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Adjuvant therapy for patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive, early breast cancer (EBC) remains challenging. The prognostic significance of HER2-low positivity in these patients is not fully understood. In our retrospective study, we analyzed 647 patients with HR-positive, HER2-negative, node-positive EBC, stratifying them into three cohorts based on axillary lymph node involvement, tumor size, and characteristics. Cohort 1 included patients with either ≥ 4 positive axillary lymph nodes or 1-3 positive nodes with histological grade 3 or tumor size ≥ 5 cm. Cohort 2 consisted of patients with 1-3 positive nodes, histological grade < 3, tumor size < 5 cm, and Ki-67 ≥ 20%. Cohort 3 comprised patients with 1-3 positive nodes, histological grade < 3, tumor size < 5 cm, and Ki-67 < 20%. We compared invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) between HER2-low (IHC1+ or IHC2+/FISH-) and HER2-zero (IHC0) groups in each cohort. In cohort 1, HER2-low patients exhibited significantly better 5-year IDFS (84.2% vs. 73.6%, p = 0.0213) and DRFS (88.2% vs. 79.8%, p = 0.0154). However, no significant differences were observed in cohorts 2 and 3. Our findings suggest HER2-low positivity as a prognostic factor in HR-positive, HER2-negative, and node-positive EBC., (© 2023. The Author(s).)

Background: Histological grade (HG) has been used in the MonrachE trial to select patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive high-risk early breast cancer (EBC). Although nuclear grade (NG) is widely used in Japan, it is still unclear whether replacing HG with NG can appropriately select high-risk patients., Methods: We retrospectively reviewed 647 patients with HR-positive, HER2-negative, node-positive EBC and classified them into the following four groups: group 1: ≥ 4 positive axillary lymph nodes (pALNs) or 1-3 pALNs and either grade 3 of both grading systems or tumors ≥ 5 cm; group 2: 1-3 pALNs, grade < 3, tumor < 5 cm, and Ki-67 ≥ 20%; group 3: 1-3 pALNs, grade < 3, tumor < 5 cm, and Ki-67 < 20%; and group 4: group 2 or 3 by HG classification but group 1 by NG classification. We compared invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) among the four groups using the Kaplan-Meier method with the log-rank test., Results: Group 1 had a significantly worse 5-year IDFS and DRFS than groups 2 and 3 (IDFS 80.8% vs. 89.5%, P = 0.0319, 80.8% vs. 95.5%, P = 0.002; DRFS 85.2% vs. 95.3%, P = 0.0025, 85.2% vs. 98.4%, P < 0.001, respectively). Group 4 also had a significantly worse 5-year IDFS (78.0%) and DRFS (83.6%) than groups 2 and 3., Conclusions: NG was useful for stratifying the risk of recurrence in patients with HR-positive, HER2-negative, node-positive EBC and was the appropriate risk assessment for patient groups not considered high-risk by HG classification., (© 2023. The Author(s).)

Background/objective: The occurrence of iatrogenic tumor cell seeding (seeding) in needle tract scars formed by core needle biopsy (CNB) or vacuum-assisted biopsy (VAB) is well known. Some risk factors for seeding have been reported, but the clinicopathological risk factors and its prognosis have not been fully investigated. We evaluated the clinical features and prognosis of seeding., Methods: We included 4405 patients who had undergone surgery (lumpectomy or mastectomy) with a diagnosis of breast cancer by preoperative CNB or VAB at our hospital between January 2012 and February 2021. Data of patients with confirmed presence of seeding in resected specimens were collected from pathological records. We analyzed the risk factors of seeding using logistic regression analysis and compared the ipsilateral breast tumor recurrence (IBTR) rate between cases based on the presence or absence of seeding in the lumpectomy group., Results: Of the 4405 patients, 133 (3.0%) had confirmed seeding. Univariate analysis revealed the association of clinicopathological features of seeding with lower nuclear grade (NG1 vs NG2-3; p = 0.043), lower Ki-67 (<30 vs. ≥30; p = 0.049), estrogen receptor (ER) positivity (positive vs negative; p<0.01), and human epidermal growth factor receptor 2 (HER2) negativity (negative vs positive; p = 0.016). Multivariate analysis showed ER positivity (odds ratio, 5.23; p<0.05) as an independent risk factor of seeding. The IBTR rate was not significantly different between the seeding and non-seeding groups., Conclusions: Seeding was more likely to occur in ER positive, HER2 negative carcinomas with less aggressive features, and may remain subclinical if adequate adjuvant treatments are administered., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Asian Surgical Association and Taiwan Robotic Surgery Association. Published by Elsevier B.V. All rights reserved.)

Purpose: The impact of progesterone receptor (PR) status on the prognosis of breast cancer after isolated locoregional recurrence (ILRR) remains unclear. This study evaluated the impact of clinicopathologic factors, including PR status of ILRR, on distant metastasis (DM) after ILRR., Methods: We retrospectively identified 306 patients with ILRR diagnosed at the National Cancer Center Hospital between 1993 and 2021 from the database. Cox proportional hazards analysis was performed to examine factors associated with DM after ILRR. We developed a risk prediction model based on the number of detected risk factors and estimated survival curves using the Kaplan-Meier method., Results: During a median follow-up time of 4.7 years after ILRR diagnosis, 86 patients developed DM, and 50 died. Multivariate analysis revealed that seven risk factors were associated with poor distant metastasis-free survival (DMFS): estrogen receptor-positive/PR-negative/human epidermal growth factor receptor 2-negative ILRR, short disease-free interval, recurrence site other than ipsilateral breast, no-resection of ILRR tumor, chemotherapy for the primary tumor, nodal stage in the primary tumor, and no endocrine therapy for ILRR. The predictive model classified patients into 4 groups based on the number of risk factors: low-, intermediate-, high-, and the highest-risk groups with 0 to 1, 2, 3 to 4, and 5 to 7 factors, respectively. This revealed significant variation in DMFS among the groups. A higher number of the risk factors was associated with poorer DMFS., Conclusion: Our prediction model, which considered the ILRR receptor status, may contribute to the development of a treatment strategy for ILRR., (© 2023. The Author(s).)

Background: Chemotherapy and radiotherapy were postulated to induce an inflamed tumour microenvironment. We aimed to evaluate the effects of adjuvant chemotherapy/radiotherapy on tumour-infiltrating lymphocytes (TILs) and programmed death-ligand 1 (PD-L1) expression in metastatic breast cancer., Methods: We identified paired primary and metastatic tumours in 85 patients with breast cancer. Stromal TILs were assessed according to international guidelines. PD-L1 expression was evaluated using the VENTANA SP142 assay., Results: TILs were significantly lower in metastatic tumours than in primary tumours (12.2 vs. 8.3%, p = 0.049). PD-L1 positivity was similar between primary and metastatic tumours (21.2 vs. 14.1%, p = 0.23). TILs were significantly lower in patients who received adjuvant chemotherapy than in those who did not (-9.07 vs. 1.19%, p = 0.01). However, radiotherapy had no significant effect on TILs (p = 0.44). Decreased TILs predicted worse post-recurrence survival (hazard ratio, 2.94; 95% confidence interval [CI]: 1.41-6.13, p = 0.003), while increased TILs was associated with a better prognosis (HR, 0.12; 95% CI: 0.02-0.08, p = 0.04)., Conclusions: TILs decreased in metastatic tumours, particularly in patients who relapsed after adjuvant chemotherapy. Changes in TILs from primary to metastatic sites could be a prognostic factor after recurrence., (© 2022. The Author(s).)

Background: /Objective: To evaluate the usefulness of combining radioisotopes (RI) and indocyanine green (ICG) and investigate discordances in sentinel lymph node (SN) reactivity using each tracer in cN0 breast cancer patients., Methods: In total, 338 cN0 primary breast cancer patients who underwent SN biopsy with RI and ICG and axillary lymph node (ALN) dissection were included. SN positivity with RI, ICG, and a combination of RI and ICG was denoted as SN(RI), SN(ICG), and SN(RI+ICG), respectively. We retrospectively estimated metastatic SN detection rates, each method's discordance rate, and the correlation of discordances in SN reactivity with postoperative N staging., Results: The combination of RI and ICG had higher metastatic SN detection rates (99.7%) than RI or ICG alone (91.7% and 96.4%, respectively; p < 0.01). The discordance rate between SN(RI) and SN(ICG) in detecting metastatic SNs was 11.3% (38/337 cases). The absence of SN(RI), cT stage (cT2-3), higher histological grade (G3), and histological type (special type) were identified as risk factors of pN2-3 disease (odds ratios: 8.64, 2.56, 1.92, and 3.28, respectively; p < 0.01)., Conclusion: Discordances in SN reactivity between RI and ICG helps in identifying SN metastasis. Although the absence of SN(RI) is rare, it is a significant sign of advanced ALN metastases. The findings of our study indicate that ALN dissection should be considered for accurate nodal staging in such cases., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2022 Asian Surgical Association and Taiwan Robotic Surgery Association. Published by Elsevier B.V. All rights reserved.)

Although the categorization of ultrasound using the Breast Imaging Reporting and Data System (BI-RADS) has become widespread worldwide, the problem of inter-observer variability remains. To maintain uniformity in diagnostic accuracy, we have developed a system in which artificial intelligence (AI) can distinguish whether a static image obtained using a breast ultrasound represents BI-RADS3 or lower or BI-RADS4a or higher to determine the medical management that should be performed on a patient whose breast ultrasound shows abnormalities. To establish and validate the AI system, a training dataset consisting of 4028 images containing 5014 lesions and a test dataset consisting of 3166 images containing 3656 lesions were collected and annotated. We selected a setting that maximized the area under the curve (AUC) and minimized the difference in sensitivity and specificity by adjusting the internal parameters of the AI system, achieving an AUC, sensitivity, and specificity of 0.95, 91.2%, and 90.7%, respectively. Furthermore, based on 30 images extracted from the test data, the diagnostic accuracy of 20 clinicians and the AI system was compared, and the AI system was found to be significantly superior to the clinicians (McNemar test, p < 0.001). Although deep-learning methods to categorize benign and malignant tumors using breast ultrasound have been extensively reported, our work represents the first attempt to establish an AI system to classify BI-RADS3 or lower and BI-RADS4a or higher successfully, providing important implications for clinical actions. These results suggest that the AI diagnostic system is sufficient to proceed to the next stage of clinical application., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: There are currently no scoring-type predictive models using only easily available pre- and intraoperative data developed for assessment of the risk of advanced axillary lymph node metastasis (ALNM) in patients with breast cancer with metastatic sentinel lymph nodes (SLNs). We aimed to develop and validate a scoring system using only pre- and intraoperative data to distinguish between non-advanced (≤ 3 lymph nodes) and advanced (> 3 lymph nodes) ALNM in patients with breast cancer with metastatic SLNs., Methods: We retrospectively identified 804 patients with breast cancer (cT1-3cN0) who had metastatic SLNs and had undergone axillary lymph node dissection (ALND). We evaluated the risk factors for advanced ALNM using logistic regression analysis and developed and validated a scoring system for the prediction of ALNM using training (n = 501) and validation (n = 303) cohorts, respectively. The predictive performance was assessed using the receiver operating characteristic (ROC) curve, area under the curve (AUC), and calibration plots., Results: Ultrasound findings of multiple suspicious lymph nodes, SLN macrometastasis, the ratio of metastatic SLNs to the total number of SLNs removed, and the number of metastatic SLNs were significant risk factors for advanced ALNM. Clinical tumor size and invasive lobular carcinoma were of borderline significance. The scoring system based on these six variables yielded high AUCs (0.90 [training] and 0.89 [validation]). The calibration plots of frequency compared to the predicted probability showed slopes of 1.00 (training) and 0.85 (validation), with goodness-of-fit for the model. When the cutoff score was set at 4, the negative predictive values (NPVs) of excluding patients with advanced ALNM were 96.8% (training) and 96.9% (validation). The AUC for predicting advanced ALNM using our scoring system was significantly higher than that predicted by a single independent predictor, such as the number of positive SLNs or the proportion of positive SLNs. Similarly, our scoring system also showed good discrimination and calibration ability when the analysis was restricted to patients with one or two SLN metastases., Conclusion: Our easy-to-use scoring system can exclude advanced ALNM with high NPVs. It may contribute to reducing the risk of undertreatment with adjuvant therapies in patients with metastatic SLNs, even if ALND is omitted., (© 2022. The Author(s).)

Background: It has been determined that axillary lymph node dissection after the detection of limited axillary lymph node metastasis does not improve the prognosis of patients with breast cancer. Thus, a need exists for less-invasive axillary surgery. However, it remains unclear whether a predictive model based on preoperative data would be sufficient to accurately predict the probability of pN2-N3 (> 3 lymph node metastases). We sought to develop an easy-to-use scoring system to distinguish between pN0-N1 (0-3 lymph node metastases) and pN2-N3 using only preoperative data and validate its predictive performance., Patients and Methods: We retrospectively identified 2687 patients diagnosed with cT1-3cN0-N1 who had undergone surgery in our hospital from 2013 to 2019. We evaluated the risk factors associated with pN2-N3 by logistic regression analysis and developed a scoring system. Predictive performance was assessed by calculating the receiver operating characteristic area under the curve (AUC) and was validated using K-fold cross-validation., Results: We identified 1987 patients with stage pN0, 522 with pN1, and 178 with pN2-N3. Multivariate analysis revealed tumor size, number of suspicious lymph nodes on axillary ultrasound examination, histologic type, histologic grade, and receptor status were significant risk factors for pN2-N3. The AUC value was 0.87, and the mean AUC of the 10-fold cross-validation was 0.88. When the cutoff score was set at 6, the negative predictive value for excluding patients with pN2-N3 was 98.4%., Conclusion: Our easy-to-use scoring system could be useful to preoperatively identify patients at lower risk of pN2-N3 and avoid unnecessary axillary lymph node dissection., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Eribulin mesylate (eribulin) is an efficient microtubule inhibitor that is used for metastatic breast cancer. However, breast cancer can develop resistance to eribulin. This resistance mechanism needs to be elucidated., Methods: A transposon mutagenesis screen was conducted using a pPB-SB-CMV-puro-SD plasmid and pCMV-PBase transposase. Viability and cytotoxicity were analyzed by MTT assay and flow cytometry, respectively. Real-time PCR and western blot were used for gene expression analysis. In addition, vivo study was also designed to analyze therapy efficiency., Results: TAB2, which is part of the nuclear factor-kappa B (NF-κB) pathway, was identified as a candidate eribulin-resistant gene. TAB2 down-regulation resulted in significantly lower cell viability and higher cytotoxicity of cells treated with eribulin, while TAB2 up-regulation showed opposite results. Similarly, combination of NF-κB inhibitors [Bay-117082 and QNZ (quinazoline derivative)] with eribulin showed significantly lower cell viability and higher drug cytotoxicity than single agent treatment with eribulin in MDA-MB-231 cells. However, QNZ increased NF-κB activity in MCF7 cells by up-regulating TAB2, which reduced the sensitivity to eribulin. Furthermore, combination of Bay-117082 with eribulin induced greater regression of MDA-MB-231 tumors compared to eribulin monotherapy in vivo., Conclusions: These results consistently illustrated that TAB2-NF-κB pathway may increases resistance to eribulin in breast cancer models. Moreover, these results support the use of a combination strategy of eribulin with NF-κB inhibitors, and provide evidence that transposon mutagenesis screens are capable of identifying drug-resistant genes.

Objective: We investigated the quantification of the response shift-adjusted treatment effect on quality-of-life (QOL) data in a randomized controlled trial of taxane versus S-1 for patients with metastatic breast cancer (SELECT-BC)., Methods: This study was a secondary data analysis of a previously published trial. The response shift-adjusted treatment effect on health-related QOL (HRQOL) data measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) was estimated using structural equation modeling techniques in addition to quantifying the "true" treatment effect. Measurement invariances in the values of the common factor loadings, intercepts, and residual variances between before treatment and at the 3-, 6-, and 12-month visits were considered the response shift effects., Results: In the taxane group, we observed positive recalibration effects for role functioning and positive reprioritization and negative recalibration effects for emotional functioning. The observed change of -4.56 for role functioning comprised +2.26 response shifts and -6.82 "true" change. The observed change of +9.41 for emotional functioning comprised +12.43 response shifts and -1.17 "true" change. In the S-1 group, we observed positive reprioritization and negative recalibration effects for emotional functioning and positive reprioritization effects for social functioning. The observed change of +10.54 for emotional functioning comprised +10.07 response shifts and +0.47 "true" change. The observed change of +2.43 for social functioning comprised +3.50 response shifts and -1.07 "true" change., Conclusion: Detailed analysis of the response shift effects will improve the evaluation reliability of observed HRQOL data during clinical trials., (Copyright © 2020 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Background: ALN dissection (ALND) is the only way to obtain information on ALN metastasis status accurately when sentinel lymph node (SLN) metastasis is present. In this study, we established a model for intraoperatively predicting non-SLN metastasis and the presence of four or more ALNs (pN2), based on the combined use of one-step nucleic acid amplification (OSNA) and histological examination following SLN biopsy., Materials and Methods: Subjects comprised 318 consecutive breast cancer patients (cTis-3, N0) who underwent SLN biopsy with a combination of OSNA and histological examination, and who were found to have SLN metastasis and were treated by ALND. We allotted points to each patient according to their SLN metastasis status as defined by both OSNA and histology, then defined the "National Cancer Center sentinel lymph node metastatic score" (NCS score) based on the total points. Correlations between the NCS score and both non-SLN metastasis and pN2 status were analyzed by logistic regression analysis. The accuracy of this score was evaluated using receiver operating characteristic (ROC) analysis., Results: The NCS score was significantly correlated with both non-SLN metastasis and pN2 status (adjusted odds ratio: 1.26 for non-SLN metastasis, 1.56 for pN2 status). The area under the ROC curve (AUC) of the NCS score demonstrated 0.74 for non-SLN metastasis, 0.91 for pN2 status., Conclusions: The NCS score was a strong independent predictor of non-SLN metastasis and pN2 status. Use of this score will facilitate the selection of optimal adjuvant therapies without requiring unnecessary ALND., Competing Interests: Declaration of competing interest None declared., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The aim of this study is to explore new salivary biomarkers to discriminate breast cancer patients from healthy controls., Methods: Saliva samples were collected after 9 h fasting and were immediately stored at - 80 °C. Capillary electrophoresis and liquid chromatography with mass spectrometry were used to quantify hundreds of hydrophilic metabolites. Conventional statistical analyses and artificial intelligence-based methods were used to assess the discrimination abilities of the quantified metabolites. A multiple logistic regression (MLR) model and an alternative decision tree (ADTree)-based machine learning method were used. The generalization abilities of these mathematical models were validated in various computational tests, such as cross-validation and resampling methods., Results: One hundred sixty-six unstimulated saliva samples were collected from 101 patients with invasive carcinoma of the breast (IC), 23 patients with ductal carcinoma in situ (DCIS), and 42 healthy controls (C). Of the 260 quantified metabolites, polyamines were significantly elevated in the saliva of patients with breast cancer. Spermine showed the highest area under the receiver operating characteristic curves [0.766; 95% confidence interval (CI) 0.671-0.840, P < 0.0001] to discriminate IC from C. In addition to spermine, polyamines and their acetylated forms were elevated in IC only. Two hundred each of two-fold, five-fold, and ten-fold cross-validation using different random values were conducted and the MLR model had slightly better accuracy. The ADTree with an ensemble approach showed higher accuracy (0.912; 95% CI 0.838-0.961, P < 0.0001). These prediction models also included spermine as a predictive factor., Conclusions: These data indicated that combinations of salivary metabolomics with the ADTree-based machine learning methods show potential for non-invasive screening of breast cancer.

The number of long-term breast cancer survivors with a risk of late recurrence is increasing. Hormone-receptor-positive patients have greater risks of late recurrence. Although several studies demonstrated that extended adjuvant endocrine therapy reduces the incidence of late recurrence, it remains unclear which hormone-receptor-positive patients have greater risks of late recurrence. Hormone-receptor-positive breast cancer patients were retrospectively selected from the prospective database of primary breast cancer patients treated at Keio University Hospital from January 1989 to December 2003. Late recurrence was defined as initial recurrence after 5 years from the initial surgery. We evaluated the clinicopathologic features of breast cancer patients with late recurrence. At a median follow-up of 10.9 years (range, 5.1-23.8), 371 patients had no recurrence, 90 had early recurrence (within 5 years), and 83 had late recurrence. Multivariate analysis revealed that >4 involved lymph nodes were significant risk factors for late recurrence (P < .001), whereas 1-3 positive nodes were not. Endocrine therapy significantly reduced the incidence of late recurrence (P < .001). After menopause, adjuvant therapy with aromatase inhibitors resulted in longer disease-free survival than tamoxifen (10-year disease-free survival: 97.6% vs 89.7%, P = .0955). High nodal involvement was significantly correlated with late recurrence in hormone-receptor-positive breast cancer patients. Hormone-receptor-positive breast cancer patients who receive adjuvant endocrine therapy with tamoxifen alone might be candidates for extended endocrine therapy., (© 2018 Wiley Periodicals, Inc.)

A 72-year-old woman with a history of surgery for left breast cancer was found to have sigmoid colon cancer and solitary pulmonary tumor of left upper lobe. We diagnosed adenocarcinoma of the unknown origin by a transbronchial biopsy. We performed left upper segmentectomy and sigmoidectomy. Left pulmonary tumor was diagnosed metastatic lung tumor from breast cancer. A right pulmonary tumor was confirmed by chest computed tomography(CT) after sigmoidectomy. It was also considered to be metastasis from breast cancer and treated with vinorelbine ditartrate. Since no effect was observed by chemotherapy, tumor was surgically removed by wedge resection. Right pulmonary tumor was pathologically diagnosed as metastasis from sigmoid colon cancer. In suspicious case of pulmonary metastases from double cancer, the possibility of different lesions from different primary site should be kept in mind.

A 33-year-old woman became aware of a right breast mass at her 28th week of pregnancy. From the biopsy results, we diagnosed her with right breast cancer. At her 33rd week of pregnancy, she underwent modified radical mastectomy (pT2N3aM0, Stage III C, ER-negative, PR-negative, HER2-positive), and she elected to receive adjuvant therapy after the surgery during her pregnancy. She received the first course of EC (epirubicin plus cyclophosphamide) therapy on the 13th postoperative day (35 weeks of gestation) and gave a natural, vaginal delivery at 36 weeks and 5 days of gestation. On the 4th day after birth, the patient noticed a contralateral left breast mass and was diagnosed with left breast cancer, after core needle biopsy. She received 4 courses of EC therapy and is currently undergoing PTX plus HER (paclitaxel plus trastuzumab) therapy. Regarding chemotherapy during pregnancy, we recommend that there is no need to perform artificial preterm birth, because chemotherapy has little influence on children after their second-trimester. After the second-trimester, chemotherapy can be safely performed.

Human breast cancer is highly metastatic to bone and drives bone turnover. Breast cancer metastases cause osteolytic lesions and skeletal damage that leads to bone fractures. Regucalcin, which plays a pivotal role as an inhibitor of signal transduction and transcription activity, has been suggested to act as a suppressor of human cancer. In the present study, we compared the clinical outcome between 44 breast cancer patients with higher regucalcin expression and 43 patients with lower regucalcin expression. Prolonged relapse-free survival was identified in the patients with increased regucalcin gene expression. We further demonstrated that overexpression of full length, but not alternatively spliced variants of regucalcin, induces G1 and G2/M phase cell cycle arrest, suppressing the proliferation of MDA-MB-231 cells, a commonly used in vitro model of human breast cancer that metastasize to bone causing osteolytic lesions. Overexpression of regucalcin was found to suppress multiple signaling pathways including Akt, MAP kinase and SAPK/JNK, and NF-κB p65 and β-catenin along with increased p53, a tumor suppressor, and decreased K-ras, c-fos and c-jun. Moreover, we found that co-culture of regucalcin-overexpressing MDA-MB-231 cells with mouse bone marrow cells prevented enhanced osteoclastogenesis and suppressed mineralization in mouse bone marrow cells in vitro. Taken together, the present study suggests that regucalcin may have important anticancer properties in human breast cancer patients. Mechanistically, these effects are likely mediated through suppression of multiple signaling pathways, upregulation of p53 and downregulation of oncogenes leading to anti-proliferative effects and reduced metastases to bone, a phenotype associated with poor clinical outcome.

A 53-year-old woman underwent breast-conserving surgery for right breast cancer (invasive ductal carcinoma, T1cN0M0, ly+, stage ⅠA, ER+, PR+, HER2-) 5 years previously. During treatment with tamoxifen, massive recurrence in the axillary lymph nodes was found. First- through fourth-line chemotherapy were tried, but they all failed. Everolimus and exemestane were administered, resulting in rapid shrinking of the tumor, but the patient developed sudden severe bleeding from the subclavian artery. Hemostasis was achieved with artery stenting. The patient also developed a thoracic duct-cutaneous fistula. The patient died from tumor regrowth 6.5 months after her first everolimus treatment. Treating tumors involving major vessels with everolimus can cause severe bleeding after rapid shrinking of the tumor.

Regucalcin serves a pivotal role as a suppressor protein in signal transduction in various types of cells and tissues. The regucalcin gene, which is localized on the X chromosome, consists of seven exons and six introns. Reductions in the gene expression of regucalcin have been suggested to serve a role in hepatocarcinogenesis in animal models and human patients, indicating a potential role as a suppressor protein in cancer. The aim of the current study was to investigate the effect of exogenous regucalcin on cell proliferation in the cloned human breast cancer MDA‑MB‑231 bone metastatic cell line in vitro. The proliferation of MDA‑MB‑231 cells was suppressed following the addition of regucalcin (0.1‑10 nM) in vitro. The suppression of proliferation was not enhanced in the presence of tumor necrosis factor‑α, PD98059, staurosporine, Bay K8644, wortmannin, 5,6‑dichloro‑1‑β‑D‑ribofuranosylbenzimidazole or gemcitabine. Exogenous regucalcin did not induce cell death in MDA‑MB‑231 cells in vitro. These data suggest that exogenous regucalcin possesses suppressive effects on the proliferation of human breast cancer MDA‑MB‑231 bone metastatic cells, and that this effect may be mediated through various intracellular signaling pathways in vitro. Exogenous regucalcin is suggested to function as a suppressor in cancer cell proliferation.

Tumor invasion into bone tissues is associated with osteoclast and osteoblast recruitment, resulting in the liberation of growth factors from the bone matrix, which can feed back to enhance tumor growth resulting in the vicious cycle of bone metastasis. Activated nuclear factor-κB (NF-κB) in breast cancer cells has been shown to play a crucial role in the osteolytic bone metastasis of breast cancer in stimulating osteoclastogenesis. The flavonoid p-hydroxycinnamic acid (HCA) mediates bone anabolic and anti-catabolic effects by stimulating osteoblastic bone formation and suppressing osteoclastic bone resorption. However, the capacity of HCA to ameliorate the negative effects of breast cancer on bone cells has not been investigated. The present study was undertaken to determine the anticancer effects of HCA on MDA-MB-231 human breast cancer bone metastatic cells in vitro models. Proliferation of MDA-MB‑231 cells was suppressed by culture with HCA (10-1000 nM) due to G1 and G2/M phase cell cycle arrest. The suppressive effects of HCA were mediated through signaling pathways that are related to NF-κB, extracellular signal-regulated kinase (ERK), protein kinase C, calcium signaling, phosphatidylinositol 3-kinase (PI3K) and nuclear transcription activity. HCA was also found to induce death of confluent cancer cells. Furthermore, co-culture with MDA-MB-231 cells suppressed mineralization and stimulated osteoclastogenesis in bone marrow cells. These alterations were prevented by HCA (10-250 nM). The present study demonstrates that HCA possesses anticancer properties in MDA-MB-231 human breast cancer cells and alleviates the negative effects on osteoblastogenesis and osteoclastogenesis in vitro. HCA may have important applications in the treatment of breast cancer bone metastasis.

Background: Discordance rates of hormone receptor (HR) and human epidermal growth factor-2 (HER2) status between primary and recurrent breast cancer were reported to be in the wide range of 10-40 %, although its prognostic relevance remains to be elucidated., Methods: Fifty-five breast cancer patients had biopsies or resections of recurrent lesions. Pathological assessments of the HR and HER2 status of primary and recurrent lesions were performed in a single laboratory at Keio University Hospital. Tumors were classified as luminal (HR+ and HER2-), luminal/HER2 (HR+ and HER2+), HER2 (HR- and HER2+), or triple negative (HR- and HER2-)., Results: Discordance rates in estrogen receptor (ER), progesterone receptor (PgR) and HER2 status between primary tumors and recurrent lesions were 16.4, 30.9 and 10.2 %, respectively. Overall, 14 patients (25.5 %) changed subtypes at recurrent lesions. Patients with a gain in ER and PgR status had a significantly longer disease-free interval compared with the corresponding concordant-negative patients (ER: 99.0 vs. 18.5 months, p = 0.037, PgR: 141.0 vs. 24.4 months, p = 0.011). Patients with a loss of HER2 status experienced a trend toward shorter time to progression, compared with patients who maintained HER2 positivity (4.0 vs. 18.4 months, p = 0.051)., Conclusions: Discordance in receptor status between primary and recurrent breast cancers were seen in 10-30 %. A gain in HR status was significantly associated with better prognosis.

Introdcution: Although nipple sparing mastectomy (NSM) has attracted increased recognition as an alternative to traditional mastectomy approaches, its oncological safety is unclear. The purpose of this study was to compare the local recurrence rate between NSM and total mastectomy (TM)., Methods: Between 2003 and 2013, 121 and 557 patients with stage 0-III breast cancer underwent NSM and TM respectively. Multivariate Cox regression and propensity score models were used to compare the two groups., Results: There was no significant difference in the five-year local recurrence rate between the NSM and TM groups (7.6% vs 4.9%, p=0.398). In multivariate analysis, NSM was not a risk factor for local recurrence (hazard ratio: 1.653, 95% confidence interval: 0.586-4.663, p=0.343). Propensity score matching found similar five-year local recurrence free survival rates between the two groups (92.3% vs 93.7%, p=0.655)., Conclusions: Our results suggest that NSM may provide oncological safety comparable with mastectomy for carefully selected patients.

Background: The growing number of antihuman epidermal growth factor receptor-2 (HER2) agents suggests the need for defining the optimal choice of neoadjuvant therapy for HER2-positive breast cancer. This study aims to assess the efficacy and safety of neoadjuvant therapy for HER2-positive breast cancer., Methods: Randomized trials that compared different anti-HER2 regimens in the neoadjuvant setting were included. The odds ratio (OR) for pathological complete response (pCR), treatment completion, and safety was utilized for pooling effect sizes. Network meta-analysis using a Bayesian statistical model was performed to combine the direct and indirect evidence of neoadjuvant therapy for HER2-positive breast cancer. All statistical tests were two-sided., Results: A database search identified 1047 articles, with 10 studies meeting the eligibility criteria. A total of 2247 patients in seven different treatment arms were assessed. Anti-HER2 agents evaluated included trastuzumab (tzmb), lapatinib (lpnb), and pertuzumab (pzmb). Network meta-analysis showed no statistically significant difference between dual targeting treatment arms; however, lpnb reduced treatment completion due to adverse events. Patients in dual targeting arms had statistically significantly more pCR than those in other treatment arms (chemotherapy [CT] + tzmb + pzmb vs CT + tzmb, OR = 2.29, 95% credibility interval = 1.02 to 5.02, P = .02). The surface under the cumulative ranking probability curve indicated that CT + tzmb + pzmb had the highest probability of being the best treatment arm in terms of pCR., Conclusions: This study indicates that combining two anti-HER2 agents with CT is the most effective treatment modality in the neoadjuvant setting for HER2-positive breast cancer., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

We report a case of primary small cell carcinoma (SCC) of the breast in a 59-year-old female. To the best of our knowledge, there are only 44 cases of this disease reported in the English literature. The patient also had regional nodal metastases, but no distant metastases. She underwent neoadjuvant chemotherapy according to a regimen of pulmonary SCC, and combination of cisplatin and etoposide (CDDP+VP16). The tumor partially responded to neoadjuvant chemotherapy. The treatment was followed by modified radical mastectomy and adjuvant chemotherapy, i.e., EC therapy (epirubicin and cyclophosphamide). She was also administered in total 50 Gy of radiation treatment to the chest wall. At this writing, the patient has evidenced no recurrence 36 months after her diagnosis.

Purpose: The objective of this retrospective study was to evaluate the efficacy of albumin-bound paclitaxel(nab-paclitaxel) treatment and the required supportive care for severe adverse events., Methods: A total of 20 patients with advanced or recurrent breast cancer received nab-paclitaxel every 3 weeks between February 1, 2011 and December 31, 2012. The treatment course was repeated for 6 cycles thereafter, until evidence of disease progression or unacceptable toxicity was noted., Results: The median number of treatment cycles was 6.0(range 2-6), the median cumulative dose was 1,560(range 440- 1,560)mg/m / / 2, and the median delivered dose intensity was 82.3(range 65.0-86.7)mg/m2week. Primary chemotherapy was associated with higher response rates than second-line or subsequent chemotherapy(42.9% v 23.1%). The response rate was 26.7% for cases with taxane pretreatment. Adverse events included neutropenia in 15 cases(75%), of Grade 4 severity in 4 cases(20%), and febrile neutropenia after 1 cycle in 1 patient(5%). In addition, Grade 3 peripheral neuropathy was observed in 2 cases(10%)during the treatment period., Conclusion: Nab-paclitaxel therapy was efficacious as primary chemotherapy and was effective for patients pretreated with taxanes. To prevent severe adverse events, supportive care is important, primarily for febrile neutropenia and neuropathy.

For a case of recurrent breast cancer with multiple bone metastasis, an oral pyrimidine fluoride-based anti-cancer drug S -1, and zoledronic acid(a third-generation bisphosphonate formulation), were prescribed in experiments to test their efficacy. S-1 was prescribed orally at doses of 100 mg/day(twice)over a 4-week period with a cessation period of 2 weeks. Zoledronic acid was commenced with a strict administration of 4 mg every 4 weeks, taken intravenously. At the conclusion of the 1st S-1 course, the tumor markers began to improve to a certain extent with an improvement in the symptoms. Following the 16 courses, there was no abnormal accumulation detected by PET. Now, at the end of the 21st course, the treatment is being continued, and there has been no recurrence of inflammation or reoccurring growth detected. No adverse effects of more than Grade 1 occurred during the elapsed process. As a form of combined therapy, we can expect zoledronic acid to be a good anti-cancer drug because of its effectiveness and tolerability in treating recurring breast cancer.

We present our experience with chemotherapy using irinotecan for lung metastases of spindle cell carcinoma of the breast. The patient is a 50-year-old female, who consulted our hospital due to a large breast tumor about 7 cm in diameter. Although computed tomography revealed invasion to the chest wall, no distant metastases were confirmed. Chemotherapy (FEC100 followed by paclitaxel) was not effective for down-staging. To improve her quality of life, standard radical mastectomy with combined partial resection of the chest wall was performed. The tumor was histologically diagnosed as spindle cell carcinoma. After the operation, multiple lung metastases appeared, and she had severe dyspnea. Thereafter irinotecan was administered. One week after the administration, metastatic lesions were reduced so that her dyspnea was remarkably relieved. The patient continued to receive irinotecan weekly until she died on the 49th day of treatment with irinotecan.

Carcinoma with a large central acellular zone (central acellular carcinoma, CAC) and matrix-producing carcinoma (MPC) have been recently noted as basal-like-type breast cancers, but the two entities are often confused. To clarify their histological differences, the histopathological sections of 15 CAC and seven MPC were examined and the following features were compared by reviewing slides: (i) mode of invasion; (ii) alteration of cancer cell adhesion in the transitional area between cellular and acellular zones; (iii) staining of the stromal matrix; (iv) lymphocyte infiltration; and (v) tumor grade. Complete agreement was required between two observers for the assessments of these features. All CAC had relatively sharp margins but showed infiltrative growth accompanied by eosinophilic intercellular matrix. In CAC there was abrupt transition between peripheral cellular and central acellular zones without alteration of cancer cell adhesion. In contrast, all MPC showed expansive growth with a well circumscribed margin, accompanied by basophilic and myxoid intercellular matrix. In MPC there was gradual transition from cellular to acellular areas with gradual loss of cancer cell adhesion. Histological grade 3 and peripheral lymphocyte infiltration were common features. It is suggested that CAC and MPC are histologically distinct entities, and that the aforementioned features are helpful for differential diagnosis.

The patient was a 56-year-old female. At the age of 35 years, she had under gone left mastectomy and axillary lymph node dissection for breast cancer. After surgery, hormonal therapy was continued for 3 years. Then, no treatment was performed. In this study, single therapy with an AI agent was started to treatbilateral supraclavicular fossa/mediastinal lymphnode metastases. After 6 months, a partial response(PR)was achieved. However, progression of the disease(PD)was noted after 1 year. Thereafter,the regimen was switched to single high-dose(120mg/day)TOR therapy. CT revealed the disappearance of the bilateral supraclavicular fossa lymphnodes and a marked reduction of the other lymphnodes. Currently, the patient is being treated, with an interval of 10 months from the start of TOR therapy.

Breast cancer confined within the lactiferous duct or lobule, without invading the stroma, is called ductal carcinoma in situ (DCIS), whereas breast cancer that has invaded the stroma through the basal membrane is called invasive cancer. Heparanase, an endo-beta-D-glucuronidase that specifically degrades heparan sulfate proteoglycans (HSPGs) in the extracellular matrix (ECM), plays an important role when breast cancer cells breach the basal membrane. Recently, we have reported that heparanase is involved in angiogenesis through direct induction of cyclo-oxygenase-2 (COX-2). COX-2 induces vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) and is thus involved in neovascularization. The present study was undertaken to analyze surgically resected breast cancer specimens for heparanase and COX-2 expression, using specimens from 59 patients with invasive cancer and 85 patients with DCIS (including 41 cases of DCIS adjacent to invasive cancer). This study yielded the following results: a) the distribution of heparanase within tumor tissue was identical to that of COX-2; b) heparanase expression was more frequent in invasive cancer than in non-invasive cancer; c) a close positive correlation was noted between heparanase and COX-2 expression (this correlation was particularly strong in cases of invasive cancer); and d) COX-2 expression was always seen in cases positive for heparanase expression. Our results indicate that heparanase expression increases during the progression of breast cancer into invasive cancer, and that this change is accompanied by increased COX-2 expression. They also suggest that heparanase may play a novel role for COX-2 mediated tumor angiogenesis in breast-cancer progression.

It was hypothesized that four histopathological types or subtypes of breast carcinoma were undifferentiated types characterized by bidirectional differentiation toward both luminal epithelial and myoepithelial cells and had characteristic molecular changes: invasive ductal carcinoma (IDC) with a large central acellular zone, atypical medullary carcinoma (a subgroup in Grade 3 solid-tubular carcinoma), matrix-producing carcinoma, and spindle-cell carcinoma (or carcinoma with spindle-cell metaplasia). In 32 cases of the undifferentiated type and 37 cases of the relatively differentiated types, we immunohistochemically examined the expressions of myoepithelial markers and KIT, epidermal growth factor receptor (EGFR), and c-erbB-2 oncoproteins. Vimentin, S-100, and alpha-smooth muscle actin were positive in 28 (88%), 22 (69%), and 15 (47%) of the undifferentiated types, but were positive in seven (19%), one (3%), and one (3%) of relatively differentiated types (P < 0.0001). KIT and EGFR overexpressions were detected more frequently in the undifferentiated types (34 and 88%, respectively) than in relatively differentiated types (3 and 3%, respectively) (P < 0.0001, for both). In 11 (85%) of 13 cases with KIT overexpression, EGFR overexpression concurred. c-erbB-2 overexpression was almost equally detected in both the undifferentiated and relatively differentiated types, and did not correlate with KIT or EGFR overexpression. Phosphotyrosine was detected in 16 (67%) of 24 cases with KIT, EGFR, and/or c-erbB-2 overexpression but only in six (18%) of 34 cases without KIT, EGFR, or c-erbB-2 overexpression (P = 0.0002). The undifferentiated-type breast carcinomas appeared to show mammary epithelial stem cell-like features, and they could be identified by KIT and/or EGFR overexpressions.

A 46-year-old woman who had received mastectomy for breast cancer 6 years earlier complained of abdominal distension. Computed tomography and ultrasonography revealed massive ascites and ovarian swelling of both sides. She was diagnosed as having primary ovarian cancer and peritoneal dissemination, and underwent a total hysterectomy as well as ovarectomy on both sides. After surgery, she received a sequential chemotherapy, ie, intraabdominal injection of carboplatin (CBDCA 300 mg/m2) and div administration of paclitaxel (PTX 180 mg/m2) as a standard regimen for advanced ovarian cancer. However, detailed histological examinations showed that the ovarian cancer had metastasized from her breast cancer. It is well-known that breast cancer easily metastasizes to the bone, liver, pleura and lymph node, but rarely to the ovarium or peritoneum when chemotherapy is conducted. Therefore, no standard therapy has been established for breast cancer metastasizing to the ovarium. Our patient received 4 cycles of weekly administration of PTX (PTX 80 mg/m2, 3 consecutive weeks, 1-week break), followed by oral administration of doxifluridine+anastrozole on an outpatient basis. No evidence of recurrence of breast cancer has been noted 1 year after surgery. This result suggests that weekly administration of PTX and intraabdominal injection of CBDCA might be beneficial in the treatment of recurrent breast cancer associated with metastatic ovarian cancer and peritoneal dissemination after operation.

Companion animal spontaneous tumors are suitable models for human cancer, primarily because both animal population and the tumors are genetically heterogeneous. Feline mammary carcinoma (FMC) is a highly aggressive, mainly hormone receptor-negative cancer, which has been proposed as a model for poor prognosis human breast cancer. We have identified and studied the feline orthologue of the HER2 gene, which is both an important prognostic marker and therapeutic target in human cancer. Feline HER2 (f-HER2) gene kinase domain is 92% similar to the human HER2 kinase. F-HER2-specific mRNA was found 3- to 18-fold increased in 3 of 3 FMC cell lines, in 1 of 4 mammary adenomas and 6 of 11 FMC samples using quantitative reverse transcription-PCR. Western blot showed that an anti-human HER2 antibody recognized a protein comigrating with the human p185HER2 in FMC cell lines. The same antibodies strongly stained 13 of 36 FMC archival samples. These data show that feline HER2 overexpression qualifies FMC as homologous to the subset of HER2 overexpressing, poor prognosis human breast carcinomas and as a suitable model to test innovative approaches to therapy of aggressive tumors.

A breast tumor in a 52-year-old female was interpreted as a malignant myoepithelioma based on morphological and immunohistochemical studies. The tumor consisted of elongated cells with clear cytoplasm and lacked glandular components. The tumor cells were stained positively for keratin, S-100 protein, glial fibrillary acidic protein (GFAP) and muscle-specific actin. Distant metastasis in the right jaw developed 8 years after the initial surgery and the metastatic deposit showed a similar morphology and immunoreactivity. Myoepithelial tumors are generally considered as benign or low-grade lesions and distant metastasis has been rarely documented. The present case presents the possibility of delayed occurrence of distant metastasis in myoepithelial tumor of the breast.

We hypothesized that invasive ductal carcinomas (IDCs) with large central acellular zones comprising necrosis, tissue infarction, collagen, and hyaline material on their cut surfaces are formed in association with myoepithelial differentiation of the carcinoma cells. To verify this, the expression of S100 protein, alpha-smooth muscle actin (alpha-SMA), and glial fibrillary acidic protein (GFAP) and keratin 14, which has been shown to represent the myoepithelial immunophenotype, was examined immunohistochemically in 18 IDCs with such central zones covering more than 30% of each tumor area, 18 IDCs without such areas as negative controls, and 10 metaplastic carcinomas as positive controls for myoepithelial differentiation. Expression of S100, detected with a polyclonal antibody, S100-alpha, S100-beta, alpha-SMA, GFAP, and keratin 14, was observed in 61%, 83%, 39%, 33%, 28%, and 39% of the IDCs with large central acellular zones, 17%, 44%, 6%, 6%, 0%, and 6% of the IDCs without such zones, and 80%, 70%, 50%, 100%, 80%, and 50% of the metaplastic carcinomas, respectively. We concluded that IDCs with large central acellular zones frequently contain carcinomas showing myoepithelial differentiation. Such histological and immunohistochemical features in IDCs would be expected to be clinicopathologically significant.

A case of breast cancer with choriocarcinomatous features (BCCF) is reported. The patient was a 38-year-old Japanese female with a long history of schizophrenia. Her nursing staff noticed a palpable mass in her right breast, which showed rapid growth. Following cytopathologic confirmation of a malignant breast tumor, she underwent mastectomy with ipsilateral axillary lymph node dissection. Histologic examination revealed BCCF, which was positive for placental alkaline phosphatase and human chorionic gonadotropin (HCG) by immunohistochemistry. The serum HCG level was high. She died 7 months postoperatively, with multiple metastases of BCCF to the chest wall, lung and liver.

A case of matrix-producing carcinoma (MPC), which is a unique variant of breast cancer, is described with cytopathological and radiographical findings. A 75-year-old female presented with a palpable mass in her right breast. After confirmation of the cytopathological diagnosis, the patient received a right mastectomy with ipsilateral axillary lymph node dissection. The histopathological examination revealed MPC. The Union Internationalis Contra Cancrum postoperative clinical stage was IIB. The patient is well and without disease 18 months after the surgery.