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)

Recent developments with chemotherapy for breast cancer have improved patient survival. However, there continue to be nonresponders to conventional anticancer agents. Multidrug resistance (MDR) is caused by the expression of P-glycoprotein (P-gp) on the cell membrane. The expression of P-gp is encoded by MDR1 mRNA in tumors and is associated with clinical drug resistance. Since P-gp appears to be involved in both acquired and congenital MDR in human cancers, P-gp could be an important target for improving the efficacy of chemotherapy. Recently, we have focused on a therapeutic approach to reduce drug resistance in chemotherapy for breast cancer. Dofequidar fumarate (Dof) is a novel, orally active quinoline derivative that reverses multidrug resistance. In preclinical studies, the inhibition of doxorubicin-resistant cancer cell lines was observed in the presence of Dof + doxorubicin. We conducted clinical trials including Dof + cyclophosphamide (C), doxorubicin (A), and fluorouracil therapy (F) for patients with advanced or recurrent breast cancer. We compared the efficacy and tolerability of Dof + CAF with CAF alone. In this randomized, placebo-controlled trial, all patients were treated with six cycles of CAF therapy. Patients received Dof (900 mg p.o.) 30 min before doxorubicin. The primary endpoint was overall response rate (partial or complete response). In total, 221 patients were evaluable. The overall response rate was 42.6% for CAF alone versus 53.1% for Dof + CAF. Although the response rate improved by more than 10% with the combination of Dof + CAF, it was not statistically significant. Initially, we were expecting more than 20% improvement in the overall response rate. However, Dof significantly improved progression-free survival in patients who were premenopausal (P=0.046), who had received no prior therapy (P<0.01), or patients with advanced (stage IV) primary tumors (P=0.017). In addition, treatment with Dof did not affect the plasma concentration of doxorubicin in patients. These clinical studies indicate that Dof was well tolerated and displayed promising efficacy in patients who had not received prior therapy. The antiestrogens, tamoxifen, and toremifene, may moderate P-gp-related drug resistance in vitro. Toremifene demonstrated a synergistic effect in combination with paclitaxel on various human breast cancer cell lines. Furthermore, a synergistic effect was observed on a multidrug-resistant cell line. This synergistic effect was more potent when paclitaxel was combined with toremifene than with tamoxifen. Clinical benefits in some patients with recurrent breast cancer were reported.
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PMID:Drug resistance in chemotherapy for breast cancer. 1627 61

A sentinel node biopsy (SNB) has been proved to be an accurate method to estimate the axillary lymph node status as a replacement for axillary lymph node dissection (AxLND) in patients with early breast cancer who have not been treated with neoadjuvant chemotherapy (NAC). We examined the feasibility and accuracy of performing SNB after NAC. Seventy breast cancer patients treated with NAC were enrolled in the current study during the period between March 2001 and June 2005. NAC performed preoperatively consisted of three to four times of CAF chemotherapy. Moreover, intra-arterial (subclavian artery and internal mammary artery) infusion of epirubicin and 5-fluorouracil was performed in addition to systemic CAF chemotherapy once to three times in patients with large breast tumors or bulky axillary lymph node metastases. The sentinel nodes were successfully identified in 63 out of 70 patients (identification rate: 90%). The mean number of sentinel nodes removed per patient was 1.5 (range 1-6). Of the 43 patients in whom AxLND was performed after the sentinel nodes were identified, 19 (44.2%) had positive sentinel nodes. In 8 of those 19 patients, the sentinel node was the only cancer positive lymph node. Among the 24 patients who had negative sentinel nodes it was found that one patient had a confirmed false negative result, thus yielding a false negative rate of 5%, and a sensitivity of 95%. There was no false negative patient who had a clinically negative lymph node status (N0) before NAC (17 patients), whereas the false negative rate was 6.3% in the subgroup of patients with a clinically positive lymph node status (N1, N2) before NAC (26 patients). As a result, SNB after NAC is thus considered to be able to effectively predict the axillary lymph node status in patients with a clinically negative lymph node status before NAC.
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PMID:Sentinel node biopsy in breast cancer patients treated with neoadjuvant chemotherapy. 1652 81

There is a well-established role for reactive oxygen and nitrogen species, chronic inflammation and immune response in the pathogenesis of breast cancer. Complex interactions between breast cancer cells and surrounding blood vessels are prerequisites for cancer growth and invasion. Reports in the literature concerning the systemic response to, and the effect of, common breast cancer therapy on NF-kappaB and antioxidative defence enzyme expression and activity under clinical conditions are scarce. We determined these parameters in whole blood cell lysate from 16 women with breast cancer before and after combined (cyclophosphamide, doxorubicin, 5-fluorouracil; CAF) therapy and compared the results with 16 healthy women. Significantly higher levels of NF-kappaB and Mn-SOD (both their protein level and their activity) were found in breast cancer patients before and after CAF therapy, in comparison with healthy women. In parallel measurements, no change in the level or activity of catalase (CAT) was detected. According to our findings, it appears that breast cancer creates conditions that increase the level of hydrogen peroxide in the circulating cells and that the applied CAF therapy fails to compensate, therefore creating systemic conditions that favour survival and invasion of breast cancer cells.
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PMID:Systemic NF-kappaB activation in blood cells of breast cancer patients. 1657 Dec 74

We performed a controlled study to compare the response to cyclophosphamide (CPA), adriamycin (ADM), and fluorouracil (5-FU) (CAF therapy) with that to uracil-tegafur (UFT) plus tamoxifen (TAM) (UFT+TAM therapy), when given as postoperative adjuvant therapy to women with breast cancer. The patients were registered from September 1991 through February 1995 at 51 institutions in the Kinki district of Japan. All patients had stage I, II, or IIIa breast cancer with four or more lymph-node metastases and underwent mastectomy. CAF therapy and UFT+TAM therapy were started within 4 weeks after surgery. CAF therapy consisted of CPA (100 mg/day) on days 1 to 14, followed by 2 weeks of rest, plus ADM (20 mg/m(2)/day) on days 1 and 8 and 5-FU (300 mg/m(2)/day) on days 1 and 8. A total of 6 courses were delivered. UFT+TAM therapy consisted of 3 years of UFT (400 mg/day) plus TAM (20 mg/day), given daily. CAF therapy and UFT+TAM therapy were each assigned to 82 patients. The 5-year survival rate was significantly higher in the UFT+TAM group (82.1%) than in the CAF group (66.2%; p=0.04, logrank test). The 5-year relapse-free survival rate was higher in the UFT+TAM group (61.8%) than in the CAF group (46.3%; p=0.07, logrank test). As for adverse events, the rates of leukopenia, anorexia, nausea and vomiting, general malaise, and hair loss were lower in the UFT+TAM group than in the CAF group. These results suggest that long-term treatment with UFT+TAM may be a useful alternative adjuvant therapy for the management of breast cancer, especially in elderly patients.
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PMID:[A randomized controlled study comparing uracil-tegafur (UFT)+tamoxifen (UFT+TAM therapy) with cyclophosphamide+adriamycin+5-fluorouracil (CAF therapy) for women with stage I , II, or IIIa breast cancer with four or more involved nodes in the adjuvant setting]. 1703 31

The purpose of this study is to evaluate the accuracy of mammography, ultrasonography, and contrast-enhanced magnetic resonance imaging for the diagnosis of intraductal spread of breast cancer following preoperative neoadjuvant chemotherapy. We evaluated a total of 168 areas of normal breast tissue outside the mass in 42 consecutive female patients with breast cancer using each imaging modality both before and after neoadjuvant chemotherapy. Neoadjuvant chemotherapy comprised two to four cycles of adriamycin-based CAF regimen. Multivariate analysis indicated that calcification on mammography and size of hypoechoic structures on ultrasonography prior to neoadjuvant chemotherapy shows a correlation with intraductal spread on pathologic study. Our study reveals that mammography and ultrasonography are useful in avoiding residual cancer cells caused by intraductal spread following conservative breast surgery.
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PMID:Diagnostic accuracy of mammography, ultrasonography and magnetic resonance imaging in the detection of intraductal spread of breast cancer following neoadjuvant chemotherapy. 1734 36

The patient was a 40-year-old woman who was admitted to our hospital because of severe cough and dyspnea due to multiple lung metastases from breast cancer, who had undergone Auchincloss operation for right breast cancer about five years earlier. While systemic chemotherapy (CAF) was started after admission,she presented with cardiac tamponade. A cardiac echogram revealed marked retention of pericardial effusion. Pericardiocentesis was carried out, and the cytology of the effusion showed class V, resulting in the diagnosis of carcinomatous cardiac tamponade due to breast cancer. She was treated with intrapericardial chemotherapy using OK-432 and mitomycin C (MMC), and has not suffered from pericardial effusion after the intrapericardial chemotherapy. Intrapericardial chemotherapy using OK-432 and MMC may be very useful for malignant pericardial effusion.
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PMID:[A case of carcinomatous cardiac tamponade due to breast cancer treated with OK-432 and mitomycin C]. 1735 39

This paper deals with the idea of balancing drug effects on tumor and normal cell populations based on a variety of criteria, which is evaluated by the oncologist for breast cancer patients at stage IIB. In this paper, the optimal controller represents the optimal drug dosage of CAF (Cyclophosphamide, Adriamycin and Fluorouracil) regimen in adjuvant chemotherapy after surgery for these patients. We determined the doses of CAF regimen by minimizing a cost function with some constraints. The cost function includes the cancer cell and the normal cell growth dynamics with prescribed weighting coefficients for each patient. The physician determines these weighting coefficients based on some individual parameters. The optimal treatment schedules are computed based on a trade-off between the cancer cell reduction and the normal cell preserving. Numerical simulations are given to illustrate the accuracy of the optimal controller.
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PMID:The optimal dose of CAF regimen in adjuvant chemotherapy for breast cancer patients at stage IIB. 1853 95

A multi-center, randomized controlled collaborative study was conducted in 310 institutions located throughout Japan for 3 years and 9 months from February 1985 until October 1988 to evaluate the efficacy of post-operative adjuvant therapy for patients who had previously undergone curative surgery for treatment of Stage IIIa breast cancer. Patients with estrogen receptor-positive [ER( + )] breast cancer were treated with two types of regimens, ie, cyclophosphamide + adriamycin + fluorouracil (CAF; 2 cycles) + Futraful (FT) or CAF (2 cycles) + FT + tamoxifen (TAM), and the clinical benefit of additional use of TAM was evaluated. Of the 509 ER( + ) patients registered for the trial, 473 patients (92.9%) were eligible for evaluation. The 5-year survival rate was 77.2% for the CAF + FT group and 74.6% for the CAF + FT+TAM group, and the 5-year disease-free survival rate was 56.7% for the CAF+FT group and 59.2% for the CAF + FT + TAM group. Neither the survival rate nor the disease-free survival rate differed significantly between the groups. Analyses by factor revealed that the 5-year disease-free rate for lymph node-negative patients in the CAF + FT + TAM group was significantly higher than that for the corresponding patients in the CAF + FT group. No differences were noted in the incidence of adverse reactions between the two treatment groups, other than an increase in LDH (the frequency of which was higher in the CAF + FT+TAM group than in the CAF + FT group). Patients with estrogen receptor-negative [ER( -)] breast cancer were treated with two types of regimens, ie, CAF + FT or CAF + FT + adriamycin (ADR), and the clinical benefit of the combined use of intermittent doses of ADR was evaluated. Of the 514 ER(-) patients registered in the trial, 478 (93.0%) were eligible for evaluation. The 5-year survival rate was 64.9% for the CAF + FT group and 63.0% for the CAF + FT + ADR group, and the 5-year disease-free survival rate was 59.2% for both CAF + FT and CAF + FT + ADR groups. Neither the survival rate nor the disease-free survival rate differed significantly between the groups. There were no significant differences between these groups in analyses by nodal or menopausal status. The incidences of adverse reactions including anorexia, nausea/vomiting and alopecia were higher in the CAF + FT+ADR group than in the CAF + FT group.
Breast Cancer 1997
PMID:Efficacy of postoperative adjuvant therapy for stage ilia breast cancer: Futraful vs futraful+tamoxifen for ER-positive patients and futraful vs futraful + adriamycin for ER-negative breast cancer. 1884 55

Stromal fibroblasts influence the behavior of breast epithelial cells. Fibroblasts derived from normal breast (NAF) inhibit epithelial growth, whereas fibroblasts from breast carcinomas (CAF) have less growth inhibitory capacity and can promote epithelial growth. We sought to identify molecules that are differentially expressed in NAF versus CAF and potentially responsible for their different growth regulatory abilities. To determine the contribution of soluble molecules to fibroblast-epithelial interactions, NAF were grown in 3D, transwell or direct contact co-cultures with MCF10AT epithelial cells. NAF suppressed proliferation of MCF10AT in both direct contact and transwell co-cultures, but this suppression was significantly greater in direct co-cultures, indicating involvement of both soluble and contact factors. Gene expression profiling of early passage fibroblast cultures identified 420 genes that were differentially expressed in NAF versus CAF. Of the eight genes selected for validation by real-time PCR, FIBULIN 1, was overexpressed in NAF, and DICKKOPF 1, NEUREGULIN 1, PLASMINOGEN ACTIVATOR INHIBITOR 2, and TISSUE PLASMINOGEN ACTIVATOR were overexpressed in CAF. A higher expression of FIBULIN 1 in normal- than cancer-associated fibroblastic stroma was confirmed by immunohistochemistry of breast tissues. Among breast cancers, stromal expression of Fibulin 1 protein was higher in estrogen receptor alpha-positive cancers and low stromal expression of Fibulin 1 correlated with a higher proliferation of cancer epithelial cells. In conclusion, expression profiling of NAF and CAF cultures identified many genes with potential relevance to fibroblast-epithelial interactions in breast cancer. Furthermore, these early passage fibroblast cultures can be representative of gene expression in stromal fibroblasts in vivo.
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PMID:Identification of molecular distinctions between normal breast-associated fibroblasts and breast cancer-associated fibroblasts. 1930 79

PURPOSE We have demonstrated that patients with HER2-amplified tumors derive more benefit from higher doses of doxorubicin-containing chemotherapy (cyclophosphamide, doxorubicin, and fluorouracil [CAF]). Because topoisomerase IIalpha (Topo-IIalpha) is a target for doxorubicin and is coamplified in 20% to 50% of HER2-amplified tumors, we postulated that Topo-IIalpha copy number might account for the benefit from CAF dose escalation in HER2-positive tumors. To address this hypothesis, we examined Topo-IIalpha and HER2 copy number, CAF dose, and clinical outcomes in Cancer and Leukemia Group B (CALGB) 8541. PATIENTS AND METHODS Topo-IIalpha and HER2 copy number were measured by fluorescent in situ hybridization (FISH) using a triple-probe system, which includes Topo-IIalpha, HER2, and chromosome 17 (CEP17). Topo-IIalpha and/or HER2 were classified as amplified (> or = two copies/CEP17, deleted (< or = 0.67 copies/CEP17) and normal copy number (> .67 to < 2.0 copies/CEP17). Results Topo-IIalpha/HER2/CEP17 measurement was successful in 624 of 687 cases. HER2 was amplified in 117 cases (19%). Topo-IIalpha was amplified in 41 cases (7%) and deleted in 69 cases (11%). Topo-IIalpha amplification was highly correlated with HER2 amplification (39 of 41; P < .0001), HER2 by immunohistochemistry, and by dual-probe FISH. Topo-IIalpha was deleted in both the HER2-amplified (30 of 69; 43%), normal (22 of 69; 32%) and HER2-deleted tumors (17 of 69; 25%). Although Topo-IIalpha-amplified tumors were nearly always HER2 amplified, these tumors did not receive benefit from increasing the dose of CAF (P = .15). CONCLUSION The correlative companion study CALGB 8541-150013 does not support the hypothesis that Topo-IIalpha amplification is the mechanism behind benefit from increased dose of anthracyclines in HER2-positive breast cancer.
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PMID:Topoisomerase II{alpha} amplification does not predict benefit from dose-intense cyclophosphamide, doxorubicin, and fluorouracil therapy in HER2-amplified early breast cancer: results of CALGB 8541/150013. 1947 Sep 42


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