Multicenter phase II trial of neoadjuvant exemestane for postmenopausal patients with hormone receptor-positive, operable breast cancer: Saitama Breast Cancer Clinical Study Group (SBCCSG-03).

This multicenter phase II trial evaluated the efficacy and tolerability of 4 months of neoadjuvant exemestane in 44 postmenopausal patients with estrogen receptor (ER)-positive and/or progesterone receptor-positive, stage II to IIIB breast cancer measuring >or=3 cm. Pathological response was assessed by a central review board using response criteria proposed by the Japanese Breast Cancer Society. Clinical response [complete or partial response (PR)] was assessed by caliper, mammography, or ultrasound. Rates of breast-conserving surgery (BCS) and adverse events were also evaluated. A pathological response was observed in 13 (43%) of 30 patients who underwent surgery at 4 months. Fourteen patients were excluded from the pathological analysis: eight continued exemestane because of PR or stable disease (SD) at 4 months, three underwent chemotherapy because of progressive disease, and three underwent surgery within 2 months because of adverse events. A clinical response was seen in 27 (66%) of 41 evaluable patients. BCS was performed in 27 (90%) of 30 patients who underwent surgery at 4 months. Of the ten patients eligible for mastectomy at baseline, six chose to continue exemestane treatment without surgery because of a PR or SD at 4 months. Adverse events, most of which were grade 1, occurred in

[Assessment of goserelin treatment in adjuvant therapy for premenopausal patients with breast cancer in Japan-zoladex breast cancer study group trial-B].

OBJECTIVE: Goserelin (GOS) therapy in an adjuvant setting for estrogen receptor(ER)-positive premenopausal patients with breast cancer was assessed in a randomised comparative study. METHODS: ER positive premenopausal patients with n + or n 0 and T > or = 3 cm received tamoxifen (TAM) 20 mg/day, GOS 3.6 mg/4 weeks or GOS + TAM for 2 years, and the clinical efficacy and safety of these regimens were assessed. RESULTS: In the data analysis of total 207 patients, hazard ratios of disease free survival (DFS) and overall survival (OS) in the GOS group compared to the TAM group were 0.87 and 2.10,respectively. The incidence of adverse drug reactions was similar (42-55%) in all three groups. Since the number of patients in this study did not reach the target number, the efficacy could not be assessed from a statistical aspect. Therefore,meta-analysis with similar foreign studies(ZIPP) was implemented. The results of meta-analysis showed that the hazard ratios of DFS and OS in the GOS group compared to the non-GOS group were 0.83 and 0.85, respectively. CONCLUSION: Although the analysis of 207 patients did not show any statistically significant difference between each of the treatment groups, the results of meta-analysis showed a significant prolongation of DFS in the GOS group. Also high tolerability of GOS was suggested. From these results, GOS was considered highly useful in adjuvant therapy for ER-positive premenopausal patients with breast cancer.

TZT-1027 elucidates antitumor activity through direct cytotoxicity and selective blockade of blood supply.

BACKGROUND: TZT-1027 is a newly developed antitumor agent derived from dolastatin 10. MATERIALS AND METHODS: The in vitro activity of TZT-1027 on MCF-7 and R-27 cells was evaluated by MTT assay. TZT-1027 1 mg/kg/week was administered i.v. for 4 weeks into nude mice bearing MCF-7 and R-27. Subsequently, primary cultured cells from xenografts were also used for CD-DST. Two mg of TZT-1027 or 40 mg docetaxel per kg were injected i.v. into nude mice bearing R-27. 0.2% Evans blue was injected to assess the blood flow. RESULTS: TZT-1027 suppressed the in vitro growth of MCF-7 cells, while R-27 cells were resistant to TZT-1027, although its in vivo antitumor activity was remarkable. TZT-1027 blockaded R-27 tumor blood flow immediately after injection; blood flow was not affected by docetaxel. CONCLUSION: TZT-1027 exerts its antitumor activity through direct cytotoxicity against MCF-7 cells and through selective blockade of tumor blood flow against R-27 cells.

Multicenter phase II trial of weekly paclitaxel for advanced or metastatic breast cancer: the Saitama Breast Cancer Clinical Study Group (SBCCSG-01).

OBJECTIVE: Weekly dosing of paclitaxel has been demonstrated to be a well-tolerated, feasible and effective administration schedule. In this study, we evaluated the efficacy and safety of weekly paclitaxel in Japanese women with advanced or metastatic breast cancer. METHODS: Seventy-four patients were enrolled in the study. Paclitaxel was administered by 1 h intravenous infusion at a dose of 80 mg/m2 every week. Administration was continued for 3 weeks followed by a 1 week rest. A short premedication, consisting of dexamethasone 10 mg, ranitidine 50 mg and diphenylhydramine 50 mg, was given prior to each dose of paclitaxel. Eligibility criteria included an Eastern Cooperative Oncology Group performance status of 0, 1 or 2 and adequate hematological, hepatic and renal function. RESULTS: Of 74 patients treated and evaluable for toxicities, 70 were evaluable for response. The mean age was 57.7 years. Forty-nine patients (66.2%) had received prior anthracyclines for metastatic diseases. The overall response rate among 74 patients was 40.5%, including 4.1% complete responses and 36.5% partial responses. The median follow-up time was 481 days (range, 24-903 days). The median time to progression was 4.8 months and median overall survival was 15.8 months. The majority of patients tolerated the treatment very well. Although alopecia was observed in most of the patients (93.2%), grade 3 or 4 neutropenia was 10.8% and grade 2 or 3 peripheral neuropathy was 13.5%. CONCLUSION: Weekly paclitaxel as a 1 h infusion was active and generally well tolerated in previously treated patients. Further study of weekly paclitaxel in combination therapy is warranted.

Combined antitumor activity of 7-hydroxystaurosporine (UCN-01) and tamoxifen against human breast carcinoma in vitro and in vivo.

BACKGROUND: 7-Hydroxystaurosporine (UCN-01) was originally isolated as a protein kinase C inhibitor and has shown antitumor activity against several human cancer cell lines. UCN-01 inhibits cell cycle progression from the G1 to the S phase and is associated with inhibition of cyclin-dependent kinase (CDK) activity and induction of intrinsic CDK inhibitor p21, leading to dephosphorylation of retinoblastoma (Rb) protein. Tamoxifen (TAM) traps cancer cells in the G1 phase, suggesting that the mechanism of action of TAM is similar to that of UCN-01. The present study was conducted to assess the antitumor activity of UCN-01 combined with TAM against human breast carcinoma cells in vitro and in vivo. MATERIALS AND METHODS: MCF-7 cells were treated with UCN-01, TAM, or UCN-01 combined with TAM at various concentrations in vitro. The antitumor effect was evaluated as the inhibition rate (I.R.%) by MTT assay. Two human breast carcinoma xenografts in nude mice, MCF-7 and Br-10, were treated with UCN-01, TAM or both agents together. The expression of p21 and the phosphorylation status of Rb protein in MCF-7 cells were detected by Western blotting. RESULTS: UCN-01 or TAM alone inhibited the proliferation of MCF-7 cells in a concentration-dependent manner. Combined treatment with UCN-01 followed by TAM inhibited the growth of MCF-7 cells synergistically and no significant differences in cytotoxicity were observed between the different sequences of UCN-01/TAM and TAM/UCN-01. Combination treatment with UCN-01 and TAM against MCF-7 and Br-10 in vivo exhibited superior antitumor effects compared with either agent treatment alone. Although 0.1 microg UCN-01 per ml (I.R.: 48.1%) or 2 microM TAM (I.R.: 31%) induced p21 expression, phosphorylation of Rb protein was not inhibited. However, combination treatment with UCN-01 and TAM at the same concentrations resulted in an I.R. of 67% and dephosphorylation of Rb protein. CONCLUSION: The present study suggests that combining UCN-01 and TAM could result in augmented cytotoxicity because of their similar mechanism of action. This combination may have potential clinical applications for breast cancer treatment, by reducing the toxicity of UCN-01.

UCN-01 (7-hydroxystaurosporine) inhibits the growth of human breast cancer xenografts through disruption of signal transduction.

BACKGROUND: 7-Hydroxystaurosporine (UCN-01), originally isolated as a phospholipid-dependent protein kinase C inhibitor, has been shown to have antitumor activity against several human cancer cell lines. UCN-01 inhibits cell cycle progression from the G1 to S phase by inhibition of cyclin-dependent kinase (CDK) activity and induction of intrinsic CDK inhibitor protein, leading to dephosphorylation of retinoblastoma (Rb) protein. MATERIALS AND METHODS: The antitumor activity of UCN-01 has been investigated against three human breast carcinoma strains serially transplanted into nude mice, including estrogen-dependent MCF-7, Br-10, and estrogen-independent MX-1. When the inoculated tumors started growing exponentially, UCN-01 (7.5 mg/kg) was administered intraperitoneally on five consecutive days a week for 2 weeks. The antitumor effect was evaluated as the lowest T/C ratio (%) during the experiments, where T was the relative mean tumor weight of the treated group and C was that of the control group. At the end of UCN-01 administration expression of p21, a protein of the CDK inhibitor family, and phosphorylated and dephosphorylated Rb protein was detected by Western blotting using treated and control tumors. RESULTS: UCN-01 had activity against MCF-7 and Br-10, with the lowest T/C ratios of 25.0% and 27.0%, respectively, while MX-1 was resistant to UCN-01 with a T/C ratio of 65.9%. The antitumor spectrum of UCN-01 was different from that of other conventional agents such as doxorubicin and cyclophosphamide which were ineffective against Br-10 but were active against MX-1. Although p21 was induced in three tested strains by UCN-01, little dephosphorylated Rb protein was expressed in MX-1 compared with Br-10 and MCF-7 (in vitro). CONCLUSION: UCN-01 appeared to be a promising agent for the treatment of breast cancer, with a different mode of action and antitumor spectrum from other currently available antitumor drugs.