Serum lipid and bone metabolism effects of Toremifene vs. Letrozole as adjuvant therapy for postmenopausal early breast cancer patients: results of a multicenter open randomized study.

A prospective randomized phase II trial was conducted to evaluate the time course effects of toremifene (TOR) and letrozole (LET), as adjuvant hormone therapy, on serum lipid profiles and bone metabolism in estrogen receptor (ER)-positive, postmenopausal breast cancer patients.Fifty-four postmenopausal breast cancer patients [ER positive, HER2 negative, T1-2, node metastases (n = 0-3), M0] who had undergone curative resection were enrolled. They were randomized to receive either TOR 40 mg/day or LET 2.5 mg/day as adjuvant hormone therapy. Serum lipids and bone markers were measured prior to, and again at 6, 12, and 24 months after initiation of treatment. Changes in serum lipids and bone markers were compared. Serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were decreased compared with the baseline values at 6 months in 6.5 and 14.0% of patients, respectively, receiving TOR. Lipid levels did not change in patients administered LET. Significant differences were observed in TC and LDL-C between the two groups at 12 and 24 months. In the TOR group, serum bone-specific alkaline phosphatase (BAP) was decreased by 25.0% at 12 months, and serum cross-linked N-telopeptide of type-I collagen (NTx) was decreased by 13.6% at 6 months, and these reductions were maintained for at least 24 months. In contrast, in the LET group, serum BAP did not change and NTx was increased by 16.0% at 6 months and by 18.6% at 24 months, as compared with the baseline.TOR and LET exert different effects on serum lipid profiles and bone metabolism markers. The effects of TOR, as adjuvant hormone therapy, on both lipids and bone metabolism in postmenopausal breast cancer patients are superior to those of LET.

Randomized phase III trial of trastuzumab monotherapy followed by trastuzumab plus docetaxel versus trastuzumab plus docetaxel as first-line therapy in patients with HER2-positive metastatic breast cancer: the JO17360 Trial Group.

We evaluated the efficacy and safety of sequential therapy with trastuzumab monotherapy (H-mono) followed by H plus docetaxel (D) after disease progression (H --> H + D) versus combination therapy with H + D as first-line therapy. Patients with human epidermal growth factor receptor type 2 (HER2)-positive metastatic breast cancer (MBC) and left ventricular ejection fraction >50% were randomly assigned to either (a) H --> H + D [H, once weekly 2 mg/kg (loading dose, 4 mg/kg); D, once every 3 weeks 60 mg/m(2)] or (b) H + D. Primary endpoints were progression-free survival (PFS) for the H-mono stage of the H --> H + D group and H + D group and overall survival (OS) for both groups. Secondary endpoints were overall response rate, time to treatment failure, second PFS and safety. The planned number of patients was 160 patients in total. Of 112 patients enrolled, 107 were eligible. After 112 patients were enrolled, the Independent Data Monitoring Committee recommended stopping enrollment because PFS and OS were greater in the H + D group than the H --> H + D group. Median PFS was 445 days in the H + D group versus 114 days for H-mono in the H --> H + D group [hazard ratio (HR), 4.24; P < 0.01]. OS was significantly longer in the H + D group (HR, 2.72; P = 0.04). H + D therapy is significantly superior to H --> H + D therapy as first-line therapy in patients with HER2-positive MBC, especially in terms of OS.

Efficacy of oral tegafur-uracil (UFT) as adjuvant therapy as compared with classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in early breast cancer: a pooled analysis of two randomized controlled trials (N.SAS-BC 01 trial and CUBC trial).

Two randomized clinical studies comparing the efficacy of oral UFT (2 years) with that of classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (six courses) have been conducted in patients with resected early breast cancer. We have performed a pooled analysis of these two randomized studies. A pooled analysis was performed using individual patient data from the two trials. Hazard ratios (HRs) were determined with a Cox model stratified by study and adjusted for clinical characteristics. We preplanned to verify the following two hypotheses: UFT is non-inferior to CMF in all patients (hypothesis 1) or in ER-positive patients (hypothesis 2) with respect to relapse-free survival (RFS). Non-inferiority of UFT versus CMF was established if the upper limit of the two-sided confidence interval (CI) of the HR for RFS did not exceed 1.30. Hochberg multiplicity adjustment for the significance level was performed. A total of 1,057 patients were analyzed (CMF, n = 528; UFT, n = 529). Median follow-up time was 5.6 years. The HR for RFS was 1.04 (95% CI, 0.78-1.40) in all patients and 0.79 (97.5% CI, 0.49-1.27) in ER-positive patients. UFT was shown to be non-inferior to CMF in ER-positive patients. An exploratory subgroup analysis showed that RFS was better with UFT than with CMF in ER-positive patients who were 50 years or older (HR, 0.58; 95% CI, 0.34-1.01). UFT is non-inferior to CMF in terms of inhibiting recurrence of ER-positive, early breast cancer.

Oral uracil and tegafur compared with classic cyclophosphamide, methotrexate, fluorouracil as postoperative chemotherapy in patients with node-negative, high-risk breast cancer: National Surgical Adjuvant Study for Breast Cancer 01 Trial.

PURPOSE: The primary aim of this study was to compare the effectiveness of oral uracil-tegafur (UFT) with that of classical cyclophosphamide, methotrexate, and fluorouracil (CMF) given as postoperative adjuvant treatment to women with node-negative, high-risk breast cancer. PATIENTS AND METHODS: Women with node-negative, high-risk breast cancer were randomly assigned to receive either 2 years of UFT or six cycles of CMF after surgery. The primary end point was relapse-free survival (RFS). Overall survival (OS), toxicity, and quality of life (QOL) were secondary end points. The hypothesis was that UFT was not inferior to CMF in terms of RFS. RESULTS: Between October 1996 and April 2001, a total of 733 patients were randomly assigned to receive either treatment. The median follow-up time was 6.2 years. The RFS rates at 5 years were 88.0% in the CMF arm and 87.8% in the UFT arm. OS rates were 96.0% and 96.2%, respectively. The hazard ratios of the UFT arm relative to the CMF arm were 0.98 for RFS (95% CI, 0.66 to 1.45; P = .92) and 0.81 for OS (95% CI, 0.44 to 1.48; P = .49). The toxicity profiles differed between the two groups. The QOL scores were better for patients given UFT than those given CMF. CONCLUSION: RFS and OS with oral UFT were similar to those with classical CMF. Given the higher QOL scores, oral UFT is a promising alternative to CMF for postoperative adjuvant chemotherapy in women with node-negative, high-risk breast cancer.

Sentinel lymph node biopsy after neoadjuvant chemotherapy in a patient with operable breast cancer.

PURPOSE: This study was undertaken to assess the feasibility of performing a sentinel lymph node biopsy (SLNB) for a patient with operable breast cancer after undergoing neoadjuvant chemotherapy (NAC). METHOD: Between January 2002 and December 2003, women with primary breast cancer who had a breast tumor measuring larger than 3 cm in unilateral diameter were eligible for NAC. All patients who had completed NAC underwent lymphatic mapping with labeled (99m)Tc phytate on the day before surgery. Sentinel lymph node biopsy followed by a full axillary lymph node (AXLN) dissection (ALND) was performed in all patients. Sentinel lymph nodes (SLN) were sent for a frozen-section examination. RESULTS: The rate of SLN identification was 71%. Both the sensitivity and negative predictive value of SLNB were 100%. The false negative rate was 0%. When candidates for SLNB were restricted to patients with a breast tumor measuring less than 3 cm and clinically negative nodes after NAC, the rate of SLN identification increased to 93% from 71% while still maintaining the 0% false negative rate. CONCLUSION: Sentinel lymph node biopsy after NAC is therefore considered to be a feasible and accurate method to predict the AXLN status in patients who have a breast tumor measuring less than 3 cm in unilateral diameter and a clinically negative AXLN status at the time of surgery after NAC.

Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II and pharmacokinetic study in Japan.

Tolerability and response rate to weekly combination chemotherapy with trastuzumab and vinorelbine in Japanese women with HER2-overexpressing breast cancer not previously receiving either therapy were assessed. Tumor response was evaluated every 4 weeks and adverse events were graded. A total of 23 patients from six participating centers in Japan were enrolled. Median dose intensity of vinorelbine was 16.9 mg/m2/week and response rate was 73% (complete response+partial response); complete response=9%, partial response=64%, and progressive disease=5%. Time to progression was 361 days, with 75.0% of liver metastases and 60% of lung metastases responding to this treatment. The most common adverse events were leukocytopenia and neutropenia (96%); however, hematologic toxicity associated with vinorelbine was manageable by adjusting the dose. No pharmacokinetic differences for vinorelbine were found between single administration and combination with trastuzumab. This combination therapy produced high response rates and good tolerability, indicating a promising role in first-line chemotherapy for HER2-overexpressing metastatic breast cancer in Japan.

Neoadjuvant paclitaxel for operable breast cancer: multicenter phase II trial with clinical outcomes.

AIM: To determine the efficacy of preoperative weekly paclitaxel for patients with operable breast cancer tumors greater than 3 cm. PATIENTS AND METHODS: Paclitaxel 80 mg/m2 weekly x 3 times every 4 weeks for 3 cycles was administered to 53 patients. Twenty-two patients were stage 11, 26 stage III, 5 stage IV Median age (range) was 53 (24-73) years, and 32 patients were negative for estrogen receptor. Thirteen patients showed HER2 overexpression. RESULTS: Eligible cases composed of 53 patients for evaluation of response. Seven patients had a clinical complete response and 29 patients had a partial response. The overall response rate was 67.9%, including three patients with a pathological complete response. In 18 patients with HER2 overexpression, a clinical complete response was observed in 5, a partial response was observed in 9, and stable disease was found in 4. No treatment, related to grade 3 neutropenia, was given for 1 patient (2%). Other hematological and non-hematological toxicity was found in only 1 patient with fatigue. CONCLUSION: Preoperative weekly paclitaxel induced a high clinical response rate with a high safety profile. HER2-overepressing tumors had a higher clinical response rate than non-HER2-overepxressing tumors (91% vs. 50%, respectively). Further studies are needed to determine whether an increase in the cycles of paclitaxel and/or adding anthracyclines may lead to higher pathological complete response and breast-conservation rates in the neoadjuvant setting.

Phase III study to evaluate the use of high-dose chemotherapy as consolidation of treatment for high-risk postoperative breast cancer: Japan Clinical Oncology Group study, JCOG 9208.

A randomized controlled trial was conducted to evaluate the efficacy of high-dose chemotherapy (HDC) as consolidation of the treatment of high-risk postoperative breast cancer. Patients under 56 years of age with stage I to IIIB breast cancer involving 10 or more axillary lymph nodes were eligible. The primary endpoint was relapse-free survival (RFS). Between May 1993 and March 1999, 97 patients were enrolled, and two patients became ineligible. The median age of the 97 patients was 46 years (range 27-55 years), and 72 (74%) were premenopausal. The median number of involved axillary nodes was 16 (range 10-49). All patients had undergone a radical mastectomy. Major characteristics were well balanced between the treatment arms. Forty-eight patients in the standard-dose (STD) arm received six courses of cyclophosphamide, doxorubicin, and 5-fluorouracil followed by tamoxifen. Forty-nine patients were assigned to undergo HDC with cyclophosphamide and thiotepa after six courses of cyclophosphamide, doxorubicin, and 5-fluorouracil followed by tamoxifen; however, 15 of these patients (31%) did not undergo HDC. HDC was well tolerated without any treatment-related mortality. At a median follow-up of 63 months, the 5-year RFS of 47 eligible patients in the STD arm and 48 eligible patients in the HDC arm was 37% and 52% on an intent-to-treat basis, respectively (P = 0.17). Five-year overall survival of all randomized patients was 62% for the STD arm and 63% for the HDC arm (P = 0.78). Although the prespecified values of the two arms were not so accurate as to allow detection of the observed difference, no advantage of HDC was observed in terms of RFS or overall survival.

Relationship between the signal ratios of HER-2/CEP17 and c-MYC/CEP17 and the pathological response of neoadjuvant therapy using docetaxel and trastuzumab in breast cancer.

The purpose of this study was to assess the efficacy and predictive biomarkers of combination docetaxel-trastuzumab in a neoadjuvant setting by means of a phase II trial. Women with histologically-confirmed advanced invasive breast cancer whose tumours overexpressed HER-2 received 4 cycles of docetaxel (70 mg/m2 every 3 weeks) and trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly thereafter). Twenty-one patients were enrolled, and all completed 4 cycles of treatment. Two patients were later found to be inoperable, and neither pathological nor clinical response was assessed. The pathological complete response rate was 21% (4/19; 95% CI, 6-46%) and the overall clinical response rate 89% (17/19; 95% CI, 67-99%). The relationship between the expression of biomarkers (HER-2, c-MYC, BRCA1 and Ki-67) and pathological response was assessed. The results suggested the possibility that tumours showing a high signal ratio of HER-2/CEP17 or c-MYC/CEP17 might be more sensitive to this combination therapy. Based on these results, it can be speculated that approximately 30% pCR might be obtained in cases with a high signal ratio of HER2/CEP17 or c-MYC/CEP17. Further trials are needed.

[Multicenter phase II trial of thrice-weekly docetaxel and weekly trastuzumab as preoperative chemotherapy in patients with HER 2-overexpressing breast cancer--Japan East Cancer Center Breast Cancer Consortium (JECBC) 02 Trial].

The efficacy and safety of combination therapy of 4 cycles with docetaxel 70 mg/m(2)every 3 weeks and trastuzumab as primary chemotherapy for operable breast cancer was determined in 21 patients (pts) by assessing the pathological complete response (pCR) rate, clinical response rate (RR), breast conservation surgery (BCS) rate and toxicities. To date, 19 pts have completed surgery. The pCR rate was 21% [95% CI 6%-46%] . The overall RR was 90% [95% CI 67%-99%] , with 5 CR, 12 PR, 2 SD and 0 PD. Grade 3 or 4 adverse events were leukopenia 48%, neutropenia 67%, hemoglobin 5%, and febrile neutropenia 10%. All non-hematological toxicities were mild and manageable. The pCR rate is not as low as that achieved in previous international studies. The combination of docetaxel and trastuzumab was a well-tolerated and very active regimen for the treatment of patients with HER 2-overexpressing operable breast cancer. This regimen promises to be one of the leading future treatments for progressive breast cancer.

[A phase-I clinical study of a combination therapy of vinorelbine and capecitabine in patients with advanced/recurrent breast cancer].

A phase-I clinical study of a combination therapy of vinorelbine and capecitabine was conducted in anthracycline- and taxane-pretreated patients with advanced/recurrent breast cancer. The objectives of this study in four medical institutions were to evaluate DLT (Dose Limiting Toxicity) and safety as primary endpoints, and tumor response and pharmacokinetics of vinorelbine as secondary endpoints. One 3-week course of treatment consisted of intravenous vinorelbine on Days 1 and 8 and oral capecitabine on Days 1 to 14, followed by a one-week rest. Vinorelbine was given at 20 mg/m(2) (Level 1) and 25 mg/m(2) (Level 2), and capecitabine was given at 1,650 mg/m(2)/day (in two divided doses, Levels 1 - 2). As the administration at each dose level in 3 patients did not cause DLT, 6 patients were additionally treated with vinorelbine at 25 mg/m(2) and capecitabine at 1,650 mg/m(2)/day (in two divided doses) to confirm safety. The major toxicities were bone marrow depression and gastrointestinal symptoms. In particular, the incidences of grade 3 or greater neutropenia (11 patients) and leukemia (10 patients) were high. They were reversible, however, and not severe enough to discontinue treatment. The response rate was 25.0% (3 PR/12). The combination with capecitabine did not affect the plasma pharmacokinetics of vinorelbine.

Combination docetaxel and trastuzumab treatment for patients with HER-2-overexpressing metastatic breast cancer: a multicenter, phase-II study.

BACKGROUND: Pre-clinical and clinical studies indicate that a combination of docetaxel and trastuzumab may effectively treat patients with human epidermal growth factor receptor-2 (HER-2) overexpressing metastatic breast cancer. We evaluated the efficacy and safety of this combination in a multicenter, open-label phase II study in Japan. METHODS: Women with metastatic breast cancer whose tumors overexpressed HER-2, as assessed by immunohistochemistry and by fluorescence in situ hybridisation, received 2 to 6 cycles of docetaxel (70 mg/m2, every 3 weeks) and trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly thereafter). The primary endpoint was tumor response. Secondary endpoints were time to disease progression and adverse events. RESULTS: Of the 40 women enrolled in the study, 27 (68%) completed 6 cycles of treatment. Three patients discontinued the study before the second cycle. Median follow-up was 20.8 months (range, 0.6 to 30.9 months). The overall response rate was 65% (26/40; 95% CI, 48% to 79%). The median time to progression was 6.8 months (range, 0.6 to 21.2 months). Of the 40 patients, 35 (88%) had grade 3 or 4 leukopenia, and 33 (83%) had grade 3 or 4 neutropenia. Most instances of leukopenia and neutropenia were manageable by reducing the dose of docetaxel or by treatment with granulocyte colony-stimulating factor. In 4 patients, left ventricular ejection fraction decreased by more than 10% from baseline. CONCLUSIONS: The combination of docetaxel and trastuzumab was as effective as reported in other similar studies and was well tolerated in these patients.

[Successful monotherapy with S-1 in three cases of recurrent/advanced breast cancer non-responsive to anthracycline and taxane anticancer drugs].

We had 3 patients with recurrent/advanced breast cancer in whom a notable reduction in the size of the targeted tumors was seen following administration of S-1 (TS-1), a new oral pyrimidine fluoride anticancer drug. All of the patients had received taxane and/or anthracycline anticancer drugs as prior therapy; however, they were judged to be non-responsive to the drugs. The size of the targeted tumor decreased to 55.7% after 3 courses of the therapy in Patient 1. The tumor disappeared at completion of the third course in Patient 2, although the therapy was temporarily suspended during the second course due to adverse drug reactions, and the therapy was then resumed after 2-week drug withdrawal. Patient 3 was able to undergo long-term therapy, consisting of 8 courses for 11 months, and the size of the tumor reduced to 58.1%. No serious adverse drug reactions to S-1 occurred in our 3 patients. It is thought that less toxicity enabled Patient 3 to undergo long-term therapy. We consider S-1 to be a useful anticancer drug for treatment of taxane and/or anthracycline resistant recurrent breast cancer.

Ipsilateral breast tumor recurrence (IBTR) after breast-conserving treatment for early breast cancer: risk factors and impact on distant metastases.

BACKGROUND: The clinical features of ipsilateral breast tumor recurrence (IBTR) after breast conserving therapy (BCT) for early stage breast cancer were analyzed from long-term follow-up of BCT in Japan. The purpose of this study was to clarify risk factors of IBTR and the impact of IBTR on development of distant metastases in this ethnic group. METHODS: Patients (N = 1901)with unilateral breast cancer < or = 3 cm in diameter who underwent BCT at 18 Japanese major breast cancer treatment institutes from 1986 to 1993 were registered in this study. Survival rates, the incidences of IBTR and distant metastases, and annual rates of IBTR and distant metastases after primary operation were calculated by the Kaplan-Meier method. A Cox proportional hazards model was used to estimate the risks of IBTR and distant metastases. A Cox model was also used to estimate the risks of distant metastases after IBTR in the group of IBTR. RESULTS: At a median follow-up time of 107 months, the 10-year overall and disease-free survival rates were 83.9% and 77.8%, respectively. The 10-year cumulative rates of IBTR were 8.5% in the patients with postoperative irradiation and 17.2% in the patients without irradiation. The 10-year cumulative distant metastasis rate was 10.9%. On multivariate analysis, young age, positive surgical margin, and omission of radiation therapy were significant predictors of IBTR. In addition, IBTR significantly correlated with subsequent distant metastases (hazard ratio, 3.93; 95% confidence interval, 2.676-5.771; P < 0.0001). Among patients who developed IBTR, initial lymph node metastases and short interval to IBTR were significant risk factors for subsequent distant metastasis. CONCLUSIONS: Young age, positive surgical margin, and omission of radiation therapy seemed to be important factors in relation to local control. The authors' results also indicated that IBTR is significantly associated with subsequent distant metastasis. Patients with positive nodal status at primary operation or with short interval from primary operation to IBTR are at especially high risk of distant metastasis. It remains unclear, however, whether IBTR is an indicator or a cause of subsequent distant metastases.

[A multicenter study to determine the efficacy and safety of strontium (89Sr) chloride for palliation of painful bony metastases in cancer patients].

PURPOSE: A multicenter study was conducted to evaluate the efficacy of strontium chloride (89SrCl2) for palliation of painful bony metastases using the Visual Analogue Scale (VAS), Brief Pain Inventory (BPI) and Functional Assessment for Cancer Therapy-General (FACT-G). METHODS: Ninety patients received a single injection of 2.0 MBq/kg and were classified as responders if VAS scores decreased without increased use of analgesics or if analgesic consumption decreased without an increase in the VAS. RESULTS: In the 69 subjects that could be evaluated, mean VAS values decreased significantly from 48.0 +/- 20.8 mm at baseline to 24.1 +/- 22.3 mm at last visit(Week 12) (p < 0.0001). VAS decreased more than 10 mm in 58.0% of these subjects, and analgesic consumption was reduced more than 10% in 39.1% of subjects. The response rates were 46.4% (95% confidence interval (CI) 34.3-58.8%) in the 69 subjects that could be evaluated and 43.3% (95% CI 32.9-54.2%) in all subjects. The scoring in BPI for interference in daily life improved together with improvement in its pain scores. Total FACT-G score showed significant improvement, as did its score in the subsection of physical well-being. Both platelets and leucocytes decreased by 22% at nadir (week 8), and such profiles of myelosuppression by 89SrCl2 were similar to those in the previous clinical studies. CONCLUSION: These results suggest the clinical utility of 89SrCl2 for pain palliation, which leads to QOL improvement in patients with painful generalized bone metastases.

Increased nuclear localization of transcription factor Y-box binding protein 1 accompanied by up-regulation of P-glycoprotein in breast cancer pretreated with paclitaxel.

PURPOSE: The Y-box binding protein 1 (YB-1) regulates expression of P-glycoprotein encoded by the MDR1 gene. There have been no previous studies regarding the involvement of YB-1 in the development of resistance to paclitaxel. The present study was done to examine how paclitaxel affects the localization and expression of YB-1 in breast cancer. EXPERIMENTAL DESIGN: We evaluated the expression and localization of YB-1 and P-glycoprotein in breast cancer tissues obtained from 27 patients before and after treatment with paclitaxel. The effect of paclitaxel on localization of cellular YB-1 was examined by using GFP-YB-1. Interaction of YB-1 with the Y-box motif of the MDR1 promoters was studied by electrophoretic mobility shift assay. The effects of paclitaxel on MDR1 promoter activity were examined by luciferase assay. RESULTS: Of 27 breast cancer tissues treated with paclitaxel, nine (33%) showed translocation of YB-1 from the cytoplasm to the nucleus together with increased expression of P-glycoprotein during the course of treatment. Twelve breast cancer tissues (44%) showed neither translocation of YB-1 nor increased expression of P-glycoprotein. Nuclear translocation of YB-1 was correlated significantly with increased expression of P-glycoprotein (P=0.0037). Confocal analysis indicated that paclitaxel induced nuclear translocation of green fluorescent fused YB-1 in MCF7 cells. Furthermore, binding of YB-1 to the Y-box of MDR1 promoter was increased in response to treatment with paclitaxel. In addition, MDR1 promoter activity was significantly up-regulated by paclitaxel in MCF7 cells (P<0.001). CONCLUSIONS: The results of the present study suggested that YB-1 may be involved in the development of resistance to paclitaxel in breast cancer.

Isolation and transplantation of highly purified autologous peripheral CD34+progenitor cells: purging efficacy, hematopoietic reconstitution following high dose chemotherapy in patients with breast cancer: results of a feasibility study in Japan.

BACKGROUND: High-dose chemotherapy with autologous stem cell support may have some therapeutic impact on certain groups of the patients with advanced breast cancer(BRCA). Since stem cell contamination by tumor cells might contribute to relapse, development of a tumor cell purging technique would improve the clinical outcome. The present study was undertaken to evaluate the purging efficacy of autologous mobilized CD34+peripheral stem cells in patients with breast cancer (BRCA) in an advanced stage or relapse. METHODS: CD34+cells were selected from autologous peripheral blood stem cells (PBSC) using a clinical scale of magnetic-activated cell sorting system (CliniMACS), followed by high-dose chemotherapy with transplantation of CD34+ selected cells. Amplification of cytokeratin 19 (CK19) and 20 (CK20) gene in leukapheresis products were measured to evaluate the performance of tumor cell elimination. RESULTS: Seven patients were entered into this study. After leukopheresis, 1 patient was dropped form this study due to poor mobilization. Among 6 patient, a total of 8 CD34+ selection was performed. The median purity and recovery rate of the CD34+ cells post selection was 85.1% (range 62.5-98.1%) and 74.2% (range 50.2-90.2%), respectively. After isolation of CD34+cells, the elimination rate in the logarithmic transformation of CK19 was 2.77 log, and that of CK20 were 2.43 log and 2.53 log. In 4 patients, high-dose chemotherapy was performed, followed by the transplantation of the isolated CD34+cells. Rapid neutrophil recovery, as well as platelet recovery was seen with a median time to reach 0.5 x 109/l neutrophils of 9 days(range 8-9), and 20 x 109/l platelets of 12 days (range 10-13). There was no treatment related death and no serious adverse events directly associated with the selection procedure or infusion of selected cells. CONCLUSIONS: The present study demonstrated that the CliniMACS system is a highly effective positive selection method and that a high purging efficacy could be obtained without compromising the hematopoietic reconstitution capacity of the graft in BRCA patients undergoing high-dose chemotherapy.

Late phase II clinical study of vinorelbine monotherapy in advanced or recurrent breast cancer previously treated with anthracyclines and taxanes.

BACKGROUND: At present, it is one of the most important issues for the treatment of breast cancer to develop the standard therapy for patients previously treated with anthracyclines and taxanes. With the objective of determining the usefulness of vinorelbine monotherapy in patients with advanced or recurrent breast cancer after standard therapy, we evaluated the efficacy and safety of vinorelbine in patients previously treated with anthracyclines and taxanes. METHODS: Vinorelbine was administered at a dose level of 25 mg/m(2) intravenously on days 1 and 8 of a 3 week cycle. Patients were given three or more cycles in the absence of tumor progression. A maximum of nine cycles were administered. RESULTS: The response rate in 50 evaluable patients was 20.0% (10 out of 50; 95% confidence interval, 10.0-33.7%). Responders plus those who had minor response (MR) or no change (NC) accounted for 58.0% [10 partial responses (PRs) + one MR + 18 NCs out of 50]. The Kaplan-Meier estimate (50% point) of time to progression (TTP) was 115.0 days. The response rate in the visceral organs was 17.3% (nine PRs out of 52). The major toxicity was myelosuppression, which was reversible and did not require discontinuation of treatment. CONCLUSION: The results of this study show that vinorelbine monotherapy is useful in patients with advanced or recurrent breast cancer previously exposed to both anthracyclines and taxanes.

Analysis of ipsilateral breast tumor recurrences after breast-conserving treatment based on the classification of true recurrences and new primary tumors.

BACKGROUND: Ipsilateral breast tumor recurrences (IBTR) after breast-conserving treatment include two different entities: true recurrence (TR) thought to occur when residual cancer cells grow gradually to detectable size and new primary (NP) thought to be de novo cancer independently arising in the preserved breast. The patients with ipsilateral breast tumor recurrence (IBTR) are potentially at high risk for subsequent distant metastasis, but many studies do not distinguish between these types of recurrence. The aim of this study is to clarify the biological difference between TR and NP, and to show the clinical significance of classifying IBTR into these two types of recurrence. PATIENTS AND METHODS: A total of 172 patients with IBTR after breast-conserving therapy from the cohort of a long-term large scale study (Research of cancer treatment from the Ministry of Health, Labor and Welfare of Japan (no.13-9)) were analyzed. We classified IBTRs as TR or NP based on tumor location and pathological findings. The characteristics of the primary tumors of TR and NP were compared. Survival rates and risk factors of each type of IBTR were examined by the Kaplan-Meier method. The results of salvage surgery were also analyzed. RESULTS: Of the 172 patients, 135 patients were classified as TR and 26 as NP. Eleven cases could not be categorized. The primary tumor of TR was characterized by a high rate of lymph node metastasis (37.8%) and short disease-free interval (mean DFI; 46.6 months) while that of NP showed a rather low lymph node positivity (8.7%) and longer DFI (62.1 months). The risk factors for TR were young age, positive surgical margin, omission of irradiation and positive lymph node metastasis. Those for NP were young age, omission of irradiation and contralateral breast cancer after the primary operation. The 5-year survival rates after IBTR were 71.0% in TR and 94.7% in NP (p=0.022). Salvage operation was performed in 136 IBTRs. Eighty-one patients underwent salvage mastectomy and 55 patients underwent repeat lumpectomy. Five-year survival rates after salvage operation were 75.7% for mastectomy and 84.2% for lumpectomy (N.S.). Twenty percent of patients who underwent repeat lumpectomy developed secondary local relapse within 5 years after salvage treatment. The risk factors for secondary local relapse were analyzed. Limited to cases of IBTR which received radiation therapy after the primary operation, NP was the only factor influencing secondary local relapse by univariate analysis. CONCLUSIONS: TR and NP show clinically quite different features; time to occurrence, characteristics of the original tumor, prognosis and risk factor profile for IBTR were all different. Classifying IBTR as TR or NP can provide clinically significant data for the management of IBTR.

[Study of three-weekly docetaxel and weekly trastuzumab treatment in HER 2-overexpressing metastatic breast cancer patients].

Docetaxel and trastuzumab can be considered to be active drugs for HER 2-overexpressing metastatic breast cancer (MBC). This study was conducted to determine the activity of combination therapy with docetaxel and trastuzumab in MBC patients (pts) by assessing the response rate (RR), time to progression (TTP) and safety. We administered the combination of docetaxel 70 mg/m2 every 3 weeks and trastuzumab using a 4 mg/kg loading dose and thereafter 2 mg/kg weekly. One cycle was three weeks. Between March 2002 and May 2003, 40 pts with HER 2-positive (3+by immunohistochemistry 39, FISH+1) MBC were enrolled in this study, and 39 pts proved eligible. The overall RR was 72% (28/39) [95%CI 55.1%-85.0%], with 6 CR, 22 PR, 7 SD, 1 PD and 3 NE. The median follow-up time was 14.3 months, while the TTP was 6.5 months (range, 0.6-19.8), median OS has not yet been reached. The number of pts assessable for safety was 40. Hematological Grade 3-4 toxicities were leukopenia 87.5% (35/40) and neutropenia 82.5% (33/40). Non-hematological Grade 3 toxicities were weight gain in 2 pts, and anorexia, neuropathy, fever and rash in one pt each. The combination of docetaxel and trastuzumab was a well-tolerated and very active regimen for the treatment of pts with HER 2-overexpressing MBC.