Overall Survival In Breast Cancer Research Articles

Acquired immune deficiency of cancer: Evaluation of NK cell number as a predictor of overall survival in breast cancer.

e13003 Background: Cancer specialists, be they molecular geneticists or oncology clinicians, now accept the fact that a cancer results after a deleterious mutation in the apoptosis program AND failure of the immune system, innate (non-specific) and adaptive (specific), to eliminate the now abnormal transformed cell and it's progeny. Just as the acquired immune deficiency syndrome existed as a syndrome BEFORE the HIV virus was described, the disease AIDS/HIV was designated because the virus explained the syndrome and made HIV/AIDS a disease. We believe cancer works the same way. Cancer is a failure of surveillance by the immune system which leads to a disease, one we have described as AIDS/cancer (J Immunol May 1, 2019, 202, 1S, 182.79). Methods: Commercially available laboratory analysis of peripheral blood (Quest Diagnostics) and standard treatment protocols for breast cancer. Results: The immune system can be evaluated with samples of peripheral blood where cell subsets, antibody levels, etc. are measurable. Here we present results from over 200 unselected breast cancer patients, independent of Stage. All patients were treated with standard protocols. The initial number of NK cells in peripheral blood, but not other cell subsets or immunoglobulin levels, are a, and likely the, most significant predictor for survival. Kaplan Meier survival analysis, done when 20% of the entire population had died, showed that none of the patients in the upper quartile for NK cell number had died. Survival differences, comparing the top 50% vs. bottom 50% in initial NK number. were also highly significant (P < 0.05). Conclusions: We conclude that the innate immune system, reflected as numbers of NK cells in the blood are the most significant predictor of survival.

Comprehensive Analysis of Fibroblast Growth Factor Receptor (FGFR) Family Genes in Breast Cancer by Integrating Online Databases and Bioinformatics.

BackgroundFibroblast growth factor receptors (FGFRs) play vital roles in the development and progression of human cancers. This study aimed to comprehensively understand the prognostic performances of FGFR1–4 expression in breast cancer (BC) by mining databases.Material/MethodsThe levels of FGFR1–4 expression in BC were analyzed by online databases, GEPIA (Gene Expression Profiling Interactive Analysis) and UALCAN. Survival analysis of FGFR1–4 was carried out by Kaplan-Meier plotter. GSE74146 was downloaded from Gene Expression Omnibus (GEO) and analyzed by GEO2R to screen the differentially expressed genes (DEGs) between FGFR2-silenced BC cells and control. Over-presentation for DEGs were done by Enrichr tool. Networks of DEGs were obtained by using Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape software. Hub genes were identified by cytoHubba Cytoscape plugin.ResultsThe online databases showed that FGFR1 was significantly downregulated whereas FGFR3 was upregulated in BC. Kaplan-Meier plotter demonstrated the upregulation of both FGFR1 and FGFR3 indicated favorable relapse free survival (RFS) whereas FGFR4 overexpression predicted unfavorable overall survival (OS) in BC patients. Importantly, our results showed FGFR2 overexpression robustly predicted favorable OS and RFS in BC. Further bioinformatics analysis of GSE74146 suggested FGFR2 mainly participated in regulating degradation and organization of the extracellular matrix and signaling of retinoic acid. Moreover, CXCL8, CD44, MMP9, and BMP7 were identified as crucial FGFR2-related hub genes.ConclusionsOur study comprehensively analyzed the prognostic values of FGFR1–4 expression in BC and proposed FGFR2 might serve as a promising biomarker. However, the underlying mechanisms remain to be elucidated.

Glucocorticoid receptors are required effectors of TGF\u03b21-induced p38 MAPK signaling to advanced cancer phenotypes in triple-negative breast cancer

BackgroundAltered signaling pathways typify breast cancer and serve as direct inputs to steroid hormone receptor sensors. We previously reported that phospho-Ser134-GR (pS134-GR) species are elevated in triple-negative breast cancer (TNBC) and cooperate with hypoxia-inducible factors, providing a novel avenue for activation of GR in response to local or cellular stress.MethodsWe probed GR regulation by factors (cytokines, growth factors) that are rich within the tumor microenvironment (TME). TNBC cells harboring endogenous wild-type (wt) or S134A-GR species were created by CRISPR/Cas knock-in and subjected to transwell migration, invasion, soft-agar colony formation, and tumorsphere assays. RNA-seq was employed to identify pS134-GR target genes that are regulated both basally (intrinsic) or by TGFβ1 in the absence of exogenously added GR ligands. Regulation of selected basal and TGFβ1-induced pS134-GR target genes was validated by qRT-PCR and chromatin immunoprecipitation assays. Bioinformatics tools were used to probe public data sets for expression of pS134-GR 24-gene signatures.ResultsIn the absence of GR ligands, GR is transcriptionally activated via p38-dependent phosphorylation of Ser134 as a mechanism of homeostatic stress-sensing and regulated upon exposure of TNBC cells to TME-derived agents. The ligand-independent pS134-GR transcriptome encompasses TGFβ1 and MAPK signaling gene sets associated with TNBC cell survival and migration/invasion. Accordingly, pS134-GR was essential for TNBC cell anchorage-independent growth in soft-agar, migration, invasion, and tumorsphere formation, an in vitro readout of cancer stemness properties. Both pS134-GR and expression of the MAPK-scaffolding molecule 14-3-3ζ were essential for a functionally intact p38 MAPK signaling pathway downstream of MAP3K5/ASK1, indicative of a feedforward signaling loop wherein self-perpetuated GR phosphorylation enables cancer cell autonomy. A 24-gene pS134-GR-dependent signature induced by TGFβ1 predicts shortened overall survival in breast cancer patients.ConclusionsPhospho-S134-GR is a critical downstream effector of p38 MAPK signaling and TNBC migration/invasion, survival, and stemness properties. Our studies define a ligand-independent role for GR as a homeostatic “sensor” of intrinsic stimuli as well as extrinsic factors rich within the TME (TGFβ1) that enable potent activation of the p38 MAPK stress-sensing pathway and nominate pS134-GR as a therapeutic target in aggressive TNBC.

SETD5 Promotes Tumor Progression and Induces Cancer Stem Cell-Like Properties Through Upregulation of AKT1 Signaling in Breast Cancer

A variety of studies have revealed the role of SET domain-containing 5 (SETD5) in post translational modifications of non-histone proteins. Although it was reported that SETD5 gene mutation is associated with the tumor progression in the several types of human cancer, including breast cancer (BC), its functional role in BC progression has not been fully elucidated. In the present study, we investigated the clinical significance and the functional role of SETD5 in BC. Our studies show that SETD5 expression in BC was correlated with poor clinical outcomes, including lymph mode metastasis and advanced clinical stage. SETD5 was an independent predictor of poor overall survival in BC. Further, our studies show that down-regulation of SETD5 significantly decreased BC cell proliferation, metastasis, angiogenesis and cancer stem cells-like (CSCs) properties, and increased apoptosis of BC cells. In addition, in vivo experiments show that blocking of SETD5 expression significantly inhibited tumor formation and lung metastases of BC cells. SETD5 regulates glycolysis of breast CSCs Mechanistic analysis showed that SETD5 contributes BC progression by interacting with AKT1 pathway. These findings indicate SETD5 is a potential prognosis marker and interventional target for the treatment of BC. Funding Statement: This study was supported by the National Natural Science Fundation of China (81760531). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: This research complied with the Declaration of Helsinki and was approved by the Human Ethics Committee and the Research Ethics Committee of Yanbian University. All animal experiments were carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocol was approved by the Yanbian University Animal Care & Use Committee.

Epigenetically Regulated DNA Rereplication as a Precursor to Inherited Gene Amplification

Genome‐wide analysis of copy number variation (CNV) in cancers has identified chromosomal regions with higher frequencies of gain or amplification. However, we do not understand the origins of many of these CNVs or whether it is possible to prevent their development. We previously demonstrated that epigenetic enzymes can regulate CNVs during S phase by inducing Transient Site‐specific Gains (TSSGs) through DNA rereplication. Regions undergoing TSSG are frequently amplified in tumors suggesting that TSSG events could precede stable inherited amplifications. These previously undetected and unanticipated transient CNVs alter how we think about tumor heterogeneity and the development of inherited CNV.To understand the origins of environmentally induced gene amplifications, we used the classical gene amplification model of the metallothionein (MT) genes. The MT locu sis amplified in cells selected by exposure to copper, zinc or cadmium. Increased expression and amplification of the MT locus correlates with poor overall survival in breast cancer. However, the mechanisms that lead to MT amplification are poorly understood.Here we describe derivation of cadmium resistant breast cancer cells that exhibit progressive amplification of the MT locus. Surprisingly, early focal, transient amplification of the MT locus (MT TSSG) precedes larger inherited gene amplifications. Using novel sequencing technology for detecting DNA rereplication, we demonstrate that the focal transient MT locus amplifications correlate with DNA rereplication. Importantly, regions of DNA rereplication resemble MT amplifications observed in breast cancer patients.We demonstrate that TSSG of the MT locus is epigenetically regulated and long‐term inhibition of epigenetic silencing pathways allows transition from focal MT TSSG to inherited gene amplifications in the absence of selective pressure from cadmium. Furthermore, we demonstrate that transition from focal transient amplifications to stable inherited MT amplifications requires the homologous recombination pathway. Our results describe a new paradigm for the origin of targeted gene amplifications where epigenetically regulated DNA rereplication precedes stable inherited gene amplification.

MicroRNA‑34a expression affects breast cancer invasion invitro and patient survival via downregulation of E2F1 and E2F3 expression.

Breast cancer is the most common cancer type and the leading cause of cancer‑associated mortality in women across the majority of countries. In general, the incidence of breast cancer has been decreasing in developed countries over the previous 20 years, while it has increased in the other areas, such as the Asian‑Pacific region. MicroRNA‑34a (miR‑34a) targets stem cell‑associated transcription factors E2F1/E2F3, and may have clinical relevance in breast cancer. The present study aimed to investigate the association between miR‑34a/E2F1/E2F3 and patient survival in breast cancer, as well as the underlying molecular mechanism of miR‑34a in suppressing factors associated with tumor aggressiveness invitro. Kaplan‑Meier survival curves were constructed and a meta‑analysis was performed to analyze the association of miR‑34a, E2F1 and E2F3 expression and overall survival in breast cancer, and the differential expression levels of E2F1 and E2F3 between breast cancer and normal breast tissues was assessed using publicly accessed datasets. Then 2D and 3D experiments on cell cultures were performed invitro on both T‑47D and MDA‑MB‑231 cells to investigate the cancer biology of miR‑34a and its effect on E2F1 and E2F3 expression using reverse transcription‑quantitative PCR. Then, caspase‑3 (CASP3) activity was measured using a CaspACE™ assay system. E2F1 and E2F3 expression levels were upregulated in breast cancer, compared with normal breast tissues. Both high miR‑34a, and low E2F1 and E2F3 mRNA levels were positively associated with longer survival times in patients with breast cancer. The invitro 2D and 3D cell experiments revealed that overexpression of miR‑34a significantly downregulated the expression of E2F1 and E2F3, and increased CASP3 activity in both T‑47D and MDA‑MB‑231 cells, and that miR‑34a treatment inhibited tumor cell proliferation, migration and invasiveness, as well as 3D spheroid formation. Thus, miR‑34a influences the aggressiveness of breast cancer and patient survival, and is a potential therapeutic tool in the clinical management of breast cancer.

Immune cell infiltration-based signature for prognosis and immunogenomic analysis in breast cancer.

Breast cancer is one of the most human malignant diseases and the leading cause of cancer-related death in the world. However, the prognostic and therapeutic benefits of breast cancer patients cannot be predicted accurately by the current stratifying system. In this study, an immune-related prognostic score was established in 22 breast cancer cohorts with a total of 6415 samples. An extensive immunogenomic analysis was conducted to explore the relationships between immune score, prognostic significance, infiltrating immune cells, cancer genotypes and potential immune escape mechanisms. Our analysis revealed that this immune score was a promising biomarker for estimating overall survival in breast cancer. This immune score was associated with important immunophenotypic factors, such as immune escape and mutation load. Further analysis revealed that patients with high immune scores exhibited therapeutic benefits from chemotherapy and immunotherapy. Based on these results, we can conclude that this immune score may be a useful tool for overall survival prediction and treatment guidance for patients with breast cancer.

Abstract P4-05-24: A stroma-adjusted ZEB1 expression signature is associated with decreased immune cell infiltration and poor overall survival in breast cancer

Abstract The epithelial-to-mesenchymal transition (EMT) is a critical physiologic process which can be activated by cancer cells to enhance metastatic and chemoresistant properties in experimental models. Recent studies have identified positive associations between the expression of EMT-associated gene signatures with both the immune response and survival in multiple cancer types. Although these studies relied upon whole-tumor RNA sequencing data, which can be confounded by infiltrating immune and stromal cells, they failed to investigate this potential confounding effect. In this study, we comprehensively dissected the associations between the expression of multiple EMT transcription factors with stromal and immune cell tumor infiltration in breast cancer. We demonstrated that previously-reported associations between the expression of EMT marker genes and immune activity were confounded by stromal cell infiltration. Adjusting for this confounding effect eliminated these reported associations. Interestingly, we discovered that stroma-adjusted ZEB1 expression has a unique, inverse association with immune cell activity in multiple cancer types, most significantly in breast cancer. Further analysis revealed that ZEB1 is significantly correlated with reduced tumor infiltration of multiple immune cell types. By deriving a high-confidence stroma-adjusted ZEB1-activated gene signature, we confirmed that ZEB1 transcriptional activity has similar associations with both tumor immune activity and stromal content as ZEB1, thus identifying potential mechanisms underlying decreased immune cell infiltration. Finally, multivariate survival analysis reveals that the ZEB1 gene signature has significant associations with reduced overall survival in breast cancer patients. In conclusion, this study identifies a novel association between stroma-adjusted ZEB1 expression and tumor immune activity and addresses the critical issue of confounding between EMT-associated genes and tumor stromal content. Citation Format: C James Block, Guojun Wu. A stroma-adjusted ZEB1 expression signature is associated with decreased immune cell infiltration and poor overall survival in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-05-24.

Abstract P6-11-03: Characteristics and survival outcomes of HIV-positive breast cancer patients: A systematic review and meta-analysis

Abstract Background: The number of people living with HIV is increasing worldwide thanks to the use of effective antiretroviral therapy. As these individuals get older, their risk of being diagnosed with cancer increases, including non-AIDS defining cancers such as breast cancer (BC). Most reports reveal that HIV+ patients (pts) with BC tend to be younger than HIV-uninfected (HIV-) pts. However, epidemiological data is yet conflicting regarding tumor stage at diagnosis, distribution of BC subtypes and overall survival (OS) of HIV+ pts as compared to HIV- pts. This meta-analysis aims to assess differences of baseline clinicopathological characteristics and OS of HIV+ vs HIV- BC pts. Methods: We performed a systematic review using MEDLINE, Scielo, and conference abstracts up to June 10, 2019, with no language restrictions. Cohort studies and consecutive series comparing baseline characteristics (age, stage at diagnosis or BC subtypes) and/or OS of HIV+ vs HIV- BC pts were included. BC subtypes were defined according to 2 classifications: 1) “classic” immunohistochemical (IHC) subtypes (ER+/HER2-; HER2+; triple-negative BC); 2) surrogate intrinsic subtypes as per the St. Gallen Consensus (luminal A-like, luminal B-like, HER2-enriched and basal-like). Summary risk estimates (pooled mean ratios [pMR] and odds ratios [pOR]) and 95% confidence intervals (CI) were calculated using random effects models. OS data were pooled as hazard ratios (HR) and 95% CI and modeled using a random effects model. The main endpoints were age (as a continuous variable), stage at diagnosis (early [0-II] vs late [III-IV]), distribution of BC subtypes and OS (using both adjusted and unadjusted HR). Subgroup analysis of each endpoint was performed according to region of the world. Results: A total of 16 studies (4 from North America and 12 from Sub-Saharan Africa [SSA]) published from 2005-2019 were included in this meta-analysis (with 1,764 HIV+ and 1,330,122 HIV- pts). HIV+ pts were younger than HIV- pts (pooled mean age of 41.1 vs 50.5 years, respectively; pMR 0.82, 95% CI 0.76-0.90, p < 0.001) and had a 45% increased risk of presenting with late stage disease (pOR 1.45, 95% CI 1.25-1.68, p < 0.001). There were no differences regarding distribution of BC subtypes, both by the “classic” IHC or by the St. Gallen classification. Overall, HIV+ pts had a 91% increased risk of dying as compared to HIV- pts (adjusted HR for OS: 1.91, 95% CI 1.06-3.45, p = 0.031 and unadjusted HR for OS: HR 1.47, 95% CI 1.10-1.95, p = 0.008). Subgroup analysis of OS according to region of the world showed that, in North America, HIV+ pts had a significantly increased risk of dying as compared to HIV- pts (adjusted HR 2.96, 95% CI 1.06-8.25, p = 0.038). In SSA, the increased mortality risk among HIV+ pts was also significant (adjusted HR 1.59, 95% CI 1.26-2.00, p < 0.001). Sensitivity analysis showed similar findings. Conclusion: This meta-analysis provides for the first time a comprehensive comparison of baseline characteristics and survival outcomes between HIV+ vs HIV- BC pts. Our results consistently demonstrate that HIV+ pts are diagnosed with BC at a younger age and at a more advanced stage. Additionally, even after adjusting for known prognostic factors, HIV+ pts have a worse OS as compared to HIV- pts, not only in developing countries (SSA) but also and particularly in developed countries (North America). There were no apparent differences in terms of distribution of BC subtypes. These results should raise the awareness of clinicians and policy makers regarding the detection and survival gap among HIV+ BC pts. This underserved population should be the focus of more research efforts, in order to better understand the reasons behind these disparities, which can be related to the HIV infection itself, to a more aggressive BC biology, and/or to a lower access to timely diagnosis and effective treatment. Citation Format: Mariana Brandão, Marco Bruzzone, Maria Alice Franzoi, Claudia De Angelis, Daniel Eiger, Rafael Caparica, Martine Piccart-Gebhart, Laurence Buisseret, Marcello Ceppi, Evandro de Azambuja, Matteo Lambertini. Characteristics and survival outcomes of HIV-positive breast cancer patients: A systematic review and meta-analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-11-03.

Cancer cell-intrinsic function of CD177 in attenuating β-catenin signaling.

Aiming to identify immune molecules with a novel function in cancer pathogenesis, we found the cluster of differentiation 177 (CD177), a known neutrophil antigen, to be positively correlated with relapse-free (RFS), metastasis-free (MFS) or overall survival (OS) in breast cancer. Additionally, CD177 expression is correlated with good prognosis in several other solid cancers including prostate, cervical, and lung. Focusing on breast cancer, we found that CD177 is expressed in normal breast epithelial cells and is significantly reduced in invasive cancers. Loss of CD177 leads to hyperproliferative mammary epithelium and contributes to breast cancer pathogenesis. Mechanistically, we found that CD177-deficiency is associated with an increase in β-Catenin signaling. Here we identified CD177 as a novel regulator of mammary epithelial proliferation and breast cancer pathogenesis likely via the modulation of Wnt/β-Catenin signaling pathway, a key signaling pathway involved in multiple cancer types.

Development of prognostic index based on autophagy-related genes analysis in breast cancer.

Background: Autophagy is a self-digesting process that can satisfy the metabolic needs of cells, and is closely related to development of cancer. However, the effect of autophagy-related genes (ARGs) on the prognosis of breast cancer remains unclear.Results: We first found that 27 ARGs were significantly associated with overall survival in breast cancer. The prognosis-related ARGs signature established using the Cox regression model consists of 12 ARGs that can be divided patients into high-risk and low-risk groups. The overall survival of patients with high-risk scores (HR 3.652, 2.410-5.533; P < 0.001) was shorter than patients with low-risk scores. The area under the receiver operating characteristic (ROC) curve for 1-year, 3-year, and 5-year survival rates were 0.739, 0.727, and 0.742, respectively.Conclusion: The12-ARGs marker can predict the prognosis of breast cancer and thus help individualized treatment of patients at different risks.Methods: Based on the TCGA dataset, we integrated the expression profiles of ARGs in 1,039 breast cancer patients. Differentially expressed ARGs and survival-related ARGs were evaluated by computational difference algorithm and COX regression analysis. In addition, we also explored the mutations in these ARGs. A new prognostic indicator based on ARGs was developed using multivariate COX analysis.

The Overall Survival of Breast Cancer Patients Depends on a Combination of Polymorphisms of Tumor Necrosis Factor Gene and HLA Haplotypes

Tumor necrosis factor (TNF) is a proinflammatory cytokine involved in the pathogenesis of a number of diseases, including oncological and autoimmune diseases. The –308(g/a)TNF and –238(G/A)TNF polymorphisms are included in the extended ancestral haplotypes covering the whole complex of HLA genes. We assumed that the previously found effect of these polymorphisms on the overall survival (OS) of breast cancer (BC) patients may be a consequence of cooperation with the genomic environment, namely, with the AH8.1 and B57 haplotypes associated with autoimmune conditions. The archival collection of DNA from 442 primary BC patients and 327 women from the control group with known –308(g/a)TNF and –238(G/A)TNF genotypes was used in the work. Four hundred and twelve BC patients were tested for AH8.1 and B57 markers. During the study, the association of –308a and –238A alleles of the TNF gene with haplotypes AH8.1 and B57, respectively, was confirmed. Analysis of the results of the study demonstrated that TNF gene polymorphisms do not affect the predisposition to BC disease, but significantly decrease the OS of BC patients; moreover, the final effect of the TNF gene polymorphisms on the disease prognosis depends on genomic context. At stage II of the disease, the carriers of the –308ag/–238GG genotype in the presence of marker AH8.1 alleles and the –308gg/–238GG carriers, regardless of AH8.1 markers, had a 10-year OS above 80%, while a 10-year OS was lower than 50% in the –308ag/–238GG carriers in the absence of AH8.1 markers and in the –308gg/–238AG genotype carriers (p = 0.0076). The mechanisms of action of –308(g/a)TNF and ‒238(G/A)TNF differ, and a decrease in OS in the carriers of minor –238A allele is mediated by its association with HLA-B*57, while a decrease in OS in the carriers of –308a, on the contrary, is not associated with the ancestral AH8.1 haplotype. Thus, two genetically determined BC patient groups that have an unfavorable prognosis in conditions of standard BC therapy were detected.

HLA class-I and class-II restricted neoantigen loads predict overall survival in breast cancer

ABSTRACT Tumors acquire numerous mutations during development and progression. When translated into proteins, these mutations give rise to neoantigens that can be recognized by T cells and generate antibodies, representing an exciting direction of cancer immunotherapy. While neoantigens have been reported in many cancer types, the profiling of neoantigens often focused on the class-I subtype that are presented to CD8 + T cells, and the relationship between neoantigen load and clinical outcomes was often inconsistent among cancer types. In this study, we described an informatics workflow, REAL-neo, for identification, quality control (QC), and prioritization of both class-I and class-II human leukocyte antigen (HLA) bound neoantigens that arise from somatic single nucleotide mutations (SNM), small insertions and deletions (INDEL), and gene fusions. We applied REAL-neo to 835 primary breast tumors in the Cancer Genome Atlas (TCGA) and performed comprehensive profiling and characterization of the detected neoantigens. We found recurrent HLA class-I and class-II restricted neoantigens across breast cancer cases, and uncovered associations between neoantigen load and clinical traits. Both class-I and class-II neoantigen loads from SNM and INDEL were found to predict overall survival independent of tumor mutational burden (TMB), breast cancer subtypes, tumor-infiltrating lymphocyte (TIL) levels, tumor stage, and age at diagnosis. Our study highlighted the importance of accurate and comprehensive neoantigen profiling and QC, and is the first to report the predictive value of neoantigen load for overall survival in breast cancer.

Stage-specific five-year survival outcomes in women treated for early stage breast cancer in Ibadan, Nigeria

Background: The disparity between the overall survival of breast cancer between high-income countries (HICs) and low- and middle-income countries (LMICs) has been majorly attributed to the high rate of diagnosis of Early Stage Breast Cancer (ESBC) in HICs, with about three-quarters and one-fifth of the total breast cancer patients diagnosed with ESBC in HICs and LMICs respectively. The median 5-year survival rate of ESBC in HICs is 86% while it is about 72% in Sub-Saharan Africa.Objectives: To determine stage-specific five-year survival outcomes in women treated for ESBC.Methods: We conducted a longitudinal, cohort study to assess the treatment and outcome of ESBC in a Nigerian tertiary hospital. Patients diagnosed and treated for ESBC over 5 years were recruited and followed up for a minimum of 5 years after treatment. Clinicopathologic parameters, disease progression and known vital status, were retrieved. A 5% level of significance was used.Results: 67(9.6%)patients of 694 new cases of breast cancer seen over the study duration was treated for ESBC, of whichsixty- three (63) were followed up over the specified follow-up period. The mean age was 43(10) years. Based on the American Joint Committee on Cancer staging, 9 patients were stage IA, 16 stage IB, 16 stage IIA and 26 stage IIB respectively. The overall 5-year survival was 77.8%.Conclusion: The survival pattern of our cohort fairly compares with reports in HICs, despite the challenges faced in the multimodal treatment protocol received by our patients. Keywords: early breast cancer,survival, survival analysis, stage-specific

Common polymorphic inversions at 17q21.31 and 8p23.1 associate with cancer prognosis

BackgroundChromosomal inversions are structural genetic variants where a chromosome segment changes its orientation. While sporadic de novo inversions are known genetic risk factors for cancer susceptibility, it is unknown if common polymorphic inversions are also associated with the prognosis of common tumors, as they have been linked to other complex diseases. We studied the association of two well-characterized human inversions at 17q21.31 and 8p23.1 with the prognosis of lung, liver, breast, colorectal, and stomach cancers.ResultsUsing data from The Cancer Genome Atlas (TCGA), we observed that inv8p23.1 was associated with overall survival in breast cancer and that inv17q21.31 was associated with overall survival in stomach cancer. In the meta-analysis of two independent studies, inv17q21.31 heterozygosity was significantly associated with colorectal disease-free survival. We found that the association was mediated by the de-methylation of cg08283464 and cg03999934, also linked to lower disease-free survival.ConclusionsOur results suggest that chromosomal inversions are important genetic factors of tumor prognosis, likely affecting changes in methylation patterns.

Infiltration tendency of internal mammary lymph nodes involvement in patients with breast cancer: anatomical characteristics and implications for target delineation

BackgroundDespite increasing clinical data suggest that internal mammary node (IMN) irradiation would improve local-regional control and overall survival in breast cancer, its role remains controversial due to increased risk of cardiac and pulmonary toxicity. The current study aims to determine the high risk areas of IMN metastases by collecting and analyzing the axial imaging of IMN involvement, in order to optimize IMN delineation for breast cancer.MethodsBreast cancer patients with IMN involvement were retrospectively identified from single-center database. All available imaging modalities including thoracic CT, breast MRI, ultrasound and PET/CT were used to diagnose IMN metastases. Anatomical characteristics from axial imaging, including distribution of involved ribs and distance from the internal mammary vessels (IMV), were collected for each metastatic IMN. What’s more,the natural infiltration tendency of IMNs from IMV was calculated in this study.ResultsIn total, 83 metastatic IMNs from 70 breast cancer patients (initial diagnosed:34 and recurrence: 36) were located from axial CT image in this study. The second intercostal space was the most likely involved in patients with single(n = 35, 53.0%) and multiple intercostal space (n = 31, 47.0%) involvement. The percentage of including IMN with a 5 mm, 6 mm and 7 mm medial/lateral distance to the IMV were 75.9% (63/83), 89.2.6% (74/83) and 92.3% (77/83) respectively. While in maximal dorsal/ventral distance, nearly 95% of the nodes were encompassed into 6 mm depth to the IMV. Over 65% of IMN adenopathy (32/49,65.3%) were found to have a growth direction close to the sternum. By retrospective reviewing diagnostic reports, MRI demonstrated a high diagnostic performance in diagnosis of IMN disease (90.3%, 28/31), while CT had a higher misdiagnosis rate (22/63, 34.9%). The diagnostic efficiency of IMN could be improved if different methods were combined.ConclusionsFor patients with indications of prophylactic IMN irradiation, a 7 mm medial and 6 mm dorsal distance to the IMV on axial CT would be optimal to cover the clinical volume of IMN; and it would be reasonable to extend clinical tumor volume (CTV) coverage towards sternum for patients with evident IMN disease. Multi-imaging modalities are recommended to improve the diagnostic specificity and sensitivity of IMN metastases.

Combination drug delivery with actively-targeted PLGA nanoparticles to overcome multidrug resistance in breast cancer

Drug resistance is a major obstacle reducing the efficacy of cancer chemotherapy that decreases overall survival in breast cancer. P-glycoprotein (P-gp) inhibitors have potential to eliminate this problem whereas systemic usage of them such as elacridar is limited due to side effects and toxicity. This study aims to develop and evaluate paclitaxel and elacridar co-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles actively targeted to transferrin receptors to deliver anti-cancer drug and simultaneously overcome multi-drug resistance in breast cancer. In this study, PLGA nanoparticles were prepared by nanoprecipitation method and decorated with transferrin. Following characterization of the nanoparticles and drug release experiments, their efficacy was evaluated on breast cancer EMT6/AR1.0 cells which have high P-gp expression and resistance to paclitaxel. The average particle size and zeta potential of transferrin-decorated paclitaxel and elacridar co-loaded PLGA nanoparticles were 226.9 nm and −3.9 mV, respectively. Their encapsulation efficiency was quite high (70–76%) and comparable for both paclitaxel and elacridar. Decoration with transferrin led to facilitated uptake of the nanoparticles by breast cancer cells and the combinatorial delivery of paclitaxel and elacridar through PLGA nanoparticles breached the resistance and enabled cytotoxicity. In conclusion, simultaneous and targeted delivery of nanoparticles co-loaded with P-gp inhibitors and anti-cancer drugs may be a promising approach for cancer therapy.

453P - Body mass index did not correlate with short term overall survival in breast cancers

BackgroundObesity is a risk factor for the development of new cases of breast cancer and also affects survival in women who have already been diagnosed with breast cancer, but in Asian women, these findings is not evident. We aimed to investigate the correlation between the body mass index (BMI) and overall survival of patients with a breast cancer. MethodsWe conducted a retrospective observational study from a single institute from January 2014 to December 2018. Among all 412 patients diagnosed and treated with breast cancer, we categorized them as three groups (low weight: BMI < 18kg/m2, normal: BMI < 25kg/m2, obesity: BMI ≥25kg/m2) and investigated overall survival according to menopausal status and adjuvant endocrine therapy. We used a kaplan-meier analysis with log-rank test. ResultsTotal 412 patients were enrolled. Mean duration of follow up was 33.3 months. Obesity, normal BMI and low BMI was 120(29.1%), 202(49.0%), and 40 (9.7%) patients, respectively. BMI was correlated with age, patients with obesity was 16% (28/174) of women with less than 50 years, but 38.6% (92/238) of women with more than 50 years. Overall survival was not significantly different among groups (Obesity group: 95%, Normal group: 95.5%, low BMI: 97.5%, p = 0.77, χ2=1.1). Women without adjuvant hormone therapy show lower overall survival, but it is not significant (Obesity group: 87.7%, Normal group: 94.4%, low BMI: 90%, p = 0.89, χ2=0.62). In women with more than 50 years, low BMI was better than normal to obese women (p = 0.89, χ2=0.6). ConclusionsObesity is not major risk factor of overall survival in Korea, but in hormone receptor negative breast cancers, it correlated with early onset death or recurrence. Not only further studies need to lighten the relationship between obesity and long-term survival, but also intervention to reduce BMI needs to know its effects on breast cancer survival in Korea. Legal entity responsible for the studyThe author. FundingHas not received any funding. DisclosureThe author has declared no conflicts of interest.

Comprehensive analysis of the lncRNA‑associated competing endogenous RNA network in breast cancer.

Long noncoding RNAs (lncRNAs) have been confirmed to be potential prognostic markers in a variety of cancers and to interact with microRNAs (miRNAs) as competing endogenous RNAs (ceRNAs) to regulate target gene expression. However, the role of lncRNA-mediated ceRNAs in breast cancer (BC) remains unclear. In the present study, a ceRNA network was generated to explore their role in BC. The expression profiles of mRNAs, miRNAs and lncRNAs in 1,109 BC tissues and 113 normal breast tissues were obtained from The Cancer Genome Atlas database (TCGA). A total of 3,198 differentially expressed (DE) mRNAs, 150 differentially DEmiRNAs and 1,043 DElncRNAs were identified between BC and normal tissues. A lncRNA-miRNA-mRNA network associated with BC was successfully constructed based on the combined data obtained from RNA databases, and comprised 97 lncRNA nodes, 24 miRNA nodes and 74 mRNA nodes. The biological functions of the 74 DEmRNAs were further investigated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The results demonstrated that the DEmRNAs were significantly enriched in two GO biological process categories; the main biological process enriched term was ‘positive regulation of GTPase activity’. By KEGG analysis, four key enriched pathways were obtained, including the ‘MAPK signaling pathway’, the ‘Ras signaling pathway’, ‘prostate cancer’, and the ‘FoxO signaling pathway’. Kaplan-Meier survival analysis revealed that six DElncRNAs (INC AC112721.1, LINC00536, MIR7-3HG, ADAMTS9-AS1, AL356479.1 and LINC00466), nine DEmRNAs (KPNA2, RACGAP1, SHCBP1, ZNF367, NTRK2, ORS1, PTGS2, RASGRP1 and SFRP1) and two DEmiRNAs (hsa-miR-301b and hsa-miR-204) had significant effects on overall survival in BC. The present results demonstrated the aberrant expression of INC AC112721.1, AL356479.1, LINC00466 and MIR7-3HG in BC, indicating their potential prognostic role in patients with BC.

A new prognostic factor of breast cancer: High carboxyl ester lipase expression related to poor survival

ObjectiveThe enzyme carboxyl ester lipase (CEL), known as bile salt-dependent lipase (BSDL) or bile salt-stimulated lipase (BSSL), is mainly expressed in pancreatic acinar cells and lactating mammary glands. To investigate the link between CEL expression of breast cancer (BC) tissues and the survival of BC patients by analyzing The Cancer Genome Atlas Breast Carcinoma (TCGA-BRCA) level 3 data. MethodsThe clinical information and RNA-sequencing (RNA-Seq) expression data were downloaded from TCGA. Patients were divided into a high CEL expression group and a low CEL expression group using the optimal cutoff value (5.611) identified from the ROC curve. Chi-square test and Fisher exact test were used to find the correlation between the expression of CEL and clinicopathologic features. To assess the diagnostic capability, the receiver operating characteristic (ROC) curve of CEL was drawn. The survival differences between high and low CEL expression groups were compared by Cox regression analysis. Log-rank test was applied to the calculation of p values and the comparison of the Kaplan–Meier curves. Furthermore, Gene Expression Omnibus (GEO) datasets were used for external data validation. ResultsAnalysis of 1104 cases of tumor data showed that CEL was over-expressed in breast cancer. There were relationships between high CEL expression and clinicopathologic features. The high CEL expression group had a lower survival. By analyzing the area under the ROC curve (AUC) of CEL, it was found to have a limited diagnostic capability. CEL expression may be an independent prognostic factor for breast cancer survival through the multivariate analysis. The validation in GEO datasets also showed that CEL expression was higher in breast tumor tissues than in normal breast tissues. High CEL expression was associated with the poor overall survival of breast cancer. ConclusionsHigh CEL expression may be an independent prognostic factor for the poor survival of breast cancer.