation; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Female; Gastrointestinal Neoplasms; Genital Neoplasms, Female; Genital Neoplasms, Male; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Monte Carlo Method

Breast cancer patients receiving chemotherapy often exhibit anemia, which contributes to symptoms such as fatigue, compromising quality of life (QOL). The present subset analysis assessed the effects of recombinant human erythropoietin (rHuEPO, epoetin alfa) on anemia and QOL in approximately 1300 patients with breast cancer, who were derived from 3 large, community-based clinical trials of epoetin alfa in anemic chemotherapy patients with various malignancies. Epoetin alfa effectively and safely corrected anemia and improved QOL scores on the Linear Analogue Self-Assessment, which measures energy, ability to perform daily activities, and QOL. Clinical, laboratory, and QOL improvements were qualitatively and quantitatively similar to those reported in the larger populations with various tumor types. The efficacy and safety of epoetin alfa did not vary according to dosing frequency (1 vs. 3 times weekly). Epoetin alfa is, therefore, effective and safe in the management of anemia in patients with breast cancer treated with chemotherapy.

Topics: Anemia; Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Epoetin Alfa; Erythropoietin; Female; Humans; Injections, Subcutaneous; Quality of Life; Recombinant Proteins; Retrospective Studies

Erythropoietin (EPO) stimulates the growth of erythroblasts in the bone marrow (C. Lacombe and P. Mayeux, NEPHROL: DIAL: TRANSPLANT:, 14 (SUPPL: 2): 22-28, 1999). We report basal and hypoxia-stimulated expression of EPO and its receptor, EPOR, in human breast cancer cells, and we demonstrate EPO-stimulated tyrosine phosphorylation and the proliferation of these cells in vitro. In 50 clinical specimens of breast carcinoma, we report high levels of EPO and EPOR associated with malignant cells and tumor vasculature but not with normal breast, benign papilloma, or fibrocystic tissue. Hypoxic tumor regions display the highest levels of EPO and EPOR expression. Enhanced EPO signaling may contribute to the promotion of human cancer by tissue hypoxia.

Topics: Biopsy; Blotting, Western; Breast Neoplasms; Erythropoietin; Gene Expression; Humans; Immunohistochemistry; Receptors, Erythropoietin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion, Autologous; Breast Neoplasms; Combined Modality Therapy; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hematopoietic Stem Cell Transplantation; Humans; Middle Aged; Platelet Transfusion; Recombinant Proteins

A fusion protein made of human granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (EPO), referred to as MEN 11303, has been tested for biologic activity using mobilized CD34(+) cells.. MEN 11303 and a combination of GM-CSF/EPO produced the same amount of colony-forming unit granulocyte-macrophage (CFU-GM), of burst-forming unit erythroid (BFU-E), and of multipotent CFU-mixed. After 15 days, liquid cultures of CD34(+) cells exposed to MEN 11303 yielded a total cell number larger than that obtained with an equimolar mixture of GM-CSF and EPO, with a clear prevalence of cells exhibiting an erythroid phenotype. A colony-forming cell assay established from CD34(+) cells precultured with MEN 11303 for 7 days yielded a greater amount of BFU-E than GM-CSF/EPO combination. Exposing CD34(+) cells to MEN 11303 for 7 days in liquid culture resulted in higher recoveries of cells expressing a comparatively less differentiated hematopoietic phenotype and of long-term culture initiating cells. A cell-based binding-competition assay using the human EPO-receptor (EPO-R) transfected murine Ba/F3EPOR cell line showed that MEN 11303 bound to EPO-R with a sixfold lower affinity but induced a more sustained receptor phosphorylation. MEN 11303 supported the growth of Ba/F3EPOR cells more efficiently than EPO and remained detectable in the spent culture medium for a longer time.. MEN 11303 and the combination of GM-CSF/EPO are equally potent in recruiting hematopoietic progenitors into cycle, but the fusion protein is superior in promoting the expansion of committed erythroid percursors. Primitive hematopoiesis is less affected by MEN110303 than GM-CSF/EPO combination. Part of these effects may reflect the peculiar interaction of the EPO moiety of MEN 11303 with the EPO-R.

Topics: Antigens, CD34; Breast Neoplasms; Cell Differentiation; Cells, Cultured; Colony-Forming Units Assay; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cells; Humans; Immunophenotyping; Membrane Glycoproteins; Ovarian Neoplasms; Phenotype; Phosphorylation; Receptors, Immunologic; Sialic Acid Binding Ig-like Lectin 1

Malignant cell contamination in autologous transplants is a potential origin of tumor relapse. Ex vivo expansion of CD34(+) blood progenitor cells (BPC) has been proposed as a tool to eliminate tumor cells from autografts. To characterize the influence of culture conditions on survival, growth, and clonogenicity of malignant cells, we isolated primary mammary carcinoma cells from pleural effusions and ascites of patients with metastatic breast cancer and cultured them in the presence of stem cell factor (SCF), interleukin-1beta (IL-1beta), IL-3, IL-6, and erythropoietin (EPO), ie, conditions previously shown to allow efficient ex vivo expansion of CD34(+) BPC. In the presence of serum, tumor cells proliferated during a 7-day culture period and no significant growth-modulatory effect was attributable to the presence of hematopoietic growth factors. When transforming growth factor-beta1 (TGF-beta1) was added to these cultures, proliferation of breast cancer cells was reduced. Expansion of clonogenic tumor cells was seen in the presence of SCF + IL-1beta + IL-3 + IL-6 + EPO, but was suppressed by TGF-beta1. Cocultures of tumor cells in direct cellular contact with hematopoietic cells showed that tumor cell growth could be stimulated by ex vivo expanded hematopoietic cells at high cell densities (5 x 10(5)/mL). In contrast, culture under serum-free conditions resulted in death of greater than 90% of breast cancer cells within 7 days and a further decrease in tumor cell numbers thereafter. In the serum-free cultures, hematopoietic cytokines and cellular contact with CD34(+) BPC could not protect the tumor cells from death. Therefore, ex vivo expansion of CD34(+) BPC in serum-free medium provides an environment for efficient purging of contaminating mammary carcinoma cells. These results have clinical significance for future protocols in autologous progenitor cell transplantation in cancer patients.

Topics: Antigens, CD34; Ascites; Breast Neoplasms; Cell Division; Cell Survival; Coculture Techniques; Culture Media; Culture Media, Serum-Free; Erythropoietin; Hematopoietic Stem Cells; Humans; Interleukin-1; Interleukin-3; Interleukin-6; Neoplasm Metastasis; Pleural Effusion; Stem Cell Factor; Transforming Growth Factor beta; Tumor Cells, Cultured

Ex vivo stroma-free static liquid cultures of granulocyte colony-stimulating factor (G-CSF)/chemotherapy-mobilized CD34+ cells were established from patients with epithelial solid tumors. Different culture conditions were generated by adding G-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF), Flt3 ligand (Flt3), megakaryocyte growth and development factor (Peg-rHuMGDF), GM-CSF/erythropoietin (EPO) hybrid protein (MEN11303), and interleukin-15 (IL-15) to the basic stem cell factor (SCF) + interleukin-3 (IL-3) + EPO combination. This study showed that, among the nine different combinations tested in our 5% autologous plasma-containing cultures, only those containing IL-3/SCF/Flt3/MEN11303 and IL-3/SCF/Flt3/MEN11303/IL-15 significantly expanded colony-forming unit granulocyte-macrophage (CFU-GM), burst-forming unit erythroid (BFU-E), long-term culture-initiating cells (LTC-IC), CD34+, and CD34+/CD38- cells after 14 days of culture. Particularly, the addition of IL-15 to IL-3/SCF/Flt3/MEN11303 combination produced a significant increase of LTC-IC, with an average 26-fold amplification as compared to input cells, without any detrimental effect on CFU-GM and BFU-E expansion. This combination also produced a statistically significant 3.6-fold expansion of primitive CD34+/CD38- cells. Moreover, this study confirms the previously described erythropoietic effect of MEN11303, which, in our experience, was the only factor capable of expanding BFU-E. Compared to equimolar concentrations of GM-CSF and EPO, MEN11303 hybrid protein showed a significantly higher capacity of expanding CFU-GM, BFU-E, LTC-IC, CD34+, and CD34+/CD38- cells when these cytokines were tested in combination with IL-3/SCF/Flt3. These cultures indicated that Peg-rHuMGDF addition to IL-3/SCF/EPO/Flt3 does not affect CFU-GM and BFU-E expansion but, unlike G-CSF or GM-CSF, it does not decrease the ability of Flt3 to expand primitive LTC-IC. These studies indicate that, starting from G-CSF/chemotherapy-mobilized CD34+ cells, concomitant expansion of primitive LTC-IC, CFU-GM, BFU-E, CD34+, and CD34+/CD38- cells is feasible in simple stroma-free static liquid cultures, provided IL-3/SCF/Flt3/MEN11303/IL-15 combination is used as expanding cocktail in the presence of 5% autologous plasma.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cells, Cultured; Colony-Forming Units Assay; Erythropoiesis; Erythropoietin; Female; fms-Like Tyrosine Kinase 3; Granulocyte Colony-Stimulating Factor; Hematopoiesis; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cells; Humans; Interleukin-15; Middle Aged; Ovarian Neoplasms; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases

Topics: Bone Neoplasms; Breast Neoplasms; Combined Modality Therapy; Diphosphonates; Erythropoietin; Female; Humans; Male; Neoplasm Metastasis; Neoplasms; Pilot Projects; Radiotherapy

Topics: Adult; Anemia; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Ductal, Breast; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Recombinant Proteins; Treatment Outcome

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Blood Transfusion; Breast Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Cost-Benefit Analysis; Epoetin Alfa; Erythropoietin; Female; Humans; Middle Aged; Neoplasms; Recombinant Proteins; Risk Assessment

To verify whether the association of granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (EPO) would allow both the acceleration and the dose escalation of the cyclophosphamide/epidoxorubicin/5-fluorouracil (CEF) regimen as first-line therapy in advanced breast cancer patients, we conducted a dose-finding study. Cohorts of three consecutive patients received cyclophosphamide (Ctx, dose range 800-1400 mg/m2), epidoxorubicin (Epidx, dose range 70-100 mg/m2), and 5-fluorouracil (5-Fu, 600 mg/m2, fixed dose) given as an intravenous bolus on day 1 every 14 days; GM-CSF at 5 micrograms/kg given as a subcutaneous injection from day 4 to day 11; and EPO at 150 IU/kg given as a subcutaneous injection three times a week. In no single patient was any dose escalation allowed. A total of 14 patients entered the study. At the 4th dose level (Ctx 1400 mg/m2, Epidx 100 mg/m2, 5-Fu 600 mg/m2), two patients had dose-limiting mucositis and one patient developed dose-limiting neutropenia. Therefore, the 3rd cohort received the maximum tolerated dose, i.e. Ctx at 1200 mg/m2, Epidx at 90 mg/m2, and 5-Fu at 600 mg/m2, given every 18.5 (+/-2.5) days. Toxicity was moderate and manageable in an outpatient setting. Only 1 admission at the 4th dose level was required. Throughout the 4 dose levels there was no toxicity-related death; grade IV leukopenia ranged from 24% to 75% of cycles and grade IV thrombocytopenia ranged from 6% to 8%. No grade IV anemia was recorded. Increasing the doses of Ctx and Epidx while maintaining a fixed dose of 5-Fu with the support of both EPO and GM-CSF allows safe acceleration and dose escalation of CEF chemotherapy. Further controlled studies will evaluate the activity and efficacy of this strategy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Breast Neoplasms; Cohort Studies; Cyclophosphamide; Dose-Response Relationship, Drug; Doxorubicin; Epirubicin; Erythropoietin; Female; Fluorouracil; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Middle Aged; Outpatients; Pilot Projects; Treatment Outcome

Multiple cycles of high-dose chemotherapy can be hematologically supported by repeated administration of peripheral blood progenitors obtained after mobilization using cytokine alone or in combination with chemotherapy. We have explored the quality of such cells and their potential to undergo ex vivo expansion. Twenty-five leukapheresis samples from 19 patients who had received extensive prior chemotherapy for stage IV breast cancer were subjected to CD34+ cell selection using immunoaffinity columns of immunomagnetic bead separation. Cells were cultured in suspension in the presence of c-kit ligand, interleukin-3, interleukin-6, erythropoietin, and granulocyte colony-stimulating factor. Ten experiments were performed using weekly exchange of media and cytokines (Delta assay). Median myeloid and erythroid progenitors expanded 15-fold at 7 days (range, 7 to 43), 40-fold at 14 days (range, 18 to 470), 46-fold at 21 days (range, 0 to 118), and 21-fold at 28 days (range, 0 to 61). In a system using gas-permeable bags without exchange of media or cytokine, median progenitors expanded 13-fold at 7 days (range, 7 to 36), 14-fold at 10 days (range, 4 to 61), 14-fold at 12 days (range, 3 to 46), and 10-fold at 14 days (range, 1 to 35). Progenitor expansion less than 10-fold occurred in 8% of experiments at day 7, in 17% at day 10, in 43% at day 12, and in 50% at day 14. When autologous plasma, autologous plasma processed (removal of cryoprecipitate, centrifugation, then filtration), or human serum were substituted for 20% fetal calf serum, the ratio of progenitor expansion at 7 days relative to 20% fetal calf serum for 10% human serum, 20% human serum, and 1% autologous plasma processed was 1.01 (range, 0.62 to 1.33), 0.88 (range, 0.61 to 1.20), and 0.96 (range, 0.55 to 1.64), respectively. These findings support the feasibility of ex vivo expansion in a system free of nonhuman proteins of CD34(+)-derived progenitors obtained from the peripheral blood of patients who have received prior chemotherapy.

Topics: Animals; Antigens, CD; Antigens, CD34; Antineoplastic Agents; Breast Neoplasms; Cell Division; Cells, Cultured; Colony-Forming Units Assay; Cytokines; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Interleukin-3; Interleukin-6; Leukapheresis; Neoplasm Staging; Stem Cell Factor

Neoplasias, especially in their more advanced stages, are often associated with chronic anemia of malignancy which impairs the patient's physical ability and quality of life.. Forty-two patients with chronic anemia associated with hematological malignancies (18 multiple myelomas, 10 myelodysplastic syndromes) or solid tumors (9 breast cancers, 5 colon cancers) were treated with 150-300 units/kg rHuEPO for a median time period of 16 weeks. Response was defined as an increase of the initial hemoglobin level by at least 2 g/dl.. The response rates for solid tumors were comparable (44.4% and 40% for breast cancer and colon cancer, respectively), whilst the response in patients with hematological malignancies depended strongly on the disease entity (77.8% for multiple myeloma, 10% for myelodysplastic syndrome). Pretreatment serum levels of endogenous erythropoietin (EPO) were significantly higher in non-responding patients than in responders. During rHuEPO therapy, EPO levels in non-responders increased even further, while they remained basically unchanged in responding patients. In responders, the WHO performance status before the start of rHuEPO therapy was more favorable and showed impressive improvement during the course of treatment. The median survival time of responders was 28.0 months as compared to only 9.2 months for non-responders. Clinical symptoms of anemia subsided or at least considerably improved under successful rHuEPO therapy. With the exception of occasional flu-like symptoms, no undesirable effects of rHuEPO treatment were observed.. In conclusion, rHuEPO treatment corrected anemia of malignancy both in patients with hematologic disease and in those with solid tumors, but responsiveness varied considerably amongst the different disease entities.

Topics: Aged; Aged, 80 and over; Anemia; Breast Neoplasms; Chronic Disease; Colonic Neoplasms; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Survival Rate; Treatment Outcome

Topics: Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Erythropoietin; Female; Humans; Middle Aged; Polycythemia

Topics: Agranulocytosis; Anemia, Aplastic; Anemia, Macrocytic; Bone Marrow Examination; Bone Neoplasms; Breast Neoplasms; Dihydrotestosterone; Erythropoiesis; Erythropoietin; Female; Hepatitis; Humans; Iron; Iron Radioisotopes; Male; Oxymetholone; Prednisolone; Sepsis; Transfusion Reaction

Topics: 5-Hydroxytryptophan; Adrenocorticotropic Hormone; Breast Neoplasms; Calcitonin; Chorionic Gonadotropin; Erythropoietin; Estradiol; Female; Gastrins; Hormones, Ectopic; Humans; Hyperkalemia; Middle Aged; Neoplasm Metastasis; Paraneoplastic Endocrine Syndromes; Parathyroid Hormone; Progesterone

Topics: Anemia; Anemia, Aplastic; Anemia, Sickle Cell; Animals; Biological Assay; Breast Neoplasms; Cachexia; Erythrocytes; Erythropoiesis; Erythropoietin; Iron; Iron Isotopes; Leukemia; Lymphoma; Male; Mice; Plasma; Polycythemia; Prostatic Neoplasms

Topics: Adrenal Glands; Adrenalectomy; Animals; Breast Neoplasms; Erythropoietin; Female; Humans; Hypophysectomy; Male; Mice; Pituitary Gland; Prostatic Neoplasms