Lower Patient Survival Research Articles

The antilymphatic metastatic effect of hyaluronic acid in a mouse model of oral squamous cell carcinoma

ABSTRACTObjectives: Lymphatic metastasis is the main cause of low patient survival in cases of oral squamous cell carcinoma (OSCC). Several animal models have been established to uncover the mechanism that regulates lymph node metastasis of OSCC cells. Unfortunately, these models often take a long time to establish. The prolonged tumor burden can lead to animal cachexia, which may ultimately affect the experimental outcome. To overcome the disadvantages of these models, we established an orthotopic metastatic animal model of OSCC that showed quick lymph node metastasis potential.Results: DiR dye-labeled CAL27 cells were injected into tongue tissues of BALB/c nude mice, and the cells metastasized to lymph nodes on day 3. Metastasis was monitored using an in vivo imaging system and confirmed by histological observation. Using this model, we investigated the role of hyaluronic acid (HA) on the cervical metastasis of OSCC cells. Surprisingly, we found that the presence of HA significantly reduced the incidence of metastasis to cervical lymph nodes compared with the control group. Further analysis revealed that the presence of exogenous HA promoted mesenchymal-epithelial transition (MET) in primary tumors while reducing the metastatic potential of OSCC.Conclusion: Our findings confirmed the establishment of a fast and reliable lymphatic metastatic mouse model of OSCC that can be used for investigating metastatic mechanisms and analyzing various antimetastasis strategies. An equally important discovery is the antimetastatic property of HA, which could provide a potential therapeutic strategy for OSCC.

The potential of micelleplexes as a therapeutic strategy for osteosarcoma disease.

Osteosarcoma (OS) is a rare aggressive bone, presenting low patient survival rate, high metastasis and relapse occurrence, mostly due to multi-drug resistant cells. To surpass that, the use of nanomedicine for the targeted delivery of genetic material, drugs or both have been extensively researched. In this review, we address the current situation of the disorder and some gene therapy options in the nanomedicine field that have been investigated. Among them, polymeric micelles (PM) are an advantageous therapeutic alternative highly explored for OS, as they allow for the targeted transportation of poorly water-soluble drugs to cancer cells. In addition, micelleplexes are PMs with cationic properties with promising features, such as the possibility for a dual therapy, which have made them an attractive research subject. The aim of this review article is to elucidate the application of a micelleplex formulation encapsulating the underexpressed miRNA145 to achieve an active targeting to OS cells and overcome multi-drug resistance, as a new and viable therapeutic strategy.

Interaction Proteomics Identifies ERbeta Association with Chromatin Repressive Complexes to Inhibit Cholesterol Biosynthesis and Exert An Oncosuppressive Role in Triple-negative Breast Cancer

Triple-negative breast cancer (TNBC) is characterized by poor response to therapy and low overall patient survival. Recently, Estrogen Receptor beta (ERβ) has been found to be expressed in a fraction of TNBCs where, because of its oncosuppressive actions on the genome, it represents a potential therapeutic target, provided a better understanding of its actions in these tumors becomes available. To this end, the cell lines Hs 578T, MDA-MB-468 and HCC1806, representing the claudin-low, basal-like 1 and 2 TNBC molecular subtypes respectively, were engineered to express ERβ under the control of a Tetracycline-inducible promoter and used to investigate the effects of this transcription factor on gene activity. The antiproliferative effects of ERβ in these cells were confirmed by multiple functional approaches, including transcriptome profiling and global mapping of receptor binding sites in the genome, that revealed direct negative regulation by ERβ of genes, encoding for key components of cellular pathways associated to TNBC aggressiveness representing novel therapeutic targets such as angiogenesis, invasion, metastasis and cholesterol biosynthesis. Supporting these results, interaction proteomics by immunoprecipitation coupled to nano LC-MS/MS mass spectrometry revealed ERβ association with several potential nuclear protein partners, including key components of regulatory complexes known to control chromatin remodeling, transcriptional and post-transcriptional gene regulation and RNA splicing. Among these, ERβ association with the Polycomb Repressor Complexes 1 and 2 (PRC1/2), known for their central role in gene regulation in cancer cells, was confirmed in all three TNBC subtypes investigated, suggesting its occurrence independently from the cellular context. These results demonstrate a significant impact of ERβ in TNBC genome activity mediated by its cooperation with regulatory multiprotein chromatin remodeling complexes, providing novel ground to devise new strategies for the treatment of these diseases based on ligands affecting the activity of this nuclear receptor or some of its protein partners.

The role of survivin in the progression of pancreatic ductal adenocarcinoma (PDAC) and a novel survivin-targeted therapeutic for PDAC.

Treating pancreatic ductal adenocarcinoma (PDAC) remains a major hurdle in the field of oncology. Less than half of patients respond to frontline chemotherapy and the pancreatic tumor microenvironment limits the efficacy of immunotherapeutic approaches. Targeted therapies could serve as effective treatments to enhance the clinical response rate. One potential therapeutic target is survivin, a protein that is normally expressed during embryonic and fetal development and has a critical impact on cell cycle control and apoptosis. In adulthood, survivin is not present in most normal adult cells, but is significantly re-expressed in tumor tissues. In PDAC, elevated survivin expression is correlated with treatment resistance and lower patient survival, although the underlying mechanisms of survivin's action in this type of cancer is poorly understood. Using patient derived xenografts of PDAC and their corresponding primary pancreatic cancer lines (PPCL-46 and PPCL-LM1) possessing increased expression of survivin, we aimed to evaluate the therapeutic response of a novel survivin inhibitor, UFSHR, with respect to survivin expression and the tumorigenic characteristics of PDAC. Cell viability and apoptosis analyses revealed that repressing survivin expression by UFSHR or YM155, a well-known inhibitor of survivin, in PPCLs effectively reduces cell proliferation by inducing apoptosis. Tumor cell migration was also hindered following treatment with YM155 and UFSHR. In addition, both survivin inhibitors, particularly UFSHR, effectively reduced progression of PPCL-46 and PPCL-LM1 tumors, when compared to the untreated cohort. Overall, this study provides solid evidence to support the critical role of survivin in PDAC progression and proposes a novel survivin inhibitor UFSHR that can become an alternative strategy for this type of cancer.

The SOX9-Aldehyde Dehydrogenase Axis Determines Resistance to Chemotherapy in Non-Small-Cell Lung Cancer.

Chemotherapy resistance and tumor relapse are the major contributors to low patient survival, and both have been largely attributed to cancer stem-like cells (CSCs) or tumor-initiating cells (TICs). Moreover, most conventional therapies are not effective against CSCs, which necessitates the discovery of CSC-specific biomarkers and drug targets. Here, we demonstrated that the embryonic transcription factor SOX9 is an important regulator of acquired chemoresistance in non-small-cell lung cancer (NSCLC). Our results show that SOX9 expression is elevated in NSCLC cells after treatment with the chemotherapeutic cisplatin and that overexpression of SOX9 correlates with worse overall survival in lung cancer patients. We further demonstrated that SOX9 knockdown increases cellular sensitivity to cisplatin, whereas its overexpression promotes drug resistance. Moreover, this transcription factor promotes the stem-like properties of NSCLC cells and increases their aldehyde dehydrogenase (ALDH) activity, which was identified to be the key mechanism of SOX9-induced chemoresistance. Finally, we showed that ALDH1A1 is a direct transcriptional target of SOX9, based on chromatin immunoprecipitation and luciferase reporter assays. Taken together, our novel findings on the role of the SOX9-ALDH axis support the use of this CSC regulator as a prognostic marker of cancer chemoresistance and as a potential drug target for CSC therapy.

Patient-Derived Colorectal Cancer Organoids Upregulate Revival Stem Cell Marker Genes following Chemotherapeutic Treatment.

Colorectal cancer stem cells have been proposed to drive disease progression, tumour recurrence and chemoresistance. However, studies ablating leucine rich repeat containing G protein-coupled receptor 5 (LGR5)-positive stem cells have shown that they are rapidly replenished in primary tumours. Following injury in normal tissue, LGR5+ stem cells are replaced by a newly defined, transient population of revival stem cells. We investigated whether markers of the revival stem cell population are present in colorectal tumours and how this signature relates to chemoresistance. We examined the expression of different stem cell markers in a cohort of patient-derived colorectal cancer organoids and correlated expression with sensitivity to 5-fluorouracil (5-FU) treatment. Our findings revealed that there was inter-tumour variability in the expression of stem cell markers. Clusterin (CLU), a marker of the revival stem cell population, was significantly enriched following 5-FU treatment and expression correlated with the level of drug resistance. Patient outcome data revealed that CLU expression is associated with both lower patient survival and an increase in disease recurrence. This suggests that CLU is a marker of drug resistance and may identify cells that drive colorectal cancer progression.

Preoperative Neutrophil Lymphocyte Ratio as a Prognostic Factor for Survival in Non-metastatic Renal Cell Carcinoma

The purpose of this study was to determine the prognostic role of preoperative neutrophil lymphocyte ratio in non-metastatic renal cell carcinoma. This retrospective study included 89 non-metastatic renal cell carcinoma patients who underwent nephrectomy between 2007 and 2017. The cut-off value of neutrophil lymphocyte ratio was determined on the basis of receiver operating characteristic analysis. Univariable and multivariable Cox regression models were performed. At a median follow-up of 6.7 y, 29 patients (34 %) had died. The cut-off value for neutrophil lymphocyte ratio was 2.5 by receiver operating characteristic analysis, with the area under the curve value of 0.77. High neutrophil lymphocyte ratio was associated with high T stage (p=0.024). Elevated neutrophil lymphocyte ratio (>2.5) was significantly associated with low overall survival. Multivariable analysis revealed that high preoperative neutrophil lymphocyte ratio was an independent risk factors for overall survival (hazard ratio 5.54, 95 % confidence interval- 1.06-28.95, p=0.043), along with age >65 (p=0.001) and large tumor size (p<0.001). Preoperative neutrophil lymphocyte ratio is an independent prognostic factor for low overall survival in patients with non-metastatic renal cell carcinoma undergoing nephrectomy.

Prognostic and clinico-pathological significance of BIN1 in breast cancer

Abstract Bridging integrator 1 (BIN1) is a potential tumor suppressor that behaves as silent or misplaced in breast, prostate, skin, lung, and colon cancers. Previous studies noted decreased BIN1 expression in breast cancer (BC). Despite this, BIN1's role in breast cancer is not well understood and remains to be elucidated. Here, we computationally analyzed BIN1 expression and its prognostic role in BC using various databases. Specifically, we found a down-regulated expression profile for the BIN1 gene in different BC subtypes using Oncomine, TCGA, and bcGenExMiner v4.2 web. The expression of BIN1 was found to be associated with various clinico-pathological conditions including estrogen receptor (ER), progesterone receptor (PR) basal-like subtype, and triple-negative breast cancer (TNBC) based on analysis of the bcGenExMiner v4.2 and TCGA databases. In addition to mRNA expression, the correlation between mRNA expression and BIN1 promoter methylation was established using TCGA datasets from UCSC Xena and ULCAN web, and we subsequently examined the relationship of BIN1 promoter methylation with different clinico-pathological conditions in BC patients. Data mining via Kaplan-Meier plotter indicated a positive association between lower BIN1 expression and low BC patient survival and various clinico-pathological conditions in BC patients. Furthermore, we identified a list of genes co-expressed with BIN1 in BC using TCGA data from the ULCAN web. Among the co-expressed genes, glycophorin C (GYPC) had the most predominant positive correlation. This correlation was further confirmed in BC using UCSC Xena and bcGenExMiner v4.2 webs. Overall, this study establishes that attenuated BIN1 expression might induce progression and poor prognosis in BC patients with GYPC association. This could be useful for clinical BC therapy.

Association between low muscle mass and survival in incurable cancer patients: A systematic review.

Current data suggest that low skeletal muscle mass provides prognostic information in patients with cancer and may even be considered a biomarker in research and clinical evaluations. The aim of this systematic review was to explore whether low muscle mass is associated with overall survival (OS) in patients with incurable cancer. A systematic search was conducted for published literature using PubMed/MEDLINE, Scopus, LILACS, and the Cochrane Library, with no restrictions on language or publication date, to examine whether low muscle mass is associated with OS in patients with incurable cancer. Eligible studies included low muscle mass evaluated using gold standard techniques (dual energy x-ray absorptiometry or computed tomography). The studies quality assessment was performed using the Newcastle-Ottawa Scale. Thirteen studies were included. The studies reported on 1959 patients between 54.3 (median) and 72.9 (mean) y of age; pancreatic cancer was the most common type of tumor. According to the survival curves and most of the multivariate analyses, there was no statistically significant association between loss of muscle mass and reduced OS. Four studies reported that overweight or obese patients with muscle mass depletion had significantly shorter OS. These results indicate that there is insufficient evidence to associate low muscle mass with OS in patients with incurable cancer. Further studies deploying other muscle measurement methods suggest that use of low muscle mass cutoff alone is still necessary in the pursuit of OS prediction in this population.

SIOP PODC adapted risk stratification and treatment guidelines: Recommendations for acute myeloid leukemia in resource-limited settings.

In low- and middle-income countries (LMICs), limited resources, suboptimal risk stratification, and disproportionate patient-to-infrastructure ratio result in low survival of patients with acute myeloid leukemia (AML). A high incidence of relapse, inherent to the biology, renders management arduous. The challenge of treating AML in LMICs is of balancing the intensity of myelosuppressive chemotherapy, which appears necessary for cure, with available supportive care, which influences treatment-related mortality. The recommendations outlined in this paper are based on published evidence and expert opinion. The principle of this adapted protocol is to tailor treatment to available resources, reduce preventable toxic death, and direct limited resources toward those children who are most likely to be cured.

Rituximab for Desensitization during HLA-Mismatched Stem Cell Transplantation in Patients with a Positive Donor Specific Anti-HLA Antibody: A Prospective Study

A prospective, clinical trial in non-manipulated haploidentical allografts was initiated to define the efficacy of a single dose of 375 mg/m2 rituximab as a desensitization regimen for donor-specific anti-HLA antibody (DSA)-positive patients with 2,000 ≤ mean fluorescence intensity (MFI) &lt; 10,000. In the clinical cohort, compared to pretransplantation [median, 4791, n=28], the median MFI levels at day 7 [0], 14 [0], 21 [0], 30 [0], and 45 [0] following transplantation were significantly decreased (P&lt;0.0001 for all). The incidence of primary poor graft function (PGF) in the clinical cohort (n=55) was comparable to that in the matched-pair cohort (n=110) negative for the DSA (5% vs. 1%, P=0.076), both of which were significantly lower than that in the historical cohort (n=22) with 2,000 ≤ MFI&lt;10,000 without receiving any treatment to cope with DSA (27%, P&lt;0.001, for all). Rituximab desensitization was associated with a reduced incidence of primary PGF (HR 0.200, P=0.023). The 3-year non-relapse mortality of patients in the clinical cohort and the matched-pair cohort were 23% and 24%, respectively, both of which were lower than that of patients in the historical cohort (37%), although no statistical significance was observed. These results led to a low 3-year overall survival in patients in the historical cohort (58%) compared to those in the clinical cohort (71%) and the matched-pair cohort (73%). These results suggest that a single dose of rituximab could be effectively used to desensitize patients and prevent the onset of primary PGF in patients who receive HLA-mismatched allografts. This study is registered at http://www.chictr.org.cn/ChiCTR-OPC-15006672. Disclosures No relevant conflicts of interest to declare.

Prostaglandin F2α-induced Prostate Transmembrane Protein, Androgen Induced 1 mediates ovarian cancer progression increasing epithelial plasticity

The role of prostaglandin (PG) F2α has been scarcely studied in cancer. We have identified a new function for PGF2α in ovarian cancer, stimulating the production of Prostate Transmembrane Protein, Androgen Induced 1 (PMEPA1). We show that this induction increases cell plasticity and proliferation, enhancing tumor growth through PMEPA1. Thus, PMEPA1 overexpression in ovarian carcinoma cells, significantly increased cell proliferation rates, whereas PMEPA1 silencing decreased proliferation. In addition, PMEPA1 overexpression buffered TGFβ signaling, via reduction of SMAD-dependent signaling. PMEPA1 overexpressing cells acquired an epithelial morphology, associated with higher E-cadherin expression levels while β-catenin nuclear translocation was inhibited. Notwithstanding, high PMEPA1 levels also correlated with epithelial to mesenchymal transition markers, such as vimentin and ZEB1, allowing the cells to take advantage of both epithelial and mesenchymal characteristics, gaining in cell plasticity and adaptability. Interestingly, in mouse xenografts, PMEPA1 overexpressing ovarian cells had a clear survival and proliferative advantage, resulting in higher metastatic capacity, while PMEPA1 silencing had the opposite effect. Furthermore, high PMEPA1 expression in a cohort of advanced ovarian cancer patients was observed, correlating with E-cadherin expression. Most importantly, high PMEPA1 mRNA levels were associated with lower patient survival.

Promotion effects of mono-2-ethyhexyl phthalate (MEHP) on migration and invasion of human melanoma cells via activation of TGF-β signals.

Malignant melanoma is one of the most leading forms of skin cancer associated with a low patient survival rate. There is an urgent need to illustrate risk factors that can trigger the motility of melanoma cancer cells. Our present study revealed that mono-(2-ethylhexyl)phthalate (MEHP) exposure can significantly increase the in vitro migration and invasion of WM983A and A375 cells. Among the tested cytokines, MEHP can increase the expression of transforming growth factor β (TGF-β). Inhibition of TGF-β via its neutralization antibody can attenuate MEHP-induced cell migration and invasion. Further, upregulation of TGF-β mediated MEHP-induced activation of Smad signals and upregulation of Snail in melanoma cells. Blocking the TGF-β/Smad signal pathway can attenuate MEHP-induced cell migration. Estrogen receptor α (ERα) was essential for MEHP-induced expression of TGF-β. In addition, MEHP can increase the expression of ERα in melanoma cells. Collectively, our study found that MEHP can stimulate the progression of melanoma via TGF-β signals. SIGNIFICANCE: Mono-(2-ethylhexyl)phthalate (MEHP) is the active and most toxic metabolite of di(2-ethylhexyl)phthalate (DEHP). Our present study revealed that MEHP can trigger the in vitro migration and invasion of melanoma cells via upregulation of TGF-β/Snail signals. It revealed that daily exposure to MEHP might be a risk factor for melanoma patients.

Surgical treatment of single and multiple thymoma recurrences.

A significant number of patients with thymoma develop a recurrence after surgery. The results of previous studies analyzing therapeutic strategies in the treatment of recurrences have been controversial. Aim of the study was to evaluate the role of surgery in the treatment of thymoma recurrences assessing prognostic factors related with survival. Between January 1993 and September 2018, 27 of 161 patients had a recurrence after complete thymoma resection. Twenty-one (13%) underwent surgical treatment of the recurrence. Primary tumor stage was: I in a patient, IIa in five, IIb in nine and III in six. The recurrence was regional in all patients and both regional and distant in four. WHO histological classification was: A in two patients, B1 in two, B2 in seven and B3 in 10 patients. Median disease-free survival from surgical treatment of the primary tumor and recurrence was 44 months (1-124). Thirty-eight operations were performed (range 1-5). Complete resection rate was 66%. Adjuvant radiotherapy and chemotherapy after surgical treatment of recurrences were performed respectively in ten and nine patients, including eight patients with multiple recurrences. Five and 10-year tumor-specific survival from recurrence was, respectively, 79% and 66%. Survival analysis showed a significant correlation between survival and WHO classification, with a significantly lower survival in patients with B3 tumors in comparison with A to B2 tumors (p = 0.026). Long-term survival was observed following surgical treatment of thymoma recurrences. These results were observed even after multiple recurrences when surgical treatment was performed within a multimodality oncological approach.

Outcomes of Liver Transplantation in Patients on Renal Replacement Therapy: Considerations for Simultaneous Liver Kidney Transplantation Versus Safety Net.

In this study, a retrospective analysis of the United Network for Organ Sharing dataset was performed to identify risk factors associated with poor outcome for patients on RRT before LT who were listed for SLK and received either SLK vs LT alone (LTA). Between January 2003 and December 2016, 8971 adult LT recipients were on RRT at the time of LT. 5359 were listed for and received LTA (Group 1). Of 3612 patients listed for SLK, 3414 (38.1%) received SLK (Group 2) and 198 (2.2%) received LTA (Group 3). Overall, Group 3 had lower graft and patient survival post-LT when compared with Groups 1 and 2 (P < 0.001). Serum creatinine at 1 year post-LT and cumulative incidence for KT at 3 years post-LT were higher for Group 3 (P < 0.001). On multivariate analysis, pre-LT diabetes (P = 0.002), Model of End-Stage Liver Disease score (P = 0.01), and donor kidney donor profile index (P = 0.025) were significant in Group 2. Recipient age >60 (P < 0.001) and RRT pre-LT (>90 days; P = 0.001) were associated with lower patient survival in Group 3. Among LT recipients on RRT before LT who were listed for SLK, RRT >90 days, and age >60 were associated with poor outcome following LTA. This suggests that programs should carefully weigh the decision to proceed with LTA vs waiting for SLK in this patient population. Future access to Safety Net KT will be an important consideration for these patients moving forward.

Verteporfin targeting YAP1/TAZ-TEAD transcriptional activity inhibits the tumorigenic properties of gastric cancer stem cells.

Gastric carcinomas (GC) are heterogeneous tumors, composed of a subpopulation of cluster of differentiation-44 (CD44)+ tumorigenic and chemoresistant cancer stem cells (CSC). YAP1 and TAZ oncoproteins (Y/T) interact with TEA domain family member 1 (TEAD) transcription factors to promote cell survival and proliferation in multiple tissues. Their activity and role in GC remain unclear. This work aimed to analyze Y/T-TEAD activity and molecular signature in gastric CSC, and to assess the effect of verteporfin, a Food and Drug Administration-approved drug preventing Y/T-TEAD interaction, on gastric CSC tumorigenic properties. Y/T-TEAD molecular signature was investigated using bioinformatical (KmPlot database), transcriptomic and immunostaining analyses in patient-derived GC and cell lines. Verteporfin effects on Y/T-TEAD transcriptional activity, CSC proliferation and tumorigenic properties were evaluated using in vitro tumorsphere assays and mouse models of patient-derived GC xenografts. High expressions of YAP1, TAZ, TEAD1, TEAD4 and their target genes were associated with low overall survival in nonmetastatic human GC patients (n = 444). This Y/T-TEAD molecular signature was enriched in CD44+ patient-derived GC cells and in cells resistant to conventional chemotherapy. Verteporfin treatment inhibited Y/T-TEAD transcriptional activity, cell proliferation and CD44 expression, and decreased the pool of tumorsphere-forming CD44+ /aldehyde dehydrogenase (ALDH)high gastric CSC. Finally, verteporfin treatment inhibited GC tumor growth in vivo; the residual tumor cells exhibited reduced expressions of CD44 and ALDH1, and more importantly, they were unable to initiate new tumorspheres in vitro. All these data demonstrate that Y/T-TEAD activity controls gastric CSC tumorigenic properties. The repositioning of verteporfin targeting YAP1/TAZ-TEAD activity could be a promising CSC-based strategy for the treatment of GC.

Genome-wide analysis and functional prediction of the estrogen-regulated transcriptional response in the mouse uterus†.

The ovarian hormones estrogen and progesterone orchestrate the transcriptional programs required to direct functions of the uterus for initiation and maintenance of pregnancy. Estrogen, acting via estrogen receptor alpha, regulates gene expression by activating and repressing distinct genes involved in signaling pathways that regulate cellular and physiological responses including cell division, water influx, and immune cell recruitment. Historically, these transcriptional responses have been postulated to reflect a biphasic physiological response. In this study, we explored the transcriptional responses of the ovariectomized mouse uterus to 17β-estradiol (E2) by RNA-seq to obtain global expression profiles of protein-coding transcripts (mRNAs) and long noncoding RNAs (lncRNAs) following 0.5, 1, 2, and 6hours of treatment. The E2-regulated mRNA and lncRNA expression profiles in the mouse uterus indicate an association between lncRNAs and mRNAs that regulate E2-driven pathways and reproductive phenotypes in the mouse. The transient E2-regulated transcriptome is reflected in the time-dependent shifting of biological processes regulated in the uterus in response to E2. Moreover, high expression of some conserved lncRNAs that are E2 regulated in the mouse uterus are predictive of low overall survival in endometrial carcinoma patients (e.g., H19, KCNQ1OT1, MIR17HG, and FTX). Collectively, this study (1) describes a genomic approach for identifying E2-regulated lncRNAs that may serve critical function in the uterus and (2) provides new insights into our understanding of the regulation of hormone-regulated transcriptional responses with implications in pregnancy and endometrial pathologies.

Overall Survival of Patients With Locoregional and Metastatic Breast Cancer: Is the Influence of Baseline Characteristics the Same?

To compare the overall survival (OS) of patients with locoregional and metastatic breast cancer (BC) considering baseline demographic, clinical and contextual characteristics. A retrospective analysis of a cancer registry was conducted, using the Kaplan-Meier and Mantel-Cox analyses for the calculation of median OS and cumulative survival. The median OS was 112 months, being longer in patients with locoregional versus those with metastatic BC at diagnosis (115 vs. 31 months, p<0.001). The cumulative survival at 1, 3 and 5 years were 94.9%, 85.6% and 76.5%, respectively. More recent year of diagnosis [hazard ratio (HR)=1.09] and age at diagnosis (≥65 vs. 40 years, HR=2.79) and presence of metastatic disease (HR=5.69) were associated with a shorter OS. The region of residence, morphology and topography of the tumor were also associated with survival in patients with BC. Rurality was only associated with lower survival in patients with metastatic BC. This study identified significant differences in the median OS of patients with locoregional and those with metastatic BC considering their baseline characteristics.

The identification of a TNBC liver metastasis gene signature by sequential CTC-xenograft modeling.

Triple‐negative breast cancer (TNBC) liver metastasis is associated with poor prognosis and low patient survival. It occurs when tumor cells disseminate from primary tumors, circulate in blood/lymph [circulating tumor cells (CTCs)], and acquire distinct characteristics during disease progression toward the metastatic phenotype. The purpose of this study was to decipher the genomic/transcriptomic properties of TNBC liver metastasis and its recurrence for potential therapeutic targeting. We employed a negative depletion strategy to isolate and interrogate CTCs from the blood of patients with TNBC, and to establish sequential generations of CTC‐derived xenografts (CDXs) through injection of patient CTCs in immunodeficient mice. The isolation and validation of CDX‐derived cell populations [analyses of CTCs were paired with bone marrow‐resident cells (BMRTCs) and liver tissue cells obtained from the same animal] were performed by multiparametric flow cytometry, immune phenotyping, and genomic sequencing of putative CTCs. Comprehensive characterization of gene expression arrays from sequentially generated CDX‐derived cell populations, online gene expression arrays, and TCGA databases were employed to discover a CTC‐driven, liver metastasis‐associated TNBC signature. We discovered a distinct transcriptomic signature of TNBC patient‐isolated CTCs from primary TNBCs, which was consistent throughout sequential CDX modeling. We established a novel TNBC liver metastasis‐specific CDX model that selectively recapitulates CTC biology for four sequential generations of mice. The evaluation of online databases and CDX‐derived populations revealed 597 genes specific to the TNBC liver metastasis signatures. Further investigation of the TNBC liver metastasis signature predicted 16 hub genes, 6 biomarkers with clinically available drugs, and 22 survival genes. The sequential interrogation of CDX‐CTCs is an innovative liquid biopsy‐based approach for the discovery of organ metastasis‐specific signatures of CTCs. This represents the first step for mechanistic and analytical validation in their application as prognostic indicators and therapeutic targets. Targeting CTC drug candidate biomarkers along with combination therapy can improve the clinical outcome of TNBC patients in general and recurrence of liver metastasis in particular.

Abstract 4385: Eukaryotic translation initiation factor 4 gamma 1 (EIF4G1): A target for cancer therapeutic intervention

Abstract Introduction: Cap-dependent mRNA translation is an essential for translation of key oncogenic proteins at optimal levels and is highly regulated by the rate limiting, initiation step in protein synthesis, thus this pathway could be exploited for therapeutic intervention in oncogene driven tumors. Eukaryotic Translation Initiation Factor 4 Gamma 1 (EIF4G1) serves as the critical scaffold for assembly of cap-dependent translation components in EIF4F complex formation. In the current study, we analyzed the role and expression of EIF4G1 in Pan human cancers panels through various approaches. Methods: Immunohistochemistry analysis of EIF4G1 protein was done on multi-organ Human Cancer tissue microarray (TMA) derived from patient’s samples from different cancers. Western blots for EIF4G1 protein was done for different cell lines in representing the different cancer type. Multiple clinical cohorts were used to analyze the EIF4G1 mRNA expression across human cancers. TCGA data analysis of EIF4G1 was done through Ualcan and c-bioportal web servers. Dependency score was calculated through Cancer Dependency Map. Results: We analyzed the EIF4G1 protein level by western blot in variety of human cancer cell lines found an elevated level of EIF4G1 protein in these cell lines. We found an increase in EIF4G1 protein levels in tissue sections from different cancer samples as compared to their respective normal tissue. EIF4G1 expression was also elevated across cancer cell lines from multiple organs. Our analysis of the TCGA data revealed the higher expression of EIF4G1 mRNA expression across human cancers. Comparison of EIF4G1 mRNA expression between tumor tissue vs normal tissue in TCGA datasets revealed higher expression of EIF4G1 in cancer tissues. We discovered that alteration frequency in EIF4G1 is prevailed across different human cancers in particular prostate cancer (~25%), ovarian cancer (~15%), Head &amp; neck cancer (~13%) and cervical cancer (~12.5%) were most affected cancer. EIF4G1 Amplification and mRNA upregulation was evident across human cancer. We further analyzed the dependency of EIF4G1 in cancer cell survival based on depletion assay through DepMap and found that EIF4G1 is required for cancer cell survival. Higher EIF4G1 mRNA level was associated with lower survival of patients in Pan Cancer analysis. Conclusions: This is the first study highlighting a broad role for EIF4G1 across pan cancers suggesting that EIF4G1 may serve as a novel target for therapy in multiple malignancies. However further studies are required to develop these concepts and test usefulness of targeting EIF4G1 in caner utilizing preclinical model systems. Citation Format: Praveen Jaiswal, Sweaty Koul, Nallasivam Palanisamy, Hari K. Koul. Eukaryotic translation initiation factor 4 gamma 1 (EIF4G1): A target for cancer therapeutic intervention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4385.