Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In 29 chemotherapy-naive patients with stage II-III breast cancer, peripheral blood stem cells (PBSCs) were mobilised following fluorouracil 500 mg m-2, epirubicin 90-120 mg m-2 and cyclophosphamide 500 mg m-2 (FEC) and granulocyte colony-stimulating factor (G-CSF; Filgrastim) 300 microgram s.c. daily. In all but one patient, mobilisation was successful, requiring three or fewer leucocytopheresis sessions in 26 patients; 28 patients subsequently underwent high-dose chemotherapy consisting of carboplatin 1600 mg m-2, thiotepa 480 mg m-2 and cyclophosphamide 6 g m-2 (CTC) followed by PBSC transplantation. Haemopoietic engraftment was rapid with a median time to neutrophils of 500 x 10(6) l(-1) of 9 days (range 8-10) in patients who received G-CSF after PBSC-transplantation; platelet transfusion independence was reached within a median of 10 days (range 7-16). Neutropenic fever occurred in 96% of patients. Gastrointestinal toxicity was substantial but reversible. Renal, neural or ototoxicity was not observed. Complications related to the central venous catheter were encountered in 64% of patients, with major vein thrombosis occurring in 18%. High-dose CTC-chemotherapy with PBSC-transplantation, harvested after mobilisation with FEC and G-CSF, is reasonably well tolerated without life-threatening toxicity and is a suitable high-dose strategy for the adjuvant treatment of breast cancer.
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PMID:High-dose carboplatin, thiotepa and cyclophosphamide (CTC) with peripheral blood stem cell support in the adjuvant therapy of high-risk breast cancer: a practical approach. 753 25

Changes which lead to excessive cyclin production or to loss of cell cycle inhibition by proteins such as p16/MTS1 may release breast tumour cells from the constraints of cell division. In order to establish the frequency of MTS1/p16 gene alteration and its relation with genetic damage to the p53 and cyclin D1 genes, we have studied these gene abnormalities in 164 human primary breast cancers and in six breast cancer cell lines. Two breast cancer cell lines and one primary tumour showed a homozygous deletion of exon 2 of the MTS1 gene. Using single-strand conformation polymorphism and subsequent sequencing analysis, one tumour showed an alteration at codon 67 (CCC-->CTC; Pro to Leu). Another tumour showed a mutation at codon 98 (without amino acid change) with an additional polymorphism at codon 140. This polymorphism was also found in 13 other tumour samples, but has no effect on (disease-free) survival. From these data we conclude that the occurrence of CDKN2 (p16/MTS1) mutation in primary breast cancer is a rare event and is not likely to be involved in human breast tumour carcinogenesis and progression.
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PMID:Infrequent CDKN2 (MTS1/p16) gene alterations in human primary breast cancer. 754 49

Rhizoxin is a new anti-tumour agent isolated from the pathogenic fungus Rhizopus chinensis. It has shown broad activity against murine tumour models and is also active against vinca alkaloid-resistant cells. The purpose of our studies was to determine the clinical activity of this compound in patients with advanced breast cancer and melanoma. Based on the results of a phase I study, 2.0 mg m-2 was administered as intravenous infusion over 5 min every 21 days. Nineteen patients were entered into the breast cancer phase II trial and received a total of 50 courses (median 2, range 1-6). Of these, dose reductions were performed in three courses because of leucopenia or stomatitis (1.5 mg m-2, one course; 1.45 mg m-2, two courses). Twenty-six patients were entered into the melanoma trial and received a total of 70 courses (median 2, range 1-12). No dose reductions were required. All patients were eligible for toxicity. Haematological toxicity included neutropenia CTC grade 3 (29/120 courses, 24.2%) and grade 4 (11/20 courses, 9.2%). Only drug-related CTC grade 1 thrombocytopenia was observed. Non-haematological toxicity included alopecia in all patients after two courses of treatment as well as CTC grade 3/4 stomatitis and asthenia. In the breast cancer study, one patient achieved a more than 50% tumour reduction after six cycles but was progressing after 6 weeks. Another patient showed a partial remission after the first course but was taken off the study because of CTC grade 3 skin toxicity. One patient was not evaluable for response (early death). No objective remissions were observed in 15 evaluable patients. In melanoma, no objective remissions were observed. We conclude that rhizoxin can be safely administered at 2.0 mg m-2 every 3 weeks. However, it has little activity in patients with advanced breast cancer and melanoma.
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PMID:Phase II clinical trials with rhizoxin in breast cancer and melanoma. The EORTC Early Clinical Trials Group. 856 49

High-dose chemotherapy with autologous bone marrow and/or peripheral blood stem cell (PBSC) support is increasingly employed in the adjuvant treatment of high-risk breast cancer. Subsequent radiotherapy has been reported to be associated with morbidity and mortality resulting from pulmonary toxicity. In addition, the course of radiation therapy may be hampered by excess myelosuppression. The aim of this study was to investigate the contribution to radiation-induced toxicity of a high-dose chemotherapy regimen (CTC) that incorporates cyclophosphamide, thiotepa and carboplatin, in patients with high-risk breast cancer. In two randomised single institution studies, 70 consecutive patients received anthracycline-containing adjuvant chemotherapy (FEC: 5-fluorouracil, epirubicin and cyclophosphamide) followed by radiotherapy to achieve maximal local control. Of these patients, 34 received high-dose CTC with autologous PBSC support. All patients tolerated the full radiation dose in the planned time schedule. Radiation pneumonitis was observed in 5 patients (7%), 4 of whom had undergone high-dose chemotherapy (P = 0.38). All 5 responded favourably to prednisone. Fatal toxicities were not observed. Myelosuppression did not require interruption or untimely discontinuation of the radiotherapy, although significant reductions in median nadir platelet counts and haemoglobin levels were observed in patients who had received high-dose chemotherapy (P = 0.0001). The median nadir of WBC counts was mildly but significantly decreased during radiotherapy (P = 0.01). Red blood cell or platelet transfusions were rarely indicated. Adequate radiotherapy for breast cancer can be safely administered after high-dose CTC with autologous PBSC support. Radiation-induced myelotoxicity is clearly enhanced following CTC, but this is of little clinical significance. Radiation pneumonitis after high-dose therapy may occur more often in patients with a history of lung disease or after a relatively high radiation dose to the chest wall. Other high-dose regimens, particularly those incorporating drugs with known pulmonary toxicity (such as BCNU), may predispose patients to radiation pneumonitis.
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PMID:The toxicity of radiotherapy following high-dose chemotherapy with peripheral blood stem cell support in high-risk breast cancer: a preliminary analysis. 891 Nov 7

Vinorelbine (VNB) shows high antitumoral activity in advanced breast cancer due to its high affinity for mitotic tubulin and differs from the other vinca alkaloids with regard to its low degree of neurotoxicity because of its low affinity for axonal tubulin. Preclinical data show the existence of different binding sites on tubulin for vinca alkaloids and paclitaxel (P), suggesting a lack of cross-resistance. Thus, VNB was chosen eligible for a phase II study to evaluate both the therapeutic efficacy and the toxicity of VNB in patients (pts) with advanced breast cancer failing first- or second-line chemotherapy with P. A total of 14 pts with advanced breast cancer pretreated with P were entered into the study. Therapy consisted of VNB at 30 mg/m2 diluted in 500 ml of normal saline given over 30 min after a minimal interval of 4 weeks since the last application of P. For the first four cycles, injections were repeated at 2-week intervals; thereafter they were repeated at 3-week intervals until evidence of progressive disease or severe toxicity developed. All but one pt was considered assessable for response and all pts were evaluable for toxicity. No objective response was observed; two pts showed no change in their disease. In four pts therapy had to be stopped because peripheral neurotoxicity increased from a pretherapeutic level after therapy with P from National Cancer Institute Common Toxicity Criteria (NCI-CTC) grade 1 (n = 3) and 2 (n = 1) to neurotoxicity grade 3 after 1, 2 (n = 2), and 3 cycles of therapy with VNB, respectively. In addition, constipation of grade 2 occurred in 10 pts. Hematologic toxicity was negligible. No other evaluable toxicity exceeded NCI-CTC grade 1. Both observations of this study, the complete resistance to VNB and the increase in peripheral neuropathy, let us assume the existence of a preclinically not anticipated but clinically relevant cross-resistance between these two spindle poisons and the presence of common functional targets. Therefore, P-pretreated pts should be excluded from consecutive VNB-containing therapies.
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PMID:Vinorelbine-induced neurotoxicity in patients with advanced breast cancer pretreated with paclitaxel--a phase II study. 899 13

Anthracyclines are effective in breast cancer and have in vitro cytotoxicity in glioma. In patients with glioma anthracyclines are not effective possibly because the hydrophilic drugs do not reach cytotoxic levels in tumor tissue. Idarubicin is more lipophilic than the other anthracyclines and is more cytotoxic in glioma cell lines. The uptake of idarubicin and its major metabolite idarubicinol in brain tumor tissue were measured in a patient with a brain metastasis from breast cancer and in 4 patients with malignant glioma after an oral dose of idarubicin (45 mg/m2 in 1 patient; 25 mg/m2 in 4 patients), given 15-24 h before brain tumor resection. The concentrations of idarubicin and of idarubicinol in tumor tissue exceeded the concurrent plasma concentrations as well as the peak plasma concentrations in all cases. The median tumor:concurrent plasma ratio of idarubicinol was 5.7 (range 1.7-18). The concentration of idarubicinol in the marginal zone between brain and tumor tissue was lower than in central tumor tissue, but was still higher than the plasma concentration in 2 of the 3 examined cases. Bone marrow suppression (platelets CTC grade 2, granulocytes CTC grade 4) occurred after a single dose of 45 ml/m2. No toxicity was seen at a dose of 25 mg/m2. These results, the in vitro activity of idarubicin in glioma, the convenience of oral administration, and its toxicity profile make clinical studies with idarubicin in malignant glioma, and perhaps also in brain metastases from breast cancer worthwhile.
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PMID:Penetration of idarubicin into malignant brain tumor tissue. 1058 71

42 breast cancer patients were treated by high-dose chemotherapy (HDC) and autologous peripheral stem-cell transplantation (ASTx) in the Donauspital between 1992 and 1999. 24 patients had stage II/III breast cancer with high risk for relapse. The other 18 patients underwent HDC and ASTx in chemosensitive stage IV. After previous conventional chemotherapy peripheral stem-cells were harvested by one cycle of mobilisation chemotherapy (epirubicin/taxol, FEC 120 or cyclophosphamide) followed by cytokine stimulation. 16 patients were treated by a tandem transplantation (conditioning protocol for 1st ASTx was melphalan 200 mg/m2 and for 2nd transplant it was CTC: cyclophosphamide 6 g/m2; thiotepa 500 mg/m2; carboplatin 800 mg/m2). The other 26 patients received one HDC with CTC as conditioning protocol. The HDC was well tolerated by all patients, there was no transplant-related mortality. The median survival and the progression-free survival (PFS) after HDC and ASTx in stage IV breast cancer patients were 28 and 11 months, respectively. The median survival and PFS were not yet reached in stage II/III patients after 55 months. The actuarial survival and PFS in that patient group were 70% after 55 months. Our data confirm the low risk and good efficacy of HDC and ASTx in breast cancer patients. Nevertheless randomised studies are necessary to evaluate the importance of HDC compared to intensified conventional protocols without ASTx.
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PMID:[High dosage therapy and autologous peripheral stem cell transplantation in breast carcinoma]. 1126 Dec 76

A phase II study was conducted to evaluate the activity of pemetrexed in patients with locally recurrent or metastatic breast cancer. 38 patients, median age 52 years (range 36-71 years), were given pemetrexed 600 mg/m(2) as a 10-min intravenous (i.v.) infusion every 3 weeks. Median time from diagnosis to study entry was 48 months (range 14.7-310 months). 33 of 38 patients had prior chemotherapy; 16 adjuvant, 12 metastatic and 5 in both settings. Sites of disease included skin and soft tissue (19/38) nodes (18/38), lung (17/38), liver (13/38) and bone (3/38). An overall response rate of 28% (95% confidence interval (CI): 14.2-45.2%) in 10/36 evaluable patients (1 complete response (CR), 9 partial responses (PR)), included reductions in hepatic and pulmonary metastases. 5 of 10 responders had received taxoid or anthracycline therapy for metastatic disease; 3 of these 5 had also received adjuvant chemotherapy. Median duration of response was 8 months (range 1.6-14+ months), and median survival was 13 months (95% CI 9.56-17.38 months). 167 courses were given (median five per patient; range 1-9), with 37 reductions and 33 delays. Reasons for reduction included neutropenia (11%) and mucositis (5%), with delays due to raised LFTs (21%), neutropenia (12%) and other non-treatment related events. The major haematological toxicities (Common Toxicity Criteria) (CTC) were grade 3/4 neutropenia (47%) and thrombocytopenia (15.7%) of patients. There was one report of a grade 3 infection. Non-haematological toxicities (all grades 2/3) included elevated transaminases (92%), vomiting (34%), nausea (34%) and mucositis (32%). One episode of grade 4 diarrhoea was reported. Other toxicities included a skin rash, grade 2 (42%), 3 (5%) and 4 (13%), which was ameliorated by the use of prophylactic dexamethasone. These results suggest that pemetrexed has significant antitumour activity in advanced breast cancer with responses in patients who had previously received anthracyclines and taxoids.
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PMID:A phase II study of pemetrexed disodium (LY231514) in patients with locally recurrent or metastatic breast cancer. 1143 66

The purpose of this study was to determine the feasibility and efficacy of multiple courses of high-dose cyclophosphamide, carboplatin and thiotepa with peripheral blood progenitor cell (PBPC) transplantation in women with advanced breast cancer. Forty-one patients with advanced hormone-refractory breast cancer were enrolled in the study. The treatment started with two courses of 5-fluorouracil 500 mg/m(2), epirubicin 120 mg/m(2) and cyclophosphamide 500 mg/m(2) (FE(120)C) followed by PBPC harvesting. The high-dose regimen consisted of three subsequent courses of 'tiny' CTC, cyclophosphamide 4000 mg/m(2), thiotepa 320 mg/m(2) and carboplatin 1060 mg/m(2) (target AUC 13.3 mg/ml/min) (tCTC) divided over 4 consecutive days. The second and third courses were scheduled to begin on day 28 after the previous transplantation. A total of 86 tCTC courses was given to 33 of the 41 enrolled patients. Major toxicities consisted of hemorrhagic cystitis (six patients), prolonged gastro-intestinal toxicity (three patients) and veno-occlusive disease (two patients). There was one therapy-related death (unknown cause). Twenty patients (49%) achieved a complete response, nine (22%) a partial response and three patients stable disease after treatment. The median follow-up of the surviving patients was 43 months (range 25-61). Six patients remain in complete remission beyond 3 years. At 4 years, the progression-free survival (PFS) and overall survival (OS) for the whole patient group were 23 and 30% with a median duration of 12 and 27 months, respectively and for FE(120)C-responsive patients 32 and 36%, respectively with a median duration of 15 and 33 months. In the patient group with a PFS > or = 18 months all patients had limited disease (metastatic disease in only one or two sites) and fewer patients had bone or liver metastases compared to the overall patient group (33% vs 51%). This report shows that three closely spaced courses of tCTC are feasible, with acceptable toxicity. Triple tCTC can achieve complete or partial remission in most patients and long-term PFS in a selected subgroup of patients who have limited metastatic disease and are responsive to conventional-dose chemotherapy.
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PMID:Phase II study of a multi-course high-dose chemotherapy regimen incorporating cyclophosphamide, thiotepa, and carboplatin in stage IV breast cancer. 1150 35

Transforming growth factor (TGF)-beta3 has been hypothesized to prevent or alleviate oral mucositis (OM) in cancer patients receiving high-dose chemotherapy (CT). Two double-blind, placebo-controlled, multicenter, phase II studies of TGF-beta3 were initiated in the United States, Europe, and Argentina in patients with lymphomas or solid tumors who were receiving highly stomatotoxic CT regimens. Patients were to apply 10-mL mouthwash applications of TGF-beta3 (25 microg/mL) or placebo four times daily (or twice daily) 1 day before and all days during CT. The patients were subsequently evaluated for OM incidence, severity, and duration using National Institute of Cancer Common Toxicity Criteria (NCI-CTC) criteria and an objective scoring system (1). After the start of the trials, negative results from new preclinical studies suggesting suboptimal formulation and/or dosing led to an interim analysis of the ongoing clinical trials. One hundred fifty-two patients from the combined studies were included in the interim analysis, with 116 patients on the TGF-beta3 four times daily and placebo arms. Most (72%) patients had breast cancer, 22% had lymphomas, and 6% had other solid tumors. Although 98% (149 of 152) of patients experienced adverse events, only 14% (22 of 152) experienced events that were judged as possibly or probably related to the study drug (primarily gastrointestinal symptoms). No clinically relevant differences were seen between the treatment and placebo arms regarding safety, nor was there evidence for systemic absorption of TGF-beta3. Finally, there was no advantage of TGF-beta3 treatment regarding the incidence (TGF-beta3 four times daily versus placebo [46% versus 47%]), onset, or duration of NCI-CTC grade 3 or 4 OM. For this dose, formulation, regimen. and patient population, TGF-beta3 was not effective in the prevention or alleviation of CT-induced OM.
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PMID:Topical transforming growth factor-beta3 in the prevention or alleviation of chemotherapy-induced oral mucositis in patients with lymphomas or solid tumors. 1156 40


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