Muneaki Sano

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

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.

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.

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.

A Phase II Study of S-1 in Patients with Metastatic Breast Cancer : A Japanese Trial by the S-1 Cooperative Study Group, Breast Cancer Working Group

BackgroundS-l is a newly developed novel oral dihydrouracil dehydrogenase inhibiting fluoro-pyrimidine drug consisting of 1 M tegafur (FT), 0.4 M 5-chloro-2, 4-dihydroxypyrimidine (gimeracil), and 1 M potassium oxonate (oteracil), with efficient antitumor activity and low gastrointestinal toxicity which is widely used in Japan against advanced gastric, head and neck cancers. We investigated its clinical efficacy against metastatic breast cancer.MethodsA non-blind phase II study was carried out to evaluate the efficacy and toxicity in metastatic breast cancer patients. Patients with measurable metastasis foci (n = 111) were enrolled, and 108 patients were regarded as eligible. S-l was administered orally at a standard dose of 80 mg/m2/day b.i.d. One course consisted of 28 consecutive days of administration followed by a 14-day rest, and courses were repeated up to six times.ResultsAmong the eligible patients, 10 had a complete response and 35 had a partial response, with an overall response rate (CRplus PR) of 41.7% (95% confidence interval: CI, 32.3–51.5%). The incidences of toxicity (≧ grade 3) were neutropenia 9.1%, anemia 0.9%, anorexia 3.6%, stomatitis 1.8%, nausea/vomiting 1.8%, diarrhea 0.9%, and fatigue 2.7%, however no treatment-related deaths were observed. The median survival time was 872 days (95% CI, 572-1,110 days). There was no difference in response rate or toxicity between the under 65-year-old group and the older group.ConclusionS-l was demonstrated to have high efficacy with low gastrointestinal toxicity even in older patients and will be a promising new chemotherapy drug for metastatic breast cancer.

Effects of toremifene (TOR) and tamoxifen (TAM) on serum lipids in postmenopausal patients with breast cancer.

This study clarified the difference in the effects on serum lipids between toremifene (TOR) and tamoxifen (TAM). To remove influencing factors, we investigated adjuvant therapy for hormone receptor-positive patients with breast cancer without lymph node metastasis. The subjects were 65 patients who were enrolled in a multicenter randomized comparative study between April 1997 and March 2001. As adjuvant therapy, 20 mg of TAM or 40 mg of TOR was administered for 1 year. The levels of triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A-1 (Apo A-1), apolipoprotein A(Apo B), and lipoprotein a (Lp(a)) were measured prior to administration and 3, 6, and 12 months after the start of administration. TC, LDL-C, Lp(a) and Apo B significantly decreased from the third month of administration compared with values before the start of administration in both the TOR and TAM groups. HDL-C significantly increased from the third month only in the TOR group. TG significantly increased in the TAM group but significantly decreased in the TOR group in the 12th month of administration. When these two groups were compared, HDL-C was significantly higher ( p < 0.01) and TG was significantly lower ( p < 0.01) in the TOR group in the 12th month. Improvement of abnormal values of TG, HDL-C and LDL-C was better in the TOR group than in the TAM group after administration for 12 months. The effect on lipid metabolism showed different profiles between the two selective estrogen receptor modulators (SERMs), and TOR gave better results than TAM.

Three-Dimensional Helical CT of the Breast: Accuracy for Measuring Extent of Breast Cancer Candidates for Breast Conserving Surgery

AbstractObjective. To evaluate the accuracy of three-dimensional (3D) helical computed tomography (CT) for assessing the extent of breast cancer of candidates for breast conserving surgery. Methods. Results of helical CT were studied in 144 lesions of 144 patients with breast cancer before breast-conserving surgery. A lesion was defined as positive if focal enhancement was detected by CT within 100s after contrast material administration. After resection, tumors were histopathologically mapped and correlated with the extent of 3D images. Results. Helical CT enabled detection of 143 tumors but not of one ductal carcinoma in situ (DCIS). The median deviation of the tumor extension revealed by 3D helical CT images from pathological assessment was 7.7mm (range 0–60mm). The extent of tumors was significantly correlated with CT measurements (r=0.714, p<0.0001). By multivariate analysis, the presence of invasive tumors with intraductal extensions beyond the edge of the invasive tumor and histologic type (DCIS) were significant risk factors for deviation of the tumor extension revealed by 3D helical CT images from pathological assessment. Conclusion. Three dimensional helical CT of the breast is an accurate preoperative imaging modality for assessing the extent of breast cancer candidates for breast conserving surgery.

Mutation of the class I β-tubulin gene does not predict response to paclitaxel for breast cancer

Mutation of the class I beta-tubulin gene has been reported to be one of the mechanisms that cause resistance to paclitaxel. To assess the relationship between paclitaxel-resistance and class I beta-tubulin gene mutation in breast cancer, Japanese patients with breast cancer were screened for the class I beta-tubulin gene mutation. Total RNA was isolated from 82 breast cancer specimens and the corresponding normal tissues. Twenty-four of the 82 patients were treated with paclitaxel preoperatively and 12 of them did not respond to the treatment. Of the 82 breast cancer patients, 15 (18.3%) had silent polymorphism in exon 4, Leu217Leu (CTG/CTA). However, no mutations showing amino acid substitution of the beta-tubulin gene were detected in any of the patients, including 12 patients who did not respond to paclitaxel. Class I beta-tubulin gene mutation with amino acid substitution was not detected in 82 breast cancer specimens. Our results suggest that mutation of the class I beta-tubulin gene is unlikely to play an important role in the mechanism of resistance to paclitaxel in breast cancer.

Staging of palpable tl-2 invasive breast cancer with helical ct

BackgroundThe purpose of this study was to evaluate the accuracy of contrast-enhanced high resolution helical computed tomography (CT) for assessing locoregional staging of palpable Tl-2 invasive breast cancer. Methods: Helical CT studies of 156 lesions from 156 patients with invasive breast cancer before breast-conserving surgery were examined. A lesion was defined as positive if focal enhancement was detected by CT within 100 seconds after contrast material administration. After resection, tumors were histopathologically mapped and comparison made with the extent of contrast enhancement.ResultsHelical CT enabled detection of all 156 index tumors. CT enabled detection of 28 of 43 multifocal lesions (65%) and five of five multicentric lesions (100%). In 24 of 33 lesions (73%), CT revealed additional cancers not seen on mammography. The extent of tumor significantly correlated with CT measurements (r=0.76,p<0.0001).ConclusionHelical CT of the breast is an accurate preoperative imaging modality for assessing the locoregional staging of Tl-2 invasive breast cancer.

Sentinel Lymph Node Biopsy After Neoadjuvant Chemotherapy in a Patient with Operable Breast Cancer

PurposeThis 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).MethodBetween 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 99mTc 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.ResultsThe 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.ConclusionSentinel 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.

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. (Cancer Sci 2008; 99: 145–151)