bluuebunny/crossref_metadata_2025_split huggingface dataset:
Eribulin ORA: A novel oral formulation of eribulin based on combination with the P-gp inhibitor HM30181A.
Authors: Pitzonka Laura , Cutler Murray , Lau Johnson Yiu-Nam , Cutler David , Kwan Rudolf , Smolinski Michael 
Published: May 2019

e12577 Background: Eribulin is a potent synthetic derivative of the marine sponge natural product Halichondrin B that uniquely targets microtubule growth to induce apoptotic cell death. Eribulin is currently administered intravenously (IV) to treat patients with breast cancer and liposarcoma refractory to taxane therapy due to its superior efficacy in taxane resistant tumor types. Methods: Utilizing a proprietary Orascovery platform, Eribulin ORA, a novel orally-administered eribulin formulation has been developed, which combines the P-glycoprotein (P-gp) inhibitor, HM30181A, with oral eribulin. Results: HM30181A significantly improves the systemic exposure of oral eribulin in rodents, which enables remarkable tumor regression in murine xenografts. HM30181A improves eribulin plasma exposure > 5-fold in mouse model (AUC0-24hr = 8224 ng*hr/mL with HM30181A vs. 1516 ng*hr/mL without HM30181A) and also improves eribulin oral bioavailability in the rat (%F = 35.0 with HM30181A vs. 16.1 without HM30181A). In vitro cell viability assays of MCF-7 and MDA-MB-231 breast cancer cell lines show eribulin is synergistic with other microtubule disrupting agents, including common first-line breast cancer therapy paclitaxel. In mice bearing orthotopic MDA-MB-231 breast tumor xenografts, oral eribulin with HM30181A was administered at eribulin doses of 0.5, 1.0, and 1.5 mg/kg Q2Dx3 (M,W,F)/week for four weeks. Only mice treated with 1.5 mg/kg (highest dose) eribulin had weight loss during treatment, with the observed weight loss was < 10%, (except for one mouse). All eribulin doses tested induced tumor regression, with 7/9 tumors in the 1.5 mg/kg eribulin group experiencing durable complete regression until study end, two-weeks post administration. Of the tumors in the Eribulin ORA-treated groups that resumed growth after treatment, the degree of tumor growth was minimal. Overall, Eribulin ORA was well tolerated and showed potent efficacy against breast cancer tumors, exhibiting nearly 100% growth inhibition at all dose levels tested. Conclusions: Eribulin ORA showed good oral absorption, efficacious systemic exposure, and importantly, excellent anti-cancer activity in a breast cancer model. In vitro studies demonstrated the synergistic potential of eribulin in combination with paclitaxel. Accordingly, the combination of Eribulin ORA with Oraxol (oral paclitaxel that has shown promising clinical data) may represent an excellent metronomic oral combination chemotherapy that warrants further investigation for patients with advanced breast cancer.
Pathological and genetic aggressiveness of left-sided breast cancer.
Authors: Abdou Yara , Asaoka Mariko , Takabe Kazuaki 
Published: May 2019

e12579 Background: Breast Cancer in women consistently occurs more frequently in the left breast, with the ratio of left to right sided breast cancer cases ranging from 1.05 to 1.26. In spite of the difference in frequency, prior studies have failed to show any significant difference in clinical characteristics between left sided and right sided cancer. Methods: Genomic and clinical features were collected from The Cancer Genome Atlas breast cancer project. LVI status, mitotic rate, nuclear score and tubular score were collected from pathology reports in TIES client 5.8. Fisher's exact test was used for group comparison and survival analysis was performed with Cox regression. Cytolytic activity (CYT) indicates anti-cancer immune response and was quantified from gene expression data. Hallmark gene-sets were used for gene set enrichment analysis (GSEA). Results: Among the 1081 women with unilateral invasive breast cancer, 561 had tumor on the left side compared to 520 on the right. Our results didn’t show any significant differences between left and right side with regards to tumor location, histology, race, and tumor characteristics including stage, tumor size, nodal status and receptor status. No statistical significant differences were observed in mitotic rate, LVI status and tubular score, however, the tumor grade was significantly higher in the left side. Moreover, there were no significant differences in mutation count, CYT and overall survival between both sides. GSEA revealed cell-cycle related gene sets like G2M checkpoint, Mitotic spindle, E2F targets and MYC targets which were significantly enriched in left sided tumor. Furthermore, out of the 865 genes which were highly expressed on the left side, we identified specific genes including BRCA1, BRCA2, BRIP1, CHEK2, FANCC, PALB2, TP53 and MSH6 which are associated primarily with breast cancer genesis and mostly have established clinical management guidelines. Conclusions: Our results suggest a more aggressive nature to left sided breast cancer with a higher pathological grade perhaps requiring more aggressive treatment. Such a hypothesis needs further study to confirm or refute its validity. If confirmed, it may have a major impact with regard to biology of breast cancer and its subsequent management.
[18F] Fluorodeoxyglucose positron emission (FDG-PET) in breast cancer: Clinical utility in neoadjuvant and metastatic setting.
Authors: Morales Murillo Serafin , Gasol Cudós Ariadna , Veas Rodriguez Joel , Canosa Morales Carles , Olivé Jordi Melé , Salud Antonia 
Published: May 2019

e12584 Background: FDG-PET in clinical practice is based on the detection of a relapse and the initial staging but its role as a predictive factor or its correlation with biological parameters is very controversial. Methods: We analyzed the SUV of FDG-PET in a cohort with 36 patients in neoadjuvant setting and 112 with metastatic disease. Results: The median of SUV in neoadjuvant was 8,95 (range 2,8-30) with higher SUV in triple negative (11,7 range 2,8-18,8) than HER2 positive (8,75 range 4-30) and luminal patients (7,9 range 4,4-16). We don´t find a correlation between the SUV with either histological and clinical variables but there was a slightly correlation with residual tumor (p:0,068) and initial node involvement (p:0,069). In the 112 metastatic cohort the median SUV was 7,95 (range 2-28) with higher SUV in triple negative (10,1 range 3,4-19) than HER2 positive (9,7 range 4-28) and luminal patients (7,6 range 2.21). We found only a correlation between the SUV and progesterone receptor value (OR 0,875 p:0,005) but not in estrogen receptor, Ki67 index and HER2 status. In the survival analysis we don´t find a correlation between the SUV value and the disease free and overall survival included the analysis for different phenotypes. Conclusions: The SUV of the FDG-PET is very variable in all phenotypes of breast cancer being higher in the triple negative phenotype and lower in the luminal. The SUV value is very similar in neoadjuvant and metastatic setting. We only correlated the SUV value with the progesterone receptor in the metastatic cohort. We don´t find a prognostic value of the initial value of SUV in the two cohorts.
Progression-free survival as a predictor of overall survival in patients with advanced breast cancer: A real-world study from the China National Cancer Center.
Authors: Mo Hongnan , Xu Binghe , Ma Fei , Li Qing , Zhang Pin , Yuan Peng , Wang Jiayu , Luo Yang , Cai Ruigang , Li Qiao , Li Yiqun , Guan Xiuwen , Lin Shaoyan , Chen Yimeng , Wang Zijing 
Published: May 2019

e12590 Background: Use of progression-free survival (PFS) as a clinical trial endpoint in first-line treatment of patients with advanced breast cancer is attractive, but would be enhanced by establishing a correlation between PFS and overall survival (OS). Methods: From January 2003 to December 2012, 1851 patients with advanced breast cancer at start of first-line therapy were enrolled in this real-world study. An independent cohort of patients hospitalized in 2013 was used for external validation. All data were collected from the Database of China National Cancer Cancer. Results: The correlation coefficient (Pearson’s r) between PFS and OS was 0.807 in patients only receiving endocrine therapy as first-line treatment, 0.643 in those treated with chemotherapy, and 0.642 in the whole cohort. Receiver operating characteristic curve indicated that PFS = 12 months was the optimal cutoff value for predicting patient’s survival. The median OS was 30.0 months (95% CI 27.8-32.2) in the PFS < 12 months group, and 69.0 months (95% CI 60.8-77.2) in the other group (P < 0.0001). Multivariate analysis revealed that compared with patients who did not progress at 12 months, the adjusted hazard ratio (HR) for death was 2.681 (95% CI, 2.301-3.124; P < 0.0001) for patients with PFS < 12 months. Subgroup analysis based on patient’s age, molecular subtype, visceral metastasis and types of first-line treatment further confirmed that PFS < 12 months was associated with significant poor prognosis in all these subgroups. In patients with luminal type of breast cancer, the HR for death was 2.567 (95%CI 2.147-3.069; P < 0.0001) for patients with PFS < 12 months. Notably, for these patients with luminal type breast cancer who had progressed within 12 months after first-line treatment, addition of chemotherapy in the second-line therapy would surprisingly have adverse effects on patients’ survival when compared with endocrine therapy alone (HR = 1.627, 95%CI 1.016-2.604, P = 0.043). The findings were externally validated in the independent cohort. Conclusions: To our knowledge, this is the first real-world study revealed that PFS at 12 months in first-line therapy predict OS of patients with advanced breast cancer.
Genome-wide chromosomal instability by cell-free DNA sequencing to predict patient survival in metastatic breast cancer.
Authors: Mo Hongnan , Wang Xiaobing , Ma Fei , Qian Ziliang , Sun Xiaoying , Yi Zongbi , Guan Xiuwen , Li Lixi , Liu Binliang , Xu Binghe 
Published: May 2019

e12591 Background: Cell-free DNA (cfDNA) could well recapitulate the genomic features of tumor with minimal invasion. For metastatic breast cancer (MBC), prior applications of cfDNA have focused on tracking specific gene locus. We aimed to evaluate the prognostic value of genome-wide chromosomal instability derived from cfDNA in patients with MBC. Methods: We retrospectively identified 65 patients with MBC who were intended to change line of therapy and had blood draw for cfDNA. We performed low-coverage whole-genome sequencing of cfDNA from plasma, and chromosomal instability was analyzed and represented by chromosomal instability (CIN) score. Results: 32 (53.3%) samples resulted to have high CIN score, with similar clinicopathologic characteristics relative to patients with low CIN. None of patient’s age (P = 0.073), receptor status (P = 0.136), disease stage at primary diagnosis (P = 0.353), or previous lines of therapy (P = 0.067) was correlated with genome-wide chromosomal instability. Different subtypes of MBC exhibit remarkably diverse copy number profiles. High CIN score was associated with significantly shorter overall survival after blood draw, median 21.2 months (95% CI 14.1-28.3) versus not reached (P = 0.006). Besides, patients with high CIN had worse progression free survival compared with the low CIN group (median 7.3 vs 11.0 months, P = 0.034). CIN score remained an independent prognostic factor in multivariate analysis (hazard ratio, 3.563; 95%CI, 1.481 to 8.572; P = 0.005). Conclusions: Here we present a framework for minimally invasive genomic characterization of different subtypes of MBC, and subsequent integration with clinicopathologic data and patient outcomes. Genome-wide chromosomal instability tracking by cfDNA is reliable and predicts survival in patients with MBC.
Fixed dose, dose-dense capecitabine in metastatic breast cancer.
Authors: O'Dea Anne , Khan Meshaal , Haines Haley Isabela , Kimler Bruce F. , Nye Lauren Elizabeth , Sharma Priyanka , Khan Qamar J. 
Published: May 2019

e12593 Background: Capecitabine (C) is the only oral chemotherapy agent for metastatic breast cancer (MBC), and compared to IV agents, can be continued indefinitely if toxicities can be managed. The optimal dose and schedule of C are not known. FDA approved dose of 2500 mg/m2 daily is associated with median PFS (progression free survival) of 4-5 months and dose reduction and discontinuation rates from toxicity of 35% and 16% respectively. According to Norton-Simon mathematical model of tumor growth in which dosing schedules are determined based on efficacy, a 7 day on and 7 days off (7-7) schedule of C was predicted as optimal. We report efficacy and toxicity of fixed dose C (1500 mg BID) on a 7-7 schedule in MBC. Methods: Retrospective chart review of patients with MBC treated at our institution between June 2013 and December 2018 and received fixed dose C (1500 mg BID) on a 7-7 dosing schedule were included. Results: 39 patients with MBC were identified; 14 (35%) had de novo MBC and 25 (62.5%) had recurrent disease. 31 (77.5%) had ER+ disease, 6 (15%) were HER2+, and8 (20.5%) had triple negative breast cancer (TNBC). 10 (25%) had received no prior chemotherapy, 15 (37.5%) had received 1 line of chemotherapy, and 14 (35%) had received ≥2 lines of chemotherapy. Median PFS was 13 months. PFS was 17 months in ER+ patients and 8 months in patients with TNBC. Palmar plantar erythrodysesthesia (PPE) was the most frequent toxicity with 11 (27.5%) having mild PPE, 2 (5%) with moderate PPE, and 5 (12.5%) with severe PPE. Mild diarrhea was experienced by 14 (35%) and one patient experienced severe diarrhea. One patient experienced grade 3 neutropenia. No patients discontinued C due to toxicity. 11 (27.5%) required a dose reduction. Conclusions: Fixed dose capecitabine (1500 mg oral BID) on a 7 day on and 7 day off schedule is associated with encouraging PFS and has limited toxicity and a low rate of dose reduction and therapy discontinuation. Randomized trial comparing this dose and schedule of capecitabine to standard dose and schedule of capecitabine is ongoing.
Prognostic significance of tartrate-resistant acid phosphatase expression in breast cancer.
Authors: Dai Ming-Shen , Lo Hao-Chan , Chen Li-Jia , Tseng Shun-Fu 
Published: May 2019

e12594 Background: Tartrate-resistant acid phosphatase (TRAP) is a metalloproteinase-like protein that is expressed in several primary and metastatic tumors, and its expression is positively correlated with the oncogenic process. Tartrate-resistant acid phosphatase is also a novel product of activated macrophage. We have previously demonstrated the clinical significance of TRAP expression in tumor-infiltrating macrophages and serum TRAP in patients with metastatic breast cancer (BC). Therefore, TRAP protein can potentially be a predictive and prognostic marker to evaluate disease progression and therapeutic response in breast cancer patients with bone metastasis. We aim to investigate the role of TRAP expression in breast cancer metastasis and survival. Methods: RNA-seq expression data were obtained from The Cancer Genome Atlas (TCGA) database. Estrogen receptor (ER)-positive, human epidermal growth factor receptor-2 (HER2)-negative, and TNBC subtypes were included in the analyses. The TRAP-overexpressed and -silenced breast cancer cells (MCF7, 4T1, MDA-MB-231) were used for validation. Survival data was also retrieved from the TCGA database to verify the prognostic biomarker. Results: Through TCGA database analysis, we found that TRAP expression correlated to the Ki-67 expression indicating the cancer cell proliferating activity. Additionally, TRAP expression positively correlated with mesenchymal markers (SNAIL, CDH1, MMP9, Fibronectin), and negatively correlated with epithelial markers (SMAD2, SOX10), implying that the TRAP expression is related to the breast cancer Epithelial-Mesenchymal-Transition process. This phenomenon was validated in TRAP-altered cell and confirmed inferior survival with TRAP-expressed breast cancer patients in TCGA database. Conclusions: Combining clinical TCGA data and cell-based analyses showed that TRAP expression was significantly associated with breast cancer proliferating activity, metastatic potential, and inferior survival. TRAP serves as a breast cancer prognostic biomarker and can be considered as a therapeutic target. Further investigation is warranted.
A comparison of platinum-based chemotherapy versus capecitabine-based chemotherapy in the treatment of breast cancer metastasis to the liver.
Authors: Chen Yimeng , Mo Hongnan , Wang Jiayu , Li Yiqun , Guan Xiuwen , Wang Zijing , Lin Shaoyan , Yi Zongbi , Xu Binghe 
Published: May 2019

e12595 Background: Liver metastasis have long been known to indicate an unfavourable disease course in breast cancer (BC). A variety of drugs have been used in first choice for anthracycline-resistant and/or taxane-resistant breast cancer. This study aimed to systematically investigate the impact of different treatments. Methods: Between January 2003 and December 2013, we examined the clinical outcome of breast cancer patients with liver metastases from database in China National Cancer Center. 284 patients who received platinum or capecitabine based chemotherapy as first-line treatment were analyzed and followed up until December 2018. Results: Overall, 284 patients (female:280/284 (98.6%); male:4/284 (1.4%)) breast cancer with liver metastasis were available for this analysis. 205/ 284 patients (72.2%) received capecitabine-based chemotherapy including docetaxel/capecitabine (TX) and vinorelbine/capecitabine(NX), while 79/284 patients (27.8%) received platinum-based chemotherapy including docetaxel/ platinum (TP) and vinorelbine/platinum(NP).The median PFS (10.1 vs 8.3 months; P = .329; 95%), and the median overall survival (OS) (35.3 vs 19.8 months; P = .012) in the TX/NX group appeared to be longer compared with those in the NP/TP group, among which NP group seemed to be the poorest. Patients aged ≥50 years who were postmenopausal were more likely to benefit from the TX/NX regimens in terms of OS, however hormone receptor and human epidermal growth factor receptor 2 status did not affect differences in PFS and OS between the TX/NX and TP/NP groups. Conclusions: Capecitabine-based chemotherapy for advanced breast cancer with liver metastasis led to longer OS than platinum-based chemotherapy. These findings should be validated in more prospective cohorts.
Real-world evidence evaluating the use of an NK-1 antiemetic in the systemic chemotherapy treatment of metastatic breast cancer.
Authors: Lord Kevin , Feinberg Bruce A. , Kish Jonathan , Laney Jalyna R. , Chopra Dhruv , Liassou Djibril 
Published: May 2019

e12599 Background: Severe and persistent nausea and vomiting (n/v) impacts quality of life and may lead to treatment discontinuation. While antiemetics assist with minimizing these effects, newer drugs can be expensive and carry their own side effect profile. Prior research has suggested that neurokinin 1 receptor inhibitor(NK-1) antiemetics are overly prescribed. Using the package insert recommendations for aprepitant, an NK-1, we evaluated the frequency of its prophylactic use to prevent emesis in patients receiving systemic chemotherapy(chemo) with moderate to high emetogenic risk. Methods: Patients were identified from a third-party, administrative claims database. Using medical and pharmacy claims, any female with ICD-9/10 codes for both breast cancer and metastases diagnosed between Jan-2013 and Dec-2017, who initiated systemic chemo and received aprepitant prophylactically were selected. Chemo regimen emetogenic potential was scored using the Hesketh scale and aggregated into two cohorts: low risk (grade 1-2 = none- < 30%), and moderate-high risk (grade 3-5: > 30- > 60%). If patients received combination chemo, the assigned risk level was the highest risk of any individual agent. The frequency of NK-1 use for each risk cohort was calculated per line of therapy independent of the previous treatment. Results: 10,342 patients met the selection criteria with 2,868 patients administered moderate-high emetogenic risk chemotherapy regimens. Mean age at initiation of treatment was 61.7 years (SD = 12.12). By line, the aprepitant utilization rate was: 1 line(L) 43% ,2L 27%, 3L 18%, 4L 16%, 5L 11% and 6L 12%. Across all lines of therapy, aprepitant was used prophylactically in 23% of patients treated with high risk chemo regimens and in 2% of patients who had received low risk regimens. Conclusions: Prophylactic use of the NK-1 inhibitor aprepitant was less than 50% in 1L moderate-high emetogenic risk chemotherapy and declined with consecutive lines of treatment. NK-1 use with low risk regimens was minimal. Further research is needed to understand the pattern of use and clinical outcomes between moderate-high emetogenic risk patients who do and don't receive NK-1 antiemetic supportive care.
Alteration of TGF-β signaling pathway predicts worse prognosis in pancreatic ductal adenocarcinoma.
Authors: Tian Bole , Li Mao , Cao Dan , Li Ang , Zhao Xiaochen , Hou Shengzhong , Lu Shan , Mou Yu , Liu Xubao , Cai Shangli 
Published: May 2019

e13006 Background: Transforming growth factor beta (TGF-β) signaling pathway is one of the core pathways involved in tumor initiation and progression. The prognostic value of TGF-β pathway genes as a functionally related group in pancreatic ductal adenocarcinoma (PDAC) is rarely studied. Methods: 72 PDAC patients who underwent surgery between November 30, 2015 and September 13, 2017 in West China Hospital, Sichuan University were identified and included in this study. Whole-exome sequencing (WES) or targeted next-generation sequencing was performed with tumor tissue from all the participants. Clinical data was retrospectively collected. Clinicopathologic characteristics and overall survival (OS) were analyzed. Results: Genetic alterations were detected in 71 patients (98.6%). While 1 patient (1.4%) had only one genetic alteration, 33 patients (45.8%) had 2-4 genetic alterations and 37 patients (51.4%) had ≥5 genetic alterations. Overall, 25 patients (34.7%) with alteration of TGF-β pathway and 47 patients (65.3%) with wild type of TGF-β pathway were identified as TGF-βm+ group and TGF-βm- group respectively. Mutation of TGF-β pathway was independently associated with inferior OS in present cohort (HR, 2.22; 95% CI, 1.05-4.70; P = 0.04), adjusted for tumor stage, metastasis, surgery method and comorbidity. Subgroup analysis showed that patients with mutation of TGF-β pathway had shorter OS after radical surgery (HR, 3.25, 95% CI: 1.01–10.49; P = 0.04). While in the subgroup of patients who underwent palliative surgery, OS was not statistically different (HR, 0.93, 95% CI: 0.41–2.09; P = 0.86). Conclusions: Inferior prognosis was observed in PDACs with mutations of TGF-β pathway. Genomic information could help screen out patients at risk after surgery and adjuvant therapy might benefit this subgroup of PDACs.