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Purpose: Elucidating the unique immunomodulatory mechanisms in breast cancer microenvironment should provide useful insights to aid the development of new therapeutic strategies for this disease. Some studies suggested the immune regulatory function of hormone receptor such as estrogen receptor-α (ER) and androgen receptor (AR), but their mechanism has not been fully understood because of the complexity of immune milieu in breast cancer microenvironment. In this study, we systematically analyzed the relationships between ER, progesterone receptor (PgR), and AR expression and the immunological profile in breast cancer tissue. Methods: Gene set enrichment analysis (GSEA) was used to screen the biological processes associated with the expression of human sex hormone receptor genes (ESR1, PGR, and AR), using a gene expression profile dataset of the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). Then, using METABRIC and a gene expression profile dataset of The Sweden Cancerome Analysis Network - Breast (SCAN-B), the correlation between the immune cell composition in breast cancer tissue (estimated with the CIBERSORTx) and hormone receptor expression was analyzed. In our previous study of 45 breast cancer tissues, we evaluated the level of human tumor infiltrating lymphocytes (hTILs), expression of human programmed death-ligand 1 (hPD-L1), and infiltration of 11 types of immune cells, using hematoxylin–eosin staining, immunohistochemistry (IHC), and multicolor flow cytometry, respectively. In this study, the levels of ER, PgR, and AR expression were further evaluated using IHC, and their relationship with the immunological profile of breast cancer tissues was analyzed. Results: GSEA showed that the expression levels of the ESR1, PGR, and AR genes were negatively correlated with multiple immunological processes, including “INFLAMMATORY RESPONSE.” Analysis of the correlations between the immune cell composition and hormone receptor gene expression showed that ESR1 expression was inversely correlated with Macrophage M1, CD4 memory activated T cells, Macrophage M0, CD8 T cells, and CD4 memory resting T cells; PGR expression was inversely correlated with Macrophage M1, CD4 memory activated T cells, and Macrophage M0; and AR expression was inversely correlated with Macrophage M0 and Macrophage M1. Immunohistochemical evaluation of ER and AR expression revealed both receptors to be inversely associated with hTIL, hPD-L1 expression, and leukocyte infiltration in breast cancer tissue. Analysis of the immune cell composition in these tissues revealed that ER expression was associated with the decreased infiltration of total T cells, CD4+ T cells, monocytes/macrophages, myeloid-derived suppressor cells, dendritic cells, and myeloid dendritic cells; PgR expression was associated with the decreased infiltration of dendritic cells; and AR expression was associated with the decreased infiltration of CD4+ T cells, monocytes/macrophages, nonclassical monocytes, myeloid-derived suppressor cells, dendritic cells, myeloid dendritic cells, and minor natural killer cells. Conclusion: The correlation of hormone receptor expression with specific immunological profiles in the breast cancer microenvironment both at the genetic and protein levels strongly suggests that hormonal signals may preferentially affect certain subsets of immune cells. Citation Format: Toru Hanamura, Shigehisa Kitano, Hiroshi Kagamu, Makiko Yamashita, Mayako Terao, Takuho Okamura, Nobue Kumaki, Katsuto Hozumi, Takayuki Iwamoto, Chikako Honda, Sasagu Kurozumi, Naoki Niikura. Hormone receptor expression is associated with specific immunological profiles in the breast cancer microenvironment [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-20-16.

Near-infrared (NIR) dyes are used in various applications such as organic solar cells and photodynamic therapy sensitizers. One example of a class of dyes, octa-arylthio-substituted phthalocyanines (Pcs), can effectively absorb NIR light above 800 nm. The substitution of the Pc’s peripheral sulfur effectively introduces extra functions without significant perturbation of the optical properties. However, the synthesis of phthalonitrile precursors containing various functionalized arylthio groups has been limited. Herein, we provide the three-component-type coupling reactions for synthesizing phthalonitriles with various functionalized chalcogen-aryl groups. Organometallic reagents were prepared from aryl halides, elemental chalcogen, and 3,6-bis(trifluoromethanesulfonyloxy)phthalonitrile can lead to functionalized phthalonitriles in a one-pot procedure. Commonly used methods were utilized to prepare the corresponding Pcs. This reaction can be extended to other group-16 elements, chemoselective organomagnesium, and organozincate reagents. The NIR absorption and fluorescence properties of Pcs were also revealed and rationalized under substitution effects.

According to a recent report, a low Ki67 level after short-term preoperative hormone therapy (post-Ki67) might suggest a more favorable prognosis compared with a high post-Ki67 level in patients with hormone receptorpositive/human epidermal growth factor 2-negative (HR+/HER2-) breast cancer with high levels of Ki67. This study aimed to evaluate the pre-treatment genetic differences between these two patient groups. Forty-five luminal B-like patients were stratified into two groups, namely, a group with high (H→H) and one with low (H→L) Ki67 levels after short-term preoperative aromatase inhibitor (AI) treatment. We compared pre-treatment gene expression profiles between the two groups. In gene level analysis, there was no significant difference between the two groups by the class comparison test. In pathway analysis, five metabolism-related gene sets were significantly upregulated in the H→L group (p≤0.05). In the search for novel targets, five genes (PARP, BRCA2, FLT4, CDK6, and PDCD1LG2) showed significantly higher expression in the H→H group (p≤0.05). Several metabolism-related pathways were associated with sensitivity to AI. In the future, it will be necessary to seek out new therapeutic strategies for the poor prognostic group with high post-Ki67.

Purpose: Emojis are commonly used for daily communication and may be useful in assessing patient-reported outcomes (PROs) in breast cancer. The purpose of this study is to develop and validate an Emoji Sticker Scale (ESS) as a new PRO measurement. Methods: Eighteen original ESS items were developed from the PRO-CTCAE. In cohort one, the ESS validity and reliability were examined in patients with breast cancer, using a semi-structured five-question survey to investigate content validity. PROs with PRO-CTCAE and ESS were examined twice to determine criteria validity and test-retest reliability. In cohort two, the responsiveness of the scales were examined in patients treated with anthracycline, docetaxel, paclitaxel, and endocrine therapy. PROs with PRO-CTCAE and ESS were investigated two or three times, depending on the therapy. Results: Patients were enrolled from August 2019 to October 2020. In cohort one (n=70), most patients had no difficulties with the ESS, but 16 patients indicated that it was difficult to understand severities in the ESS. For criterion validity, Spearman rank correlation coefficients (rs) between PRO-CTCAE and ESS items were ≥0.41, except for “Decreased appetite.” For test-retest reliability, κ coefficients of the ESS were ≥0.41 for 16/18 items (88.9%). Response time was significantly shorter for the ESS than for PRO-CTCAE (ps≥0.41. Conclusion Parts of the original ESS developed from PRO-CTCAE require updating. However, this study provides a comprehensive confirmation of the validity, reliability, and responsiveness of the ESS.

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Purpose: To examine gene expression differences between pre- and post-neoadjuvant systemic therapy (NST) specimens of breast cancers and identify biologic changers that may lead to new therapeutic insights.Methods: Gene expression data from prechemotherapy fine needle aspiration specimens were compared with resected residual cancers in 21 patients after 4 to 6 months of NST. We removed stroma-associated genes to minimize confounding effects. PAM50 was used to assign molecular class. Paired t test and gene set analysis were used to identify differentially expressed genes and pathways.Results: The ER and HER2 status based on mRNA expression remained stable in all but two cases, and there were no changes in proliferation metrics (Ki67 and proliferating cell nuclear antigen expression). Molecular class changed in 8 cases (33.3%), usually to normal-like class, which was associated with low residual cancer cell cellularity. The expression of 200 to 600 probe sets changed between baseline and post-NST samples. In basal-like cancers, pathways driven by increased expression of phosphoinositide 3-kinase, small G proteins, and calmodulin-dependent protein kinase II and energy metabolism were enriched, whereas immune cell–derived and the sonic hedgehog pathways were depleted in residual cancer. In non–basal-like breast cancers, notch signaling and energy metabolism (e.g., fatty acid synthesis) were enriched and sonic hedgehog signaling and immune-related pathways were depleted in residual cancer. There was no increase in epithelial–mesenchymal transition or cancer stem cell signatures.Conclusions: Our data indicate that energy metabolism related processes are upregulated and immune-related signals are depleted in residual cancers. Targeting these biologic processes may represent promising adjuvant treatment strategies for patients with residual cancer. Clin Cancer Res; 18(4); 1109–19. ©2012 AACR.

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Supplementary Tables XLS file - 236K, Supplementary Table 1: Comparison of ER- and ErbB2-status determined using gene expression profiling and immunohistochemistry Supplementary Table 2: Validation of the algorithm to identify transcription factor activation Supplementary Table 3: Description of the public nIBC data sets Supplementary Table 4: Molecular data of IBC and nIBC samples Supplementary Table 5: List of 491 probe sets differentially expressed between IBC and nIBC samples in a molecular subtype-independent manner Supplementary Table 6: IPA analysis of the list of 443 unique genes differentially expressed between IBC and nIBC Supplementary Table 7: Networks identified by IPA analysis of the list of 443 unique genes differentially expressed between IBC and nIBC Supplementary Table 8: Uni- and multivariate analyses for DMFS in the public pooled nIBC data set

Table S1: Clinico-pathological features for samples in the PROGNOSTIC collection; Table S2: Clinico-pathological features for samples in the TAM collection; Table S3: Clinico-pathological features for samples in the CHEMO collection; Table S4: Output of immune cluster refinement in ER-HER2- samples. Five years DMFS for high, intermediate and low expression groups and log-rank test p-values (average and standard deviation of 100 10-fold cross-validations) are reported as a function of the number of genes; Table S5: Output of immune cluster refinement in HER2+ samples. Five years DMFS for high, intermediate and low expression groups and log-rank test p-values (average and standard deviation of 100 10-fold cross-validations) are reported as a function of the number of genes; Table S6: Output of proliferation cluster refinement in 508 ER+HER2- samples. Five-years DMFS for high, intermediate and low expression groups and log-rank test p-values (average and standard deviation of 100 10-fold cross-validations) are reported as a function of the number of genes; Table S7: Output of ER-related cluster refinement in 394 high proliferation ER+HER2- samples. Five-years DMFS for high, intermediate and low expression groups and log-rank test p-values (average and standard deviation of 100 10-fold cross-validations) are reported as a function of the number of genes; Table S8: Univariable Cox regression analysis for the CTM in the combined dataset or in each dataset for ER- or HER2+ cases or separately for ER-HER2- and HER2+ subgroups; Table S9: Univariable and multivariable Cox regression analysis in 205 ER-HER2- and HER2+ samples from the CHEMO collection (all biomarkers were used as continous variables); Table S10: Univariable Cox regression analysis for the combined proliferation and ER-related metagenes in ER+HER2- cases from the combined dataset or from each dataset

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Background: Inflammatory breast cancer (IBC) is a poorly characterized form of breast cancer. So far, the results of expression profiling in IBC are inconclusive due to various reasons including limited sample size. Here, we present the integration of three Affymetrix expression datasets collected through the World IBC Consortium allowing us to interrogate the molecular profile of IBC using the largest series of IBC samples ever reported.Experimental Design: Affymetrix profiles (HGU133-series) from 137 patients with IBC and 252 patients with non-IBC (nIBC) were analyzed using unsupervised and supervised techniques. Samples were classified according to the molecular subtypes using the PAM50-algorithm. Regression models were used to delineate IBC-specific and molecular subtype-independent changes in gene expression, pathway, and transcription factor activation.Results: Four robust IBC-sample clusters were identified, associated with the different molecular subtypes (P < 0.001), all of which were identified in IBC with a similar prevalence as in nIBC, except for the luminal A subtype (19% vs. 42%; P < 0.001) and the HER2-enriched subtype (22% vs. 9%; P < 0.001). Supervised analysis identified and validated an IBC-specific, molecular subtype-independent 79-gene signature, which held independent prognostic value in a series of 871 nIBCs. Functional analysis revealed attenuated TGF-β signaling in IBC.Conclusion: We show that IBC is transcriptionally heterogeneous and that all molecular subtypes described in nIBC are detectable in IBC, albeit with a different frequency. The molecular profile of IBC, bearing molecular traits of aggressive breast tumor biology, shows attenuation of TGF-β signaling, potentially explaining the metastatic potential of IBC tumor cells in an unexpected manner. Clin Cancer Res; 19(17); 4685–96. ©2013 AACR.

Supplementary Figures PDF file - 529K, Supplementary Figure 1: Application of the Gaussian mixture model to ESR1- and ERBB2-expression data Supplementary Figure 2: Normalization Supplementary Figure 3: Silhouette Analysis Supplementary Figure 4: Silhouette Analysis (P-Values) Supplementary Figure 5: Validation of Limma-corrected IBC/nIBC signature Supplementary Figure 6: Networks overrepresented in IBC Supplementary Figure 7: Networks overrepresented in nIBC Supplementary Figure 8: Prognostic value of the IBC/nIBC signature in nIBC

Purpose: Estrogen receptor-positive (ER+) and -negative (ER) breast cancers are molecularly distinct diseases. We hypothesized that p53 mutations may lead to different transcriptional changes and carry different prognostic value in these two different types of cancers.Experimental Design: We developed a 39-gene p53 signature derived from 213 ER+ and a separate 30-gene signature from 38 ER− cancers with known mutation status and tested their prognostic and chemotherapy response predictive values in ER+ and ER− cancers, respectively.Results: External validation to predict p53 status (n = 103) showed sensitivity and specificity of 89% and 54% for the 39-gene signature, and 82% and 61% for the 30-gene signature. The 39-gene signature was predictive of worse distant metastasis free survival in ER+ cancers in two separate prognostic data sets (n = 255, HR: 2.3, P = 0.005 and n = 198, HR: 2.17, P = 0.09). It also predicted for poor prognosis even with adjuvant tamoxifen therapy (n = 277, HR = 2.43, P < 0.0001) but it was not prognostic in ER− cancers. It was also associated with higher chemotherapy sensitivity in ER+ but not in ER− cancers. The prognostic and predictive values remained significant in multivariate analysis. The 30-gene, ER−, p53 signature showed no prognostic or predictive values in ER+ cancers but it was associated with better prognosis in ER− cancers. It also had no chemotherapy response predictive value in ER− or ER+ cancers.Conclusions: P53 dysfunction is prognostically most relevant in ER+ cancers and supports the hypothesis that different predictive or prognostic markers will be needed for different molecular subsets of breast cancer. Clin Cancer Res; 17(8); 2591–601. ©2011 AACR.

Supplementary Figures S1-S5; Supplementary Methods; Supplementary Tables S1-S6.

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PDF file, 351K, Silencing endogenous TIG1 in SUM149 IBC cells inhibits cell proliferation (S1); Silencing endogenous TIG1 in KPL-4 IBC cells inhibits cell proliferation, migration, and invasion (S2); TIG1 depletion affects the growth of SUM149 cells in 3-dimensional culture (S3); Heat map of 19 selected candidates from 183 probe sets differentially expressed between SUM149 cells transfected with control siRNA and SUM149 cells transfected with siRNA targeting TIG1 (siTIG1)(S4); Representative images of crystal violet staining of migration and invasion assays for Axl-restored shTIG1-A cells (S5); TIG1 colocalized with Axl in KPL-4 cells (S6); SGI-7079 treatment inhibits the invasion of KPL-4 cells (S7).

Different kinases are expressed in different clinical subsets of breast cancer. In this study, we assessed kinase expression patterns in different clinical subtypes of breast cancer, evaluated the prognostic and predictive values of kinase metagenes, and investigated their functions in vitro. Four hundred twenty-eight protein kinases in gene expression data were examined from 684 cases of breast cancer and 51 breast cancer cell lines to identify kinase expression patterns. We tested the prognostic value of kinase metagenes in 684 node-negative patients who received no adjuvant therapy and the predictive value in 233 patients who received uniform neoadjuvant chemotherapy. Twelve kinases were overexpressed in estrogen receptor (ER)–positive/human epidermal growth factor receptor 2 (HER2)–negative, 7 in HER2+, and 28 in ER−/HER2− cancers, respectively. We examined the functional role of 22 kinases overexpressed in ER−/HER2− cancers using siRNA. Downregulation of these kinases caused significant subtype-specific inhibition of cell growth in vitro. Two robust kinase clusters, including an immune kinase cluster and a mitosis kinase cluster, were present in all clinical subgroups. High mitosis kinase score was associated with worse prognosis but higher pathologic complete response (pCR) in ER+/HER2− cancers, but not in ER−/HER2− or HER2+ cancers, in univariate and multivariate analyses including other genomic predictors (MammaPrint, genomic grade index, and the 76-gene signature). Conversely, higher immune kinase score was associated with better survival in ER+/HER2− and HER2+ tumors and also predicted higher probability of pCR in HER2+ cancers. Taken together, our results indicate that kinases regulating mitosis and immune functions convey distinct prognostic information that varies by clinical subtype. Cancer Res; 70(21); 8852–62. ©2010 AACR.

Supplementary Figure 1 from Prognostic and Therapeutic Implications of Distinct Kinase Expression Patterns in Different Subtypes of Breast Cancer

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PDF file, 72K, Candidate functional partners of TIG1 selected using DNA microarray analysis.

PDF file, 76K, Relation between TIG1 expression status and clinicopathologic factors of the IBC patient tissues.

Supplementary Tables 1-11 from Prognostic and Therapeutic Implications of Distinct Kinase Expression Patterns in Different Subtypes of Breast Cancer

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Supplementary Figures 2-5 from Prognostic and Therapeutic Implications of Distinct Kinase Expression Patterns in Different Subtypes of Breast Cancer

Background: Trastuzumab Deruxtecan (T-DXd) is a novel antibody-drug conjugate that targets human epidermal growth factor receptor 2 (HER2) with a DNA topoisomerase I inhibitor payload and has demonstrated antitumor activity in clinical trials. Based on the results of a global Phase II clinical trial (DESTINY-Breast01, NCT03248492), T-DXd was conditionally approved for the treatment of patients with HER2+ unresectable or metastatic breast cancer who had received ≥2 prior anti-HER2 based therapies (US, EU, UK, etc) or after prior chemotherapy (Japan). With regards to the safety profile, the incidence of cumulative toxicities such as peripheral neuropathy and edema was lower with T-DXd as compared to what has been observed with taxanes. However, chemotherapy-induced nausea and vomiting (CINV), fatigue, and neutrophil count decrease were observed as treatment emergent adverse events (TEAE). Interstitial lung disease (ILD)/pneumonitis was especially observed in 15.2% of patients treated with T-DXd, leading to death in 2.7% of patients. These adverse events need appropriate monitoring and management in daily clinical practice. We hypothesized that electronic patient-reported outcomes (ePROs) monitoring would allow early detection of adverse events due to T-DXd and thus improve patient safety and quality of life (QoL). Study design: This is an open-label, multicenter, randomized controlled study comparing ePRO monitoring with routine follow-up of patients with HER2+ advanced or metastatic breast cancer who receive T-DXd in routine clinical practice. Patients randomized to the ePRO group are monitored through weekly PRO-CTCAE assessment as well as daily temperature and SpO2 measurement using the ePRO application on the patient's mobile device. Changes in symptoms are monitored by the attending physician using an electronic chart. In addition, an e-mail alert is sent to the site medical staff if any symptoms exceed a predetermined threshold. The primary endpoint of the study is the change from baseline in the EORTC QLQ-C30 (Global QoL) score at 24 weeks. Secondary endpoints include time to deterioration of Global QoL, EORTC FA12 score change, overall survival, progression-free survival, and adherence to the ePRO monitoring as assessed by the proportion of patients completing the questionnaires. Analysis of primary endpoint will be done using mixed effects models for repeated measures (MMRM) and sample size will be estimated based on the Wald test for differences between groups in mean parameters at 24 weeks. To detect 10-points score difference between the groups with a standard deviation of 24, with a two-sided alpha level of 10%, and a power of 87%, 55 patients would be required in each group. Enrollment started in March 2021. Clinical trial identification: jRCTs031200387 Citation Format: Takafumi Sangai, Yuichiro Kikawa, Mitsuchika Hosoda, Yohei Hamanaka, Yuko Tanabe, Tatsuya Yoshida, Kaori Tane, Daisuke Takabatake, Tetsuhiko Taira, Kazuhiro Araki, Takayuki Iwamoto, Mamoru Takada, Kazutaka Narui, Takeshi Yamaguchi, Akimitsu Yamada, Tomoko Miura, Yukari Uemura, Tomohiko Aihara, Hirofumi Mukai, Naruto Taira. Randomized study comparing electronic patient reported outcomes (ePROs) monitoring with routine follow up during trastuzumab deruxtecan treatment in patients with inoperable or metastatic breast cancer (PRO-DUCE study) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-12-08.

Background It is unclear what interventions can sustain long-term higherphysical activity (PA) to improve breast cancer outcomes. Thus, this study aimed to evaluate the long-term effects of interventions on PA after breast cancer treatment. Methods This was an open-label randomized controlled trial for patients with stage 0-III breast cancer evaluating the efficacy of exercise and educational programs on long-term PA compared with usual care. The primary endpoint was proportion of patients with recreational PA (RPA) ≥5 metabolic equivalents(METs)/week at 1 year after registration. Results From 01/03/2016 to 15/03/2020, breast cancer patients were registered in the control (n = 120), education (n = 121), or exercise (n = 115) group. There were no significant differences in proportion of RPA ≥5 METs/week at 1 year between the exercise and control groups (54% and 53%, P = 0.492) and between the education and control groups (62% and 53%, P = 0.126). Significant difference in reductions from baseline at 1 year were noted on body weight (P = 0.0083), BMI (P = 0.0034), and body fat percentage (P = 0.0027) between education and control groups. Similarly, the exercise group showed significant difference in reduction in body fat percentage (P = 0.0038) compared to control group. Conclusions Although there were no significant effects on RPA 1 year after exercise and educational programs for breast cancer survivors, both interventions reduced body composition. Future studies on PA should investigate appropriate interventions to improve overall survival. Trial registration UMIN000020595 at UMIN Clinical Trial Registry Date of first registration: 01/03/2016

Background Elucidating the unique immunoregulatory mechanisms in breast cancer microenvironment may help develop new therapeutic strategies. Some studies have suggested that hormone receptors also have immune regulatory functions, but their mechanisms are not fully understood. In this study, we have comprehensively analyzed the relationship between the expressions of estrogen (ER), progesterone (PgR), and androgen receptors (AR), and the immunological profile in breast cancer. Methods Using publicly available gene expression profile datasets, METABRIC and SCAN-B, the associations between the expressions of hormone receptors and the immune cell compositions in breast cancer tissue, estimated by CIBERSORTx algorithm, were analyzed. We histologically evaluated tumor-infiltrating lymphocytes (hTIL), PD-L1 (hPD-L1) expression, and the infiltration of 11 types of immune cells by flow cytometry (FCM) for 45 breast cancer tissue samples. The relationships between them and the expressions of ER, PgR, and AR of tumor tissues, evaluated immunohistochemically, were analyzed. Results Expressions of ESR1, PGR, and AR were negatively correlated with overall immune composition. Expressions of ER and AR, but not that of PgR, were inversely associated with hTIL and hPD-L1 expression. FCM analysis showed that the expressions of ER and AR, but not that of PgR, were associated with decreased total leukocyte infiltration. Both CIBERSORTx and FCM analysis showed that ER expression was associated with reduced infiltration of macrophages and CD4+ T cells and that of AR with reduced macrophage infiltration. Conclusion Hormone receptor expression correlates with specific immunological profiles in the breast cancer microenvironment both at the gene and protein expression levels.

Objective This study examined the pharmacokinetics, safety and anti-tumor activity of docetaxel at a dose of 100 mg/m2 in Japanese patients with advanced or recurrent breast cancer. Methods Japanese patients with advanced or recurrent breast cancer received docetaxel at a dose of 100 mg/m2 intravenously every three weeks. The pharmacokinetics were assessed during the first cycle. The patients were allowed to receive supportive care drugs based on the indications and dosages in Japan. Results Six eligible patients aged 39-65 years old and 27 treatment cycles were analyzed. All patients experienced one or more adverse events (AEs). The common AEs were neutropenia, thrombocytopenia, alopecia, rash, diarrhea, neuropathy (sensory), fatigue, nausea, fever, hypoalbuminemia, alanine transaminase (ALT) increased, constipation, and taste alteration. Grade 3 or 4 AEs included neutropenia, leukopenia, anemia, lymphopenia, decreased appetite, γ-glutamyl transpeptidase (GTP) increased, aspartate transaminase (AST) increased, ALT increased, hypertension and cellulitis which were all reversible. There were no cases of febrile neutropenia, serious AEs or deaths. The median number of cycles was six. Dose reductions were not observed and most cycles were administered at their intended doses. No complete response and three partial responses were observed in four assessable patients with evaluable lesions. The maximum concentration and area under the blood concentration-time curve were 3,417.5 ng/mL and 4.35 μg・hr/mL (mean), respectively. Conclusion Docetaxel at a dose of 100 mg/m2 was tolerable with acceptable safety profiles and effective for Japanese patients with advanced or recurrent breast cancer with appropriate supportive therapies, and pharmacokinetic (PK) profiles which corresponded approximately with the findings of previous clinical studies.