Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278488 (metastatic breast cancer)
 7,812 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Taxanes are the most active drugs in the treatment of metastatic breast and ovarian cancer. Weekly therapy with paclitaxel produces notable activity, with remarkably low toxicity. Moreover, combination therapy with paclitaxel and fluorouracil (5-FU) exhibits high activity in anthracycline-pretreated breast cancer patients: recent studies report response rates of 54% to 69%. UFT plus oral leucovorin constitutes an orally administered compound that provides activity comparable to that of intravenously administered 5-FU plus leucovorin. An open-label phase I study was initiated to determine the maximum tolerated dose and dose-limiting toxicities of the combination of weekly paclitaxel and UFT plus leucovorin administered to patients with anthracycline-resistant metastatic breast cancer.
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PMID:A phase I study. UFT/leucovorin combined with paclitaxel for anthracycline-pretreated advanced breast cancer. 1109 92

From June 1997 through December 1999, we treated twenty-two metastatic breast cancer patients with Docetaxel (60 mg/m2 administered intravenously every four weeks). All patients had received prior chemotherapy including anthracycline, and also another agent such as MMC-VDS, HDMTX-5-FU or CPT-11. One CR, 5 PR, and 4 Long NC were achieved. Grade 3/4 leukocytopenia occurred in 16 patients. Using the Kaplan Meier method, the median time to progression was 179 days, and the median survival time was 369 days. No serious adverse effects were observed. In this study Docetaxel seems to have shown significant activity, even for poor candidates, with intensive prior therapy.
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PMID:[Efficacy of docetaxel for anthracycline-resistant metastatic breast cancer]. 1138 11

Although drugs such as the taxoids and vinorelbine have increased the options available for anthracycline-resistant metastatic breast cancer, new therapeutic options are needed, particularly for taxoid-refractory tumours. Increasing emphasis is being placed on the development of oral agents, which many patients prefer provided efficacy is not compromised, particularly if the oral agents are less toxic than current intravenous agents. Capecitabine, a new, oral fluoropyrimidine, mimics continuous infusion 5-FU and is activated preferentially at the tumour site. Phase II studies of capecitabine have demonstrated encouraging response rates in patients with few further treatment options (20% response with an additional 43% achieving stable disease in paclitaxel-refractory patients; 36% response with a further 23% achieving stable disease in anthracycline-refractory patients). In addition, a randomized, phase II trial demonstrated a response rate of 30% (95% Cl: 19-43%) with capecitabine as first-line treatment for metastatic breast cancer, compared with 16% (95% Cl: 5-33%) in patients receiving low-dose CMF. These trials also showed that capecitabine has a favourable safety profile typical of infused fluoropyrimidines. Both alopecia and myelosuppression were rare. Capecitabine may therefore provide an effective, well-tolerated and convenient alternative to intravenous cytotoxic agents, not only in taxoid-resistant patients, but also in anthracycline-resistant metastatic breast cancer or as first-line therapy. Furthermore, the low incidence of myelosuppression makes capecitabine an attractive agent for incorporation into combination regimens with agents such as epirubicin/doxorubicin, the taxoids and vinorelbine.
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PMID:Oral fluoropyrimidines among the new drugs for patients with metastatic breast cancer. 1138 89

5-Fluorouracil (5-FU) given by continuous infusion (c.i.) allows higher dose delivery, causes less myelosuppression, and may interfere with repair of DNA damage caused by epirubicin and cyclophosphamide. With this rationale, we conducted a phase II study to test the activity and toxicity of 5-FU c.i., epirubicin, and cyclophosphamide in patients with metastatic breast cancer (MBC). Twenty-eight patients with MBC were entered in the trial. 5-FU (200 mg/m(2)) was administered by c.i. from day 1 to day 20. Epirubicin (35 mg/m(2)) and cyclophosphamide (400 mg/m(2)) were administered from day 2 to day 4, every 4 weeks. All patients were evaluable for response and toxicity. A total of 125 courses of chemotherapy were administered, with a median of 4 per patient (range: 2--6). Toxicity, assessed using World Health Organization criteria, was as follows: nausea and vomiting grade III--IV occurred in 36%, alopecia (grade III) in 86%, neutropenia (grade III--IV) in 50%, and cardiac toxicity grade I--II in 11% of patients. Five patients (17.9%) had a complete response to therapy, and 16 (57.1%) had a partial response (response rate 75%, 95% CI 55--89%). Disease stability and progression occurred in 4 (14.3%) and 3 (10.7%) patients, respectively. Median time to progression was 13.1 months (range: 3.4--66.9+), and median survival time was 27.7 months (range: 5.4--67.1+). Outpatient treatment with combined 5-FU c.i., epirubicin, and cyclophosphamide shows high activity in advanced breast cancer and gives prolonged remission with acceptable toxicity.
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PMID:Combined 5-fluorouracil infusion with fractionated epirubicin and cyclophosphamide in advanced breast cancer. 1147 71

Capecitabine (Xeloda, Roche, Monza), a fluoropyrimidine carbamate, is an orally administered drug that delivers fluorouracil (5-FU) selectively to the tumor. The drug has demonstrated activity in metastatic breast cancer, pancreatic cancer and colorectal cancer. In this case report the authors describe an unusually and reversible cardiac side effect which occurs to 39-year-old patient treated with capecitabine 2000 mg/m2/day for advanced gastric cancer. It is important to note that the safety data from clinical trials indicate that capecitabine has a toxicity profile typical of infused fluoropyrimidines. However, none of the studies described cardiac side effects.
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PMID:Acute cardiotoxicity during capecitabine treatment: a case report. 1150 78

To date, in cases of advanced or recurrent breast cancer, combination chemotherapy including anthracycline have been used for 1st-line treatment. Mitomycin C and oral 5-FU were used for cases refractory to such treatment, but the response rate was not satisfactory. Docetaxel is one of the most promising drugs to have emerged in recent years, with phase II studies in previously untreated metastatic breast cancer indicating a high overall response rate of approximately 60%, in the refractory cases for anthracyclines, indicating an overall response rate of 40% using docetaxel at 75 to 100 mg/m2 as a 1-hour intravenous infusion every 21 days. In Japan, the overall response rate was reported as about 50% using single docetaxel given at 60 mg/m2 every 21 days. The dose-limiting toxicity is myelosuppression, which is dose-but not schedule-dependent. In most published studies, there is a 90-95% incidence of grade 3 or 4 neutropenia when docetaxel is administered every 3 weeks. In recent studies, for the purpose of reducing the severity of myelosuppression, weekly docetaxel seems to be an effective and feasible treatment for advanced or recurrent breast cancer.
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PMID:[Docetaxel]. 1168 Dec 43

Measurement of molecular markers predictive of response to therapy should enable more selective and effective utilization of anticancer agents. The predictive value of HER2 remains a complex and inconclusive subject. In metastatic breast cancer, HER2-positive, ER-positive patients can show responses to endocrine treatment, but experience shorter time to progression and survival than HER2-negative patients. In the adjuvant setting, weak, retrospective evidence suggests that tamoxifen is potentially harmful in HER2-positive patients and that there is no benefit from prolonged tamoxifen therapy. It has not yet been demonstrated conclusively that HER2 positivity increases resistance to adjuvant cyclophosphamide, methotrexate, 5-FU (CMF), but there are indications that HER2-positive patients benefit more from adequately dosed anthracyclines than from CMF. The greatest value of HER2 as a predictive marker lies in the prediction of response to therapies that target HER2, such as Herceptin. Patients with strongly HER2-positive breast cancer derive significant clinical benefit from single-agent and combined Herceptin therapy. HER2 testing has become an integral part of the optimal management of the breast cancer patient. Best current practice in adjuvant breast cancer therapy based on the current knowledge of the potential predictive power of HER2 constitutes not denying tamoxifen to HER2-positive, ER-positive patients or CMF to HER2-positive patients. Outside of clinical trials, adequately dosed anthracycline-based chemotherapy is the current preferred adjuvant treatment option for HER2-positive patients.
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PMID:The predictive value of HER2 in breast cancer. 1169 91

To evaluate the antitumor efficacy against metastatic breast cancer of fluoropyrimidines alone and combined with other chemotherapeutic agents, we developed a murine model of breast cancer metastatic to the lung by orthotopically implanting MDA-MB-435S breast tumors into mice. MDA tumor cells greatly metastasized to lung tissue only after the orthotopically implanted tumors were surgically removed. Measurement of the expression of enzymes involved in 5-FU metabolism showed significantly higher activity of dihydropyrimidine dehydrogenase (DPD) and lower activity of thymidylate synthase (TS) in the MDA metastases than in the orthotopically implanted tumors. Based on the enzymatic properties of metastatic tumors, the minimum toxic doses of UFT (17.5 mg/kg/day) as a DPD-inhibitory fluoropyrimidine (DIF), and of 5'-DFUR (120 mg/kg/day) as a non-DIF, were orally administered to mice with pulmonary metastasis of the breast tumor. The results showed that UFT significantly inhibited the growth of pulmonary metastases of the breast tumors, but 5'-DFUR did not. UFT seemed to inhibit the growth of the pulmonary metastases of the breast tumors in combination with paclitaxel (50 mg/kg) more than in combination with 5'-DFUR, although the antitumor efficacy of neither combination was significantly different from that of paclitaxel alone. These results suggest that combination of DIF with other chemotherapeutic drugs, such as taxanes, is required to attain high antimetastatic and antitumor efficacy against breast tumor metastases, based on the molecular characteristics of the metastatic tumors.
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PMID:[Antimetastatic and antitumor effects of fluoropyrimidines alone and combined with taxanes in a murine model of breast cancer metastatic to the lung]. 1181 85

The extreme drug resistance (EDR) assay has not been widely studied in the setting of non-metastatic breast cancer. We evaluated the feasibility of performing the assay in 144 primary breast tumor specimens from two institutions by determining the rate of successful tumor culture for assays, number of drugs evaluated per assay, and time from tumor biopsy to receipt of results. We also sought to determine factors that are associated with assay success. An exploratory analysis was performed to detect possible associations between estrogen receptor (ER), progesterone receptor (PR) and HER2/NEU over-expression and extreme drug resistance demonstrated by the assay for specific chemotherapeutic agents. Of 144 tumor specimens submitted, tumor was successfully cultured for assay in 101(70%) of cases. A median of five drugs was evaluated per assay (range 2-9). Results were obtained in a median of 8 days (range 2-29). Young age, high tumor grade, PR negativity, and higher tumor submission weight were predictive for a successful assay. EDR was observed in 7-15% of tumors to doxorubicin, cyclophosphamide, 5-fluorouracil (5FU) and mitoxantrone, but EDR to paclitaxel was observed in 35%. Extreme drug resistance to 5-FU was associated with negative ER and PR status. There was a trend toward association between EDR to paclitaxel and HER2/NEU over-expression. The EDR assay may be successfully performed in the majority of tumors, and assay results are available in a timely fashion such that adjuvant treatment drug selection could be guided by results. These results may be helpful for designing possible future trials that evaluate the assay's role in adjuvant chemotherapy selection.
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PMID:Factors associated with success of the extreme drug resistance assay in primary breast cancer specimens. 1188 14

Although the anti-neoplastic activity of 5-Fluorouracil (5-FU) is improved by continuous infusion or biochemical modulation, the need for in-dwelling central venous catheters and toxicity have proved to be major impediments. Capecitabine (Xeloda, N4-pentyloxycarbonyl-5'-deoxy-5-fluoro-cytidine), an oral fluoropyrimidine, has been synthesized in the laboratory as an inactive precursor that passes intact through the intestinal mucosa and is sequentially converted to 5'-deoxy-5-fluorocytidine (5'-DFCR), 5'-deoxy-5-fluorouridine (5'-DFUR) and finally 5-FU in the liver and tumour tissues selectively. Preclinical studies provided evidence of preferential conversion of inactive 5'-DFUR to active 5-FU in solid tumours due to the relative overexpression of the final anabolising enzyme, thymidine phosphorylase (TP), in neoplastic tissues more than in normal counterparts. Phase I/II studies exploring toxicity and the appropriate dosing resulted in the evaluation of the intermittent schedule (2510 mg/m2/day for 14 days every 3 weeks) in subsequent trials. Two large phase III studies in patients with metastatic colon cancer established at least equivalent efficacy and improved tolerability for capecitabine compared to the Mayo Clinic bolus 5-FU/folinic acid regimen. Phase II studies established remarkable activity in women with heavily pretreated metastatic breast cancer. Moreover the combination with a taxane yielded a unique survival benefit compared to the previous gold standard of taxane monotherapy in a phase III trial of women with anthracycline resistant breast cancer. The commonest side-effects are hand and foot syndrome, diarrhoea and stomatitis with serious adverse events occurring in a minority of patients. Myelosuppression was minimal or absent. Toxic manifestations are easily managed with a significant reduction in the frequency of hospitalizations and medical resource use, as shown in appropriate studies. Capecitabine is expected to find a role in the treatment of other tumour types as well as adjuvant administration. It represents an advance in modern drug development, stressing the current shift towards rational development of new agents and home-based outpatient regimens.
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PMID:The rational development of capecitabine from the laboratory to the clinic. 1255 61


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