U2AF2-SNORA68 promotes triple-negative breast cancer stemness through the translocation of RPL23 from nucleoplasm to nucleolus and c-Myc expression.

BACKGROUND: Small nucleolar RNAs (snoRNAs) play key roles in ribosome biosynthesis. However, the mechanism by which snoRNAs regulate cancer stemness remains to be fully elucidated. METHODS: SNORA68 expression was evaluated in breast cancer tissues by in situ hybridization and qRT‒PCR. Proliferation, migration, apoptosis and stemness analyses were used to determine the role of SNORA68 in carcinogenesis and stemness maintenance. Mechanistically, RNA pull-down, RNA immunoprecipitation (RIP), cell fractionation and coimmunoprecipitation assays were conducted. RESULTS: SNORA68 exhibited high expression in triple-negative breast cancer (TNBC) and was significantly correlated with tumor size (P = 0.048), ki-67 level (P = 0.037), and TNM stage (P = 0.015). The plasma SNORA68 concentration was significantly lower in patients who achieved clinical benefit. The SNORA68-high patients had significantly shorter disease-free survival (DFS) (P = 0.036). Functionally, SNORA68 was found to promote the cell stemness and carcinogenesis of TNBC in vitro and in vivo. Furthermore, elevated SNORA68 expression led to increased nucleolar RPL23 expression and retained RPL23 in the nucleolus by binding U2AF2. RPL23 in the nucleolus subsequently upregulated c-Myc expression. This pathway was validated using a xenograft model. CONCLUSION: U2AF2-SNORA68 promotes TNBC stemness by retaining RPL23 in the nucleolus and increasing c-Myc expression, which provides new insight into the regulatory mechanism of stemness.

The small nucleolar RNA SNORA51 enhances breast cancer stem cell-like properties via the RPL3/NPM1/c-MYC pathway.

Breast cancer stem cells (BCSCs) are key players in carcinogenesis and development. Small nucleolar RNAs (snoRNAs) seem to have a crucial influence on regulating stem cell-like properties in various cancers, but the underlying mechanism in breast cancer has not been determined. In this study, we first found that the expression of SNORA51 might be strongly and positively related to BCSCs-like properties. SNORA51 expression was assessed in breast cancer tissues (n = 158 patients) by in situ hybridization. Colony formation, cell counting kit-8, and sphere formation assays were used to detect cell proliferation and self-renewal, respectively. Wound healing and transwell assays were used to detect cell migration. Coimmunoprecipitation and molecular docking were used to determine the underlying mechanism through which SNORA51 regulates BCSCs-like properties. High SNORA51 expression was associated with a worse prognosis, overall survival, and disease-free survival, in 158 breast cancer patients and was also closely related to lymph node status, ER status, the Ki-67 index, histological grade, and TNM stage. Further analysis proved that SNORA51 could enhance and maintain stem cell-like properties, including cell proliferation, self-renewal, and migration, in breast cancer. Moreover, high SNORA51 expression could reduce nucleolar RPL3 expression, induce changes in the expression of NPM1 in the nucleolus and nucleoplasm, and ultimately increase c-MYC expression. Taken together, our findings demonstrated that SNORA51 could enhance BCSCs-like properties via the RPL3/NPM1/c-MYC pathway both in vitro and in vivo. Therefore, SNORA51 might be a significant biomarker and potential therapeutic target and might even provide a new viewpoint on the regulatory mechanism of snoRNAs in breast cancer or other malignant tumors.

An insight into the invasion of breast ductal carcinoma in situ based on clinical, pathological and hematological data.

Background: Ductal carcinoma in situ (DCIS) has become a non-negligible part of breast cancers owing to the greatly increased incidence. While its natural history was not fully elucidated, which is the reason for current controversies in clinical treatment. Exploration of this issue from a clinical perspective is meaningful. Methods: Medical records of 389 patients diagnosed with DCIS or DCIS with invasive ductal carcinoma (IDC) were reviewed. All of them received appropriate medical care in our center. All 324 patients in training cohort were divided into invasion and non-invasion groups based on pathology. Differences in DCIS immunohistochemical markers and hematological indicators between them were analyzed. In the invasion group, differences between DCIS and matched IDC were compared to explore changes in the tumor heterogeneity during invasion. Conclusions are validated in the validation cohort of 65 patients. Results: Patients in invasion and non-invasion groups were balanced in baseline characteristics and no statistically significant differences were noticed for DCIS immunohistochemical markers. For hematological indicators, high expression of platelet >291.50) (odds ratio, 2.46; CI [1.35-4.46]; p = 0.003) and SII (>347.20) (odds ratio, 2.54; CI [1.56-4.12]; p < 0.001) were established as independent predictors for invasion by logistic analysis and were validated in the validation cohort. Ki-67 of IDC was significantly higher than that of matched DCIS (p < 0.001). HER2 expression and histological grade of DCIS were separately linearly related to those of IDC. Conclusion: The change in hematological indicators is an independent predictor for invasion and can be incorporated into the treatment decision-making process for DCIS. Invasion tumor cells exhibit a stronger proliferative capacity compared with the in-situ ones. There are linear relationships in HER2 expression and histological grades between DCIS and matched IDC. DCIS subclones with different histological grades will develop into invasive carcinomas separately.

Axillary management for early invasive breast cancer patients: Who will truly benefit?

Background: The implementation of sentinel lymph node biopsy (SLNB) and further completion axillary lymph node dissection (cALND) after positive sentinel lymph nodes (SLNs) on early invasive breast cancer patients should be cautiously tailored. Identifying predictors for SLN and non-sentinel lymph node (nSLN) metastases can help surgeons make better surgical decisions. Methods: A retrospective case-control study was designed and a total of 560 eligible patients were enrolled consecutively. They were all diagnosed in our center and received appropriate medical care. According to the metastasis of SLN and nSLN, they were divided into metastatic and non-metastatic groups on two successive occasions to investigate the relationship between clinical factors, pathological factors, hematological factors and lymph node metastasis. Results: In total, 101 (18.04%) patients developed SLN metastases, including 98 patients with macro-metastases and 3 patients with micro-metastases. Out of 97 patients receiving further cALND, 20 patients (20.62%) developed nSLN metastases. Multivariate analysis revealed that "high expression of Ki-67" and "lymphatic invasion" predicted a higher risk of SLN metastasis; and "increased number of positive SLNs" and "increased systemic inflammation index (SII)" predicted a higher risk of nSLN metastasis. Conclusion: Surgery for early invasive breast cancer patients should be more customized and precise. Appropriate axillary management is necessary for patients with the associated predictors.

A novel HIF-2α targeted inhibitor suppresses hypoxia-induced breast cancer stemness via SOD2-mtROS-PDI/GPR78-UPRER axis.

Hypoxic tumor microenvironment (TME) plays critical roles in induction of cancer stem cell-like phenotype in breast cancer and contribute to chemoresistance. However, the mechanism underlying stemness reprogramming of breast cancer cells (BCs) by hypoxic TME remains largely unknown. In the present study, we illustrated that HIF-2α, but not HIF-1α, induces stemness in BCs under hypoxia through SOD2-mtROS-PDI/GRP78-UPRER pathway, linking mitochondrial metabolic state to endoplasmic reticulum (ER) response via mitochondrial reactive oxygen species (mtROS) level. HIF-2α activates endoplasmic reticulum unfolded protein response (UPRER) in drug-sensitive MCF7 and T47D cells to induce drug-resistant stem-like phenotype. Genetic depletion or pharmacological inhibition (YQ-0629) of HIF-2α abolished hypoxia-induced stem-like phenotype in vitro and in vivo. Mechanistically, HIF-2α activates transcription of superoxide dismutase 2 (SOD2) under hypoxia and thereby decreases mtROS level. With less mtROS transported to endoplasmic reticulum, the expression and activity of protein disulfide isomerase (PDI) is suppressed, allowing glucose-regulated protein 78 (GRP78) to dissociate from receptor proteins of UPRER and bind misfolded protein to activate UPRER, which eventually confer chemoresistance and stem-like properties to BCs. Moreover, the increase in mtROS and PDI levels caused by HIF-2α knockdown and the subsequent UPRER inhibition could be substantially rescued by mitoTEMPOL (a mtROS scavenger), 16F16 (a PDI inhibitor), or GRP78 overexpression. Overall, we reported the critical roles of HIF-2α-SOD2-mtROS-PDI/GRP78-UPRER axis in mediating hypoxia-induced stemness in BCs, highlighting the interaction between organelles and providing evidence for further development of targeted HIF-2α inhibitor as a promising therapeutic strategy for chemoresistant breast cancer.

Breast Lesions Diagnosed as Ductal Carcinoma In Situ by Ultrasound-Guided Core Needle Biopsy: Risk Predictors for Concomitant Invasive Carcinoma and Axillary Lymph Node Metastasis.

BACKGROUND: The major concern over preoperatively diagnosed ductal carcinoma in situ (DCIS) of breast via ultrasound-guided core needle biopsy (US-CNB) is the risk of missing concomitant invasive carcinoma. It is crucial to identify risk predictors for such a phenomenon and evaluate its impact on axillary conditions to help surgeons determine which patients should receive appropriate axillary lymph node management. METHODS: Medical records of 260 patients preoperatively diagnosed with DCIS via 14-gauge CNB were retrospectively analyzed. All of them underwent subsequent surgery at our institution and were successively divided into invasive and non-invasive groups, and metastatic and non-metastatic groups according to pathology of resected specimens and metastasis of axillary lymph nodes (ALNs). Predictive value of preoperative physical examinations, imaging findings, histopathological findings, and hematological indexes for pathological underestimation and metastasis of ALN was assessed by logistic regression analysis. RESULTS: The concomitant invasive carcinoma was overlooked in 75 out of 260 patients (29.3%). Multivariate analysis revealed that presence of microinvasion, presence of abnormal lymph node on ultrasound, and absent linear or segmental distributed calcification on mammography were independent risk predictors for invasive carcinoma. Fourteen patients had lymph node metastasis, and five of them were in the non-invasive group. The presence of abnormal lymph node on ultrasound and increased ratio of platelet distribution width to platelet crit (PDW/PCT) (>52.85) were identified as independent risk predictors for ALN metastasis. CONCLUSION: For patients diagnosed with DCIS preoperatively, appropriate ALN management is necessary if they have risk predictors for concomitant invasive carcinoma and ALN metastasis.

PRPF6 promotes androgen receptor/androgen receptor-variant 7 actions in castration-resistant prostate cancer cells.

Androgen receptor (AR) and its variants play vital roles in development and progression of prostate cancer. To clarify the mechanisms involved in the enhancement of their actions would be crucial for understanding the process in prostate cancer and castration-resistant prostate cancer transformation. Here, we provided the evidence to show that pre-mRNA processing factor 6 (PRPF6) acts as a key regulator for action of both AR full length (AR-FL) and AR variant 7 (AR-V7), thereby participating in the enhancement of AR-FL and AR-V7-induced transactivation in prostate cancer. In addition, PRPF6 is recruited to cis-regulatory elements in AR target genes and associates with JMJD1A to enhance AR-induced transactivation. PRPF6 also promotes expression of AR-FL and AR-V7. Moreover, PRPF6 depletion reduces tumor growth in prostate cancer-derived cell lines and results in significant suppression of xenograft tumors even under castration condition in mouse model. Furthermore, PRPF6 is obviously highly expressed in human prostate cancer samples. Collectively, our results suggest PRPF6 is involved in enhancement of oncogenic AR signaling, which support a previously unknown role of PRPF6 during progression of prostate cancer and castration-resistant prostate cancers.

MRPL13 is a Prognostic Cancer Biomarker and Correlates with Immune Infiltrates in Breast Cancer.

OBJECTIVE: To study the expression of MRPL13 in breast cancer tissues using TCGA database, analyze the correlation between the expression and clinicopathological characteristics of patients, and explore the role of MRPL13 in the development of breast cancer (BC). METHODS: The BC mRNA data and clinical information were downloaded from TCGA database. The correlation between MRPL13 expression and clinicopathological parameters was analyzed. Cox regression multivariate analysis was used to explore the factors affecting the prognosis of BC patients. The UALCAN database was used to analyze the expression level of MRPL13 in BC and its relationship with clinical pathological factors. The GSEA method was used to predict the possible regulatory pathways of MRPL13. Immune responses of MRPL13 expression were analyzed using TISIDB and CIBERSORT. Additionally, GEPIA, K-M survival analysis and data from the HPA were used to validate the outcomes. RESULTS: The expression of MRPL13 in BC tissues was significantly higher than normal counterparts, patients with low MRPL13 expression had a better survival prognosis, also indicated an independent prognostic factor. GSEA analysis showed that the regulation of cell migration, positive regulation of endothelial cell migration, and Notch signaling pathway were enriched in tissues with low expression of MRPL13. Additionally, depleting MRPL13 expression inhibited invasion in MCF-10A and MCF-7 cells. Furthermore, PCR showed that MRPL13 affected VEGFA and MMP gene expression. CIBERSORT analysis revealed that the amount of NK cells decreased when MRPL13 expression was high. CONCLUSION: The expression of MRPL13 mRNA is upregulated in BC tissues, and the expression level of MRPL13 is significantly related to the clinicopathological factors of patients. High MRPL13 expression is a poor prognostic factor for BC, and it can be used as a molecular marker for prognosis judgment and as a potential therapeutic target.

Coexpression Network Analysis of Genes Related to the Characteristics of Tumor Stemness in Triple-Negative Breast Cancer.

Cancer stem cells (CSCs) are subsets of cells with the ability of self-renewal and differentiation in neoplasm, which are considered to be related to tumor heterogeneity. It has been reported that CSCs act on tumorigenesis and tumor biology of triple-negative breast cancer (TNBC). However, the key genes that cause TNBC showing stem cell characteristics are still unclear. We combined the RNA sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA) database and mRNA expression-based stemness index (mRNAsi) to further analyze mRNAsi with regard to molecular subtypes, tumor depth, and pathological staging characteristics of breast cancer (BC). Secondly, we extract the differential gene expression of tumor vs. normal group and TNBC vs. other subtypes of BC group, respectively, and intersect them to achieve precise results. We used a weighted gene coexpression network analysis (WGCNA) to screen significant gene modules and the functions of selected genes including BIRC5, CDC25A, KIF18B, KIF2C, ORC1, RAD54L, and TPX2 were carried out through gene ontology (GO) functional annotation. The Oncomine, bc-GenExMiner v4.4, GeneMANIA, Kaplan-Meier Plotter (KM-plotter), and GEPIA were used to verify the expression level and functions of key genes. In this study, we found that TNBC had the highest stem cell characteristics in BC compared with other subtypes. The lower the mRNAsi score, the better the overall survival and treatment outcome. Seven key genes of TNBC were screened and functional annotation indicated that there were strong correlations between them, relating to nuclear division, organelle fission, mitotic nuclear division, and other events that determine cell fate. Among these genes, we found four genes that were highly associated with adverse survival events. Seven key genes identified in this study were found to be closely related to the maintenance of TNBC stemness, and the overexpression of four showed earlier recurrence. The overall survival (OS) curves of all key genes between differential expression level crossed at around nine-year follow-up, which was consistent with the trend of the OS curve related to mRNAsi. These findings may provide new ideas for screening therapeutic targets in order to depress TNBC stemness.

The Expression and Prognostic Significance of Claudin-8 and Androgen Receptor in Breast Cancer.

PURPOSE: Claudin-8 (CLDN8) has been identified as an androgen-regulated gene in prostate cancer. However, the role of CLDN8 has not been fully explored in breast cancer. We aimed to explore the expression of CLDN8 and androgen receptor (AR), determine the correlation between CLDN8 and AR, assess the prognostic value of CLDN8 and AR co-expression, and investigate the possible CLDN8 expression molecular mechanism in breast cancer. MATERIALS AND METHODS: Twenty-eight pairs of fresh tumor tissues and adjacent noncancerous tissues were evaluated by Western blot for CLDN8. Then, 142 breast cancer samples were determined by immunohistochemistry for CLDN8 and AR. The association of clinicopathological features with CLDN8, AR and CLDN8, and AR co-expression was examined. The Cancer Genome Atlas (TCGA) was used to demonstrate the expression of CLDN8 and correlation between CLDN8 and AR. Kaplan-Meier survival analysis was performed to assess the prognostic impact of CLDN8 and AR co-expression. The mechanisms related to CLDN8 expression in breast cancer were explored by Gene Set Enrichment Analysis (GSEA). RESULTS: CLDN8 was downregulated in breast cancer tissues and positively correlated with none lymph node metastasis (P=0.016), low histological grade (P=0.006), positive ER (P=0.014), positive PR (P=0.003), low Ki-67 index (P=0.017) and molecular subtypes (P=0.012). CLDN8 level was significantly associated with AR level (r=0.348; P<0.001). CLDN8 and AR co-expression was positively correlated with none lymph node metastasis (P=0.007), low histological grade (P=0.017), positive ER (P=0.019), positive PR (P=0.015) and low Ki-67 index group (P=0.038). CLDN8 and AR co-expression had a better clinical prognosis. CONCLUSION: The expression of CLDN8 is directly related to the expression of AR. CLDN8 and AR co-expression might be a potential prognostic evaluation factor for breast cancer patients.

Nomogram for predicting the risk of bone metastasis in breast cancer: a SEER population-based study.

BACKGROUND: Bone is the most common metastasis site of breast cancer. The prognosis of bone metastasis is better than other distant metastases, but patients with skeletal related events (SREs) have a poor quality of life, high healthcare costs and low survival rates. This study aimed to establish an effective nomogram for predicting risk of bone metastasis of breast cancer. METHODS: The nomogram was built on 4,895 adult/female/primary invasive breast cancer patients with complete clinicopathologic information, captured by the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2015. Five biological factors (age, grade, histologic type, surgery of breast lesions and subtypes) were assessed with logistic regression to predict the risk of bone metastases. The predictive accuracy and discriminative ability of the nomogram were determined by the Receiver Operating Characteristic (ROC) curves and the calibration plot. Results were validated on a separate 2,093 cohort using bootstrap resampling from 2010 to 2015 as an internal group and a retrospective study on 120 patients in the First Affiliated Hospital of China Medical University from 2010 to 2014 at the same situation as an external group. RESULTS: On multivariate logistic regression of the primary cohort, independent factors for bone metastases were age, grade, histologic type, surgery of breast lesions and subtypes, which were all selected into the nomogram. The calibration plot for probability of incidence showed good agreement between prediction by nomogram and two observations. The ROC curves presented a good statistical model for risk of bone metastasis, and the corresponding AUC value of the development group, internal validation group and external validation group were 0.678, 0.689 and 0.704 respectively. CONCLUSIONS: The proposed nomogram resulted in more-accurate prognostic prediction for breast cancer patients with bone metastases.

A PAK5-DNPEP-USP4 axis dictates breast cancer growth and metastasis.

Although clinically associated with the progression of multiple cancers, the biological function of p21-activated kinase 5 (PAK5) in breast cancer remains largely unknown. Here, we reveal that the PAK5-aspartyl aminopeptidase (DNPEP)-ubiquitin-specific protease 4 (USP4) axis is involved in breast cancer progression. We show that PAK5 interacts with and phosphorylates DNPEP at serine 119. Functionally, we demonstrate that DNPEP overexpression suppresses breast cancer cell proliferation and invasion and restricts breast cancer growth and metastasis in mice. Furthermore, we identify USP4 as a downstream target of the PAK5-DNPEP pathway; DNPEP mediates USP4 downregulation. Importantly, we verify that DNPEP expression is frequently downregulated in breast cancer tissues and is negatively correlated with PAK5 and USP4 expression. PAK5 decreases DNPEP abundance via the ubiquitin-proteasome pathway. Consistently, analyses of clinical breast cancer specimens revealed significantly increased PAK5 and USP4 levels and an association between higher PAK5 and USP4 expression and worse breast cancer patient survival. These findings suggest a pivotal role for PAK5-elicited signaling in breast cancer progression.

Hierarchically Nanostructured Fe3O4/C Composite as a Promising Magnetic Targeted Drug Nanocarrier.

Nanostructured Fe3O4/C composites are very attractive for high-performance magnetic targeted drug carriers. Herein, Fe3O4/C composite nanospheres with good dispersity are prepared by a simple one-step hydrothermal synthesis and subsequent heat treatment in Ar. The composite nanospheres consist of clustered primary nanoparticles, and exhibit a hierarchical architecture with a high specific surface area of 119.3 m² g-1. The Fe3O4/C composite nanospheres show a high saturation magnetization value of 101 emu g-1 and good biocompatibility. In particular, the composite nanospheres deliver a large loading content (85.8%) of epirubicin hydrochloride (EPI), resulting from their unique composition and microstructure. More importantly, the release of EPI from the EPI-loaded magnetic carrier (Fe3O4/C-EPI) may be enhanced by both a slightly acidic environment and a rotating magnetic field induced by a simple motor-driven magnet system. The above favorable properties make the hierarchical Fe3O4/C composite sample a promising candidate for magnetic targeting nanocarriers of EPI.

Interleukin enhancer binding factor 2 is a prognostic biomarker for breast cancer that also predicts neoadjuvant chemotherapy responses.

Interleukin enhancer binding factor 2 (ILF2) participates in several aspects of DNA and RNA metabolism and regulates gene expression at multiple levels; however, its role in breast cancer remains undefined. The variant statuses of ILF2 in human breast cancer were evaluated using the COSMIC database. Altered ILF2 expression in normal breast tissue relative to cancer tissue and in breast cancer patients with different clinicopathological characteristics, molecular subtypes, clinical outcomes and chemotherapy responses were examined using the Oncomine, GOBO, Kaplan-Meier plotter and GEO datasets. To explore possible biological networks connected to ILF2 in breast cancer, we performed ingenuity pathway analysis on ILF2-related differentially expressed genes. We found that many breast cancers had increased ILF2 copy number variations and increased ILF2 expression. We also observed that elevated ILF2 expression was correlated with aggressive features, such as high histological grade, BRCA1 mutations, and the triple-negative/basal-like subtype, which resulted in shorter survival in these cases. Moreover, ILF2 expression predicted responses to anthracycline/taxane-based treatment. Ingenuity pathway analysis revealed that ILF2-related biological functions included promoting cell survival, viability, and proliferation, as well as cell cycle progression and DNA repair. Certain well-known oncogenes (MYC and HGF), cytokines (CSF2, IFNG and IL5) and microRNAs (miR-21, miR-155-5p and let-7) may participate in the ILF2 expression network in breast cancer. In summary, ILF2 is involved in the development and progression of breast cancer and may be a predictive biomarker for better responses to anthracycline/taxane-based treatments.

TUFT1 is expressed in breast cancer and involved in cancer cell proliferation and survival.

Tuftelin 1 (TUFT1), which plays an important role in the initial stages of the mineralization of ectodermal enamel, is widely expressed in different embryonic and adult tissues and some tumor cells. However, since the roles of this gene have not been thoroughly investigated in tumors, its function in the development of breast cancer remains unclear. We proved both human specimens studies and cell line studies, that TUFT1 expression levels are increased in breast cancer samples, and the increased expression of TUFT1 was shown to be positively correlated with tumor size, histological grade, lymph node metastasis rate, and poor prognosis. Further in vitro studies showed that the inhibition of TUFT1 expression in T-47D and MDA-MB-231 breast cancer cells significantly affected cell proliferation, induced apoptosis, and led to G1-phase cell cycle arrest. Moreover, reduced TUFT1 expression restrained tumor growth compared with the control group in vivo. Furthermore, microarray and pathway analysis demonstrated that TUFT1 inhibition led to significant changes of several signaling pathways and semi-quantitative western blot analysis showed that a decrease in TUFT1 expression was accompanied by changes in MAPK signaling pathway components. The obtained results suggest that TUFT1 may represent a novel breast cancer marker and a potentially effective therapeutic target.

Clinical significance of MSKCC nomogram on guiding the application of touch imprint cytology and frozen section in intraoperative assessment of breast sentinel lymph nodes.

The widely practiced intra-operative methods for rapid evaluation and detection of sentinel lymph node (SLN) status include frozen section (FS) and touch imprint cytology (TIC). This study optimized the use of TIC and FS in the intra-operative detection of breast SLNs based on the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram. Three hundred forty-two SLNs were removed from 79 patients. SLN metastatic probability was assessed by the MSKCC nomogram. The SLNs underwent intra-operative TIC and FS, as well as routine post-operative paraffin sections (RPSs). The relationships between TIC, FS, and SLN metastatic probability were analyzed. Overall, TIC was more sensitive than FS (92.31% vs. 76.92%), while TIC specificity was inferior to FS specificity (84.85% vs. 100%). In addition, the best cut-off value for TIC based on the MSKCC nomogram was inferior to the best FS cut-off value (22.5% vs. 34.5%). All patients with a MSKCC value <22.5% in the present study were negative based on FS and RPS, while the true-negative and false-positive rates for TIC were 92.5% and 7.5%, respectively. Thus, early breast cancer patients, based on a MSKCC value <22.5%, can safely avoid FS, but should have TIC performed intra-operatively. Patients with a MSKCC value >22.5% should have TIC and FS to determine the size of metastases, whether or not to proceed with axillary lymph node dissection, and to avoid easily missed metastases.

Can axillary radiotherapy replace axillary dissection for patients with positive sentinel nodes? A systematic review and meta-analysis.

OBJECTIVE: To compare the efficacy of axillary radiotherapy (ART) with that of completion axillary lymph node dissection (cALND) in clinically node-negative breast cancer patients with a positive sentinel lymph node. METHODS: A literature search was performed in PubMed, EMBASE and Cochrane Library by using the search terms "breast cancer", "sentinel lymph node biopsy", "axillary radiotherapy" or "regional node irradiation" for articles published between 2004 and 2016. Only randomized controlled trials that included patients with positive sentinel nodes were included in the meta-analysis. RESULTS: Two randomized controlled trials and three retrospective studies were identified. The reported overall survival rate (hazard ratio [HR] = 1.09, 95% confidence interval [CI]: 0.75-1.43, P = 0.365), disease-free survival rate (HR = 1.01, 95% CI: 0.58-1.45, P = 0.144), and axillary recurrence rate (1.2% and 0.4%, and 1.3% and 0.8%, respectively) were similar in both groups. The absence of knowledge on the extent of nodal involvement in the ART group appeared to have no major impact on the administration of adjuvant systemic therapy. CONCLUSIONS: ART is not inferior to cALND in the patients with clinically node-negative breast cancer who had a positive sentinel lymph node. Information obtained by using cALND after SLNB may have no major impact on the administration of adjuvant systemic therapy.