[Show abstract][Hide abstract] ABSTRACT: Breast cancer is a hormone-dependent cancer and usually treated with endocrine therapy using aromatase inhibitors or anti-estrogens such as tamoxifen. A majority of breast cancer, however, will often fail to respond to endocrine therapy. In the present study, we explored miRNAs associated with endocrine therapy resistance in breast cancer. High-throughput miRNA sequencing was performed using RNAs prepared from breast cancer MCF-7 cells and their derivative clones as endocrine therapy resistant cell models, including tamoxifen-resistant (TamR) and long-term estrogen-deprived (LTED) MCF-7 cells. Notably, miR-21 was the most abundantly expressed miRNA in MCF-7 cells and overexpressed in TamR and LTED cells. We found that miR-378a-3p expression was downregulated in TamR and LTED cells as well as in clinical breast cancer tissues. Additionally, lower expression levels of miR-378a-3p were associated with poor prognosis for tamoxifen-treated patients with breast cancer. GOLT1A was selected as one of the miR-378a-3p candidate target genes by in silico analysis. GOLT1A was overexpressed in breast cancer specimens and GOLT1A-specific siRNAs inhibited the growth of TamR cells. Low GOLT1A levels were correlated with better survival in patients with breast cancer. These results suggest that miR-378a-3p-dependent GOLT1A expression contributes to the mechanisms underlying breast cancer endocrine resistance.
[Show abstract][Hide abstract] ABSTRACT: Advanced breast cancer patients have a higher risk of postoperative recurrence than early-stage breast cancer patients. Recurrence is believed to be caused by the increase in micrometases, which were not eradicated by preoperative or postoperative chemotherapy. Therefore, a new therapeutic strategy that can improve treatment efficacy is mandatory for advanced breast cancer. S-1 was shown to be effective and safe in Japanese metastatic breast cancer patients treated with previous chemotherapy, including anthracyclines. Thus, in this study, we evaluated S-1 as adjuvant chemotherapy in breast cancer patients after standard primary systemic chemotherapy.
The treatment consisted of 18 courses (a 2-week administration and a 1-week withdrawal; one year) administered at 80-120 mg/body/day. In cases judged to require postoperative radiotherapy, it was concurrently initiated on Day 1 of the study. If the estrogen receptor and/or human epidermal growth factor receptor 2 were positive, endocrine therapy and/or trastuzumab were permitted, concurrently.
Of the 45 patients enrolled between September 2007 and September 2009 from 3 institutions, 43 patients were eligible. Thirty-two of the 43 (74.4%) patients received concurrent radiotherapy. Twenty-two of the 43 (51.2%) patients completed the scheduled courses of chemotherapy. The most common reasons for withdrawal of treatment were subjective symptoms, such as nausea, anorexia, or general fatigue during the first 9 courses of treatment in 9/43 (20.9%) patients, recurrence in 7/43 (16.3%) patients, and adverse events in 5/43 (11.6%) patients. The cumulative percentage of administration for 365 days was 66.4% (95% confidence interval: 50.8-79.1%). Although grade 3 neutropenia (9.3%), leukopenia (4.7%), and diarrhea (4.7%) were observed, they were manageable. No grade 4 adverse effects were observed.
The percentage of Japanese breast cancer patients completing the 18-course treatment and the cumulative percentage of administration for 365 days using S-1 after standard primary systemic chemotherapy were similar with the results of another study of adjuvant chemotherapy for the Japanese gastric cancer patients with no severe adverse effects. A phase III trial investigating the usefulness of adjuvant S-1 is now ongoing in Japan, and it is expected that S-1 will have a significant survival benefit in breast cancer patients. UMIN000013469.
BMC Cancer 04/2015; 15(1):253. DOI:10.1186/s12885-015-1289-7 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It may be difficult to achieve complete cure for most metastatic breast cancer patients;thus, prolongation of overall survival and maintenance of the quality of life are often the main focus of treatment. In the treatment of metastatic breast cancer patients, it is important to choose the most appropriate therapeutic strategy based on substantial evidence that considers the biology of the tumor, including estrogen receptor(ER), progesterone receptor(PgR), and human epidermal growth factor receptor 2(HER2)status;the site and extent of the metastatic focus;the time to recurrence;prior treatment regimens;age; menopausal status;performance status;and the preference of the patient. A clinical subtype classification that is based on the tumor biology is typically utilized for devising a treatment strategy specific to each subtype. Expressly, first-line treatment options may include hormone therapy for hormone-positive breast cancers, antiHER2 therapy for HER2-positive breast cancers, and chemotherapy for hormone-negative and HER2-negative(triple negative)breast cancers. In recent years, with the development of regimens that are effective for every subtype, the treatments for breast cancer have undergone significant changes. In this section, we introduce the progress in the treatment for metastatic breast cancer, focusing specifically on second-line therapies according to each subtype.
Gan to kagaku ryoho. Cancer & chemotherapy 04/2015; 42(4):408-15.
[Show abstract][Hide abstract] ABSTRACT: We conducted a phase I study of a weekly nab-paclitaxel and S-1 combination therapy in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer. The primary objective was to estimate the maximum tolerated and recommended doses. Each treatment was repeated every 21 days. Levels 1, 2a, 2b, and 3 were set depending on the S-1 dose (65 or 80 mg/m(2) ) and nab-paclitaxel infusion schedule (days 1 and 8 or days 1, 8, and 15). Fifteen patients were enrolled. Dose-limiting toxicity was observed in 1 patient at Level 3 (100 mg/m(2) nab-paclitaxel on days 1, 8, and 15 with 80 mg/m(2) S-1 daily for 14 days, followed by 7 days of rest). Although the maximum tolerated dose was not reached, the recommended dose was determined to be Level 3. Neutropenia was the most frequent grade 3-4 treatment-related adverse event. For patients with measurable lesions, the response rate was 50.0% and the median time to treatment failure and median progression free survival were 13.2 and 21.0 months, respectively. The present results show the feasibility and enabling long-term administration of this combination therapy. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Cancer Science 03/2015; 106(6). DOI:10.1111/cas.12658 · 3.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Most primary breast cancers express estrogen receptor α and can be treated via endocrine therapy using anti-estrogens such as tamoxifen; however, acquired endocrine resistance is a critical issue. To identify tamoxifen response-related microRNAs (miRNAs) in breast cancer, MCF-7 cells infected with a lentiviral miRNA library were treated with 4-hydroxytamoxifen (OHT) or vehicle for 4 weeks, and the amounts of individual miRNA precursors that had integrated into the genome were evaluated by microarray. Compared to the vehicle-treated cells, 5 'dropout' miRNAs, which were downregulated in OHT-treated cells, and 6 'retained' miRNAs, which were upregulated in OHT-treated cells, were identified. Of the dropout miRNAs, we found that miR-574-3p expression was downregulated in clinical breast cancer tissues as compared with their paired adjacent tissues. In addition, anti-miR-574-3p reversed tamoxifen-mediated suppression of MCF-7 cell growth. Clathrin heavy chain (CLTC) was identified as a miR-574-3p target gene by in silico algorithms and luciferase reporter assay using the 3' untranslated region of CLTC mRNA. Interestingly, loss and gain of miR-574-3p function in MCF-7 cells causes CLTC to be upregulated and downregulated, respectively. These results suggest that functional screening mediated by miRNA libraries can provide new insights into the genes essential for tamoxifen response in breast cancer.
[Show abstract][Hide abstract] ABSTRACT: Purpose
Optical imaging techniques for measuring tissue hemoglobin concentration have been recently accepted as a way to assess tumor vascularity and oxygenation. We investigated the correlation between early optical response to single-agent bevacizumab and treatment outcome.
Seven patients with advanced or metastatic breast cancer were treated with single-agent bevacizumab followed by addition of weekly paclitaxel. Optical imaging of patient's breasts was performed to measure tumor total hemoglobin concentration (tHb) and oxygen saturation (stO2) at baseline and on days 1, 3, 6, 8, and 13 after the first infusion of bevacizumab. To assess early metabolic response, 2-deoxy-2-(18F)-fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT), 18F-fluoromisonidazole (FMISO)-PET/CT, and magnetic resonance imaging were performed at baseline and after two cycles of the regimen.
Seven patients were grouped as responders (n = 4) and nonresponders (n = 3) on the basis of metabolic response measured by FDG-PET/CT. The responders showed remarkable tumor shrinkage and low accumulations of FMISO tracer relative to those of the nonresponders at the completion of two cycles of chemotherapy. Tumors of both groups showed remarkable attenuation of mean tHb as early as day 1 after therapy initiation. The nonresponders had lower baseline stO2 levels compared with adjacent breast tissue stO2 levels along with a pattern of steadily low stO2 levels during the observation window. On the other hand, the responders appeared to sustain high stO2 levels with temporal fluctuation.
Low tumor stO2 level after single-agent bevacizumab treatment was characteristic of the nonresponders. Tumor stO2 level could be a predictor of an additional benefit of bevacizumab over that provided by paclitaxel.
PLoS ONE 06/2014; 9(6):e98715. DOI:10.1371/journal.pone.0098715 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose: Near-infrared diffuse optical spectroscopy (DOS) imaging can noninvasively measure tumor hemoglobin (Hb) concentration using high contrast to normal tissue, thus providing vascularity and oxygenation status. We assessed the clinical usefulness of DOS imaging in primary breast cancer.Materials and Methods: In all, 118 women with a histologically confirmed diagnosis of primary malignant tumor were enrolled. All participants underwent testing using time-resolved DOS before treatment initiation. Visual assessment of DOS imaging for detecting tumors was double-blindedly performed by two readers. Relative total Hb (rtHb) and oxygen saturation (stO2) of the tumors were compared with clinicopathological variables and 10-year prognosis was calculated.Results: Sensitivity for detecting a tumor based on the rtHb breast map was 62.7% (74/118). The sensitivity depended on T stage: 100% (7/7) for T3, 78.9% (45/57) for T2, 44.7% (17/38) for T1, and 31.3% (5/16) for Tis. Tumors showed unique features of higher rtHb with a wider range of stO2 than normal breast tissue, depending on a histological type. There was a significant correlation of rtHb with tumor size, lymphatic vascular invasion, and histological grade, and of stO2 with age and tumor size. Neither rtHb nor stO2 correlated with intrinsic biomarkers such as estrogen receptor, progesterone receptor, or HER2; rtHb inversely correlated with 10-year relapse-free survival and overall survival, with statistical significance.Conclusion: DOS imaging has limited utility for the early detection of breast cancer; nonetheless, the findings suggest that the degree of tumor angiogenesis and hypoxia may be associated with tumor aggressiveness and poor prognosis.This article is protected by copyright. All rights reserved.
Cancer Science 04/2014; 105(7). DOI:10.1111/cas.12432 · 3.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Near-infrared optical imaging targeting the intrinsic contrast of tissue hemoglobin has emerged as a promising approach for visualization of vascularity in cancer research. We evaluated the usefulness of diffuse optical spectroscopy using time-resolved spectroscopic (TRS) measurements for functional imaging of primary breast cancer.
Fifty-five consecutive TNM stageI/II patients with histologically proven invasive ductal carcinoma and operable breast tumors (<5 cm) who underwent TRS measurements were enrolled. Thirty (54.5%) patients underwent 18F-fluoro-deoxy-glucose (FDG) positron emission tomography with measurement of maximum tumor uptake. TRS was used to obtain oxyhemoglobin, deoxyhemoglobin, and total hemoglobin (tHb) levels from the lesions, surrounding normal tissue, and contralateral normal tissue. Lesions with tHb levels 20% higher than those present in normal tissue were defined as "hotspots," while others were considered "uniform." The findings in either tumor type were compared with clinicopathological factors.
"Hotspot" tumors were significantly larger (P = 0.002) and exhibited significantly more advanced TNM stage (P = 0.01), higher mitotic counts (P = 0.01) and higher levels of FDG uptake (P = 0.0004) compared with "uniform" tumors; however, other pathological variables were not significantly different between the two groups.
Optical imaging for determination of tHb levels allowed for measurement of tumor vascularity as a function of proliferation and glucose metabolism, which may be useful for prediction of patient prognosis and potential response to treatment.
BMC Cancer 10/2013; 13(1):514. DOI:10.1186/1471-2407-13-514 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Breast cancer is primarily a hormone-dependent tumor that is regulated by the status of the estrogen and progesterone receptors. We previously identified EBAG9 as an estrogen-responsive gene in MCF-7 human breast carcinoma cells. Upregulation of EBAG9 expression has been observed in several malignant tumors such as advanced breast cancers, indicating that EBAG9 might contribute to tumor progression.
In the present study, we generated a monoclonal antibody against EBAG9, and then performed immunohistochemical analysis of EBAG9 expression in specimens obtained from breast cancer patients treated with tamoxifen as an adjuvant therapy.
EBAG9 immunoreactivity was detected in the cytoplasm of breast cancer cells and was significantly elevated in breast cancer samples from patients who relapsed during or after adjuvant tamoxifen treatment. Positive EBAG9 immunoreactivity was significantly correlated with poor patient prognosis.
These results suggest that EBAG9 expression in tumor regions is associated with an unfavorable prognosis in breast cancer patients treated with tamoxifen.
Clinical Breast Cancer 10/2013; 13(6). DOI:10.1016/j.clbc.2013.08.015 · 2.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We had previously reported a close association between pathological response and the maximum tumor standardized uptake value (SUVmax) measured by (18)F-fluorodeoxyglucose positron emission tomography prior to chemotherapy in estrogen receptor (ER)-positive breast cancer. We hypothesized that glucose hypermetabolism by luminal B tumors may result in chemotherapy responsiveness. Using a single-gene expression assay, TargetPrint® (Agendia) and a 70-gene expression classifier, MammaPrint® (Agendia), we divided 20 patients with ER-positive primary breast cancer into luminal A and luminal B subtypes and compared the tumor SUVmax value between the two groups. A significantly higher SUVmax was measured for luminal B tumors (n=10; mean±SD, 7.6±5.6) than for luminal A tumors (n=10; mean±SD, 2.6±1.2; p=0.01). Glucose hypermetabolism could help predict intrinsic subtyping and chemotherapy responsiveness as a supplement to ER, progesterone receptor, HER2, and Ki-67 histochemical scores.
Journal of Breast Cancer 09/2013; 16(3):342-4. DOI:10.4048/jbc.2013.16.3.342 · 1.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Sunitinib is an oral multi-targeted tyrosine kinase inhibitor approved for use in patients with advanced renal cell carcinoma (RCC). However, despite its preclinical biological effect on breast cancer, it is yet to be proven effective for clinical use in patients with breast cancer. The present report describes a case of a 69-year-old woman with advanced clear-cell RCC and a luminal B subtype invasive ductal carcinoma of the right breast that showed a partial response to monotherapy with sunitinib. This is the first report of the effect of sunitinib monotherapy in a patient with early-stage breast cancer.
[Show abstract][Hide abstract] ABSTRACT: We report a case of a trastuzumab-resistant human epidermal growth factor receptor-2(HER2)-positive breast cancer patient with extensive liver metastases and associated impaired liver function, who showed an excellent response to the combination of trastuzumab and capecitabine. The patient was a 59-year-old postmenopausal woman with multiple liver metastases at first examination. She first received anthracycline-based chemotherapy, and after progression was followed up with a combination of trastuzumab and paclitaxel. Despite an initial response to this treatment, liver metastases rapidly progressed. Although palliative treatment was considered because of her impaired liver function, she received capecitabine while continuing trastuzumab. This combination therapy showed an excellent response, and a good quality of life(QOL)was maintained for a long time without any severe adverse events. The continuation of trastuzumab is considered effective after having progressed by trastuzumab including pretreatment, and we consider it worth while to give a combination of trastuzumab and capecitabine to patients with extensive liver metastases and associated impaired liver function, because of the treatment's synergistic effect and low risk of causing severe adverse events.
Gan to kagaku ryoho. Cancer & chemotherapy 02/2013; 40(2):225-7.
[Show abstract][Hide abstract] ABSTRACT: A 62-year-old woman was diagnosed with primary left breast cancer during a follow-up for an ovarian tumor. She had at first undergone surgical resection of an ovarian tumor, and a pathological examination had revealed ovarian cancer. Gynecologists decided to treat her ovarian cancer with chemotherapy, and we were initially planning to provide treatment for breast cancer after that was completed. Sentinel lymph node biopsy performed before chemotherapy revealed no axillary metastases. The patient received six courses of intravenous PTX (175 mg/m2 on day 1, every 3 weeks) and intravenous CBDCA (AUC6 on day 1, every 3 weeks) as combination therapy. Abdominal lymph node dissection was performed between chemotherapy courses 3 and 4. The lump in the left breast showed partial clinical response, and partial resection of the left breast was performed after completion of chemotherapy. In Japan, few cases of primary breast cancer treated preoperatively using carboplatin-containing regimens have been described.
Gan to kagaku ryoho. Cancer & chemotherapy 06/2012; 39(6):1013-6.
[Show abstract][Hide abstract] ABSTRACT: Controversy surrounds the reliability of sentinel lymph node biopsy after primary systemic chemotherapy. In this study, we assessed axillary ultrasound for selecting patients most likely to optimally benefit from biopsy.
The study included 87 patients who received primary systemic chemotherapy and underwent a sentinel lymph node biopsy followed by axillary lymph node dissection. Lymph nodes >10 mm in diameter, irregularly swollen, round, and homogeneously hypoechoic without an echo-rich center were considered axillary ultrasound positive.
In axillary ultrasound-negative patients before and after primary systemic chemotherapy, identification, sensitivity, and false-negative rates were 81%, 100%, and 0%, respectively. However, in patients whose lymph nodes converted from positive to negative after primary systemic chemotherapy, these values were 83%, 70.8%, and 29.2%, respectively.
Axillary ultrasound-negative patients before and after primary systemic chemotherapy were suitable for sentinel lymph node biopsy. Axillary ultrasound should be used during primary systemic chemotherapy and before surgery.
American journal of surgery 04/2012; 204(4):487-93. DOI:10.1016/j.amjsurg.2011.09.026 · 2.29 Impact Factor