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Background: We evaluated the relationship between the immunohistochemically determined expression of the cell polarity protein scribble to prognosis in different environments of estrogen receptor (ER) expression and epithelial-to-mesenchymal transition (EMT)., Methods: We immunohistochemically evaluated the expression level of scribble in primary tumors and lymph node metastases of 225 node-positive breast cancer patients who had received chemotherapy. We then evaluated metastasis-free survival (MFS) in the absence or presence of ER and the EMT-related protein vimentin., Results: Among patients with ER-positive tumors, patients with low scribble expression in the primary tumor had a significantly shorter MFS than patients with high scribble expression (p = 0.0225). Furthermore, among patients with vimentin-negative tumors, patients with low expression of scribble in the primary tumor had significantly shorter MFS than patients with high expression of scribble (p = 0.0463). In contrast, among patients with vimentin-positive tumors, patients with high expression of scribble in the primary tumor had significantly shorter MFS than patients with low expression of scribble (p = 0.0343). Moreover, among patients with ER-negative tumors, patients with high expression of scribble in lymph node metastases showed significantly higher expression of E-cadherin in metastases (p = 0.0407) and had significantly shorter MFS than patients with low expression of scribble (p = 0.0064)., Conclusions: The prognostic significance of cell polarity depended on the ER expression and EMT. Furthermore, the preservation of cell polarity in metastases was associated with mesenchymal-to-epithelial transition and worse prognosis. Cell polarity promotes the diversity of metastasis in combination with malignancy grade in breast cancer patients.

The BRCA-like phenotype is a feature that some sporadic breast cancers share with those occurring in BRCA1 or BRCA2 mutation carriers. As tumors with the phenotype have defects in the DNA damage response pathway, which may increase sensitivity to drugs such as DNA cross-linking agents and PARP inhibitors, a method to identify this phenotype is important. The prediction of chemoresistance, which frequently develops in these tumors, is also crucial for improving therapy. We examined genomic aberrations and BRCA1 promoter methylation in tumors of 73 breast cancer (20 HR-/HER2- and 53 HR+/HER2-) patients, who received neoadjuvant chemotherapy with anthracycline, cyclophosphamide, and taxane, using SNP array CGH and quantitative PCR. The methylation and/or loss or uniparental disomy (UPD) of BRCA1 (BRCA1 alterations) and the loss or UPD of BRCA2 (BRCA2 alterations) were detected in 27 (37%) and 21 (29%), respectively, of the 73 tumors. Tumors with BRCA1 or BRCA2 alterations were associated with a higher number of genomic aberrations (P < 0.001 and P < 0.001) and higher percentage of TP53 alterations (P < 0.001 and P < 0.001) than those without. Overall survival (OS) rates were similar between patients with or without BRCA1 or BRCA2 alterations. However, when 27 patients with BRCA1-altered tumors were classified into those with or without the loss or UPD of PALB2, PAGR1, RAD51B, FANCM, MLL4, or ERCC1/2 in tumors, patients with additional defects in DNA damage response genes had worse OS (P = 0.037, 0.045, 0.038, 0.044, 0.041, or 0.019) than those without. These defects may confer chemoresistance and predict poor outcomes in patients with BRCA1-altered breast cancer., (© 2017 Wiley Periodicals, Inc.)

Purpose: The high reliability and utility of core needle biopsy (CNB) have been previously described. Our aim in this study was to clarify the host and histopathological factors influencing the discrepancies in ER, PgR, and HER2 status between CNB and surgically excised tumors (SET)., Methods: All patients diagnosed with operable invasive breast cancer in our hospital between January 2005 and April 2015 were included in the study; patients who required neoadjuvant chemotherapy were excluded. ER, PgR, and HER2 expression were assessed between paired CNB and SET samples. ER and PgR status were determined using immunohistochemistry(IHC). HER2 status was determined using IHC and scored from 0 to 3+. Fluorescence in-situ hybridization analysis was carried out in HER2 2+ cases. The cut off point for ER and PgR positivity was set at 1%., Results: A total of 1307 patients were assessed. The concordance rates of ER, PgR, and HER2 status in CNB and SET were 95%, 84% and 97%, respectively. Factors of discrepancy were nuclear grade, histological type, and menopausal status for ER and PgR, and none detected for HER2. The discrepancy factors were assessed with univariate and multivariate analysis., Conclusions: Using the largest known dataset to date of paired samples from a single institution, we evaluated the accuracy of CNB and the discrepancy factors between CNB and SET in breast cancer patients. We conclude that CNB for ER and PgR assessment in postmenopausal patients before treatment should be used with caution. Further research will contribute to increased CNB accuracy, improving patient treatment decisions., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Obesity is known to decrease the efficacy of neoadjuvant chemotherapy (NAC) against breast cancer; however, the relationship between actual body composition and NAC outcomes remains unknown. Therefore, we determined the effect of body composition on NAC outcomes. A total of 172 advanced breast cancer patients who underwent surgery after NAC were retrospectively analyzed. Body composition parameters including abdominal circumference (AC), subcutaneous fat area (SFA), visceral fat area (VFA), and skeletal muscle area (SMA) were calculated using computed tomography volume-analyzing software. VFA/SFA ratio was used to evaluate visceral obesity. The associations of body composition parameters with pathological complete remission (pCR) and survival were analyzed. AC, SFA, and VFA were significantly correlated with body mass index (BMI) (all P < 0.05; r = 0.82, r = 0.71, and r = 0.78, respectively). AC, SFA, and VFA increased significantly and SMA decreased significantly after menopause (all P < 0.05). VFA/SFA ratio increased significantly after menopause, even though BMI remained unchanged. Body composition parameters were not associated with pCR. Distant disease-free survival (DDFS) was significantly worse in the high VFA group than in the low VFA group (P < 0.05). Furthermore, in the high VFA group, postmenopausal patients had significantly shorter DDFS than premenopausal patients (P < 0.05). VFA was independently associated with DDFS in the multivariate analysis (P < 0.05). High visceral fat is associated with worse NAC outcomes in breast cancer patients, especially postmenopausal patients. Interventions targeting visceral fat accumulation will likely improve NAC outcomes., (© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Although radiofrequency ablation (RFA) is promising for the local treatment of breast cancer, data concerning the longterm results are limited. The present study attempted to evaluate the safety and efficacy of RFA and to clarify patient outcomes after treatment. The study included 26 breast cancer patients treated with RFA between 2006 and 2010. There were no acute complications such as burns. All subjects were followed-up after breast radiation and systemic therapies. At the median follow-up period of 88 months, no local recurrence or distant metastases had occurred. After treatment, a hard lump was formed around the ablated area, which gradually decreased in size in all cases (p<0.001). The lumps were calcified in 9 cases. Nipple retraction persisted in 2 cases. However, it is necessary to recognize that a cosmetic result of RFA was not excellent in all cases, RFA appears to be a safe local treatment technique for breast cancer patients.

A 44 -year-old woman presented at the outpatient department with a chief complaint of swelling in the right breast. MRI showed a huge breast tumor accompanied by solitary enhanced masses in the pectoralis major muscle. After receiving neoadjuvant chemotherapy, she underwent mastectomy (Halsted operation) and axillary dissection. Pathological examination revealed an E-cadherin-positive infiltrating lobular carcinoma (ILC), and the absence of residual tumor in the muscle was confirmed. In cases of solitary metastasis in the muscle, treatment selection is sometimes difficult. Further research is needed to determine whether surgery contributes to local control in cases of advanced ILC with muscle metastasis.

The objective of this study is to investigate interactions between adipocytes and breast cancer cells, and identify the responsible factors for the observed effects. In 27 breast cancer patients undergoing mastectomy, mammary adipose tissue was obtained from the breast quadrant bearing the tumor and corresponding non-tumoral quadrant. Isolated normal breast adipocytes (NBAs) and cancer-associated adipocytes (CAAs) were cultured in collagen gels to mimic the in vivo environment. Immunohistochemistry, qRT-PCR, and cell proliferation assays were performed to analyze adipocyte phenotypes. MCF7 and MDA-MB-231 breast cancer cell lines were co-cultured with adipocytes to detect phenotypic changes. Migration of MCF7 and MDA-MB-231 cells was assessed in NBA- and CAA-conditioned media. Cytokine levels in conditioned media were measured by cytokine array. Migration assays were repeated using conditioned media containing neutralizing antibodies. NBAs and CAAs lost their morphological phenotype in culture, acquiring a spindle-like shape, and CAAs showed higher cell proliferation, suggesting reversion to an immature phenotype. In co-cultures with MCF7 or MDA-MB-231 cells, NBAs exhibited increased cell proliferation, indicating acquisition of the immature phenotype of CAAs. MCF7 and MDA-MB-231 showed higher migration in a CAA-conditioned medium than in an NBA-conditioned medium. Cytokine array analysis of conditioned media revealed higher levels of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) in the CAA-conditioned medium. Neutralization experiments using antibodies against IL-6 or MCP-1 showed abrogation of migration-enhancing effects of the CAA-conditioned medium. Adipocytes revert to an immature and proliferative phenotype in the presence of breast cancer cells, and promote cancer cell migration via adipokines including IL-6 and MCP-1.

The aim of the present study was to investigate the relationships between the automated bone scan index (aBSI) and skeletal-related events (SRE) in breast cancer patients with bone metastasis. A computer-aided software (BONENAVI™) that was developed using an Artificial Neural Network (Artificial Neural Network) was used for the present analysis. Forty-five patients diagnosed with bone metastasis due to breast cancer from April 2005 through March 2013 were retrospectively analyzed. Before and after the time of initial treatment, aBSI, Artificial Neural Network score, and hotspot number were calculated, and the relationships between these scores and SRE were analyzed. Twenty cases showed decreased (improved) aBSI values after initial treatment (Group A), and 25 cases showed unchanged/increased (worsened) aBSI values (Group B). Chi-square analysis revealed a significant difference in incident numbers of SRE between the two groups--one case in Group A and 12 in Group B (P<0.001). Event-free survival was significantly shorter in Group B (hazard ratio: 8.31, 95% CI: 1.33-12.14, log-rank test; P<0.05). The groups were also divided by the results of 2 radiologists' visual scan interpretations, and no significant differences were shown in the number of SRE (P=0.82, P=0.10). When correlation analyses were performed between aBSI and bone metabolic or tumor markers, alkaline phosphatase was significantly correlated with aBSI at the time of initial treatment (R=0.69, P<0.05). In conclusion, aBSI is proposed as a useful and objective imaging biomarker in the detection of breast-cancer patients with bone metastasis at high risk of SRE.

Background: Conventional imaging does not always accurately depict the pathological response to neoadjuvant chemotherapy (NAC). Diffusion-weighted imaging (DWI) may provide additional insight into the chemotherapeutic effect. This study assessed whether the apparent diffusion coefficient (ADC) correlated with pathological outcome and prognosis in breast cancer patients receiving NAC., Methods: Fifty-six patients with locally advanced breast cancer received surgery after NAC. Dynamic contrast-enhanced (DCE) and DWI were performed before and after NAC. The pathological response was classified into five categories from no response to complete response according to amount of residual cancer. The correlation between ADC and postoperative pathologic and prognostic outcome was assessed., Results: The distribution of the pathological response classification was as follows: no response, 3 cases; mild response, 22 cases; moderate response, 12 cases; marked response, 11 cases; complete response, 8 cases. ADC after NAC correlated with pathological response, but ADC before NAC did not. The change in ADC after chemotherapy had better correlation coefficient (r = 0.67) than change in size (r = 0.58) and ADC after NAC (r = 0.64). Although the group with larger change of tumor size showed only marginal significance compared with the smaller change group (p = 0.089), the group with higher change of ADC showed significantly better prognosis than the lower one (p = 0.038)., Conclusions: Change in ADC after chemotherapy better correlated with pathological outcome and prognosis than change in tumor size. DWI has potential in evaluating the pathological outcome of NAC in breast cancer patients.

Background: We designed MRI-guided quadrantectomy using 2-dimensional images reconstructed from MRI to enable virtual simulation of breast-conserving surgery. This study evaluated the efficacy of our approach, which involved projection of the 2-dimensional reconstruction images directly onto the breast to guide planned resection compared with the conventional approach with preoperative localization with hooked wires, for patients with ductal carcinoma in situ (DCIS) detected by mammographic calcifications., Study Design: Eighty-six patients with calcifications ≥2 cm in diameter on mammogram who were diagnosed with DCIS on preoperative percutaneous biopsy underwent breast-conserving surgery. In 32 patients, lesion localization was done using the conventional technique of hooked wires. In 54 patients, preoperative planning was performed using supine MRI and projection of reconstructed 2-dimensional images directly onto the breast surface. Surgical outcomes in the 2 groups were compared. In the latter group, we also compared accuracy of DCIS detection between supine MRI and specimen mammography., Results: Final pathologic assessment of the 86 patients was DCIS in 67 and DCIS with microinvasion (T1mic) in 19 patients. The rate of additional intraoperative margin resection and presence of DCIS at the surgical margin were significantly lower with our MRI-guided technique vs the hooked-wire approach. Supine MRI detected a considerably larger area of DCIS than did specimen mammography., Conclusions: Compared with a conventional approach using hooked wires, our MRI-guided quadrantectomy might be useful for patients with DCIS and DCIS with T1mic detected by mammographic calcifications, due to the superior ability to detect DCIS on MRI compared with mammography., (Copyright © 2014 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

The aim of the present study was to analyze the effect of subtype and body mass index (BMI) on neo-adjuvant chemotherapy (NAC) and postoperative prognosis. Two-hundred and forty nine patients who underwent surgery after NAC were included. A multivariate analysis and survival analysis were used to clarify the relationship between BMI, subtype, and NAC. In the logistic regression model, the pCR rate had a significant relationship with the subtype and tumor stage. In the non-pCR group, more overweight patients had significantly a worse disease-free survival (DFS) compared to normal range patients (Log lank test, p < 0.05). In the Cox proportional hazards model, subtype and tumor stage were significantly associated with decreased DFS. In conclusion, patients with the ER (+), HER (-) type and a high BMI had a high risk for recurrence when they achieved non-pCR after NAC., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: The systemic management of metastatic breast cancer (MBC) is usually based on ER or HER2 status of the primary tumor. However, the hormonal status or the overexpression of human epidermal growth factor 2 (HER2) may change in every metastatic site because of the effects of the long-term treatment of metastatic cancer with endocrine therapy, chemotherapy, or biological agents. The purpose of this study was to investigate the frequency of change in HER2 expression in primary and distant metastatic tumors in breast cancer patients. Another objective of the study was to examine the effect of the clinical therapy on the basis of HER2 expression in a metastatic tumor., Materials and Methods: In our hospital between 1991 to December 2010, retrospectively, 156 patients had biopsy or surgical resection of their metastatic site. All sample were analyzed pathologically to confirm metastatic disease and, second, to evaluate HER2 status by immunohistochemistry or by FISH., Results: The recurrence lesions were resected from the breast or lymph node (n = 67, local lesion), brain (n = 27), lung (n = 16), liver (n = 20), bone (n = 16), and from the stomach, intestine, ovary, and uterus (n = 10). Loss, increase, or no change in HER2 overexpression was observed in 3, 5, and 92%, respectively. Positive changes of HER2 in metastatic sites were 3 (4%) local lesion, 3 (11%) brain, 1 (7%) lung, 0 (0%) liver, 2 (17%) bone, and 0 (0%) others. In 3 of these 8 patients, trastuzumab was administered. In 2 of 3 patients, trastuzumab achieved long stable disease. The negative conversion rate of HER2 expression in metastatic lesions was 37% in patients treated with trastuzumab and 6% in those not treated with trastuzumab, a significant difference between the two groups (P < 0.05)., Conclusions: The results of this study emphasize the significance of confirming HER2 expression in a recurrence lesion. For patients with positive conversion of HER2 status, more treatment options may be available. On the other hand, the rate of loss of HER2 expression was high in patients treated with trastuzumab, suggesting that the results of biopsy may provide an opportunity to reconsider treatment strategies for these patients.

Background: Chemotherapy with trastuzumab is widely used for patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer, but a significant number of patients with the tumor fail to respond, or relapse. The mechanisms of recurrence and biomarkers that indicate the response to the chemotherapy and outcome are not fully investigated., Methods: Genomic alterations were analyzed using single-nucleotide polymorphism arrays in 46 HER2 immunohistochemistry (IHC) 3+ or 2+/fluorescent in situ hybridization (FISH)+ breast cancers that were treated with neoadjuvant chemotherapy with paclitaxel, cyclophosphamid, epirubicin, fluorouracil, and trastuzumab. Patients were classified into two groups based on presence or absence of alterations of 65 cancer-associated genes, and the two groups were further classified into four groups based on genomic HER2 copy numbers or hormone receptor status (HR+/-). Pathological complete response (pCR) and relapse-free survival (RFS) rates were compared between any two of the groups., Results and Discussion: The pCR rate was 54% in 37 patients, and the RFS rate at 3 years was 72% (95% CI, 0.55-0.89) in 42 patients. The analysis disclosed 8 tumors with nonamplified HER2 and 38 tumors with HER2 amplification, indicating the presence of discordance in tumors diagnosed using current HER2 testing. The 8 patients showed more difficulty in achieving pCR (P=0.019), more frequent relapse (P=0.018), and more frequent alterations of genes in the PI3K pathway (P=0.009) than the patients with HER2 amplification. The alterations of the PI3K and estrogen receptor (ER) pathway genes generally indicated worse RFS rates. The prognostic significance of the alterations was shown in patients with a HR+ tumor, but not in patients with a HR- tumor when divided. Alterations of the PI3K and ER pathway genes found in patients with a HR+ tumor with poor outcome suggested that crosstalk between the two pathways may be involved in resistance to the current chemotherapy with trastuzumab., Conclusions: We recommend FISH analysis as a primary HER2 testing because patients with IHC 2+/3+ and nonamplified HER2 had poor outcome. We also support concurrent use of trastuzumab, lapatinib, and cytotoxic and anti-hormonal agents for patients having HR+ tumors with alterations of the PI3K and ER pathway genes.

Background: Aldehyde dehydrogenase 1 (ALDH1)-positive cells exhibit stem-like or progenitor ability and have been considered a clinically important diagnostic and therapeutic target in patients with breast cancer. In this study, the authors evaluated responsiveness to chemotherapy of ALDH1-positive cells in primary and metastatic lesions and its relation to prognosis for patients with lymph node-positive breast cancer., Methods: In total, 115 patients who had breast cancer with cytologically confirmed lymph node metastases and who underwent surgery after neoadjuvant chemotherapy (NAC) were evaluated. By using ALDH1 immunohistochemistry in core-needle biopsy specimens of the primary tumor, cytology samples of axillary lymph nodes before NAC, and pathologic samples of each after NAC, the clinical significance of ALDH1-positive cell status was evaluated in primary and metastatic lesions before and after NAC., Results: The presence of ALDH1-positive cancer cells, but not ALDH1-negative cancer cells, in primary and metastatic lesions after NAC was associated with a worse prognosis. In multivariate analysis, only ALDH1-positive cells in metastatic lesions after NAC correlated with overall survival. The responsiveness of ALDH1-positive cells to chemotherapy differed between primary and metastatic lesions, and the findings indicated that ALDH1-positive cells in metastatic lesions after NAC may clinically precede those in the primary lesion., Conclusions: The responsiveness of ALDH1-positive cells to chemotherapy in primary and metastatic lesions and its prognostic significance were clarified in patients with breast cancer. The authors concluded that ALDH1-positive status may represent a surrogate marker as a new concept in patients with lymph node-positive breast cancer., (Copyright © 2011 American Cancer Society.)

Purpose: Breast cancer is the most frequent malignancy in women. However, no useful serum markers with high sensitivity and specificity for the detection of early breast cancer have been identified. The search for biological markers of early breast cancer is of continual interest in experimental and clinical breast cancer research. We recently described a simple and highly reproducible three-step proteome analysis for identifying potential disease-marker candidates among the low-abundance serum proteins., Methods: Serum samples from breast ductal carcinoma in situ (DCIS) patients and normal controls were subjected to a three-step serum proteome analysis. The steps were the following: first, immunodepletion of most abundant proteins; second, fractionation using reverse-phase high-performance liquid chromatography; and third, separation using two-dimensional electrophoresis (2-DE). Differences revealed by protein staining were further confirmed by Western blotting, immunohistochemical staining, and enzyme-linked immunosorbent assays (ELISA)., Results: Twenty-two upregulated and 26 downregulated spots were detected on the 2-DE gels, and a total of 33 proteins were identified by liquid chromatography and tandem mass spectrometry. Western blotting confirmed that the level of vitronectin was significantly increased in DCIS patients compared with that of normal controls. Immunohistochemical staining of vitronectin in breast cancer tissue revealed high expression in small vessel walls surrounding cancer cells and the extracellular matrix of stroma. Moreover, vitronectin serum concentrations, as measured by ELISA, were significantly increased in patients with DCIS or more advanced breast cancer compared with those of normal controls., Conclusions: Vitronectin could serve as a promising serum marker for the detection of primary breast cancer.

Background: The use of neoadjuvant chemotherapy for breast cancer is effective as postoperative adjuvant therapy, permits more lumpectomies, and can be used to study breast cancer biology. Although pathological response is the strongest prognostic factor, response rates vary according to various parameters, such as dissociation between breast and axillary node responses., Purpose: To clarify the correlation of response rates between breast tumors and metastasized lymph nodes and to identify the clinical significance; response rates measured on imaging were evaluated among breast cancer patients with axillary lymph node involvement., Material and Methods: Subjects consisted of 98 patients diagnosed with node-positive breast cancer who received chemotherapy before surgery. The response to the therapy was evaluated by changes in the largest dimensions of the breast mass and of regional lymph nodes measured on a multidetector row helical CT before and after chemotherapy. The percent reduction was calculated as a response rate. The correlation between response rate and patient outcome was analyzed retrospectively., Results: Breast tumor response rates correlated statistically well with those of lymph nodes (p < 0.001). Disease-free cases had a greater tumor and/or nodal response rates than recurrence cases (p = 0.021, p < 0.001, respectively), regardless of tumor size, histological grade and HER2 amplification. Cancer-associated death was observed more frequently in cases with lower response rates compared to surviving cases (p = 0.007, p = 0.021, respectively). The prognostic difference was found most strongly in nodal response rates (p = 0.001)., Conclusion: The present series evaluated the therapeutic effect of NAC on breast tumors and metastasized lymph nodes, and a significant correlation with patient outcome was observed. Evaluating the response rate measured by imaging could be used as a surrogate marker for prognosis before assessment of the pathological response which is ordinarily obtained after surgery.

Background: Primary chemotherapy (PCT) for breast cancer is effective as postoperative adjuvant therapy, which permits more lumpectomies and can be used to study breast cancer biology. Many reports indicate that the presence or absence of residual cancer after PCT has been proposed as a critical prognostic factor for prolonged disease-free and overall survival. However, pathological complete response (pCR) has not been obtained for all cases, and the majority of the patients indicate partial response to PCT., Methods: The subjects consisted of 41 breast cancer patients failing to achieve a pCR to PCT. Enhanced MRI using a 1.5-T system was carried on just before chemotherapy induction and before surgery. The correlation between tumor reduction rate derived from MRI and occurrence of early events in breast cancer patients was analyzed retrospectively., Results: In the median, 40 (23-48) months' follow-up, 14 recurrences and 7 deaths were observed. Disease-free cases had a greater tumor reduction rate than recurred cases (p = 0.0035). If the average of 56% was chosen as the cutoff value, the significant difference was found between the groups with high and low tumor reduction rates (p = 0.0036) with a hazard ratio 2.62. Moreover, cancer-associated deaths were often observed in the cases with the lower tumor reduction rate compared with alive patients (p = 0.0003)., Conclusions: The evaluation of tumor reduction rates on MRI was considered to be useful for predicting early outcome among breast cancer patients who cannot achieve pCR after PCT.

There is growing evidence that tumor-associated macrophages (TAMs) promote tumor growth and dissemination. Many individual reports have focused on the protumor function of molecules linked to the recruitment of macrophages, but little is known about which factor has the strongest impact on recruitment of macrophages in breast cancer. To elucidate this question, we performed RT-PCR using species-specific primers and evaluated tumoral and stromal mRNA expression of macrophage chemoattractants separately in human breast tumor xenografts. The correlation between the tumoral or stromal chemoattractant mRNA expression including monocyte chemoattractant protein-1 (MCP-1) (CCL2), MIP-1alpha (CCL3), RANTES (CCL5), colony-stimulating factor 1, tumor necrosis factor alpha, platelet-derived growth factor (PDGF)-BB and macrophage infiltration were compared. There was significant positive correlation between stromal MCP-1 expression and macrophage number (r = 0.63), and negative correlation between tumoral RANTES expression and macrophage number (r = -0.75). However, no significant correlation was found for the other tumoral and stromal factors. The interaction between the tumor cells and macrophages was also investigated. Tumor cell-macrophage interactions augmented macrophage-derived MCP-1 mRNA expression and macrophage chemotactic activity in vitro. Treatment of immunodeficient mice bearing human breast cancer cells with a neutralizing antibody to MCP-1 resulted in significant decrease of macrophage infiltration, angiogenetic activity and tumor growth. Furthermore, immunohistochemical analysis of human breast cancer tissue showed stromal MCP-1 had a significant correlation with relapse free survival (p = 0.029), but tumoral MCP-1 did not (p = 0.105). These findings indicate that stromal MCP-1 produced as a result of tumor-stromal interactions may be important for the progression of human breast cancer and macrophages may play an important role in this tumor-stroma interaction., (2009 UICC)

Background: Neoadjuvant chemotherapy (NAC) has been widely accepted for advanced breast cancer patients, and pathological complete remission (pCR) was revealed to be an important prognostic factor. The pCR status of cytologically proven axillary metastases (ALN-pCR) offers a more powerful prognostic predictor than pCR of the main tumor. This study evaluated the clinical significance of residual micrometastases and discusses screening methods after NAC in patients with cytologically proven axillary metastases., Methods: Eighty patients with a diagnosis of cytologically proven axillary metastases received NAC. All dissected lymph nodes were evaluated using multislice sectioning and cytokeratin immunohistochemistry, and categorized into four groups: no metastases (ALN-pCR), and with metastases 0.2 mm but 2 mm (ALN-mac). Disease-free survival (DFS) and overall survival (OS) were calculated by Kaplan-Meier method based on the status of residual metastases., Results: DFS in patients with ALN-pCR and ALN-itc was significantly longer than that with ALN-mic (P = 0.007, P = 0.045, respectively). OS with ALN-pCR was significantly longer than that with ALN-mic (P = 0.004). There was no significant difference in DFS or OS between ALN-mac and ALN-mic. These data showed the clinical significance of microresidual metastases >0.2 mm after NAC in patients with cytologically proven axillary metastases., Conclusions: Using multislice sectioning, screening for ALN-mic after NAC was clinically important, and that for ALN-itc was not clinically essential.

It has been revealed that sentinel lymph nodes (SLNs) from patients with node-negative breast cancer involve RT-PCR detected micrometastases and isolated tumour cells. However, the prognostic significance of the pathologically undetectable micrometastases is still controversial. In this study, we evaluated Foxp3 positive regulatory T cells (Treg) in SLNs as host-side immune marker that has the potential to detect these micrometastases. In the analyses of training set (n=30), elevated Treg was strongly associated with the pathologically undetectable micrometastases. In the analyses of validation set (n=129) in patients with node-negative, relapse-free survival in patients with elevated Treg was significantly shorter than those with lower Treg (p=0.005). Furthermore, in multivariate analyses, elevated Treg was correlated with relapse-free survival (p=0.012). Our data indicate that Treg may increase in the microenvironment of SLNs along with pathologically undetectable micrometastases and is a prognostic predictor in patients with node-negative breast cancer.

Purpose: Radiofrequency ablation (RFA) has recently been used to treat small breast cancer. However, there are no data on the long-term morphological features after the procedure. The present study attempts to clarify the characteristics of and changes in the ablated lesion., Materials and Methods: A total of 17 breast cancer patients underwent RFA using a single needle featuring an internally cooled electrode; this was followed by whole-breast irradiation and adjuvant systemic therapy. Magnetic resonance imaging (MRI) using a 1.5-T system was performed before and 1, 3, 6, and 12 months after ablation, and the morphological characteristics and the size of the ablated lesion were evaluated. Mammography was also performed for a comparison with the MRI measurement., Results: MRI displayed no residual enhancement of the tumor after RFA; there was an altered signal intensity with peripheral enhancement, however, and the area decreased in size gradually at a rate of 3.3% per month. Mammography showed a ring surrounding a roundish area whose size was equal to that seen with MRI., Conclusion: Our current series demonstrated the morphological characteristics on breast imaging after RFA plus radiation therapy. The size of the ablated area decreased over time. These findings are valuable for clinical follow-up of breast cancer patients undergoing RFA.

We report a rare case of breast cancer with cartilaginous and/or osseous metaplasia. A 59-year-old woman had a large lump in her left breast, which had enlarged gradually over a period of 2 years. Mammography, ultrasonography and aspiration cytology suggested phyllodes tumor with carcinoma. She underwent wide excision and sentinel lymph node biopsy. Because of the existence metastatic tumor cells in the sentinel lymph node on frozen section, sequential axillary lymph node dissection was conducted consequently. Histologically, the tumor consisted of invasive ductal carcinoma and spindle-cell carcinoma, including cartilaginous metaplasia. Adjuvant chemotherapy and whole-breast irradiation were performed. However, she died of multiple metastases to the liver 2 years after surgery. Breast cancer with cartilaginous and/or osseous metaplasia belongs to a special type of invasive carcinoma, and the incidence is very low. We here present our case and a review of the literature.

Background: In this study, we report a breast-conserving surgery (BCS) approach that uses projection and reproduction techniques of breast MRI obtained in the surgical position to the breast surface in patients with ductal carcinoma in situ (DCIS) of the breast., Study Design: Between February 2005 and January 2007, a total of 104 patients with operable breast cancer at our hospital had surgical-position breast MRI examinations. The 24 patients with relatively localized DCIS received BCS using the projection and reproduction techniques of the surgical-position breast MRI. During the same time period, 28 patients with relatively localized DCIS in whom prone-position breast MRI was performed, had conventional BCS using mammography-guided hookwires. In this study, we compared the surgical outcomes of our surgical approach with those of the conventional approach in a total of 52 patients with relatively localized DCIS., Results: Average volume of the pathologic specimens in the new technique group (27.5 cm(3)) was substantially smaller than that in the conventional BCS group (57.6 cm(3), p = 0.0007). In addition, the positive margin rate was substantially lower in the new technique group (12.5%) than in the conventional BCS group (39.3%; p = 0.029)., Conclusions: This study demonstrates that BCS can be done guided by the precise projection and reproduction techniques of the lesion obtained by surgical-position breast MRI. To the best of our knowledge, this is the first report of BCS technique for DCIS in this manner. Our surgical approach can be clinically useful in surgical planning and management in patients with DCIS.

Background: Success of breast-conserving surgery (BCS) following neoadjuvant chemotherapy (NAC) depends on accurate assessment of the initial lesion. We developed a new procedure (NIPR) in which initial naked magnetic resonance images are projected onto the skin before BCS., Methods: Thirty-five breast cancer patients underwent supine oblique MRI of the operative area. In 20 DCIS patients, the metallic clips were reproduced by projection on the skin using NIPR, and discrepancies between the projection site and clip were measured on X-rays. Fifteen patients (T1;3,T2;8,T3;4 cases) treated with NIPR were compared to 20 (T1;5 , T2;15 cases) treated using the conventional method with regard to excision area and additional excision rate of BCS after NAC., Results: The median discrepancy (linear distance) was 2.6 mm. NIPR significantly reduced the excision area and additional excision rate in T1 and T2 compared to the conventional method (P<0.05)., Conclusions: NIPR is a reliable technique for BCS following NAC with significant reductions in excision area and additional excision rate and superior cosmetic results.

Human breast cancer frequently metastasizes to bone, and effective therapies for patients with bone metastasis are required. However, the molecular mechanism for the bone metastasis of human breast cancer has not yet been fully elucidated. The present study aimed to evaluate the importance of active osteoclasts and bone-derived insulin-like growth factors (IGFs) for the survival and growth of breast cancer cells in bone. Human breast cancer cell line MCF-7 cells were injected into human adult bone (HAB) implanted into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. The mice were then treated with recombinant human osteoclastogenesis inhibitory factor/osteoprotegerin (rhOCIF/OPG), a decoy receptor for receptor activator of NF-kappaB ligand (RANKL), or an anti-human IGF monoclonal antibody. Histomorphometric analyses revealed that both treatments significantly decreased the tumor area of MCF-7 cells in cross-sections of the implanted HAB to about 30% of the tumor area in control mice, but had no effect on the growth of subcutaneously injected MCF-7 cells. Consistent with the results for the tumor area in HAB, there were fewer osteoclasts in the implanted HAB in rhOCIF/OPG-treated mice than in vehicle-treated mice. However, treatment with the anti-human IGF monoclonal antibody had no effect on the number of osteoclasts in HAB. The results indicate that the active osteoclasts induced by RANKL and the IGFs released as a result of bone resorption by these osteoclasts play crucial roles in the survival and growth of human breast cancer cells in bone and suggest that neutralization of bone-derived IGFs will be effective in preventing the development of bone tumors in breast cancer patients.

We report a case of angiosarcoma arising in the breast following breast-conserving surgery with radiation therapy for breast carcinoma. The patient, a 49-year-old postmenopausal woman, had undergone breast-conserving surgery for invasive ductal carcinoma of the left breast (pT2 pN0 M0 Stage IIA). Adjuvant radiotherapy (50 Gy with a booster dose to the tumor bed of 10 Gy) was then performed for the residual breast tissue and the patient was treated with hormone therapy (tamoxifen, 20 mg daily) for 5 years. She presented with skin erosion with bleeding 10 years after the initial operation. Incisional biopsy revealed angiosarcoma of the breast, and total mastectomy was subsequently performed. The patient was the treated with chemotherapy (weekly paclitaxel, 80 mg/m2 x cycles) and has remained well without evidence of local or distant recurrence.

Background: Primary chemotherapy for breast cancer is effective as postoperative adjuvant therapy. However, one of the critical disadvantages was a treatment delay for patients with progressive disease. The present study attempts to clarify quantitative parameters on MRI which can be used to predict the sensitivity to treatment in breast cancer patients., Methods: The subjects consisted of 26 patients with invasive ductal breast cancer who received primary chemotherapy before surgery. The mean maximum tumor dimension was 3.3cm, and 21 cases had nodal involvements. Three cases demonstrated histological grade 3. Dynamic enhanced MRI was evaluated at three different time periods; prior to, in the midst of preoperative chemotherapy, and just before the initial operation. The signal intensity ratio (SIR) and early contrast uptake (ECU) were calculated, as well as the correlation between these dynamic data and the tumor reduction rates were analyzed retrospectively. P-values of less than 0.05 were considered to indicate statistically significant., Results: Responders to chemotherapy had the significantly higher SIR and ECU values than non-responders (p=0.0454 and 0.0334, respectively). ECU value significantly decreased as tumor reduction by chemotherapy (p=0.0028). Pathological tumor dimension was significantly correlated with the tumor size estimated on presurgical MRI (p<0.0001)., Conclusions: Our current series demonstrated the significant correlation between pretreatment MRI data and tumor reduction by chemotherapy in breast cancer patients. With these results, it seems possible to define good and non-responders prior to treatment.

Background: Lymphatic mapping and sentinel lymph node (SN) biopsy has rapidly replaced axillary lymph node dissection for clinically node-negative breast cancers. Because of a short follow-up period when the procedure was new, there were few reports of the clinical recurrence rate in breast cancer patients treated with SN biopsy. The present study attempts to clarify the occurrence of distant failure after SN biopsy, especially in breast cancer patients with SN micrometastasis., Methods: The subjects consisted of 375 cases with clinically node-negative breast cancer, who had undergone SN biopsies. Chemotherapy and/or hormonal therapy was recommended based on the pathological primary tumor characteristics. The patients with SN micrometastasis also received adjuvant therapy equal to node-positive patients., Results: Examinations of lymph nodes indicated metastases in 73 cases. Among the invasive cancers, 54 cases had macrometastasis, 19 cases had micrometastasis and 241 cases had a tumor free SN. The median follow-up period ws 30 months (range 6 to 66 months). Distant relapse rates per person-years were 0.3% in the cases with tumor free SN and 3.3% among the macrometastatic cases. However, systemic disease was not observed in the cases with SN micrometastasis., Conclusions: These results may show that upstaging due to SN investigation increases the number of cases who should receive anti-cancer drugs, and consequently reduces the distant relapse rate. Further studies in a large number of cases as well as longer follow-up are needed to determine the prognostic significance of SN micrometastasis.

The purpose of this study was to assess the relationship between functional parameters derived from dynamic MR imaging and the histological findings of breast ductal carcinoma in situ (DCIS) and DCIS with invasive foci, and to evaluate whether these parameters might predict DCIS patient outcome. Two parameters, amplitude A and k(21), were determined from multicompartmental pharmacokinetic analyses of dynamic MR mammography in 39 patients with needle biopsy-proven primary DCIS. After surgery, the histological tumor characteristics, including microvessel density (MVD) (anti-CD-34), vascular permeability (anti-VEGF antigen) and histological grade, were evaluated. Histology revealed 27 pure DCIS and 12 DCIS with invasive foci. In pure DCIS, positive correlations between MVD and amplitude A (r=0.56, P<0.0025) and between MVD and k(21) (r=0.43, P=0.02) were found. As for histological grade, the differences in both functional parameters of grade 1 versus grade 2 and grade 1 versus grades 2 and 3 combined were significant (P<0.05). No significance was found in the analysis of DCIS with invasive foci. Our results indicated that functional MRI-based parameters might possess the potential to predict the outcome of patients with DCIS. Further study will be needed with larger series over longer periods.

Background: Breast microcalcifications are difficult to depict by ultrasound (US). However, recent advances in US equipment and the refinement of breast imaging techniques have improved the detection and characterization of small breast lesions. The present study attempts to determine whether US examination is able to demonstrate nonpalpable breast lesions associated with mammographically detected microcalcifications without mass density or distortion, and to evaluate the clinical reliability of US-guided procedures, especially in cases of ductal carcinoma in situ(DCIS)of the breast., Methods: The subjects consisted of 73 patients with breast cancer diagnosed preoperatively as DCIS by stereotactic core needle biopsies, all of whom had microcalcifications without other abnormalities on mammography. The radiological appearance and size of the clustered microcalcifications were evaluated. US examinations were performed preoperatively, and the detection rates were assessed. Sonographically detected lesions underwent US-guided wire localization followed by surgical excision., Results: The lesions associated with microcalcifications were identified sonographically in 54 of 73 cases (74%), and the pathological examination revealed breast cancer in all of the corresponding specimens. Lesions with linear-branching shape, segmental-linear distribution and category-5 calcifications on mammography had a high level of visibility on US. The US visible cases had a larger size of calcified area on mammography when compared with US invisible cases. Pathologically, the lesions were more frequently seen on US in cases with minimally invasive cancer or with comedo type DCIS., Conclusions: US examination is an effective method for identifying and localizing breast microcalcifications, and can be used as an alternative to stereotactic localization in selected patients with early breast cancer.

Background: The clinical practice of sentinel lymph node biopsy for breast cancer patients started in 1999 in our hospital, to obviate unnecessary axillary lymph node dissection. The present study examines the pathological false-negative cases on intraoperative sentinel lymph node investigations and evaluates their outcomes., Methods: The subjects consisted of 183 cases with clinically node-negative breast cancer who had undergone sentinel node biopsy. When the sentinel node was noted to contain malignant cells intraoperatively, a complete axillary lymph node dissection was performed subsequently. The patients with tumor free sentinel nodes underwent no further axillary surgery. The pathological false-negative cases in this series were defined as patients with lymph node involvement which was revealed postoperatively, despite negative intraoperative sentinel node examinations. After these surgeries and/or adjuvant therapies, interval clinical evaluations were performed for all patients., Results: Intraoperative diagnosis of the sentinel node was 96.2% accurate compared with the results of permanent sections. There were six pathological false-negative cases, a false-negative rate of 4.1%, all of which had only micrometastasis. Five cases received systemic adjuvant therapy and have been disease-free, however, one patient who refused further therapy developed infraclavicular lymph node metastasis two years after surgery., Conclusions: In the management of the patients with postoperatively revealed sentinel node micrometastasis, systemic adjuvant therapies might reduce local relapse without secondary lymph node dissection.

Objective: To clarify the usefulness of imprint cytology for intraoperative investigations of sentinel lymph nodes in breast cancer, comparing the results with those of examinations using frozen and permanent sections., Study Design: The material consisted of 303 sentinel lymph nodes from 124 cases of clinically node negative breast cancer. Touch imprint cytologic slides and frozen sections were obtained from the same cut surface of the sentinel nodes. Correlations with the final histopathologic results in paraffin sections were evaluated., Results: The sensitivity, specificity and accuracy of imprint cytology were 70.3%, 99.6% and 96.0%, and those of frozen sections were 83.8%, 100%, 98.0%, respectively. The values were improved when the 2 methods were combined (89.2%, 99.6%, 98.3%), though the concordance between imprint cytology and frozen section was 91.9%., Conclusion: Both imprint cytology and frozen section are useful for evaluating sentinel lymph node status in breast cancer. However, the 2 techniques should be combined to improve the diagnostic sensitivity.

Breast carcinoma is usually accompanied by an invasive component with an intraductal component, and each component shows different morphological features. We evaluated whether the presence or absence of comedonecrosis is correlated with prognosis and biological features in node-negative invasive breast carcinoma. Ninety-four node-negative breast carcinomas with an intraductal component were classified into two types: comedo type (n = 36) showing comedonecrosis partly or extensively in the intraductal component, and non-comedo type (n = 58) showing either an absence or small foci of necrosis. The Kaplan-Meier method was used to calculate disease-free survival. Immunohistochemical examination for p53 and HER-2 was conducted on the comedo (n = 35) and non-comedo (n = 47) type tumor specimens. Disease-free survival was significantly shorter in the comedo type than in the non-comedo type (P = 0.019). The expression of p53 was observed in 16 (45.7%) of the 35 comedo type cases, but only in two (4.3%) of the 47 non-comedo type cases (P < 0.0001). HER-2 overexpression was observed in seven (20.0%) of the 35 comedo type cases, while none of the 47 non-comedo type cases overexpressed HER-2 (P < 0.0001). These results suggest that the presence of comedonecrosis may be predictive of an unfavorable prognosis with aggressive biological behavior in node-negative invasive breast carcinoma.

We examined a 31-year-old woman with a solid mass in her left axilla. Physical examination and ultrasonography confirmed a 2 cm well-defined mass. Fine needle aspiration biopsy suggested fibroadenoma of breast. Excisional biopsy revealed benign phyllodes tumor of the ectopic breast tissue. Phyllodes tumor in ectopic breast tissue is an extremely rare occurrence. Only nine cases have been reported, including tumors of the vulva, inguinal region and axilla. This is the second case in the axillary region.

Background: Dynamic magnetic resonance imaging (MRI) has improved the detection of breast malignancies. The method is based on estimating the velocity of contrast enhancement taking into account increased angiogenesis in tumor. Microvessel density correlates with breast carcinoma metastasis. Thus, we hypothesized that contrast enhancement on MRI correlates with metastasis in breast cancer patients. The present study attempts to clarify the quantitative assessment of dynamic data, and examines the correlation between MRI enhancement and breast carcinoma metastasis., Methods: The subjects consisted of 31 patients with invasive ductal breast cancer. Twenty patients were disease free for five years (group A), and eleven patients suffered from metastatic disease at distant sites concurrently or postoperatively (group B). Dynamic MRI was performed preoperatively using a 1.5T system in all cases. Using the dynamic data, the signal intensity (SI)ratio and SI index were determined and analyzed retrospectively taking into account the presence of distant metastases., Results: The values of the SI ratio were 2.2+/-0.7 in group A and 2.3+/-0.4 in group B, respectively, with no significant difference seen between the groups. The SI index value was significantly higher in group B (28.5+/-32.8) than in group A (10.3+/-5.5, p<0.05)., Conclusions: The current series suggests that the SI index could distinguish patients with high risk of distant metastasis from disease free patients, preoperatively. If a suitable borderline value were established, the quantitative dynamic parameter determined by MRI may be useful for predicting the prognosis of breast cancer patients.

Background: Controversy surrounds the correct injection site of radioisotope (RI) and blue dye for sentinel node biopsy (SNB) in breast cancer, and there have been some reports on the advantages of subareolar (SA) injection. We carried out a study to assess whether SA injection is useful for all patients undergoing SNB., Methods: In this prospective study, 20 patients with T1 or T2 tumors clinically node negative, were enrolled. Injection of 99mTc-phytate (0.5 mCi) was performed two times (3 to 5 days before surgery and the day of surgery) for each patient. The first RI injection was SA, and the second RI injection was subdermal (SD). The location and number of hot nodes were assessed by lymphoscintigraphy (LSG) and hand-held gamma probe., Results: There were no patients in whom hot nodes on LSG were visualized in clearly different locations between the SA and SD injection sites. However, there were 2 patients in whom hot nodes were identified at different locations with a gamma probe. Seven patients had more hot nodes on LSG with SD injection than SA injection. Eight patients had a higher RI count of hot nodes by SD injection than SA injection. The mean RI count of hot nodes by SA injection was higher than that after SD injection., Conclusion: SA and SD lymphatic flow run into the same node in most patients, however, SD injection is more useful than SA injection in some patients. Though SA injection is a useful technique, it may not identify sentinel lymph nodes correctly in patients with multiple lesions or tumors in the upper outer quadrant.