bluuebunny/crossref_metadata_2025_split huggingface dataset:
Shugoshin as a key mediator in the metastasis of triple negative breast cancer.
Authors: Hernandez Valeria Julia , Jusino Shirley , Rivera Rivera Yainyrette , Chardon Colon Camille , Rodriguez Rodriguez Patrcia C. , Roman Gonzalez Janeishly , Isidro Angel , Saavedra Harold I. 
Published: June 2023

e13098 Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by the lack of estrogen, progesterone, or human epidermal growth factor 2 (HER2) receptor expression. TNBC has poor prognosis due to its high metastatic potential and limited treatment options. Shugoshin-1 (Sgo1), a centromeric protein that maintains stability in chromatids during mitosis, has been thought to play an important role in the progression of TNBC. Previous publications from our group have shown that the transient downregulation of Sgo1 in TNBC cells decrease the epithelial-to-mesenchymal transition (EMT), which is a precursor of metastasis. Our purpose with this study is to evaluate the role of long-term effects of Sgo1 downregulation in cell invasion, cell migration, tumor growth, and metastasis. Methods: To achieve our goal, MDA-MB-231 cells were stably transfected with a lentivirus containing a shRNA Sgo1 sequence or a scramble shRNA control. Cell invasion and migration were evaluated by Boyden chamber assays. Meanwhile, tumor growth and metastasis were evaluated using an immunocompromised orthotopic mice model. Female NOD-SCID Gamma (NSG) mice were injected either with 2.5 X 106 shRNA Control (n= 10) or shRNA Sgo1 (n= 10) MDA-MB-231 cells. Tumor growth was measured for eight weeks using a vernier caliper. Afterwards, primary, and metastatic tumors as well as primary organs were harvested. Lung and liver samples were embedded in paraffin and stained with hematoxylin and eosin. A Student t test was used to evaluate the differences between groups. A p-value < 0.05 was considered significant. Results: Our results show a significant reduction in cell invasion and migration in MDA-MB-231 cells treated with shRNA Sgo1. Moreover, we observed a significant reduction in tumor growth and metastasis to lymph nodes, liver, and lungs in the mice treated with shRNA Sgo1 when compared to shRNA Control group. Conclusions: These results suggest that Sgo1 is an important regulator in TNBC tumor growth and metastasis through the modulation of EMT genes. Thus, targeting Sgo1 early in the course of TNBC can be a potential therapeutic treatment of TNBC.
Identification of a novel squalene epoxidase function in breast cancer brain metastasis.
Authors: Wang Shu-Ping , Yeh Jia-Yun , Lee Pony Yu-Ling , Lin Kun-Yuan , Chang Chao Di , Yang Chih-Chieh , Cheng Shan-Yun , Hung Ya Wen , Yu Yung-Lung 
Published: June 2023

e13101 Background: Brain metastases are serious complications of breast cancer and there is no effective treatment. The major therapeutic issues can be attributed to the unique brain microenvironment as well as the difficulty of drug delivery to the brain due to the blood-brain barrier (BBB). BBB limits access of nutrients from the circulation and thereby makes the brain in a special condition that is hypoxic and composed of depleted metabolites, growth factors, and proteins. Nevertheless, tumor cells that are able to metastasize to the brain can necessitate metabolic adaptations for their nutrient availability and thereby succeed to colonize in the brain. However, it is still poorly understood how breast cancer cells alter their metabolic systems to manipulate brain metastasis by overcoming nutritional limitations. Methods: To probe the molecular mechanism of breast cancer to brain metastasis, we compared gene signatures in primary breast tumors and breast-to-brain metastatic tumors, and identified that SQLE (encodes squalene epoxidase, the second rate-limiting enzyme in the cholesterol biosynthesis) could be a leading-edge gene in breast-to-brain metastasis. Using the brain metastatic MDA-MB-231-BR (231-BR) and its parental MDA-MB-231 (231) cell line expressing SQLE shRNAs, we evaluated the effects of SQLE loss on cancer cell migration, invasion, and stemness by wound-healing, transwell invasion/migration, and tumorsphere formation assays. The in vitro cell-based BBB model and in vivo mouse models that develop 231-BR brain metastases were established to verify our hypothesis. Results: While loss of SQLE greatly attenuated cell invasiveness and stemness in both 231 and 231-BR cells, loss of SQLE could only affect the cell migration activity on 231 cells but not 231-BR cells. Since the ability to invade, migrate, and penetrate is critical for invasion of cancer cells, our results strongly imply the novel function of SQLE in breast cancer cell invasion, penetration, and colonization in the brain. Our RNA-seq data further identified a subset of SQLE-affected genes that is uniquely enriched in 231-BR cells and favors brain extravasation and colonization. The in vitro cell-based BBB model and in vivo mouse models that develop 231-BR brain extravasation and colonization finally verified our hypothesis that SQLE may play a unique function to promote breast cancer metastasis into the brain. Conclusions: Our findings provide new insights into contributions by SQLE in breast-to-brain extravasation and colonization and indicate that targeting SQLE may represent a therapeutic opportunity for breast cancer brain metastases.
Survival outcomes and clinicopathological factors analysis of breast cancer patients. A single-institution cohort from 2012 to 2020 in a Mexican population.
Authors: Grajales Rocio , Gutierrez Alicia , Pichardo Christian , Gutierrez Marcos , Dip Borunda Abdel Karim 
Published: June 2023

e13104 Background: In Mexico, The Instituto Mexicano del Seguro Social (IMSS) is a tripartite contribution which provides care to more than 74 million beneficiaries, which represents more than 50% of the general population of the country. Although Mexican breast cancer statistics have been reported, it is imperative to know the updated statistics on the epidemiology in our Institution. The aim of this study is to describe the survival outcomes and the clinical-pathological characteristics of patients with breast cancer. Methods: Records of breast cancer patients treated at the Oncology Hospital from Centro Medico Nacional Siglo XXI of IMSS, from January 2012 to December 2020 were included. We analyzed clinical and demographic characteristics of the population, as well as survival outcomes at 5-years. Results: A cohort of 5,264 patients was included. Median follow up was 54.9 months. Forty-three percent (n = 2,274) were diagnosed in early-stage breast cancer (I–IIA), 43.1% (n = 2,269) in stages IIB-III, and 7% (n = 383) in stage IV. The most common immunophenotype was hormone receptor (HR) positive, HER2-negative (70.8%, n = 3,726). HER2-positive represents 19.3% (n = 1011), among HR-positive were 12.4% (n = 650) and HR-negative, 6.9% (n = 361). 527 patients (10.1%) were triple negative. At 5-years, disease-free survival was 74.9% (95% CI, 73.5 to 76.3) and overall survival was 90.4% (95% CI, 89.4 to 91.3). High histologic grade (HR 1.51; 95% CI, 1.33 to 1.7; p < 0.001) and lymphovascular invasion (HR 1.84; 95% CI, 1.62 to 2.1; p < 0.001) were associated with higher risk of recurrence. Adjuvant chemotherapy was significantly associated to a 42% reduction in the risk of recurrence, HR 0.58 (95% CI, 0.49 to 0.69; p < 0.0001), and 54% in the risk of death, HR 0.46 (95% CI, 0.33 to 0.63; p < 0.0001) in stage III. Lobular histology was also associated with worse survival, HR 1.41 (95% CI, 1.069 to 1.859; p = 0.015). Conclusions: An update of breast cancer Mexican patients treated at IMSS is presented. We highlight the impact of adjuvant treatment and pathological risk factors for recurrence and death. This work can contribute to evaluate areas for improvement in management and outcomes in our population.
A pilot study of the combination of entinostat with capecitabine in high-risk breast cancer after neoadjuvant therapy.
Authors: Humphrey Clare , Millard Trish Ann , Brenin Christiana , Dhakal Ajay , Falkson Carla Isadora , Petroni Gina R. , Wages Nolan , Dillon Patrick Michael 
Published: June 2023

e13107 Background: Breast cancer has an unacceptably high recurrence rate when residual disease is found following neo-adjuvant treatment of high-risk disease. Based on clinical data suggesting an adjuvant role for epigenetic modifying agents in breast cancer and preclinical data suggesting synergistic activity of entinostat combined with capecitabine, we conducted a phase I, open label study of these agents in metastatic breast cancer (MBC). Both agents have published doses for use in combination therapy, but the agents had not previously been combined with each other in a human trial. Methods: A multisite phase I dose escalation study was performed at two academic centers. Patients with pretreated, HER2 negative MBC, and measurable disease were enrolled. Dual dose escalation was performed via a Bayesian partial order continual assessment method. Dose levels ranged from entinostat 3mg to 5mg and capecitabine 800mg/m2 to 1000mg/m2. Results: Thirteen patients with MBC and a median of 4 lines of prior therapy were enrolled across four dose level combinations. The most common toxicities were neutropenia, thrombocytopenia, and palmar- plantar erythrodysesthesia, which were expected toxicities. No new safety signals were observed. One dose-limiting toxicity was observed, which did not exceed a pre-specified toxicity rate of 25%. The median treatment duration was 2.37 months. No partial nor complete responses were observed. The study was halted early prior to entering an expansion phase. Conclusions: The tested dosing combinations of entinostat and capecitabine are likely safe in heavily pretreated metastatic breast cancer patients. Entinostat clinical investigation in breast cancer was halted while this study was ongoing. Clinical trial information: NCT03473639 .
Prognosis of patients with HER2-low breast cancer brain metastasis: A single-institution experience.
Authors: Xu Hangcheng , Wang Yan , Han Yiqun , Wu Yun , Sa Qiang , Wang Jiayu 
Published: June 2023

e13109 Background: Many patients with breast cancer were reported to suffer from brain metastasis in the advanced setting. Traditionally, the HER2-low entity was classified as HER2-negative when evaluating prognosis and administrating treatment in patients with breast cancer brain metastasis (BCBM). Trastuzumab deruxtecan (T-DXd) was proved to have potent efficacy in HER2-low breast cancer, even with brain metastasis, which made this subtype a distinct entity. However, the evidence regarding HER2-low BCBM is scarce. Methods: Based on the clinical database of our institution, the BCBM patients with available HER2 status between January 2010 and July 2021 were selected. The enrolled patients with HER2 1/2+ in immunohistochemistry and negative for fluorescence in situ hybridization (FISH) were classified as HER2-low. The comparisons were conducted between HER2-low and HER2-zero category. We predefined the primary endpoint as the overall survival (OS) after the diagnosis of BCBM, which were further analyzed basing the status of hormone receptor (HR). The Kaplan–Meier curves with log-rank test and Cox proportional hazards model were utilized to analyze the survival outcomes. Results: A total of 272 cases were included in the database, among which the patients with HER2-zero (n=64) and HER2-low (n=71) subtypes were analyzed eventually. The OS of patients with HER2-low BCBM was better than the HER2-zero counterparts in the overall population (p=0.002) and the HR-negative group (p=0.008), while the similar tendency was not observed in the HR-positive patients. Moreover, the Cox regression analysis demonstrated that the HER2-low status was a significant prognostic factor for the better clinical outcome in the HR-negative patients (p=0.046 for multivariate analysis). Conclusions: The patients with HER2-low BCBM had better prognosis than the HER2-zero counterparts, especially in the HR-positive subgroup. The low expression of HER2 is supposed to be related to the long-term survival of BCBM patients.
Cancer recurrence: Detection and diagnostic intervals in Danish primary care.
Authors: Grooss Kasper , Rasmussen Linda Aagaard , Christensen Kaj Sparle , Pedersen Anette Fischer , Vedsted Peter 
Published: June 2023

e13110 Background: Danish cancer survivors receive hospital-based, specialized follow-up care with one central aim to detect cancer recurrence (CR) at an early stage. Nevertheless, CR is frequently detected outside of scheduled follow-up visits as 40-60% of CR patients encounter and present symptoms. The family physician (FP) is presumed to facilitate most of these diagnostic pathways. However, little is known about CR detection in primary care. We aim to examine diagnostic intervals, actions taken by the FP and sub-optimal events for patients presenting symptoms of CR in primary care. Methods: We are conducting a retrospective, national cohort study based on questionnaire data linked to register data at the individual level. Patients diagnosed with CR of melanoma, lung, breast, colorectal, bladder, ovarian and endometrial cancer between Jan 2022 and May 2024 are included. Patients are identified consecutively using validated, register-based algorithms. All Danish citizens have access to free healthcare and 99% are listed with a specific FP. The affiliated FP is invited to complete a questionnaire on the diagnostic pathway utilizing the patient medical record. Danish health registers provide information on the primary cancer, CR diagnosis date, comorbidity, education, sex, and age. Results: We aim to include 3,000 CR patients and expect to receive information on 1,000 CR diagnostic pathways initiated in primary care. We will present preliminary results from the first 500 responders. The proportion of diagnostic pathways initiated in primary care was 33%, hospital-based follow-up was 44%, and another route was 23%. The FPs initiated the diagnostic pathway by referral to cancer specific urgent pathway for 31% of patients, by referral to specialized private or hospital-based physician including diagnostic imaging for 30% of patients. For 31% of diagnostic pathways, the FPs reported sub-optimal or delaying events. The most frequently reported sub-optimal event was regarding clinical decisions by the FP (12%). For patients with CR of breast cancer (n=53), the mean diagnostic interval (time from first contact to CR diagnosis) was 86 days [95% CI = 61 to 112days]. Conclusions: One third of diagnostic pathways for CR was initiated in primary care. This project will provide novel, comprehensive evidence on these diagnostic pathways to inform the efforts for early detection of CR and survivorship in primary care.
B-TREUH results: A single-arm phase II pilot study of euthyroid hypothyroxinemia in metastatic breast carcinoma.
Authors: Trehan Shruti , Cheng Suzan S. , Rawal Anisha , Amos Mary , Collins Kathleen , Hercbergs Aleck 
Published: June 2023

e13111 Background: Thyroid abnormalities are prevalent in up to 1/3 breast cancer patients. T4/L-thyroxine is the most commonly prescribed treatment for hypothyroidism. However, T4 has been shown to be a potent pro-oncogenic agent by stimulating mitogenesis and angiogenesis, and inhibiting apoptosis, anti-PDL-1 and radiation effects. T3/triiodothyronine is significantly less oncogenic and mitogenic. Hence, using T3 rather than T4 might have anti-oncogenic effects, resulting in slower disease progression and improved outcomes. Methods: Adults with metastatic breast carcinoma on active treatment with estimated life expectancy of > 3months and hypothyroidism on T4 and normal TSH were eligible. Following informed consent, participants discontinued T4 and initiated T3 after a washout period. T3 dosing and titration was based on their previous dose of T4 and thyroid function testing to maintain levels of free T4 at < 50% normal range. The treatment period was 9 months and follow up for 12 months. The primary endpoint was progression free survival. Secondary endpoints were prevalence of hypothyroidism in the cohort, overall survival, quality of life, and time to achieve euthyroid hypothyroxinemia. Results: The trial was terminated early due to the pandemic and relocation of the PI and Sub-I. 7 female patients from a community medical oncology practice were enrolled between March 2019 and March 2022, Duration of metastatic breast cancer 7-223 months (average 62 months). Progression-free survival at 9 months was 5/7 (71%). Progression free survival (PFS) at 12 months, calculated in 6 patients due to data cut-off deadline and premature study closure, was 4/6 (67%). Overall survival at 9 months was 6/7 (85%). 1 patient died due to disease progression. The prevalence of hypothyroidism was 26/126 (21%). Euthyroid hypothyroxinemia was achieved in 100%, in average time of 59.6 days. 0% of the 14 serious adverse events were attributed to T3. Quality of life FACT-B scores on T4 vs T3 were not statistically significant. Conclusions: B-TREUH is the first prospective trial of euthyroid hypothyroxinemia in hypothyroid metastatic breast cancer. The transition from T4 to T3 was well tolerated with no serious adverse side effects or on quality of life. In this heavily pretreated population, PFS was 71% at 9 months and 67% at 12 months. The small number and heterogeneity of this cohort make interpretation of the PFS challenging. This unique study is simple yet provocative. Larger, broader studies are needed to explore this concept further. The low cost and easy availability of T3 and high prevalence of hypothyroidism make it an exceptionally attractive agent for future oncology research. Clinical trial information: NCT03787303 .
The mutational landscape of Chinese breast cancer by liquid biopsy.
Authors: Fan Jing , Yin Yan , Hu Bo , Peng Bo 
Published: June 2023

e13117 Background: Breast cancer is the most common malignancy worldwide. The novel technique of liquid biopsy provides further prospect of breast cancer management. However, the clinical application of liquid biopsy for breast cancer remains clearly defined. Methods: Blood samples of 145 Chinese patients diagnosed as breast cancer were collected. cfDNA were analyzed by next-generation sequencing technique using Haplox HapOnco panel. The mutations of cfDNA were analyzed and compared with genomic mutations detected within tumor tissues of breast cancer patients. Results: In total, 327 genetic mutations were detected in 145 patients using cfDNA. The top 5 high frequent alterations were TP53(50.3%), PIK3CA (42.8%), SYNE1 (16.6%), ESR1 (10.3%), CSMD3 (9.0%). Within TP53 mutations, 13.7% were frame shift insertions or deletions, 5.5% were in-frame insertions or deletions, 9.6% were splice site mutations. Within PIK3CA mutations, 1.6% were in-frame insertions or deletions, 1.6% were copy number variations. The average number of mutations for each patient was 7.2 (5.5 to 9.0, 95% CI). The mutated genes in cfDNA were compared with those in tumor tissues in publications. 208 mutated genes in tumor tissues were also detected in cfDNA. There was no significant difference in mutation rate for 83.6% genes in blood and tumor tissues. Conclusions: Most mutated genes in tumor tissues of breast cancer patients could be detected in cfDNA. The mutation rate for most genes had no significant difference in blood and tumor tissues, which indicated that liquid biopsy using cfDNA is a promising technique to improve breast cancer management.
Prognosis factors for long-term eribulin response in a cohort of patients with HER2-negative metastatic breast cancer.
Authors: El Kaddissi Antoine , Curtit Elsa , Mansi Laura , Borg Christophe , Meynard Guillaume 
Published: June 2023

e13120 Background: Eribulin is a drug used since 2010 in metastatic breast cancer. Some prognosis criteria for long progression-free survival are already described in small cohorts. We present an historic cohort to determine new prognosis criteria for long-term eribulin response in HER2-negative metastatic breast cancer. Methods: Our retrospective cohort include female patient with HER2-negative metastatic breast cancer treated with eribulin in Franche-Comté, France. We defined a long-term response as six months of eribulin treatment. The primary endpoint is the analysis of criteria that differ according to the progression-free survival. Secondaries outcomes concern overall survival, response rate and analysis of MDM2/p53 axis. Results: Median progression free survival (PFS) is 3.2 months. 23.6 percent of patients have a long-term response to eribulin. Four discriminant criteria appear to separate progression free survival in two arms (PFS < 3 months or > 6 months) predicting nearly 78% the probability of a prolonged response to eribulin: histological grade, presence of meningeal metastasis, response to prior chemotherapy and OMS status. We have developed a nomogram combining these 4 criteria. Median overall survival is 8.5 months. MDM2 amplification appear not being predictive of therapeutic response in metastatic breast cancer. Conclusions: Eribulin response in metastatic breast cancer can be drive by clinical and biological factors. The application of the nomogram proposed by our analysis can assist the clinician in the therapeutic strategy and prescription of eribulin. These results should be confirmed in real life. Multivariate logistic regression to predict PFS < 3 months vs > 6 months. [Table: see text]