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Mingkai Gong,1 Xiangping Liu,2 Wu Yang,3 Hongming Song,1 Xian Zhao,1 Xiancheng Ai,1 Shuo Wang,1 Haibo Wang1 1Center of Diagnosis and Treatment of Breast Disease, The Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of China; 2Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of China; 3Department of International Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of ChinaCorrespondence: Haibo WangCenter of Diagnosis and Treatment of Breast Disease, The Affiliated Hospital of Qingdao University, Qingdao, 266003, People’s Republic of ChinaEmail hbwang66@126.comBackground: Cancer metabolism and specifically lipid metabolism play an important role in breast cancer (BC) progression and metastasis. However, the role of lipid metabolism-associated genes (LMGs) in the prognosis of breast cancer remains unknown.Methods: The expression profiles and clinical follow-up information of 1053 BC were downloaded from The Cancer Genome Atlas (TCGA), and metabolic genes were downloaded from the Gene Set Enrichment Analysis (GSEA) dataset. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses were performed on the differentially expressed metabolism-related genes. Then, the formula of the metabolism-related risk model was composed, and the risk score of each patient was calculated. The breast cancer patients were divided into high-risk and low-risk groups with a cutoff of the median expression value of the risk score, and the prognostic analysis was also used to analyze the survival time between these two groups. Finally, we analyzed the expression, interaction and correlation among the lipid metabolism-associated genes risk model.Results: The results from the prognostic analysis indicated that the survival was significantly poorer in the high-risk group than in the low-risk group in TCGA, and single-sample gene set enrichment analysis (ssGSEA) shows it is plausible that lipid metabolism is highly correlated with tumor immunity.Conclusion: Lipid metabolism-associated genes may become a new prognostic indicator predicting the survival of BC patients. The prognostic genes (n = 16) may help provide new strategies for tumor therapy.Keywords: bioinformatics, lipid metabolism-associated genes, breast cancer, lipid metabolism, TCGA

Xiao-Ying Shen,1,* Yu-Ping Lin,2,* Run-Na Miao,3 Xue Yao,4 Hui Sun,5 Wei Yang5 1Second Clinical Medical College, Harbin Medical University, Harbin, People’s Republic of China; 2School of Nursing, Fudan University, Shanghai, People’s Republic of China; 3Department of Nursing, Health Science Centre, Xi’an Jiaotong University, Xi’an, People’s Republic of China; 4School of Nursing, Shandong University, Shandong, People’s Republic of China; 5Heilongjiang Second Hospital, Harbin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiao-Ying ShenSecond Clinical Medical College, Harbin Medical University, Harbin, 150086, People’s Republic of ChinaTel +86 13351883728Email 337372672@qq.comBackground: Type C behavior is a cancer-prone behavior that can affect the occurrence and development of cancer. This study aimed to investigate the prevalence of type C behavior in patients with breast cancer during postoperative chemotherapy and determine its associated factors.Methods: This study enrolled 161 patients with breast cancer who received postoperative chemotherapy. Type C personality behavior pattern questionnaire was used to assess type C behavior patterns. The following instruments were employed: medical coping modes questionnaire, social support scale, social relational quality scale, Herth hope index. logistic regression was used to identify the factors affecting type C behavior.Results: The incidence of type C behavior was 28%. Participants aged 45– 59 years (OR = 3.62, 95% CI = 1.04– 12.56, P = 0.043), and who adopted a resignation coping style (OR = 1.25, 95% CI = 1.03– 1.50, P = 0.021), were more likely to develop type C behavior. Type C behavior was less common in patients with employment (OR = 0.38, 95% CI = 0.15– 0.97, P = 0.043), with a high level of social support (OR = 0.89, 95% CI= 0.80– 0.98, P = 0.023), and more hope (OR = 0.83, 95% CI = 0.71– 0.98, P = 0.079).Conclusion: In this study, 28% patients with breast cancer during postoperative chemotherapy exhibited type C behavior. Associated factors with type C behavior were identified, which could guide health care professionals to reduce the prevalence of type C behavior through guiding patients to adopt positive coping styles and improving their level of social support and hope, especially in those aged 45 to 59 years or in those without employment.Keywords: breast cancer, type C behavior, coping style, social support, social relational quality, hope

Maojian Chen,1,* Chanchan Xiao,2,* Wei Jiang,3 Weiping Yang,4 Qinghong Qin,1 Qixing Tan,1 Bin Lian,1 Zhijie Liang,5 Changyuan Wei1 1Department of Breast Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People’s Republic of China; 2Department of Microbiology and Immunology, School of Medicine and Public Health, Jinan University, Guangzhou, Guangdong, 510632, People’s Republic of China; 3Department of Medical Oncology, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People’s Republic of China; 4Department of Ultrasound Diagnosis, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People’s Republic of China; 5Department of Gland Surgery, The Fifth Affiliated Hospital of Guangxi Medical University & The First People’s Hospital of Nanning, Nanning, Guangxi 530022, People’s Republic of China*These authors contributed equally to this workCorrespondence: Changyuan WeiDepartment of Breast Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, People’s Republic of ChinaTel/Fax +86 0771 5308593Email changyuanwei@gxmu.edu.cnBackground: As a natural compound extracted from a variety of hot peppers, capsaicin has drawn increasing attention to its anti-cancer effects against multiple human cancers including breast cancer. FBI-1 is a major proto-oncogene negatively regulating the transcription of many tumor suppressor genes, and plays a vital role in tumorigenesis and progression. However, whether FBI-1 is involved in capsaicin-induced breast cancer suppression has yet to be ascertained. This study aimed to investigate the effects of capsaicin on proliferation and apoptosis and its association with FBI-1 expression in breast cancer.Methods: CCK-8 and morphological observation assay were employed to detect cell proliferation. Flow cytometry and TUNEL assay were conducted to detect cell apoptosis. RNA interference technique was used to overexpress or silence FBI-1 expression. qRT-PCR and/or Western blot analysis were applied to detect the protein expression of FBI-1, Ki-67, Bcl-2, Bax, cleaved-Caspase 3, Survivin and NF-κB p65. Xenograft model in nude mice was established to assess the in vivo effects.Results: Capsaicin significantly inhibited proliferation and induced apoptosis in breast cancer in vitro and in vivo, along with decreased FBI-1, Ki-67, Bcl-2 and Survivin protein expression, increased Bax protein expression and activated Caspase 3. Furthermore, FBI-1 overexpression obviously attenuated the capsaicin-induced anti-proliferation and pro-apoptosis effect, accompanied with the above-mentioned proteins reversed, whereas FBI-1 silencing generated exactly the opposite response. In addition, as a target gene of FBI-1, NF-κB was inactivated by p65 nuclear translocation suppressed with capsaicin treatment, which was perceptibly weakened with FBI-1 overexpression or enhanced with FBI-1 silencing.Conclusion: This study reveals that FBI-1 is closely involved in capsaicin-induced anti-proliferation and pro-apoptosis of breast cancer. The underlying mechanism may be related to down-regulation of FBI-1-mediated NF-κB pathway. Targeting FBI-1 with capsaicin may be a promising therapeutic strategy in patients with breast cancer.Keywords: capsaicin, breast cancer, proliferation, apoptosis, FBI-1, NF-κB

Lijuan Shen,1,2,* Xiaowen Ma,2,3,* Tingting Jiang,2,3 Xigang Shen,2,3 Wentao Yang,3,4 Chao You,2,3 Weijun Peng2,3 1Shanghai Institute of Medical Imaging, Shanghai, People’s Republic of China; 2Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 3Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 4Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weijun Peng; Chao YouFudan University Shanghai Cancer Center, No. 270, Dongan Road, Xuhui District, Shanghai 200032, People’s Republic of ChinaTel +86-15026544096; +86-21-64175590Fax +86-21-64174774Email cjr.pengweijun@vip.163.com : youchao8888@aliyun.comPurpose: To explore the potential factors influencing the malignancy risk of amorphous calcifications and establish a predictive nomogram for malignancy risk stratification.Patients and Methods: Consecutive mammograms from January 2013 to December 2018 were retrospectively reviewed. Traditional clinical features were recorded, and mammographic features were estimated according to the 5th BI-RADS. Included calcifications were randomly divided into the training and validation cohorts. A nomogram was developed to graphically predict the risk of malignancy (risk) based on stepwise multivariate logistic regression analysis. The discrimination and calibration performance of the model were assessed in both the training and validation cohorts.Results: Finally, 1018 amorphous calcifications with final pathological results in 907 women were identified with a malignancy rate of 28.4% (95% CI: 25.7%, 31.3%). The malignancy rates of subgroups divided by the distribution of calcifications, quantity of calcifications, age, menopausal status and family history of cancer were significantly different. There were 712 cases and 306 cases in the training and validation cohorts. The prediction nomogram was finally developed based on four risk factors, including age and distribution, maximum diameter and quantity of calcifications. The AUC of the nomogram was 0.799 (95% CI: 0.761, 0.836) in the training cohort and 0.795 (95% CI: 0.738, 0.852) in the validation cohort.Conclusion: On mammography, the distribution, maximum diameter and quantity of calcifications are independent predictors of malignant amorphous calcifications and can be easily obtained in the clinic. The nomogram developed in this study for individualized malignancy risk stratification of amorphous calcifications shows good discrimination performance.Keywords: breast cancer, mammography, calcifications, malignancy risk stratification, nomogram

Weiping Yang,1 Piguo Gong,1 Yifeng Yang,1 Chunyan Yang,2 Baohui Yang,3 Lijun Ren1 1Department of Thyroid Breast Surgery, Qingdao Chengyang People’s Hospital, Qingdao 266109, Shandong, People’s Republic of China; 2Obstetric Breast Health Clinic, Qingdao Haici Medical Center, Qingdao 266033, Shandong, People’s Republic of China; 3Department of Internal Medicine, Qingdao Chengyang Second People’s Hospital, Qingdao 266109, Shandong, People’s Republic of ChinaCorrespondence: Lijun RenDepartment of Thyroid Breast Surgery, Qingdao Chengyang People’s Hospital, No. 600, Changcheng Road, Chengyang District, Qingdao, Shandong, People’s Republic of ChinaEmail eijylo@163.comBackground: Paclitaxel (PTX) is one of the widely used chemotherapy drugs in breast cancer (BC) treatment. Unfortunately, the survival rate of metastatic BC patients remains poor due to PTX resistance. Therefore, uncovering the underlying mechanism behind the PTX resistance of BC cells is crucial for BC therapy.Methods: The enrichment of circular RNA ATP binding cassette subfamily B member 10 (circ-ABCB10), let-7a-5p and dual specificity phosphatase 7 (DUSP7) was measured by quantitative real time polymerase chain reaction (qRT-PCR) in PTX-resistant and PTX-sensitive BC tissues and cells. Chemoresistance, apoptosis, invasion and autophagy of BC cells were measured by 3-(4, 5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, transwell invasion assay and Western blot assay, respectively. The binding sites between let-7a-5p and circ-ABCB10 or DUSP7 were predicted by Starbase bioinformatic software, and the combination was confirmed by dual-luciferase reporter assay. The protein expression of DUSP7 was examined by Western blot assay. Murine xenograft model was established to confirm the role of circ-ABCB10 in vivo.Results: Circ-ABCB10 depletion promoted the PTX sensitivity and apoptosis while suppressed the invasion and autophagy of PTX-resistant BC cells. Circ-ABCB10 could bind to let-7a-5p in BC cells, and circ-ABCB10 contributed to PTX resistance of BC cells via let-7a-5p. DUSP7 is a direct target of let-7a-5p in BC cells, and the accumulation of DUSP7 reversed the promoting effects of let-7a-5p overexpression on the PTX sensitivity and apoptosis and the inhibitory impact on the invasion and autophagy of PTX-resistant BC cells. Circ-ABCB10 interference suppressed the growth of BC tumors in vivo.Conclusion: Circ-ABCB10 mediated PTX resistance, apoptosis, invasion and autophagy of BC cells via let-7a-5p/DUSP7 axis.Keywords: breast cancer, paclitaxel, chemoresistance, circ-ABCB10, let-7a-5p, DUSP7

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC. ispartof: NPJ BREAST CANCER vol:7 issue:1 ispartof: location:United States status: published

Immunotherapy has been found to be efficient in a variety of cancers and, therefore, may be a promising strategy for breast cancer (BC), particularly due to the limited therapeutic options currently available for triple-negative BC (TNBC). However, heterogeneity of tumor mutation burden (TMB), immune gene expression and mismatch repair (MMR) gene activity across BC subtypes has not been well characterized. In the present study, a comprehensive analysis of TMB, expression levels of immune cell type marker genes, and expression levels of MMR-associated genes was performed. A total of 5 MMR-associated genes, including MLH1, MLH3, MSH2, MSH6 and PMS2, were analyzed. Patients that harbored at least two MMR genes with expression levels in the lower 10% percentile across the cohort were considered as potentially aberrant (lost expression). Hormone receptor (HR)-negative BC is associated with a higher TMB and immune gene expression compared with HR-positive BC [TMB, estrogen receptor (ER)-negative vs. ER-negative, 55 vs. 32, respectively; P=4.1×10-13; progesterone receptor (PR)-negative vs. PR-positive, 53 vs. 31, respectively; P

Wei Shi,* Fang Dong,* Yujia Jiang, Linlin Lu, Changwen Wang, Jie Tan, Wen Yang, Hui Guo, Jie Ming,* Tao Huang* Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China *These authors contributed equally to this work Background: Despite the advances in early detection and treatment methods, breast cancer still has a high mortality rate, even in those patients predicted to have a good prognosis. The purpose of this study is to identify a microRNA signature that could better predict prognosis in breast cancer and add new insights to the current classification criteria. Materials and methods: We downloaded microRNA sequencing data along with corresponding clinicopathological data from The Cancer Genome Atlas (TCGA). Of 1,098 breast cancer patients identified, 253 patients with fully characterized microRNA profiles were selected for analysis. A three-microRNA signature was generated in the training set. Subsequently, the performance of the signature was confirmed in a validation set. After construction of the signature, we conducted additional experiments, including flow cytometry and the Cell Counting Kit-8 assay, to illustrate the correlation of this microRNA signature with breast cancer cell cycle, apoptosis, and proliferation. Results: Three microRNAs (hsa-mir-31, hsa-mir-16-2, and hsa-mir-484) were identified to be significantly and independently correlated with patient prognosis, and performed with good stability. Our results suggest that higher expression of hsa-mir-484 indicated worse prognosis, while higher expression of hsa-mir-31 and hsa-mir-16-2 indicated better prognosis. Moreover, additional experiments confirmed that this microRNA signature was related to breast cancer cell cycle and proliferation. Conclusion: Our results indicate a three-microRNA signature that can accurately predict the prognosis of breast cancer, especially in basal-like and hormone receptor-positive breast cancer subtypes. We recommend more aggressive therapy and more frequent follow-up for high-risk groups. Keywords: microRNA, breast cancer, TCGA, prognosis

Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls., info:eu-repo/semantics/published

Background One of the major challenges in managing invasive breast cancer (BC) is the lack of reliable biomarkers to track response. Circulating tumor DNA (ctDNA) from liquid biopsy, as a candidate biomarker, provides a valuable assessment of BC patients. In this retrospective study, we evaluated the utility of ctDNA to reflect the efficacy of treatment and to monitor resistance mechanisms. Methods Targeted next‐generation sequencing (NGS) of 416 cancer‐relevant genes was performed on 41 plasma biopsy samples of 19 HER2+ and 12 HER2‐ BC patients. Longitudinal ctDNA samples were analyzed in three BC patients over the treatment course for detecting acquired mutations. Results In HER2+ BC patients, ERBB2 somatic copy numbers in ctDNA samples were significantly higher in patients progressed on HER2‐targeted therapy than those who were still responding to the treatment. Recurrent acquired mutations were detected in genes including ERBB2, TP53, EGFR, NF1, and SETD2, which may contribute to trastuzumab resistance. In longitudinal analyses, the observed mutation allele frequencies were tracked closely in concordance with treatment responses. A novel ERBB2 p.(Leu869Arg) mutation was acquired in one patient upon resistant to trastuzumab therapy, which was further validated as an oncogenic mutation in vitro and contributed to resistance. In HER2‐ BC patients with chemotherapy resistance, genetic alterations on TP53, PIK3CA, and DNA damage repair genes were frequently observed. Conclusions In summary, ctDNA monitoring, particularly longitudinal analyses, provides valuable insights into the assessment of targeted therapy efficacy and gene alterations underlying trastuzumab resistance and chemotherapy resistance in HER2+ and HER2‐ BC patients, respectively., ctDNA molecular alterations in HER2+ patients developed acquired resistance to trastuzumab and Longitudinal analyses of multiple somatic mutations in ctDNA in patients with acquired resistance to trastuzumab.

Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting., info:eu-repo/semantics/published

OBJECTIVES: To analyze copy number alterations(CNAs) of the genes involved in the G1/S checkpoint signaling pathway of triple-negative breast cancer (TNBC) and non- triple-negative breast cancer(non-TNBC) and in order to find specific CNAs associated with overall survive for TNBC.In all,to provide an effective target for future treatment. METHODS: We selected the samples randomly form Tianjin Cancer Hospital between August, 2006 and August, 2007,which contained one hundred TNBC cases and one hundred non-TNBC cases. Quantitative mμlti-gene fluorescence in situ hybridization (QM-FISH) was used to study CNAs of the genes involved in the G1/S checkpoint signaling pathway, including CCND1,c-Myc,p21, CHEK2, p16, Rb1, Mdm2and p53. RESULTS: The amplification rates of c-Myc and the deletion rates of p53 in TNBC tended to be higher than those in non-TNBC, whereas the amplification rates of CCND1 and Mdm2 in non-TNBC tended to be higher than those in TNBC. In Kaplan-Meier analysis, the amplification of CCND1 (P = 0.02) and c-Myc (P = 0.02) as well as the deletion of p53 (P = 0.01) predicted worse survival in the TNBC group. While in the non-TNBC group, the amplification of CCND1 (P = 0.01) and Mdm2 (P = 0.04) as well as the deletion of p53 (P = 0.049) were associated with worse survival. The amplification of c-Myc and the deletion of p53 in TNBC were associated with higher mortality risk (HR,2.87;95%CI,1.14-7.21[P = 0.03]; HR, 3.34;95%CI, 1.22-9.09 [P = 0.02]), whereas the mortality risk tended to be higher in the patients with amplification of CCND1 (HR, 4.35;95%CI,1.23-15.39 [P = 0.02])in non-TNBC. CONCLUSIONS: The amplification rates of c-Myc and deletion rates of p53 in TNBC tended to be higher than those in non-TNBC, whereas the amplification rate of CCND1 and Mdm2 tended to be higher in non-TNBC. c-Myc and p53 were independent prognostic factors for TNBC, while CCND1 was the independent prognostic factors for non-TNBC. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-02-04.