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Tumor-resident microbiota in breast cancer promotes cancer initiation and malignant progression. However, targeting microbiota to improve the effects of breast cancer therapy has not been investigated in detail. Here, we evaluated the microbiota composition of breast tumors and found that enterotoxigenic Bacteroides fragilis (ETBF) was highly enriched in the tumors of patients who did not respond to taxane-based neoadjuvant chemotherapy. ETBF, albeit at low biomass, secreted the toxic protein BFT-1 to promote breast cancer cell stemness and chemoresistance. Mechanistic studies showed that BFT-1 directly bound to NOD1 and stabilized NOD1 protein. NOD1 was highly expressed on ALDH+ breast cancer stem cells (BCSCs) and cooperated with GAK to phosphorylate NUMB and promote its lysosomal degradation, thereby activating the NOTCH1-HEY1 signaling pathway to increase BCSCs. NOD1 inhibition and ETBF clearance increase the chemosensitivity of breast cancer by impairing BCSCs., (© The Author(s) 2024. Published by Oxford University Press on behalf of Higher Education Press.)

Co-occurrence and mutual exclusivity of genomic alterations may reflect the existence of genetic interactions, potentially shaping distinct biological phenotypes and impacting therapeutic response in breast cancer. However, our understanding of them remains limited. Herein, we investigate a large-scale multi-omics cohort (n = 873) and a real-world clinical sequencing cohort (n = 4,405) including several clinical trials with detailed treatment outcomes and perform functional validation in patient-derived organoids, tumor fragments, and in vivo models. Through this comprehensive approach, we construct a network comprising co-alterations and mutually exclusive events and characterize their therapeutic potential and underlying biological basis. Notably, we identify associations between TP53 mut -AURKA amp and endocrine therapy resistance, germline BRCA1 mut -MYC amp and improved sensitivity to PARP inhibitors, and TP53 mut -MYB amp and immunotherapy resistance. Furthermore, we reveal that precision treatment strategies informed by co-alterations hold promise to improve patient outcomes. Our study highlights the significance of genetic interactions in guiding genome-informed treatment decisions beyond single driver alterations., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Molecular profiling guides precision treatment of breast cancer; however, Asian patients are underrepresented in publicly available large-scale studies. We established a comprehensive multiomics cohort of 773 Chinese patients with breast cancer and systematically analyzed their genomic, transcriptomic, proteomic, metabolomic, radiomic and digital pathology characteristics. Here we show that compared to breast cancers in white individuals, Asian individuals had more targetable AKT1 mutations. Integrated analysis revealed a higher proportion of HER2-enriched subtype and correspondingly more frequent ERBB2 amplification and higher HER2 protein abundance in the Chinese HR + HER2 + cohort, stressing anti-HER2 therapy for these individuals. Furthermore, comprehensive metabolomic and proteomic analyses revealed ferroptosis as a potential therapeutic target for basal-like tumors. The integration of clinical, transcriptomic, metabolomic, radiomic and pathological features allowed for efficient stratification of patients into groups with varying recurrence risks. Our study provides a public resource and new insights into the biology and ancestry specificity of breast cancer in the Asian population, offering potential for further precision treatment approaches., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Digital pathology allows computerized analysis of tumor ecosystem using whole slide images (WSIs). Here, we present single-cell morphological and topological profiling (sc-MTOP) to characterize tumor ecosystem by extracting the features of nuclear morphology and intercellular spatial relationship for individual cells. We construct a single-cell atlas comprising 410 million cells from 637 breast cancer WSIs and dissect the phenotypic diversity within tumor, inflammatory and stroma cells respectively. Spatially-resolved analysis identifies recurrent micro-ecological modules representing locoregional multicellular structures and reveals four breast cancer ecotypes correlating with distinct molecular features and patient prognosis. Further analysis with multiomics data uncovers clinically relevant ecosystem features. High abundance of locally-aggregated inflammatory cells indicates immune-activated tumor microenvironment and favorable immunotherapy response in triple-negative breast cancers. Morphological intratumor heterogeneity of tumor nuclei correlates with cell cycle pathway activation and CDK inhibitors responsiveness in hormone receptor-positive cases. sc-MTOP enables using WSIs to characterize tumor ecosystems at the single-cell level., (© 2023. Springer Nature Limited.)

Intratumor heterogeneity (ITH) profoundly affects therapeutic responses and clinical outcomes. However, the widespread methods for assessing ITH based on genomic sequencing or pathological slides, which rely on limited tissue samples, may lead to inaccuracies due to potential sampling biases. Using a newly established multicenter breast cancer radio-multiomic dataset ( n = 1474) encompassing radiomic features extracted from dynamic contrast-enhanced magnetic resonance images, we formulated a noninvasive radiomics methodology to effectively investigate ITH. Imaging ITH (IITH) was associated with genomic and pathological ITH, predicting poor prognosis independently in breast cancer. Through multiomic analysis, we identified activated oncogenic pathways and metabolic dysregulation in high-IITH tumors. Integrated metabolomic and transcriptomic analyses highlighted ferroptosis as a vulnerability and potential therapeutic target of high-IITH tumors. Collectively, this work emphasizes the superiority of radiomics in capturing ITH. Furthermore, we provide insights into the biological basis of IITH and propose therapeutic targets for breast cancers with elevated IITH.

Hormone receptor-positive (HR + )/human epidermal growth factor receptor 2-negative (HER2 - ) breast cancer is the most prevalent type of breast cancer, in which endocrine therapy resistance and distant relapse remain unmet challenges. Accurate molecular classification is urgently required for guiding precision treatment. We established a large-scale multi-omics cohort of 579 patients with HR + /HER2 - breast cancer and identified the following four molecular subtypes: canonical luminal, immunogenic, proliferative and receptor tyrosine kinase (RTK)-driven. Tumors of these four subtypes showed distinct biological and clinical features, suggesting subtype-specific therapeutic strategies. The RTK-driven subtype was characterized by the activation of the RTK pathways and associated with poor outcomes. The immunogenic subtype had enriched immune cells and could benefit from immune checkpoint therapy. In addition, we developed convolutional neural network models to discriminate these subtypes based on digital pathology for potential clinical translation. The molecular classification provides insights into molecular heterogeneity and highlights the potential for precision treatment of HR + /HER2 - breast cancer., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The molecular heterogeneity and distinct features of HER2-low breast cancers, particularly in the Chinese population, are not well understood, limiting its precise management in the era of antibody‒drug conjugates. To address this issue, we established a cohort of 434 Chinese patients with HER2-low breast cancer (433 female and one male) and integrated genomic, transcriptomic, proteomic, and metabolomic profiling data. In this cohort, HER2-low tumors are more distinguished from HER2-0 tumors in the hormone receptor-negative subgroup. Within HER2-low tumors, significant interpatient heterogeneity also exists in the hormone receptor-negative subgroup: basal-like tumors resemble HER2-0 disease, and non-basal-like HER2-low tumors mimic HER2-positive disease. These non-basal-like HER2-low tumors are enriched in the HER2-enriched subtype and the luminal androgen receptor subtype and feature PIK3CA mutation, FGFR4/PTK6/ERBB4 overexpression and lipid metabolism activation. Among hormone receptor-positive tumors, HER2-low tumors show less loss/deletion in 17q peaks than HER2-0 tumors. In this work, we reveal the heterogeneity of HER2-low breast cancers and emphasize the need for more precise stratification regarding hormone receptor status and molecular subtype., (© 2023. Springer Nature Limited.)

Estrogen receptor (ER)-positive luminal breast cancer is a subtype with generally lower risk of metastasis to most distant organs. However, bone recurrence occurs preferentially in luminal breast cancer. The mechanisms of this subtype-specific organotropism remain elusive. Here we show that an ER-regulated secretory protein SCUBE2 contributes to bone tropism of luminal breast cancer. Single-cell RNA sequencing analysis reveals osteoblastic enrichment by SCUBE2 in early bone-metastatic niches. SCUBE2 facilitates release of tumor membrane-anchored SHH to activate Hedgehog signaling in mesenchymal stem cells, thus promoting osteoblast differentiation. Osteoblasts deposit collagens to suppress NK cells via the inhibitory LAIR1 signaling and promote tumor colonization. SCUBE2 expression and secretion are associated with osteoblast differentiation and bone metastasis in human tumors. Targeting Hedgehog signaling with Sonidegib and targeting SCUBE2 with a neutralizing antibody both effectively suppress bone metastasis in multiple metastasis models. Overall, our findings provide a mechanistic explanation for bone preference in luminal breast cancer metastasis and new approaches for metastasis treatment., (© 2023. The Author(s) under exclusive licence to Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences.)

Background: We established a radiogenomic model to predict pathological complete response (pCR) in triple-negative breast cancer (TNBC) and explored the association between high-frequency mutations and drug resistance., Methods: From April 2018 to September 2019, 112 patients who had received neoadjuvant chemotherapy were included. We randomly split the study population into training and validation sets (2:1 ratio). Contrast-enhanced magnetic resonance imaging scans were obtained at baseline and after two cycles of treatment and were used to extract quantitative radiomic features and to construct two radiomics-only models using a light gradient boosting machine. By incorporating the variant allele frequency features obtained from baseline core tissues, a radiogenomic model was constructed to predict pCR. Additionally, we explored the association between recurrent mutations and drug resistance., Results: The two radiomics-only models showed similar performance with AUCs of 0.71 and 0.73 (p = 0.55). The radiogenomic model had a higher predictive ability than the radiomics-only model in the validation set (p = 0.04), with a corresponding AUC of 0.87 (0.73-0.91). Two highly frequent mutations were selected after comparing the mutation sites of pCR and non-pCR populations. The MED23 mutation p.P394H caused epirubicin resistance in vitro (p < 0.01). The expression levels of γ-H2A.X, p-ATM and p-CHK2 in MED23 p.P394H cells were significantly lower than those in wild type cells (p < 0.01). In the HR repair system, the GFP positivity rate of MED23 p.P394H cells was higher than that in wild-type cells (p < 0.01)., Conclusions: The proposed radiogenomic model has the potential to accurately predict pCR in TNBC patients. Epirubicin resistance after MED23 p.P394H mutation might be affected by HR repair through regulation of the p-ATM-γ-H2A.X-p-CHK2 pathway., (© 2022. The Author(s).)

Despite increased overall survival rates, curative options for metastatic breast cancer remain limited. We have previously shown that metadherin (MTDH) is frequently overexpressed in poor prognosis breast cancer, where it promotes metastasis and therapy resistance through its interaction with staphylococcal nuclease domain-containing 1 (SND1). Through genetic and pharmacological targeting of the MTDH-SND1 interaction, we reveal a key role for this complex in suppressing antitumor T cell responses in breast cancer. The MTDH-SND1 complex reduces tumor antigen presentation and inhibits T cell infiltration and activation by binding to and destabilizing Tap1/2 messenger RNAs, which encode key components of the antigen-presentation machinery. Following small-molecule compound C26-A6 treatment to disrupt the MTDH-SND1 complex, we showed enhanced immune surveillance and sensitivity to anti-programmed cell death protein 1 therapy in preclinical models of metastatic breast cancer, in support of this combination therapy as a viable approach to increase immune-checkpoint blockade therapy responses in metastatic breast cancer., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

An emerging view regarding cancer metabolism is that it is heterogeneous and context-specific, but it remains to be elucidated in breast cancers. In this study, we characterized the energy-related metabolic features of breast cancers through integrative analyses of multiple datasets with genomics, transcriptomics, metabolomics, and single-cell transcriptome profiling. Energy-related metabolic signatures were used to stratify breast tumors into two prognostic clusters: cluster 1 exhibits high glycolytic activity and decreased survival rate, and the signatures of cluster 2 are enriched in fatty acid oxidation and glutaminolysis. The intertumoral metabolic heterogeneity was reflected by the clustering among three independent large cohorts, and the complexity was further verified at the metabolite level. In addition, we found that the metabolic status of malignant cells rather than that of nonmalignant cells is the major contributor at the single-cell resolution, and its interactions with factors derived from the tumor microenvironment are unanticipated. Notably, among various immune cells and their clusters with distinguishable metabolic features, those with immunosuppressive function presented higher metabolic activities. Collectively, we uncovered the heterogeneity in energy metabolism using a classifier with prognostic and therapeutic value. Single-cell transcriptome profiling provided novel metabolic insights that could ultimately tailor therapeutic strategies based on patient- or cell type-specific cancer metabolism., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Purpose: Resistance to paclitaxel remains a major challenge in treating breast cancer. Our preclinical study suggested that TEKT4 germline variations in breast cancer are associated with paclitaxel resistance and increase vinorelbine sensitivity. This clinical trial compared the efficacy of paclitaxel and vinorelbine in breast cancer neoadjuvant chemotherapy., Methods: In this open-label, single-center, phase II trial, female patients with human epidermal growth factor receptor 2 (HER2)-negative, stage IIB-IIIC breast cancer harboring TEKT4 germline variations were randomly assigned to the paclitaxel plus epirubicin (PE) or vinorelbine plus epirubicin (NE). The primary endpoint was the pathologic complete response (pCR) rate, and the secondary endpoints were the objective response rate (ORR) and safety. Targeted sequencing of a panel comprising 484 breast-related genes was performed to identify pCR-associated somatic mutations in each group., Results: 91 Patients were assigned to PE (46 patients) or NE (45 patients). NE numerically increased the pCR rate (22.2% versus 8.7%, P = 0.074). The ORRs for NE and PE were 82.2% and 76.1%, respectively. Interestingly, NE (15.4%) showed a significantly higher pCR rate than PE (0%) in the hormone receptor (HR)-positive subgroup (P = 0.044). Both regimens were well tolerated, with grade 3 and 4 toxicities reported at the expected levels. The biomarker analysis showed that UNC13D mutation predicted the pCR rate in NE (P = 0.011)., Conclusions: Although the primary endpoint was not met, NE might bring clinical benefit to HR-positive patients or patients simultaneously carrying UNC13D mutations.

The remarkable advances in next-generation sequencing technology have enabled the wide usage of sequencing as a clinical tool. To promote the advance of precision oncology for breast cancer in China, here we report a large-scale prospective clinical sequencing program using the Fudan-BC panel, and comprehensively analyze the clinical and genomic characteristics of Chinese breast cancer. The mutational landscape of 1,134 breast cancers reveals that the most significant differences between Chinese and Western patients occurred in the hormone receptor positive, human epidermal growth factor receptor 2 negative breast cancer subtype. Mutations in p53 and Hippo signaling pathways are more prevalent, and 2 mutually exclusive and 9 co-occurring patterns exist among 9 oncogenic pathways in our cohort. Further preclinical investigation partially suggests that NF2 loss-of-function mutations can be sensitive to a Hippo-targeted strategy. We establish a public database (Fudan Portal) and a precision medicine knowledge base for data exchange and interpretation. Collectively, our study presents a leading approach to Chinese precision oncology treatment and reveals potentially actionable mutations in breast cancer.

SNAI2/SLUG, a metastasis-promoting transcription factor, is a labile protein that is degraded through the ubiquitin proteasome degradation system. Here, we conducted comprehensive gain- and loss-of-function screens using a human DUB cDNA library of 65 genes and an siRNA library of 98 genes, and identified USP20 as a deubiquitinase (DUB) that regulates SNAI2 ubiquitination and stability. Further investigation of USP20 demonstrated its function in promoting migration, invasion, and metastasis of breast cancer. USP20 positively correlates with SNAI2 protein level in breast tumor samples, and higher USP20 expression is associated with poor prognosis in ER - breast cancer patients., (© 2020 Li et al.; Published by Cold Spring Harbor Laboratory Press.)

Acquired therapy resistance is a major problem for anticancer treatment, yet the underlying molecular mechanisms remain unclear. Using an established breast cancer cellular model, we show that endocrine resistance is associated with enhanced phenotypic plasticity, indicated by a general downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers. Consistently, similar gene expression changes are found in clinical breast tumours and patient-derived xenograft samples that are resistant to endocrine therapies. Mechanistically, the differential interactions between oestrogen receptor α and other oncogenic transcription factors, exemplified by GATA3 and AP1, drive global enhancer gain/loss reprogramming, profoundly altering breast cancer transcriptional programs. Our functional studies in multiple culture and xenograft models reveal a coordinated role of GATA3 and AP1 in re-organizing enhancer landscapes and regulating cancer phenotypes. Collectively, our study suggests that differential high-order assemblies of transcription factors on enhancers trigger genome-wide enhancer reprogramming, resulting in transcriptional transitions that promote tumour phenotypic plasticity and therapy resistance.

Background: Estrogen receptor-positive (ER+) breast cancers represent approximately two-thirds of all breast cancers and have a sustained risk of late disease recurrence. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have shown significant efficacy in ER+ breast cancer. However, their effects are still limited by drug resistance. In this study, we aim to explore the role of long noncoding RNA TROJAN in ER+ breast cancer., Methods: The expression level of TROJAN in breast cancer tissue and cell lines was determined by quantitative real-time PCR. In vitro and in vivo assays as well as patient derived organoid were preformed to explore the phenotype of TROJAN in ER+ breast cancer. The TROJAN-NKRF-CDK2 axis were screened and validated by RNA pull-down, mass spectrometry, RNA immunoprecipitation, microarray, dual-luciferase reporter and chromatin immunoprecipitation assays., Results: Herein, we showed that TROJAN was highly expressed in ER+ breast cancer. TROJAN promoted cell proliferation and resistance to a CDK4/6 inhibitor and was associated with poor survival in ER+ breast cancer. TROJAN can bind to NKRF and inhibit its interaction with RELA, upregulating the expression of CDK2. The inhibition of TROJAN abolished the activity of CDK2, reversing the resistance to CDK4/6 inhibitor. A TROJAN antisense oligonucleotide sensitized breast cancer cells and organoid to the CDK4/6 inhibitor palbociclib both in vitro and in vivo., Conclusions: TROJAN promotes ER+ breast cancer proliferation and is a potential target for reversing CDK4/6 inhibitor resistance.

Luminal breast cancer is the most common subtype of breast cancer, representing more than 60% of all breast cancers. Endocrine resistance and late recurrence are two challenges in the treatment of luminal breast cancer. To overcome endocrine resistance in multiple levels, high-dose-fulvestrant can inhibit estrogen-receptor (ER)-dependent pathways, while targeted drugs can block ER-independent pathways.To reduce the risk of late recurrence in luminal breast cancer, recurrence prediction model should be formed. For patients with high risk of late recurrence, extended endocrine therapy, combination of ovarian function suppression (OFS) or vascular endothelial growth factor (VEGF) inhibitor could be utilized. Based on the challenges of the treatment, scientific research achievements can be used in clinical practice, and finally optimize the clinical treatment strategy.

Background: Endocrine therapy is the preferred treatment for patients with hormone receptor -positive metastatic breast cancer (MBC). While visceral metastasis is a negative prognostic factor, few studies have distinguished between the prognoses of patients with metastases at different visceral sites., Patients and Methods: In total, 398 patients receiving fulvestrant 500 mg at a single center over a 6-year period were analyzed. Logistic regression models were used to identify the prognostic factors associated with progression-free survival (PFS). Kaplan-Meier analysis was used to compare the PFS of patients with lung and liver metastases., Results: Baseline visceral metastases were present in 233 patients, including 138 with lung w/o liver metastases (lung metastases without liver involvement), 51 with liver w/o lung metastases (liver metastases without lung involvement) and 41 with lung and liver metastases. The median PFS was 6.8 months (5.6 and 9.2 months for visceral and nonvisceral metastases, respectively, P = .028). PFS was longer in patients with lung w/o liver metastases than in those with liver w/o lung metastases or lung and liver metastases (9.6, 3.7 and 3.2 months, respectively, P < .001; liver w/o lung vs. lung w/o liver hazard ratio (HR) 1.70; lung and liver vs. lung w/o liver HR 2.85). Patients with liver metastases experienced significantly worse PFS than those without liver involvement (3.7 vs. 9.2 months, P < .001). PFS benefits were observed in patients with longer disease-free intervals, no liver metastases, and no previous chemotherapy., Conclusion: Fulvestrant treatment benefited patients with lung w/o liver or nonvisceral metastases. When treating hormone receptor-positive/HER2-negative MBC patients with endocrine therapy, it is important to differentiate patients with lung metastases from those with liver metastases., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: With the improvement in the survival of breast cancer, developing second primary malignancy becomes a serious health issue. The aim of this study was to explore the survival of breast cancer patients with second primary malignancy, and to evaluate the impact of chemotherapy on the risk of different cancer sites., Method: Obtaining data from the Surveillance, Epidemiology, and End Results database, we calculated the standardized incidence ratio (SIR) for second primary malignancy in breast cancer survivors between 2000 and 2014. Overall survival and cancer-specific survival were analyzed with Kaplan-Meier method. Then, we further conducted stratified sub-analyses according to chemotherapy., Results: The overall risk of second primary cancer for all sites was significantly elevated in breast cancer patients (SIR = 1.15, 95% CI 1.14-1.16). Overall survival and cancer-specific survival of the patients with breast cancer only were significantly better than the patients with multiple primary cancers (both P < 0.001). Chemotherapy was associated with increased incidences for all sites, except lymphoma, myeloma, and chronic lymphocytic leukemia (SIR = 0.80, 95% CI 0.72-0.88; SIR = 0.85, 95% CI 0.71-1.01; SIR = 0.57, 95% CI 0.43-0.74, respectively). The risk for developing second acute myeloid leukemia after chemotherapy in breast cancer patients varied with age and latency., Conclusion: Female breast cancer patients showed higher incidence of second primary malignancy, which was associated with poorer prognosis. Chemotherapy benefits should be weighed against the risks of second primary malignancy.

Background : Estrogen receptor-positive, progesterone receptor-positive, and HER2-positive breast cancers (triple-positive breast cancers, TPBCs) account for 5% to 10% of all breast cancers. The clinical and molecular features of TPBCs remain elusive. In this study, we aim to analyze the multiomics landscape and responsiveness of TPBCs to trastuzumab. Methods : We employed five cohorts. The first cohort was from the Surveillance, Epidemiology, and End Results database (n=32,056) and was used to determine the clinical characteristics of TPBC. The second, third and fourth cohorts were from The Cancer Genome Atlas (n=162), GSE2603 (n=37) and GSE2109 (n=30) datasets, respectively, and were used to examine the genomic features and molecular classification of TPBC. The fifth cohort comprised TPBC patients treated at Fudan University Shanghai Cancer Center (FUSCC, n=171) and was used to investigate an immunohistochemistry-defined luminal A-like subgroup of TPBC. Results : Patients with TPBC had a significantly better prognosis than those with ER-PR-HER2+ breast cancer. Genomic analysis revealed that TPBCs showed a lower TP53 mutation rate (30% vs. 69%, P < 0.001) and lower levels of HER2 mRNA and protein expression than ER-PR-HER2+ breast cancers. More than 40% of TPBCs were classified as the luminal A intrinsic subtype, with an even lower HER2 expression level. Based on the immunohistochemical detection of CDCA8, BCL2 and STC2, we identified a luminal A-like subgroup of TPBCs in the FUSCC cohort (CDCA8-negative, BCL2- and/or STC2-positive). Patients with luminal A-like TPBC had a better prognosis and benefited less from trastuzumab than those with TPBC of other subtypes. Conclusions : TPBCs consist of clinically and genomically heterogeneous subgroups that may require different therapeutic strategies. The luminal A-like subgroup of TPBCs is associated with a better prognosis and reduced benefit from trastuzumab., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Objectives: To identify clinicopathologic and ultrasound (US) variables that were associated with a heavy nodal tumor burden, which was defined as 3 or more lymph nodes involved with metastasis to the axilla after invasive breast carcinoma., Methods: With ethical approval, 621 patients with a pathologic diagnosis of invasive breast carcinoma were retrospectively analyzed for clinical, pathologic, and US data. Pathologic findings were ascertained by the final paraffin pathologic analysis. Ultrasound characteristics were evaluated on the basis of the American College of Radiology's Breast Imaging Reporting and Data System (BI-RADS). Univariate and multivariate logistic regression analyses were used to assess the clinicopathologic and US variables that were associated with a heavy nodal tumor burden at the axilla., Results: There were 107 cases (17.2%) of invasive breast carcinoma with a heavy tumor burden at the axilla. The independent clinicopathologic variables for a heavy tumor burden at the axilla included a tumor size of 2 to 5 cm (odds ratio [OR], 1.86; P = .036), the presence of lymphovascular invasion (OR, 23.52; P < .001), the presence of papillary invasion (OR, 2.93; P = .043), and a non-triple-negative subtype (OR, 2.34; P = .04). The independent US features of breast tumors that were associated with a heavy tumor burden at the axilla included BI-RADS category 5 (OR, 5.50; P = .024) and a posterior acoustic shadow (OR, 1.94; P = .024)., Conclusions: A large tumor size, lymphovascular invasion, papillary invasion, and a non-triple-negative subtype on the pathologic analysis as well as BI-RADS category 5 and a posterior acoustic shadow on a US assessment were associated with a heavy nodal tumor burden at the axilla. These US characteristics of the primary breast carcinoma might provide additional information to axillary US for the prediction of axillary nodal tumor loads., (© 2018 by the American Institute of Ultrasound in Medicine.)

Estrogen receptor-positive, progesterone receptor-negative, and human epidermal growth factor receptor 2 (HER2)-negative (ER+PR-HER2-) breast cancer comprise a special type of breast cancer that constitutes ~10% of all breast cancer patients. ER+PR-HER2- tumor benefits less from endocrine therapy, while its genomic features remain elusive. In this study, we systematically assessed the multiomic landscape and endocrine responsiveness of ER+PR-HER2- breast cancer. Methods: This study incorporated five cohorts. The first and second cohorts were from the Surveillance, Epidemiology, and End Results database (n=130,856) and Molecular Taxonomy of Breast Cancer International Consortium (n=1,055) for analyzing survival outcomes and endocrine responsiveness. The third cohort was from The Cancer Genome Atlas (n=630) for multiomic analysis and endocrine-resistant subgroup exploration. The fourth cohort, from the MD Anderson database (n=92), was employed to assist gene selection. The fifth cohort was a prospective observational cohort from Fudan University Shanghai Cancer Center (n=245) that was utilized to validate the gene-defined subgroup by immunohistochemistry (IHC). Results: Clinically, ER+PR-HER2- tumors showed lower endocrine responsiveness than did ER+PR+HER2- tumors. Genomically, copy number loss or promoter methylation of PR genes occurred in 75% of ER+PR-HER2- tumors, collectively explaining PR loss. ER+PR-HER2- tumors had higher TP53 (30.3% vs. 17.0%) and lower PIK3CA mutation rates (25.8% vs. 42.7%) and exhibited more ZNF703 (21.5% vs. 13.6%) and RPS6KB1 (18.5% vs. 7.8%) amplification events than ER+PR+HER2- tumors. Among ER+PR-HER2- tumors, nearly 20% were of the PAM50-defined non-luminal-like subgroup and manifested lower endocrine sensitivity scores and enriched biosynthesis, metabolism and DNA replication pathways. We further identified the non-luminal-like subgroup using three IHC markers, GATA3, CK5, and EGFR. These IHC-defined non-luminal-like (GATA3-negative, CK5-positive and/or EGFR-positive) tumors received limited benefit from adjuvant endocrine therapy. Conclusion: ER+PR-HER2- breast cancer consists of clinically and genomically distinct groups that may require different treatment strategies. The non-luminal-like subgroup was associated with reduced benefit from endocrine therapy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

DSCAM-AS1 is one of the few intensively studied lncRNAs with high specific expression in luminal breast cancer. It is directly regulated by estrogen receptor α (ERα) and plays vital roles in tumor proliferation, invasion, and tamoxifen resistance. However, the detailed function of DSCAM-AS1 in tumor progression and its clinical significance remain unclear. We reveal that DSCAM-AS1 regulates cell proliferation and colony formation by inducing the G1/S transition. RNA-seq analysis demonstrated that DSCAM-AS1 participates in crucial biological processes, including DNA replication, the G1/S phase transition, sister chromatid cohesion, chromosome segregation, protein localization to the chromosome and DNA recombination. Most importantly, in the retrospectively registered clinical analysis, high expression of DSCAM-AS1 is a poor prognostic factor in patients with luminal breast cancer treated with endocrine therapy. In conclusion, DSCAM-AS1 is a promising clinical therapeutic target that may prolong survival of luminal breast cancer patients treated with endocrine therapy., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

In order to investigate clinicopathological characteristics and prognosis of mixed invasive ductal and lobular carcinoma (IDC-L), 209,109 primary breast cancer patients diagnosed with invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC) or IDC-L were included. It was found that IDC-L patients had lower tumor grade and higher hormone receptor positive proportions than IDC patients. Moreover, IDC-L patients were younger and had a similar hormone receptor status compared with ILC patients. Kaplan-Meier plots showed that the breast cancer-specific survival (BCSS) of IDC-L patients was significantly better than IDC patients (P < 0.001) and tended to be better than ILC patients (P = 0.166). However, after adjusting for clinicopathological factors, survival advantage of IDC-L disappeared. Subgroup analysis indicated that IDC-L had higher hazard ratios (HRs) than IDC in grade 1, grade 2, ER-positive and ER-negative subgroups. Survival analysis in ER-positive and ER-negative subgroups showed that IDC-L predicted a worse prognosis than IDC. In conclusion, IDC-L is a distinct histological subtype compared with IDC and ILC. Lower grade and higher ER-positive proportions mainly contribute to its better prognosis. In both ER-positive and ER-negative subgroups, IDC-L predicts worse prognosis than IDC, which suggested the inadequacy of IDC-based therapy and the need of escalated therapy.

Purpose: The optimal time from surgery to initiation of adjuvant chemotherapy of breast cancer is still controversial. We investigated the influence of time to adjuvant chemotherapy on survival outcomes according to breast cancer subtype., Results: Longer delay of initiation of adjuvant chemotherapy (≤4 weeks versus >8 weeks)) significantly decreased the DFS (adjusted hazard ratio [HR] of 1.86; 95% confidence interval [CI], 1.19-2.90) and OS (adjusted HR of 2.02; 95% CI, 1.10-3.71). However, a moderate delay (≤4 weeks versus 4-8 weeks) did not significantly influence the survival. We further investigated the effect of time to adjuvant chemotherapy (≤8 versus >8 weeks) on survival according to subtypes. Patients with luminal-A tumors who received delayed chemotherapy had no increased risk of recurrence (HR of 1.15; 95% CI, 0.54-2.43). In contrast, patients with luminal-B, triple-negative, or trastuzumab-untreated HER2-positive tumors would have decreased DFS because of delayed chemotherapy, with HR of 1.93 (95% CI, 1.10-3.34), 2.55 (95% CI, 1.25-5.18), and 2.41 (95% CI, 1.36-4.26), respectively., Methods: Operable women with stage I-IIIa breast cancer between 2003 and 2006 in our institution were included. 1,408 patients were divided into 3 groups according to the time to adjuvant chemotherapy: ≤4 weeks, 4-8 weeks, and >8 weeks. Disease-free survival (DFS) and overall survival (OS) were calculated., Conclusion: Longer delay of adjuvant chemotherapy was associated with worse survival and early initiation of adjuvant chemotherapy should be performed for patients with aggressive tumor subtypes.

Tumour-initiating cells, or cancer stem cells (CSCs), possess stem-cell-like properties observed in normal adult tissue stem cells. Normal and cancerous stem cells may therefore share regulatory mechanisms for maintaining self-renewing capacity and resisting differentiation elicited by cell-intrinsic or microenvironmental cues. Here, we show that miR-199a promotes stem cell properties in mammary stem cells and breast CSCs by directly repressing nuclear receptor corepressor LCOR, which primes interferon (IFN) responses. Elevated miR-199a expression in stem-cell-enriched populations protects normal and malignant stem-like cells from differentiation and senescence induced by IFNs that are produced by epithelial and immune cells in the mammary gland. Importantly, the miR-199a-LCOR-IFN axis is activated in poorly differentiated ER - breast tumours, functionally promotes tumour initiation and metastasis, and is associated with poor clinical outcome. Our study therefore reveals a common mechanism shared by normal and malignant stem cells to protect them from suppressive immune cytokine signalling.

Purpose: Intra-tumor heterogeneity (ITH) plays a pivotal role in driving breast cancer progression and therapeutic resistance. We used a mutant-allele tumor heterogeneity (MATH) algorithm to measure ITH and explored its correlation with clinical parameters and multi-omics data., Methods: We assessed 916 female breast cancer patients from The Cancer Genome Atlas. We calculated the MATH values from whole-exome sequencing data and further investigated their correlation with clinical characteristics, somatic mutations, somatic copy number alterations (SCNAs), and gene enrichment., Results: The patients were divided into low, intermediate, and high MATH groups. High T stage, African American race, and triple-negative or basal-like subtype were associated with a higher MATH level (all P < 0.001). In hormone receptor-positive and human epidermal growth factor receptor-negative patients, the high MATH group showed a tendency toward a worse overall survival (P = 0.052); Furthermore, the TP53 mutation rate increased as MATH was elevated (P < 0.001), whereas CDH1 mutations were correlated with a lower level of MATH (P = 0.002). Several focal and arm-level SCNA events were more common in the high MATH group (P < 0.05), including Chr8q24 with only the MYC gene in the "peak" region. Similarly, high MATH was associated with gene set enrichment related to the MYC pathway and proliferation., Conclusion: Our integrative analysis reveals the clinical and genetic relevance of ITH in breast cancer. These results also suggest the origin and natural history of clonal evolution and intra-tumor genetic heterogeneity, which warrant further investigation.

Purpose: Somatic mutations in the tyrosine kinase domain of human epidermal growth factor receptor 2 (HER2) may be an alternative mechanism to HER2 activation and can affect the sensitivity toward HER2-targeted therapies. We aimed to investigate the prevalence, clinicopathologic characteristics, and functional relevance of novel HER2 mutations in breast cancer., Experimental Design: We performed Sanger sequencing of all exons of the HER2 gene in 1,248 primary tumors and 18 paired metastatic samples. Novel HER2 mutations were functionally characterized., Results: The total HER2 somatic mutation rate was 2.24% (28/1,248). Of the seven novel HER2 mutations, L768S and V773L were only detected in HER2-negative tumors, whereas K753E was found in HER2-positive disease. L768S and V773L mutations exhibited a significant increase in tyrosine kinase-specific activity and strongly increased the phosphorylation of signaling proteins in various cell lines. Xenograft experiments showed that NIH3T3 cells bearing the L768S and V773L mutations displayed more rapid growth. MCF10A, BT474, and MDA-MB-231 cells bearing the K753E mutation were resistant to lapatinib, but could be inhibited by neratinib. Finally, comparison of HER2 mutations in 18 pairs of primary and metastatic lesions revealed that the drug-resistant HER2 mutations (K753E and L755S) were enriched in metastatic lesions., Conclusions: HER2-negative breast cancer with activating mutations can benefit from HER2-targeted therapies. Meanwhile, mutations in the HER2 kinase domain might be a key mechanism of resistance to HER2-targeted therapy, and irreversible tyrosine kinase inhibitors such as neratinib may offer alternative treatment options. Clin Cancer Res; 22(19); 4859-69. ©2016 AACR., (©2016 American Association for Cancer Research.)

The value of sentinel lymph node biopsy (SLNB) in post-neoadjuvant chemotherapy (NCT) patients is still controversial. We aimed to identify predictors and construct a nomogram for predicting the pathologically complete response (pCR) of axillary lymph nodes (ALNs) after NCT in node positive breast cancer patients. In total, 426 patients with pathologically proven ALN metastasis before NCT were enrolled, randomized 1:1 and divided into a training set and a validation set. We developed a nomogram based on independent predictors for ALN pCR identified by multivariate logistic regression as well as clinical significant predictors. The multivariate logistic regression analysis showed that hormone receptor (HR) status, human epidermal growth factor 2 (HER2) status and Ki67 index were independent predictors. The nomogram was thereby constructed by those independent predictors as well as tumor size and NCT regimens. The areas under the receiver operating characteristic curve of the training set and the validation set were 0.804 and 0.749, respectively. We constructed a nomogram for predicting ALN pCR in patients who received NCT. Our nomogram can improve risk stratification, accurately predict post-NCT ALN status and avoid unnecessary ALN dissection.

Background: The response to neoadjuvant chemotherapy has been proven to predict long-term clinical benefits for patients. Our research is to construct a nomogram to predict pathological complete response of human epidermal growth factor receptor 2 negative breast cancer patients., Methods: We enrolled 815 patients who received neoadjuvant chemotherapy from 2003 to 2015 and divided them into a training set and a validation set. Univariate logistic regression was performed to screen for predictors and construct the nomogram; multivariate logistic regression was performed to identify independent predictors., Results: After performing the univariate logistic regression analysis in the training set, tumor size, hormone receptor status, regimens of neoadjuvant chemotherapy and cycles of neoadjuvant chemotherapy were the final predictors for the construction of the nomogram. The multivariate logistic regression analysis demonstrated that T4 status, hormone receptor status and receiving regimen of paclitaxel and carboplatin were independent predictors of pathological complete response. The area under the receiver operating characteristic curve of the training set and the validation set was 0.779 and 0.701, respectively., Conclusions: We constructed and validated a nomogram to predict pathological complete response in human epidermal growth factor receptor 2 negative breast cancer patients. We also identified tumor size, hormone receptor status and paclitaxel and carboplatin regimen as independent predictors of pathological complete response.

Precision medicine is an emerging medical strategy that takes into account individual molecular variations of disease to guide accurate prevention and treatment.Tumor molecular markers closely related to aggressive behavior and treatment response will be identified by integrating clinical information and multiple-omics, and will be verified in well-designed clinical trials. Breast cancer is a highly heterogeneous disease. Its treatment based on molecular subtyping has achieved initial success. However, drug resistance and tumor heterogeneity are still major challenges. This review will focus on the recent progress and future prospects of clinical research on breast cancer in the era of precision medicine.

Medullary breast carcinoma (MBC) is a unique histological subtype of breast cancer. Our study was designed to identify difference in characteristics and outcomes between MBC and invasive ductal carcinoma (IDC), and further confirm the prognostic factors of MBC. Utilizing Surveillance, Epidemiology, and End Results (SEER), we identified 84,764 eligible patients, including 309 MBC and 84,455 IDC. Compared with the IDC group, the MBC group was associated with younger age at diagnosis, higher grade, more advanced stage, larger tumor size, and higher proportion of triple-negative breast cancer (TNBC). Kaplan-Meier analysis and univariate Cox proportional hazard regression model showed that patients with IDC had significantly better breast cancer-specific survival (BCSS) compared to MBC, but they had similar overall survival (OS). However, MBC histology was no longer a surrogate for worse BCSS or OS after 1:1 matching by age, American Joint Committee on Cancer (AJCC) stage, grade and breast subtype. In addition, it was exposed that not married status, high grade, large tumor size, positive nodal status, the subtype of TNBC and no receipt of radiation therapy were significantly associated with poor BCSS and OS. In conclusion, MBC demonstrated more aggressive behavior but similar outcomes compared to IDC, which may be determined by prognostic factors such as breast subtype. These results not only confer deeper insight into MBC but contribute to individualized and tailored therapy, and thereby may improve clinical management and outcomes., Competing Interests: The authors have declared that no competing interests exist.

Luminal breast cancer constitutes a group of highly heterogeneous diseases with a sustained high risk of late recurrence. We aimed to develop comprehensive and practical nomograms to better estimate the long-term survival of luminal breast cancer.Patients with luminal breast cancer diagnosed between 1990 and 2006 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database and randomly divided into the training (n = 87,867) and validation (n = 88,215) cohorts. The cumulative incidence function (CIF) and a competing-risks model were used to estimate the probability of breast cancer-specific survival (BCSS) and death from other causes. We integrated significant prognostic factors to build nomograms and subjected the nomograms to bootstrap internal validation and to external validation.We screened 176,082 luminal breast cancer cases. The 5- and 10-year probabilities of overall death were 0.089 and 0.202, respectively. The 5- and 10-year probabilities of breast cancer-specific mortality (BCSM) were 0.053 and 0.112, respectively. Nine independent prognostic factors for both OS and BCSS were integrated to construct the nomograms. The calibration curves for the probabilities of 5- and 10-year OS and BCSS showed excellent agreement between the nomogram prediction and actual observation. The C-indexes of the nomograms were high in both internal validation (0.732 for OS and 0.800 for BCSS) and external validation (0.731 for OS and 0.794 for BCSS).We established nomograms that accurately predict OS and BCSS for patients with luminal breast cancer. The nomograms can identify patients with higher risk of late overall mortality and BCSM, helping physicians in facilitating individualized treatment.

Background: The clinical significance of progesterone receptor (PgR) expression in estrogen receptor-negative (ER-) breast cancer is controversial. Herein, we systemically investigate the clinicopathologic features, molecular essence, and endocrine responsiveness of ER-/PgR+/HER2- phenotype., Methods: Four study cohorts were included. The first and second cohorts were from the Surveillance, Epidemiology, and End Results database (n = 67,932) and Fudan University Shanghai Cancer Center (n = 2,338), respectively, for clinicopathologic and survival analysis. The third and fourth cohorts were from two independent publicly available microarray datasets including 837 operable cases and 483 cases undergoing neoadjuvant chemotherapy, respectively, for clinicopathologic and gene-expression analysis. Characterized genes defining subgroups within the ER-/PgR+/HER2- phenotype were determined and further validated., Results: Clinicopathologic features and survival outcomes of the ER-/PgR+ phenotype fell in between the ER+/PgR+ and ER-/PgR- phenotypes, but were more similar to ER-/PgR-. Among the ER-/PgR+ phenotype, 30% (95% confidence interval [CI] 17-42%, pooled by a fixed-effects method) were luminal-like and 59% (95% CI 45-72%, pooled by a fixed-effects method) were basal-like. We further refined the characterized genes for subtypes within the ER-/PgR+ phenotype and developed an immunohistochemistry-based method that could determine the molecular essence of ER-/PgR+ using three markers, TFF1, CK5, and EGFR. Either PAM50-defined or immunohistochemistry-defined basal-like ER-/PgR+ cases have a lower endocrine therapy sensitivity score compared with luminal-like ER-/PgR+ cases (P <0.0001 by Mann-Whitney test for each study set and P <0.0001 for pooled standardized mean difference in meta-analysis). Immunohistochemistry-defined basal-like ER-/PgR+ cases might not benefit from adjuvant endocrine therapy (log-rank P = 0.61 for sufficient versus insufficient endocrine therapy)., Conclusions: The majority of ER-/PgR+/HER2- phenotype breast cancers are basal-like and associated with a lower endocrine therapy sensitivity score. Additional studies are needed to validate these findings.

Invasive cribriform carcinoma (ICC) is a rare histologic subtype of breast cancer. We aimed to investigate the clinicopathological characteristics and survival outcomes of ICC.Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified 233,337 female patients diagnosed with ICC (n = 618) or infiltrating ductal carcinoma (IDC) (n = 232,719). Univariate and multivariate survival analyses were utilized to calculate and compare disease-specific survival (DSS) and overall survival (OS). A 1:1 paired match was carried out on age, tumor stage, tumor grade, estrogen receptor (ER) status, and progesterone receptor (PR) status. Baseline characteristics and survival outcomes were also analyzed in ER-positive tumors. Subgroup analyses summarized the hazard ratio (HR) of IDC versus ICC using a forest plot.ICCs presented smaller size, lower grade, higher ER and PR positive rate, less nodal metastasis, and were less likely to be treated with mastectomy compared to IDCs. Five-year DSS rates were significantly better for patients with ICC than for patients with IDC (98.8% vs. 93%, P < 0.001). Five-year OS rates were 95.3% versus 90.1% (P < 0.001). After adjustment for common clinicopathological factors in the multivariate analysis, patients with ICC showed limited DSS advantage over the IDC group (HR = 0.75, 95% CI: 0.38-1.51, P = 0.421). No significant difference in DSS nor OS was observed in matched groups between ICC and IDC. Analysis among ER-positive patients revealed similar prognostic factors as among all patients. Survival analysis in different tumor grade subgroups showed no significant difference between ICC and IDC.ICCs have unique clinicopathological characteristics, higher rates of breast-conserving surgery, and more favorable prognosis compared to the overall IDC population. Difference in tumor grade between the 2 groups may partially explain the different outcome. Improved clinical and biological understanding of ICC might lead to more individualized and tailored therapy for breast cancer patients.

Background: Toll-like receptors (TLRs) regulate the balance between the innate and adaptive immune responses. Missense single nucleotide polymorphisms (SNPs) in TLRs might be functional and thus influence the risks of chronic infection and cancer development. Here, we investigated the association of two missense SNPs, rs3775291 (c.1234G>A) in the TLR3 gene and rs4833095 (c.743T>C) in the TLR1 gene, with relapse-free survival (RFS) in a cohort of prospectively observed breast cancer patients., Methods: In this prospective observational study, rs3775291 in TLR3 and rs4833095 in TLR1 were genotyped in 715 patients with primary breast cancer in a Chinese population., Results: Univariate analysis revealed that the patients with the AA genotype of rs3775291 had a shorter RFS compared with those carrying the G allele in the recessive model (P<0.01), but this finding was not observed with the dominant model (P = 0.31). The results remained significant after adjusting for the clinical parameters in the recessive model (HR = 3.53, 95% confidence interval [CI]: 1.98-6.31, P<0.01). Further survival analysis indicated that this SNP was significant in the luminal-B, triple-negative breast cancer (TNBC), and human epidermal growth factor receptor 2-positive (HER2+) patients using the recessive model but that it was not significant in the luminal-A patients. The SNP rs4833095 showed a non-significant tendency toward an increased RFS rate in the patients with the TT genotype., Conclusion: Our results suggest that the SNP rs3775291 in TLR3 may influence patient outcome. Further studies with larger sample sizes should be conducted to validate our findings.

Purpose: Poor prognosis associated with metastasis in breast cancer patients highlights the critical need to develop an effective evaluation model for metastatic potential (MP). We hypothesized that MP could be also indicated by primary tumor size and involved lymph nodes (LNs)., Methods: The expected number of involved LNs is defined as tumor size (cm) divided by 1.5. The effect of the surrogate for MP (defined as difference between the number of observed and expected involved LNs) on breast cancer-specific survival (BCSS) was investigated in the first cohort from SEER (n = 108,814). Validation was performed in another SEER cohort (n = 50,414) and a third cohort (n = 3,755)., Results: MP is an independent predictor for BCSS in the overall population [hazard ratio (HR) for high MP: 2.92; 95% confidence interval (CI): 2.80-3.03] and in subgroups. The effect of surrogate for MP on survival was independent to intrinsic subtype, with adjusted HRs of 3.46 (95%CI, 2.02-5.93), 2.30 (95%CI, 1.64-3.24), 4.05 (95%CI, 2.85-5.76), and 1.45 (95%CI, 1.04-2.03) in luminal-A, luminal-B, triple-negative, and HER2-positive subtypes, respectively., Conclusions: Difference between the observed and expected number of involved LNs serves as an indicator for MP, which is independent to intrinsic subtype and could predict survival. Our findings need further validation.

Chinese breast cancer patients living in the United States (US) can experience different disease patterns than Caucasians, which might allow for predicting the future epidemiology of breast cancer in China. We aimed to compare the clinicopathologic characteristics and outcomes of Caucasian and Chinese female breast cancer patients residing in the US. The study cohort consisted of 3868 Chinese and 208621 Caucasian women (diagnosed from 1990 to 2009) in the US Surveillance, Epidemiology, and End Results (SEER) database. Compared with the Caucasian patients, the US-residing Chinese patients had a younger age at diagnosis and a higher family income, remained married longer, and more frequently lived in metropolitan areas. Other tumor characteristics were similarly distributed between the two races. Compared with the Caucasians, the Chinese patients had a significantly improved overall survival (OS) but similar breast cancer-specific survival (BCSS). Our analysis suggested that US-residing Chinese patients had significant differences in age, family income, marital status and area of residence, compared with their Caucasian counterparts. No significant disparities were noted in BCSS between the two races, whereas the Chinese patients had a significantly better OS. These findings warrant further investigation and should be considered in the screening and treatment of breast cancer.

The hormone receptor (HR) status and human epidermal growth hormone receptor 2 (HER2) status of patients with breast cancer may change following neoadjuvant chemotherapy (NCT). This prospective observational study aimed to evaluate the prognostic impact of receptor conversion in breast cancer patients treated with NCT.Of the 423 consecutive patients who had residual disease in the breast after NCT, 55 (13.0%) changed from HR (+) to HR (-), 23 (5.4%) changed from HR (-) to HR (+), 27 (6.4%) changed from HER2 (+) to HER2 (-), and 13 (3.1%) changed from HER2 (-) to HER2 (+). A total of 54 (12.8%) changed to the triple-negative (TN) tumor phenotype. The loss of HR positivity was an independent prognostic factor for worse disease-free survival (DFS) and worse overall survival (OS) in multivariate survival analysis. Furthermore, the switch to the TN phenotype after NCT was another independent prognostic factor for worse survival for both DFS and OS. In conclusion, patients with breast cancer may experience changes in HR status, HER2 status and tumor phenotype after NCT. The loss of HR positivity and the switch to the TN phenotype after NCT were associated with a worse patient outcome.

Objective: To explore the clinical features, diagnosis and treatment of primary breast diffuse large B- cell lymphoma (PBDLBCL)., Methods: Clinical records of 9 PBDLBCL patients treated in Department of Hematology of Yijishan Hospital Affiliated to Wannan Medical College from August 2001 to January 2014 were analyzed retrospectively., Results: All of the 9 patients were female, with an average age of 48 years (range 28 to 75), 8 cases had unilateral breast tumors and 1 case had bilateral. According to the Ann Arbor stage standard, 2 cases were of stage IE and 7 were IIE. None of them was concurrent with B symptoms; 6 cases had IPI (International prognostic Index) score 0 and 3 had score 1. 2 cases belonged to germinal center B cells type (GCB) and 7 belonged to non-GCB. Double-Hit lymphomas were presented in 3 cases. Out of 9 cases, 3 cases were diagnosed by using tubular needle biopsy, 5 cases were diagnosed by using resection of breast mass, and 1 case was diagnosed by using modified radical mastectomy. 1 case received radical mastectomy, 1 case received unilateral breast removal, 1 case gave up, 1 case received mass excision with chemotherapy and radiotherapy, 5 cases received mass excision with chemotherapy and 1 case received central prophylaxis. A complete response (CR) was observed in 6 cases after first-line chemotherapy. The median follow-up time was 18 months (range 0.1 to 150), 3 cases relapsed and 5 cases died., Conclusion: PBDLBCL mostly occurs in female. The main pathological type is non-GCB coupled with Double-Hit lymphoma. Tubular needle biopsy offers benifit in the diagnosis of PBL, R-CHOP or R-CHOP combined with chemotherapy/radiotherapy produce best outcome among all the treatments. Intrathecal injection of chemotherapy drugs may help to prevent recurrence of PBL central.

Background: Few studies have been undertaken to evaluate the prognostic value of age at diagnosis for determining breast cancer survival in a large population., Methods: Using the U.S. National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database consisting of 18 population-based cancer registries, this study identified 331,969 female patients with a diagnosis of breast cancer from 1 January 1990, to 31 December 31. Breast cancer-specific mortality (BCSM) was compared among patients in different age groups using Kaplan-Meier plots. The Cox proportional hazards model was used for multivariate analysis., Results: In the multivariate analysis, the hazard ratios (HRs) of BCSM in the different age groups formed a U-shaped curve, with patients younger than 30 years and patients older than 79 years experiencing the worst survival rates (HR, 1.19; 95 % confidence interval [CI], 1.06-1.33; P = 0.003 and HR, 2.16; 95 % CI, 2.05-2.27; P < 0.001, with age 50-59 years as the reference, respectively). When the interaction between age at diagnosis and hormone receptor (HoR) status for prediction of BCSM was further analyzed, the findings showed that in the HoR-positive group, patients younger than 30 years and patients older than 79 years had the worst survival rates (HR, 1.52; 95 % CI, 1.30-1.76; P < 0.001 and HR, 2.07; 95 % CI, 1.94-2.20; P < 0.001, respectively), whereas patients ages 40 to 49 years had the best survival rate (HR, 0.93; 95 % CI, 0.89-0.98; P = 0.005). This pattern, however, was different in the HoR-negative group. Patients younger than 60 years had nearly the same BCSM (P = 0.356, 0.199, and 0.036 for ages <30 years, 30-39 years, and 40-49 years, respectively), with BCSM starting to increase with age only for patients older than 60 years and peaking for patients older than 79 years (HR, 2.39; 95 % CI, 2.20-2.59; P < 0.001)., Conclusions: The study findings show different patterns in the prognostic value of age for determining BCSM, depending on the HoR status. These data underscore the importance of age-specific studies for different HoR groups to individualize treatment and improve outcomes for breast cancer patients.

Background: Girdin was identified as a novel Akt substrate that contributes to a positive feedback loop between Girdin and Akt. Although several recent studies have demonstrated that Girdin is involved in tumor metastasis, the clinical implications of Girdin in breast cancer remain unclear., Methods: To retrospectively evaluate the prognostic value of Girdin in breast cancer, we performed an immunohistochemistry screening for Girdin using tissue microarrays constructed from 250 patients who were histologically confirmed as having invasive ductal breast carcinoma at the Fudan University Shanghai Cancer Center., Results: Our results demonstrated that the levels of Girdin in different subcellular distributions, including Girdin in the nucleus (GN) and the cytoplasm (GC) were each associated with the clinical parameters of breast cancer, including phospho-Akt (S473) [p = 0.014 for GN], phospho-Akt (T308) [p = 0.045 for GC], estrogen receptor (ER) [p = 0.012 for GN and p = 0.004 for GC], progesterone receptor (p = 0.028 for GC) and human epidermal growth factor receptor 2 status (p = 0.004 for GC). Moreover, we showed that elevated expression of GN indicated a worse disease-free survival (p = 0.032) and overall survival (p = 0.011) exclusively in the ER-positive breast cancer population., Conclusions: Cumulatively, our findings suggest that GN might serve as an important prognostic factor for ER-positive breast carcinoma.

Purpose: Neoadjuvant chemotherapy (NCT) is a standard treatment option for locally advanced breast cancer. However, the lack of an efficient method to predict treatment response and patient prognosis hampers the clinical evaluation of patient eligibility for NCT. An elevated lymphocyte-to-monocyte ratio (LMR) has been reported to be associated with a favorable prognosis for certain hematologic malignancies and for nasopharyngeal carcinoma; however, this association has not been investigated in breast cancer. The purpose of this study was to evaluate whether pre-NCT LMR analysis could predict the prognosis of patients with locally advanced breast cancer., Methods: A retrospective cohort of 542 locally advanced breast cancer patients (T3/T4 and/or N2/N3 disease) receiving NCT followed by radical surgery was recruited between May 2002 and August 2011 at the Fudan University Shanghai Cancer Center. Counts for pre-NCT peripheral absolute lymphocytes and monocytes were obtained and used to calculate the LMR., Results: Univariate and multivariate analysis revealed that higher LMR levels (≥4.25) were significantly associated with favorable DFS (P = 0.009 and P = 0.011, respectively). Additionally, univariate analysis revealed that a higher lymphocyte count (≥1.5×109/L) showed borderline significance for improved DFS (P = 0.054), while a lower monocyte count (<0.4×109/L) was associated with a significantly better DFS (P = 0.010)., Conclusions: An elevated pre-NCT peripheral LMR level was a significantly favorable factor for locally advanced breast cancer patient prognosis. This easily obtained variable may serve as a valuable marker to predict the outcomes of locally advanced breast cancer.

We investigated the loss of somatic mutations in TP53 and PIK3CA in breast cancer tissue after neoadjuvant chemotherapy (NCT) and the clinical relevance of the observed mutation profiles. Samples were derived from three cohorts: Cohort 1 consisting of 206 patients undergoing NCT with matched pre- and postchemotherapy tumor tissues; Cohort 2 consisting of 158 additional patients undergoing NCT; and Cohort 3, consisting of 81 patients undergoing chemotherapy with prechemotherapy tumor tissues. In the first cohort, somatic mutations in TP53 or PIK3CA were identified in 24.8% of the pre-NCT tumor samples but in only 12.1% of the post-NCT tumor samples (P < 0.001). Patients with initial TP53 and PIK3CA mutations who became negative for the mutations after NCT had a higher Miller-Payne score (P = 0.008), improved disease-free survival, and improved overall survival than those with no change or the opposite change. The association of loss of mutations in TP53 and PIK3CA and improved survival was successfully validated in the second cohort. In addition, 28.4% of the tumors showed intratumoral heterogeneity of somatic mutations in TP53 or PIK3CA, whereas 71.6% were homogeneous, either with or without the mutations. Our data reveal the novel concept that chemotherapy may reduce mutation frequency in patients with breast cancer. Furthermore, the loss of somatic mutations in TP53 and PIK3CA may be translated to biomarkers for prognosis via further verification, which may optimize the choice of sequential therapy and improve patient survival., (©2014 American Association for Cancer Research.)

Among chemotherapeutic agents, paclitaxel has shown great efficacy against breast cancer. Prediction of paclitaxel response may improve patient outcomes. Here we show, using exome sequencing, that in comparison with pre-treatment biopsies, two TEKT4 germline variations are enriched in post-treatment tumours. We find TEKT4 variations in ~ 10% of an independent cohort of 84 pairs of samples. Tektin4 (encoded by TEKT4) associates closely with tubulin in doublet microtubules and helps stabilize these structures. These two TEKT4 germline variations in a high cis linkage are biologically relevant, as the ectopic expression of variant TEKT4 deregulates the microtubule stability, antagonizes the paclitaxel-induced stabilizing effect of microtubules and increases paclitaxel resistance. Furthermore, TEKT4 germline variations are associated with reduced disease-free survival and overall survival compared with wild-type TEKT4 in patients undergoing paclitaxel-based chemotherapy. Taken together, we reveal a potential mechanism of resistance to paclitaxel through the acquisition of germline variations in breast cancer.

Background: The GATA3 gene (GATA-binding protein 3) is one of the most frequently mutated genes in breast cancer. The objective of the current study was to determine the clinicopathologic characteristics of patients with breast cancer harboring GATA3 mutations., Methods: The authors examined the somatic mutation status of GATA3 and performed survival analysis in The Cancer Genome Atlas (TCGA) cohort (n=934) and the Fudan University Shanghai Cancer Center (FUSCC) cohort (n=308). Patient characteristics, including age; menopausal status; tumor laterality; tumor size; lymph node status; tumor grade; molecular subtypes; adjuvant radiotherapy, chemotherapy, and endocrine therapy; and prognosis, together with PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) and TP53 (tumor protein p53) mutation status, were collected., Results: GATA3 mutations were detected in 8.8% of patients (82 of 934 patients) in the TCGA cohort and 14.9% of patients (46 of 308 patients) in the FUSCC cohort. GATA3 mutations were found to be significantly associated with luminal-like breast cancer (P=.002 in the TCGA cohort and P<.001 in the FUSCC cohort), and were highly mutually exclusive to PIK3CA mutations (P=.001 in the TCGA cohort and P=.003 in the FUSCC cohort) and TP53 mutations (P<.001 in both cohorts). Furthermore, GATA3 mutations were correlated with improved overall survival in the entire population (P=.025 in the TCGA cohort and P = .043 in the FUSCC cohort) as well as in patients with luminal-like disease who received adjuvant endocrine therapy., Conclusions: GATA3 mutations mainly occur in patients with luminal-like breast cancer and have identifiable clinicopathologic and genetic characteristics, highlighting a subgroup of patients with breast cancer in whom limited therapy may be appropriate., (© 2014 American Cancer Society.)

Background: Reduced overall survival has been observed in patients with left-sided versus right-sided breast cancer due to cardiac toxicity after radiotherapy. However, the effect of laterality and primary tumor site on breast cancer-specific mortality (BCSM) remains unclear., Patients and Methods: We analyzed data from 305,443 women ages 20- to 79-years-old diagnosed with breast cancer between 1990 and 2009. The data were obtained from the population-based Surveillance, Epidemiology, and End Results (SEER) program of the U.S. National Cancer Institute. The survival outcomes with regard to laterality and primary tumor site were compared using univariate and multivariate (Cox proportional hazards regression model) methods., Results: In the multivariate analysis, BCSM was affected by the primary tumor site (P<0.0001) but not laterality (P = 0.331). The combined effect was piecewise: using the left upper-outer quadrant as the reference, the BCSM hazard ratio (HR) was not significant in the right upper quadrant (P = 0.755) and the right central portion (P = 0.329). The BCSM HR was slightly increased in the left central portion as well as the left and right lower-outer quadrants (HRs from 1.136 to 1.145; P<0.0001). The BCSM HR was significantly increased in the upper-inner and lower-inner quadrants (HRs from 1.242 to 1.372; P<0.0001) on both sides. Laterality only impacted BCSM in patients with breast cancer located in the central portion (HR, 1.100; P = 0.013, using the right side as the reference)., Conclusion: Patients with tumors in the upper-outer quadrant of both sides and the right central portion have a better prognosis than patients with tumors at other locations. Laterality is not regarded as a prognostic factor in breast cancer.

Purpose: This study sought to investigate the prognostic value of the autophagy marker microtubule-associated protein chain 3B (LC3B) in patients with residual tumors after neoadjuvant chemotherapy (NCT) for locally advanced breast cancer (LABC)., Patients and Methods: The expression of LC3B in residual breast cancer cells was assessed by immunohistochemistry in surgical specimens from 229 patients diagnosed with histologically proven invasive breast cancer. All patients underwent NCT followed by mastectomy and were considered nonpathologic complete responders (non-pCR) after a pathologic evaluation. The prognostic value of various clinicopathologic factors was evaluated., Results: The LC3B density was similar between the peripheral and central area of the tumors (P = 0.328) but was significantly lower in the extratumoral area (P < 0.001 and P < 0.001, respectively). Furthermore, LC3B density, which correlated with Beclin-1 expression, Ki-67 index, and breast cancer subtype, served as an independent prognostic factor for both relapse-free survival (RFS; P = 0.012) and overall survival (OS; P = 0.008); the prognostic value of LC3B was most significant in triple-negative patients. Using a combination of LC3B expression and the status of residual involved lymph nodes, the patients were classified into four groups with different risks of relapse and death (P < 0.001 for RFS and P = 0.003 for OS)., Conclusion: LC3B can be used as a prognostic marker in patients with non-pCR after NCT for breast cancer, which highlights the importance of autophagy in the biologic behavior of chemoresistant cancer cells. Furthermore, evaluating and targeting autophagy in the neoadjuvant setting may help prevent disease relapse in patients with non-pCR., (©2013 AACR.)