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Background In this study, we aimed to investigate the expression and clinical significance of miR-145-5p and its tumor-suppressive effect in breast cancer patients. Methods We used luciferase reporter assay, real-time quantitative reverse transcription polymerase chain reaction and Western blot to identify sex-determining region Y-box2 (SOX2) as the target gene of miR-145-5p. Their expression levels in breast cancer tissues (n = 122) were detected by real-time quantitative polymerase chain reaction. We also applied 3-(4,5-dimethyl- 2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay and flow cytometry to reveal the effect of miR-145-5p on proliferation in breast cancer. Results miR-145-5p expression is downregulated in breast cancer tissues and negatively correlated with SOX2 expression. Decreased miR-145-5p expression was significantly associated with larger tumor size, distal metastasis, higher Ki67 expression level, and shorter overall survival. miR-145-5p inhibits breast cancer cell proliferation via targeting SOX2, and multivariate regression showed that both miR-145-5p and SOX2 were unfavorable prognostic factors. Conclusions miR-145-5p played a suppressive role in the proliferation of breast cancer cells by targeting SOX2, and miR-145-5p is a putative biomarker for risk assessment in patients with breast cancer.

More than half patients who undergo axillary lymph node (ALN) surgery are ALN negative in early-stage invasive breast cancer (EIBC). Thus, to avoid excessive treatment, we aim to establish and validate a novel nomogram model for the preoperative diagnosis of ALN status in patients with EIBC. In total, 864 patients with EIBC from two independent centers were enrolled in our study. For the discovery set, miRNAs expression profiling with functional roles in ALN metastasis was discovered by microarray analysis and validated by quantitative polymerase chain reaction (PCR). For the training and validation cohorts, we used PCR to quantify miRNAs expression in a model development cohort and assessed miRNAs signature in an internal validation cohort and external independent validation cohort. Multivariable logistic regression analyses were used to establish a nomogram model for the likelihood of ALN metastasis from miRNAs signature and clinical variables. A signature of nine-miRNA was significantly associated with ALN status. The predictive ability of our nomogram that included miRNAs signature and clinical-related variables (age, tumor size, tumor location and axillary ultrasound-reported ALN status) was significantly greater than a model that only considered clinical-related factors (concordance index: 0.856, 0.796) and also performed well in the two validation cohorts (concordance index: 0.841, 0.747). Our nomogram is a reliable prediction method that can be conveniently used to preoperatively predict ALN status in patients with EIBC. Therefore, after further confirmation in prospective and multicenter clinical trial, omission of axillary surgery may be feasible for some patients with EIBC in the future.

// Weige Tan 1, 2, * , Wei Luo 1, * , Weijuan Jia 1 , Gehao Liang 1 , Xinhua Xie 3 , Wenbo Zheng 2 , Erwei Song 1, 4 , Fengxi Su 1 , Chang Gong 1 1 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China 2 Department of Breast Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China 3 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China 4 Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University, Guangzhou, China * These authors have contributed equally to this work Correspondence to: Chang Gong, email: changgong282@163.com Fengxi Su, email: fengxisu@vip.163.com Keywords: breast cancer, pathologic complete response, neoadjuvant chemotherapy, Nottingham prognostic index, IHC4 Received: July 13, 2016 Accepted: November 07, 2016 Published: November 24, 2016 ABSTRACT Pathologic complete response (pCR) prediction after neoadjuvant chemotherapy (NAC) is important for clinical decision-making in breast cancer. This study investigated the predictive value of Nottingham prognostic index (NPI), Immunohistochemical four (IHC4) score and a new predictive index combined with them in estrogen-positive (ER+) breast cancer following NAC. We retrospectively gathered clinical data of 739 ER+ breast cancer patients who received NAC from two cancer centers. We developed a new predictive biomarker named NPI+IHC4 to predict pCR in ER+ breast cancer in a training set (n=443) and validated it in an external validation set (n=296). The results showed that a lower IHC4 score, NPI and NPI+IHC4 were significantly associated a high pCR rate in the entire cohort. In the study set, NPI+IHC4 showed a better sensitivity and specificity for pCR prediction (AUC 0.699, 95% CI 0.626-0.772) than IHC4 score (AUC 0.613, 95% CI 0.533-0.692), NPI (AUC 0.576, 95% CI 0.494-0.659), tumor size (AUC 0.556, 95% CI 0.481-0.631) and TNM stage (AUC 0.521, 95% CI 0.442-0.601). In the validation set, NPI+IHC4 had a better predictive value for pCR (AUC 0.665, 95% CI 0.579-0.751) than IHC4 score or NPI alone. In addition, ER+ patients with lower IHC4, NPI and NPI+IHC4 scores had significantly better DFS in both study and validation sets. In summary, NPI+IHC4 can predict pCR following NAC and prognosis in ER+ breast cancer, which is cost-effect and potentially more useful in guiding decision-making regarding NAC in clinical practice. Further validation is needed in prospective clinical trials with larger cohorts of patients.

// Weige Tan 1, 5 , Xinhua Xie 2, 3, 5 , Laisheng Li 4, 5 , Hailin Tang 2, 3 , Xigang Ye 1 , Lun Chen 1 , Wei Tang 1 , Jin Gao 1 , Lingxiao Pan 1 , Xiaoshen Zhang 1 , Feng Ye 2, 3 , Xing Li 2, 3 , Lu Yang 2, 3 , Xiaoming Xie 2, 3 , Wenbo Zheng 1 1 Department of Breast Surgery, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China 2 Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China 3 Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China 4 Department of Laboratory Medicine, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China 5 These authors contributed equally to this work Correspondence to: Wenbo Zheng, email: wenbo_zheng@163.com Xiaoming Xie, email: xiexm@sysucc.org.cn Keywords: MACC1, breast cancer, diagnosis, biomarker, serum Received: September 07, 2016 Accepted: October 14, 2016 Published: October 25, 2016 ABSTRACT Metastasis-associated in colon cancer-1 (MACC1) promotes colorectal cancer progression and predicts prognosis. The aim of our study was to determine the diagnostic and prognostic value of preoperative serum MACC1 levels in breast cancer patients. Serum MACC1 levels were measured in 378 breast cancer patients, 120 patients with benign breast disease, and 40 healthy volunteers using an ELISA. Serum MACC1 levels were higher in breast cancer patients than patients with benign disease or healthy volunteers. Increased serum MACC1 was associated with breast cancer TNM stage ( P < 0.001), tumor size ( P < 0.001), lymph node metastasis ( P < 0.001), and Ki-67 status ( P = 0.014). Serum MACC1 measurement successfully discriminated breast cancer patients from normal and healthy controls (AUC = 0.785, 95% CI: 0.746–0.825) with an optimal cut-off value of 38.35 pg/ml (sensitivity = 0.725, specificity = 0.696). Moreover, serum MACC1 exhibited significant prognostic value in breast cancer (AUC = 0.757, 95% CI: 0.700–0.814), and high MACC1 was associated with poor disease-free survival (HR 5.63, 95% CI: 3.51–9.04; P < 0.001). Our findings demonstrated that circulating MACC1 could serve as a reliable diagnostic and prognostic biomarker for breast cancer.

Intraoperative radiotherapy differs from the more commonly used external beam radiation with respect to fractionation, radiation energy, dose rate, and target volume, which may influence the irradiated cells in a complex manner. However, experimental studies of intraoperative radiotherapy are limited. Intrabeam is a frequently used intraoperative radiotherapy device; we evaluated its effects on the proliferation, apoptosis, migration, and invasion of MCF-7 human breast cancer cells. We performed colony formation assays for cells irradiated with single radiation doses of 0 to 16 Gy. Other cells were irradiated with single radiation doses of 0 to 6 Gy and then continued to be cultured. We measured cell-cycle distributions and apoptosis rates 24 hours later, using flow cytometry, and performed wound-healing assays, Transwell tests, and terminal deoxynucleotidyl transferase–mediated 2′-deoxyuridine 5′-triphosphate nick-end labeling staining 4 weeks later. Colony formation assays showed no positive colonies from cells irradiated with doses of ≥6 Gy. In flow cytometry, the experimental groups had higher late-apoptosis/necrosis rates ( P < .01) and higher percentages of cells arrested in G1 phase ( P < .01). Experimental groups also had much lower scratch-repair rates in the wound healing assay ( P < .001) and higher apoptosis rates in the terminal deoxynucleotidyl transferase–mediated 2′-deoxyuridine 5′-triphosphate nick-end labeling assay ( P < .05). In Transwell tests, the 4 Gy and 6 Gy groups had fewer invading cells than the control group ( P < .05). Single-dose irradiation of 6 Gy with the Intrabeam device can effectively inhibit proliferation, migration, and invasiveness and promote apoptosis in MCF-7 cells with long-lasting effects.

Nipple-sparing mastectomy combined with breast reconstruction helps to optimize the contour of the breast after mastectomy. However, the indications for nipple-sparing mastectomy are still controversial. Local radiation to the nipple–areola complex may play some roles in improving the oncological safety of this procedure. From January 2014 to December 2017, 41 consecutive patients who underwent nipple-sparing mastectomy combined with Intrabeam intraoperative radiotherapy to the nipple–areola complex flap and breast reconstruction were enrolled in this prospective study. The prescribed radiation dose at the surface of the spherical applicator was 16 Gy. In eight cases, carcinomas were in the central portion of the breast. Partial necrosis of the nipple–areola complex occurred in three cases. Over 90% of patients reported “no or poor sensation” of the nipple–areola complex postoperatively. With a median follow-up time of 26 months, no recurrences or metastases were identified; however, breast-cancer mortality occurred in one patient. Pathologic evaluation of paraffin-embedded sections showed ductal carcinoma in situ in the remaining tissues deep to the nipple–areola complex flap in two patients. Although no further treatment was administered to the nipple–areola complexes postoperatively, no recurrences or metastases were identified 20 months and 24 months later, respectively. Optical microscopy and transmission electron microscopy revealed changes in some normal tissues immediately after Intrabeam intraoperative radiotherapy. Karyopyknosis were observed in gland tissues, and the collagenous fibers became sparse and arranged chaotically. As assessed by thermoluminescence, radiation doses at different sites in the nipple–areola complex flap varied considerably and were about 10 Gy at the areola surface. No Intrabeam intraoperative radiotherapy-related acute or chronic radiation injuries of the lung, heart or bone marrow were identified. Our findings indicate that Intrabeam intraoperative radiotherapy during nipple-sparing mastectomy combined with breast reconstruction is safe and feasible. The current study was approved by the Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University (registering order 201750). All participants gave their written informed consent.

Purpose of the study To investigate whether CCL18 is involved in breast cancer, and the relationship between CCL18 and MVD (MVD was recognized by CD34) which is a well-accepted angiogenic maker of multiple cancers including breast cancer. Patients and methods Immunohistochemistry staining for CCL18 and CD34 was performed on 179 cases, including 29 normal cases as control, 47 cases with benign breast diseases, and 103 cases with breast cancer. Results We found that CCL18 was significantly up-regulated in breast cancer samples as compared with benign tumors or normal breast tissues. Moreover, the expression level of CCL18 increased with the size of tumors, the number of lymph node metastasis, and advancing tumor stage, suggesting that CCL18 expression correlates with tumor malignancy scales. At the same time, we found that MVD was also significantly over-expressed in cancer tissues as compared with normal control group and benign tumor group, but it was not significantly differentially expressed among tumors with different malignancy scale like CCL18, while the expression of MVD in CCL18 positive breast cancer cases was higher than in the CCL18 negative breast cancer cases (P = 0.016, P Conclusion CCL18 is involved in the development of breast cancer. CCL18 is a better biomarker than MVD in determining whether the tumor is malignant and the severity of malignancy of breast cancer.

The aim of the present study was to evaluate whether the level of expression of tissue or plasma miR-106b can be used to predict clinical outcomes in breast cancer patients.Both tissue and plasma samples were collected and analyzed from 173 patients with primary breast cancer and a set of 50 women with fibroadenoma. The relative expression levels of miR-106b were determined using real-time quantitative reverse transcription polymerase chain reaction and in situ hybridization.The levels of miR-106b were upregulated in both tissue and plasma samples from breast cancer patients. The expression levels showed a linear correlation (rs = 0.748, P 0.001) and were significantly correlated with tumor size, Ki67 expression, and lymph node metastasis (all P 0.05). Patients with high miR-106b expression levels tended to have shorter disease-free survival times and overall survival times (P 0.001). In a Cox regression model, high-level tissue and plasma miR-106b expression were unfavorable prognostic factors, and receiver-operating characteristic analysis revealed that the tissue and plasma miR-106b levels provided considerable diagnostic accuracy, yielding an area under the ROC curve of 0.785 and 0.856, respectively.MiR-106b was found to be associated with a high risk of recurrence of breast cancer, and miR-106b is a putative plasma marker for risk assessment in patients with breast cancer.

Background Despite the advancement and increasing use of breast-conserving surgery, mastectomies, including nipple-sparing mastectomy (NSM), are still carried out in a portion of breast cancer patients. However, the role of NSM is still controversial, mainly because of concern about the oncologic safety of the nipple-areola complex (NAC). INTRABEAM (Carl Zeiss, Oberkochen, Germany) is the most widely used mobile intraoperative radiotherapy (IORT) device to date. This pilot study aims to broaden the application of the INTRABEAM system for breast cancer, investigating the feasibility of INTRABEAM IORT in NSM with breast reconstruction. Patients and Methods From December 2012 to June 2013, 7 female patients with breast cancer were enrolled in the study. NSM with or without axillary dissection was performed first. After confirming negative retroareolar frozen section results and no poor local bleeding in the NAC, INTRABEAM IORT was carried out with a single dose of 16 Gy, followed by breast reconstruction. The complications and short-term outcomes were assessed. Results The median radiation time was 13 minutes 14 seconds in the 7 cases. One patient complained of mild pain in the radiation field on the skin in the first 2 weeks. All 7 patients were followed for a median of 7 months. No acute radiation injury with symptoms (heart, lung, or hematologic system), NAC necrosis, local recurrence, or metastasis was observed. Although every patient had reduction in NAC sensitivity, the contours of the breasts (including the NAC) were satisfactory. Conclusions INTRABEAM IORT may be a feasible and convenient approach for NSM with breast reconstruction in patients with breast cancer.

3139 Background: The 10-miRNA risk score is a prognostic 10-gene expression signature specifically developed in luminal breast cancer associated with relapse-free survival. Since high-risk patients identified by10-miRNA RS had worse prognosis but better outcome with chemotherapy than low-risk patients (Gong C et al, EBioMedicine. 2016), this model may facilitate personalized therapy-decision making for luminal breast cancer patients. Therefore, we seek to validate whether high-risk group are more sensitive to chemotherapy than low-risk group by assessing the predictive value of 10-miRNA RS for pathological complete response (pCR) in patients receiving neoadjuvant chemotherapy (NAC). Methods: The 10-miRNA gene expression and clinicopathological data were prospectively gathered from 251 pretreated biopsy-diagnosed luminal breast cancer patients from 4 breast cancer centers. Formalin-fixed paraffin-embedded tissues from basal line biopsy were used for the detection of 10-miRNA expression to calculate the RS. The correlation between pCR and the 10-miRNA RS classification were identified. Results: In this prospective, multicenter study, the overall pCR rate was 13.6% (34/251). The 10-miRNA RS of the pCR group was significantly higher than the non-pCR group ( P = 0.015). Fifty-one percent of patients were classified as low-risk according to the 10-miRNA RS classification and 49% as high-risk with a RS cut-off point of 2.144. The 10-miRNA RS classification was associated with a pCR rate of 9.4% in the low-risk group and 17.8% in the high-risk group ( P = 0.041). The correlation between the pCR and the 10-miRNA RS classification was significant in subgroup analysis stratified by molecular subtypes (8% vs. 13.2% in luminal B1; 14.7% vs. 30.1% in luminal B2; no pCR was observed in all 13 luminal A subtype). In multivariate analysis, the 10-miRNA RS remained significantly associated with pCR and independent from subtype, ki67 and other clinicopathological characteristics. Conclusions: 10-miRNA RS clearly defined that high-risk patients are more sensitive to chemotherapy which leads to a higher pCR rate in NAC patients. Thus, 10-miRNA RS is not only a prognostic factor but an effective method in determining whether a patient would undergo surgery or receive NAC prior to surgery. Clinical trial information: ChiCTR-DDD-17013651.

Background Three strategies using lamivudine have been proposed to prevent chemotherapy-induced HBV (hepatitis B virus) reactivation in the clinical setting. The purpose of this meta-analysis is to evaluate the efficacy of the early preemptive strategy, deferred preemptive strategy and therapeutic strategy in patients with HBsAg-positive breast cancer during chemotherapy. Methods Clinical studies published from database inception until Nov 1, 2014, were included for analysis. The primary outcomes were overall survival, rate of chemotherapy disruption and virological and clinical reactivation. The secondary outcomes were the rates of HBV-related chemotherapy disruption, HBV-related mortality, YMDD mutations and withdrawal hepatitis. Results Four hundred and thirty patients in four studies that compared the early preemptive strategy with a therapeutic strategy were included. Application of early preemptive lamivudine was superior in reducing HBV recurrence (pooled OR: 0.12, 95% CI, 0.04 to 0.31, P< 0.0001), the incidence of HBV-related hepatitis (pooled OR: 0.13, 95% CI, 0.04 to 0.37, P< 0.0001) and the rate of chemotherapy disruption (pooled OR: 0.37, 95% CI, 0.23 to 0.60, P< 0.0001). In these two groups, no significant difference was found in overall mortality (P = 0.32), YMDD mutant rate (P = 0.13) or incidence of withdrawal hepatitis (P = 0.38). Of the two studies that compared the efficacy of an early and a deferred preemptive strategy, one showed that an early preemptive strategy significantly reduced the incidence of hepatitis (P = 0.046), whereas the other showed no significant difference (P = 0.7). Conclusions An early preemptive strategy is superior to a therapeutic strategy in decreasing the incidence of HBV reactivation, incidence of HBV-related hepatitis and rate of chemotherapy disruption in patients with breast cancer. A deferred preemptive strategy might be an alternative approach to controlling viral replication.