bluuebunny/crossref_metadata_2025_split huggingface dataset:
CDK4/6 inhibitors in advanced hormone receptor-positive/HER2-negative breast cancer: A network meta-analysis (NMA) of randomized controlled trials (RCTs).
Authors: Husnain Muhammad , Riaz Irbaz Bin , Gondal Farva R. , Malik Saad , Sipra Qurat Ul Ain Riaz , Raina Ammad , Islam Mahnoor , Lopes Gilberto 
Published: May 2019

e12545 Background: Palbociclib(P), Ribociclib(R) and Abemaciclib(A) in combination with Endocrine therapy (ET) have demonstrated progression free survival (PFS) in patients with metastatic hormone receptor positive, HER2-negative breast cancer as compared to ET alone. In the absence of head to head clinical trials and to provide clinical guidance, we performed an indirect comparison for P, R and A using network Meta-Analysis (NMA). Methods: MEDLINE, EMBASE and the Cochrane Library were searched to identify RCTs comparing P+ET, R+ET, A+ ET vs ET alone. NMA for PFS and toxicity endpoints was conducted using a multivariate random-effects meta-regression, using a consistency model, as described by White and colleagues. We used a frequentist approach and provided a point estimate from the network and a 95% CI from the frequency distribution of the estimate. We also estimated the relative ranking of the different treatments for each outcome using the distribution of the ranking probabilities and the surface under the cumulative ranking curves (SUCRA). Risk of bias was assessed using Cochrane Collaboration tool. Results: 8 RCTs were identified including 4580 patients. Risk of bias was low. 5 RCTs tested CDK 4/6 inhibitors in endocrine naive and 2 in the refractory setting, while MONALESSA-3 included patients both with endocrine naive and endocrine resistant disease. In the endocrine naïve patients, PFS for P was similar when compared indirectly with R (HR, 0.95, 95% CI 0.67-1.35) or A (HR, 1.00, 95% CI 0.62-1.61). Similarly, indirect comparison between R vs A did not show any statistical significant (HR, 0.95, 95% CI 0.62-1.45). In endocrine refractory patients, P showed no difference when compared indirectly to A (HR 1.12, 95% CI 0.67-1.87) or R (HR 0.98, 95% CI 0.52-1.86). R vs A did not show any statistically significant PFS either (HR, 1.14, 95% CI 1.61-4.51). P was ranked first in terms of PFS in frontline setting (SUCRA of 70.5) while R ranked first in the refractory setting (SUCRA of 39.5). QT prolongation was reported for R only. P caused more neutropenia while A caused more fatigue, anemia and diarrhea, although the results were not statistically significant. Conclusions: The efficacy of using either palbociclib, ribociclib or abemaciclib in combination with ET was similar in terms of PFS in either endocrine naïve or resistant disease. Palbociclib causes more neutropenia, abemaciclib causes more fatigue, anemia and diarrhea while ribociclib causes QT prolongation.
CENP-U function on TNBC.
Authors: Zhang Jin 
Published: May 2019

e12546 Background: Centromere protein (CENP-U) gene, as an important constitutive kinetochore component, plays significant roles in cell caryomitosis. Our previous research found that about 25 % of transgenic mice with CENP-U amplified had suffered breast cancer in body surface. Also, in highly aggressive breast cancer cell lines, CENP-U presented the highest expression. Furthermore, the CENP-U protein expression obviously increased in human invasive breast carcinoma compared with the normal gland and intra-ductal tissue. Methods: Gene knockdown was accomplished by transient transfection. In addition, cell proliferation was analyzed with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and 5-Ethynyl-2'-deoxyuridine (EdU) assay while cell apoptosis was measured by flow cytometry using an annexin V-FITC apoptosis detection kit. Then, VEGF secretion in the supernatant was detected with an enzyme-linked immunosorbent assay (ELISA). Furthermore,Vascular endothelial markers of nude mouse were discovered by immunohistochemistry. And the signaling activation in the breast cancer cells was accessed by western blot using specific antibodies. Results: The MTT and EdU assay showed that CENP-U promoted the proliferation of the triple negative breast cancer (TNBC) cells while CENP-U downregulated promoted cell apoptosis. Furthermore, the ELISA results revealed that CENP-U significantly promoted the production and secretion of VEGF in TNBC cells. In addition, CENP-U downregulated inhibits tumor growth and angiogenesis in vivo. Importantly, CENP-U targeted HIF-1α,VEGFA, p-AKT and stat3, which were shown by the specific antibodies in the western blot. Conclusions: The results showed that CENP-U influence the proliferation, apoptosis and angiogenesis especially of TNBC cells. But the affected signaling pathways require further study.
The role of miR200c in leptin-mediated triple-negative breast cancer progression to an epithelial-to-mesenchymal transition.
Authors: Wang Lucas , Harlow Brittany , Bowers Laura , Hursting Stephen , deGraffenried Linda A , Brenner Andrew Jacob 
Published: May 2019

e12548 Background: Almost 40% of women with breast cancer are obese at diagnosis. Obesity is associated with a worse prognosis in triple negative breast cancer (TNBC). Preclinical studies have shown that leptin is an important factor associated with TNBC by promoting cancer stem cell (CSC) enrichment and/or epithelial-to-mesenchymal transition (EMT). Transcription factors SNAIL, TWIST and ZEB are critical components in enhancing EMT in cancer cells. The specific mechanism(s) by leptin regulates SNAIL, TWIST and ZEB expression remain unclear, limiting the development of effective interventions to improve outcomes in obese TNBC patients. Recent studies have demonstrated that miR200c, downstream of leptin receptor signaling, regulates the expression of SNAIL1, TWIST and ZEB. We will test the hypothesis that leptin contributes to obesity-induced EMT/CSC in TNBC through modulation of miR200c. Methods: Ob-R (leptin receptor) expression was suppressed in TNBC MDA-MB-231 and E-Wnt cells using shRNA (Ob-R null). Ob-R and Ob-R null cells were exposed to sera pooled from lean or obese women, as well as lean sera supplemented with leptin, after which expression of SNAIL, TWIST, ZEB and miR200c was measured by qPCR, while activation of the JAK-STAT pathway was assessed by Western blotting. Results: TNBC cells exposed to obese and high leptin conditions demonstrated increased expression of EMT markers compared to levels expressed under lean conditions. The Ob-R WT and null cells were used to determine the specific role of leptin signaling in regulating expression of SNAIL, TWIST and ZEB through miR200c. Conclusions: Both obese and high leptin conditions result in increased expression of EMT regulators, suggesting that effective targeting of this pathway may provide clinical benefit in the obese breast cancer patient. Elucidating the specific mediators of this pathway will guide development of novel and more potent medical therapies.
Effect of RNA-binding protein MSI2 deficiency on progression in triple-negative breast cancer via stabilizing TP53INP1.
Authors: Wei Ping , Li Ming , Yang Wentao , Zhou Xiaoyan 
Published: May 2019

e12555 Background: The RNA-binding protein Musashi-2 (MSI2) has been implicated in the tumorigenesis and tumor progression of human cancers. This study investigated the clinical significance of MSI2 and the potential molecular mechanisms involved in triple-negative breast cancer (TNBC) progression. Methods: The Illumina sequencing platform was used to analyze the mRNA transcriptome in TNBC vs. normal tissues, while quantitative reverse transcription–polymerase chain reaction and immunohistochemistry validated MSI2 expression in breast cancer tissues and the effects of MSI2 on TNBC cells were assayed in vitro and in viv o. RNA immunoprecipitation (RIP) DNA and RNA sequencing was performed to identify the potential MSI2-targeted mRNAs. RIP and luciferase analyses were used to confirm the mRNA targets of MSI2. Results: MSI2 expression was significantly downregulated in TNBC vs. normal tissues and was associated with a poor overall survival of patients. MSI2 overexpression in vitro and in vivo inhibited TNBC cell proliferation and invasion as well as the extracellular signal-regulated kinase 1/2 (ERK1/2) activity. Molecularly, MSI2 expression promoted the stability of TP53INP1 mRNA by its interaction with the TP53INP1 mRNA 3ʹ-untranslated region. Furthermore, knockdown of TP53INP1 expression was able to reverse MSI2-induced suppression of TNBC cell invasion, whereas ectopic expression of TP53INP1 and inhibition of the ERK1/2 activity blocked MSI2 knockdown-induced TNBC cell invasion. Conclusions: The current study demonstrated that downregulated MSI2 expression was associated with TNBC progression and a poor prognosis and that MSI2 expression inhibited TNBC proliferation and invasion by induction of TP53INP1 stability and inhibition of ERK1/2 activity.
Innate and adaptive immunotherapy: An orchestration of immunogenic cell death by overcoming immune suppression and activating NK and T-cell therapy in patients with third line or greater TNBC.
Authors: Nangia Chaitali Singh , Kistler Mira , Sender Leonard S. , Lee John H. , Jones Frank R. , Jafari Omid , Soon-Shiong Patrick 
Published: May 2019

e12566 Background: Triple-negative breast cancer (TNBC) is a heterogenous subtype of breast cancer that is frequently aggressive and has limited treatment options. We hypothesize that effective and sustained response against TNBC requires a coordinated approach that: 1. reverses the immune-suppressive tumor microenvironment, 2. induces immunogenic tumor cell death and 3. reengages NK and T-cell tumor response against a 4. cascade of tumor antigens. To test this hypothesis, we have developed a temporospatial approach that combines metronomic low dose chemotherapy, SBRT, off-the-shelf cryopreserved allogeneic NK cells, yeast and adenoviral tumor-associated antigen vaccines, an IL-15RαFc superagonist, and checkpoint inhibition. Methods: A phase 1b trial in patients with previously-treated metastatic TNBC was initiated. Treatment occurred in 3-week cycles of low-dose chemotherapy (aldoxorubicin, cyclophosphamide, cisplatin, nab-paclitaxel, 5-FU/L), antiangiogenic therapy (bevacizumab), SBRT, engineered allogeneic CD16 NK-92 cells (haNK), IL-15RαFc (N-803), adenoviral vector-based CEA, MUC1, brachyury, and HER2 vaccines, yeast vector-based Ras, brachyury and CEA vaccines, and an IgG1 PD-L1 inhibitor, avelumab. The primary endpoint is incidence of treatment-related adverse events (TRAEs). Secondary endpoints include ORR, DCR, PFS, and OS. Results: 8 subjects with 3rd-line or greater TNBC have received at least 3 treatment cycles (mean = 6 cycles). All treatment was administered in an outpatient setting. All subjects had at least 1 grade ≥3 TRAE, primarily chemotherapy-related neutropenia. Grade ≥3 haNK-related AEs (fever and fatigue) were observed in 2 subjects. 2 subjects experienced SAEs. 7 subjects remain alive, with 6 subjects receiving ongoing study treatment. 1 CR (confirmed) and 2 PRs (one confirmed) have been observed to date. Conclusions: These preliminary data suggest that low-dose chemo-radiation combined with innate and adaptive immunotherapy can be administered safely in an outpatient setting with a manageable safety profile. Clinical trial information: NCT03387085.
Asymptomatic versus symptomatic metastatic breast cancer: Potential effects on prognosis and treatment strategies.
Authors: Kuba Sayaka , Yamanouchi Kosho , Maeda Shigeto , Yano Hiroshi , Minami Shigeki , Moriuchi Hiroki , Matsumoto Megumi , Otsubo Ryota , Morita Michi , Sakimura Chika , Inamasu Eiko , Yamaguchi Junzo , Kanetaka Kengo , Takatsuki Mitsuhisa , Nagayasu Takeshi , Eguchi Susumu 
Published: May 2019

e12568 Background: Early breast cancer (BC) patients in Japan can receive a follow-up CT scan, which can diagnose asymptomatic metastatic (M)BC. How symptomatic and asymptomatic MBC differ regarding prognosis and whether treatment strategies should differ is unclear. Methods: A retrospective, multicenter, cohort study was performed. We reviewed records of MBC women treated at four institutions between 2008 and 2018. Follow-up CTs were not routinely performed. Patients were divided into three BC subtypes: Luminal (ER+, PgR+, or both, but HER2-), HER2 (HER2+), and triple negative (TN) (ER-, PgR-, HER2-). Results: Of 205 MBC patients, 120 were luminal, 51 HER2, and 34 TN. Ninety were diagnosed with symptomatic and 115 with asymptomatic MBC. Symptomatic MBC patients had the following symptoms: locoregional metastasis (43%), bone pain (25%), cough or dyspnea (16%), and brain-related symptoms (10%). Diagnosis of asymptomatic MBC was based on follow-up imaging (71%) and elevated tumor markers (27%). The proportion of the patients with symptomatic MBC were different in each subtype: 38% luminal, 45% HER2, and 65% TN (p = 0.02). Among luminal patients, median overall survival (OS) after metastasis was longer for those with asymptomatic versus symptomatic MBC (62 vs 41 M, respectively; p = 0.04), although disease-free interval (48 vs 54 M, respectively; p = 0.40) and OS after breast surgery (119 vs 126 M, respectively; p = 0.93) did not differ significantly. Conversely, among TN patients, those with asymptomatic MBC had significantly longer median OS after metastasis and after breast surgery. Although the median period of cumulative endocrine therapy after metastasis did not differ between groups, luminal BC patients with asymptomatic MBC received chemotherapy longer than those with symptomatic MBC (20 vs 12 M, respectively; p = 0.02). Most patients switched to chemotherapy because of endocrine resistance without life threatening disease. To diagnose asymptomatic MBC might lead to longer use chemotherapy. Conclusions: Physicians should take symptomatic versus asymptomatic MBC into consideration in predicting prognosis to optimize treatment strategies.
Hybrid capture-based genomic profiling of circulating tumor DNA from patients with metastatic breast cancer.
Authors: Guan Xiaoxiang , Zhu Hong , Xie Wenzhuan , Zhao Jing , Wang Guoqiang , Zhang Yuzi , Zhao Zhengyi , Cai Shangli 
Published: May 2019

e12569 Background: Breast cancer is the most common malignancy among women worldwide. It is particularly important to provide precise therapies based on genomic alterations, especially for metastatic breast cancers (MBC), which exhibit a high tumor heterogeneity and dynamic changes during the course of disease progression. However, genomic sampling upon metastatic tissue biopsy frequently encountered difficulties due to its inherent invasive approach such as insufficient samples and clinical risks. Our study aims to assess the genomic alternation landscape of metastatic breast cancer detected by blood-based circulating tumor DNA (ctDNA) and evaluate the assay performance. Methods: We performed hybrid capture-based next-generation sequencing (NGS) of 150 genes on ctDNA from 203 female patients with MBC. The mean sequencing depth was more than 3000×. The results were compared with our internal tissue genomic database (297 female patients with MBC) tested by NGS and TCGA database (N=982) tested by whole exome sequencing. Genomic alterations including single nucleotide variation (SNV), insertions/deletions, copy number variations, gene rearrangement and fusions were assessed. Results: Genomic data from 203 female patients with metastatic breast cancer were analyzed via ctDNA [median age 53 years (range, 46–61 years)]. Evidence of ctDNA as estimated by the maximum somatic allele frequency (MSAF) was detected in 95.6% of the patients (median=7.1 alterations/patient), and 97.0% of the patients had at least one characterized altered gene. The most frequently mutated genes identified for SNV occurred in TP53 (47.8%), PIK3CA (36.0%), and ESR1 (16.3%) upon ctDNA analysis and TP53 (73.2%), PIK3CA (38.4%), and ESR1 (4.0%) from our internal tissue database. However, in TCGA cohort, where most patients were presented with early stage diseases, the most mutated gene in terms of SNV was PIK3CA (32.5%), followed by TP53 (30.7%) and TTN (16.0%). The status of ERBB2 amplifications had a high concordance among ctDNA (14.8%), tissue (14.9%), and TCGA database (13.5%). The MSAF level was significantly higher for the fusion-present cases (P=0.048) or amplification cases (p<0.0001) than non-fusion or non-amplification cases. Conclusions: Our study has suggested that ctDNA profiling is a feasible approach for the molecular analysis in metastatic breast cancer and may better capture the mutational landscape of MBC for further clinical implications.
Histological growth pattern as a potential prognostic factor in patients operated for breast cancer liver metastases.
Authors: Bohlok Ali , Botzenhart Lara , Lucidi Valerio , Noel Jean Christophe , Demetter Pieter , Larsimont Denis , Donckier Vincent , Vermeulen Peter B. 
Published: May 2019

e12576 Background: Indications for surgery in patients with breast cancer liver metastases (BCLM) remain ill-defined. Recently, the histological growth pattern (HGP), such as desmoplastic (dHGP), associated with angiogenesis and inflammation, or replacement (rHGP), associated with vessel co-option and in the absence of immune infiltrate, has been demonstrated as a significant prognostic factor in patients operated for colorectal liver metastases. In BCLM, the distribution and the prognostic value of HGP are poorly documented. We aimed to characterize HGP in a series of patients undergoing liver resection for BCLM and correlate these patterns with postoperative outcomes. Methods: A consecutive series of 58 patients undergoing liver resection for BCLM was reviewed. Clinicopathologic parameters of these patients were analyzed. HGPs were assessed in archival H&E stained tissue sections, according to international consensus guidelines. The proportions of rHGP and dHGP were determined in each metastasis. In case of multiple metastases, mean HGP was calculated for each patient. Patients were categorized as pure (100% rHGP or dHGP) or dominant phenotype ( > 50% rHGP or dHGP, on the entire tumor/normal liver interface). All these factors were correlated with overall and disease-free survivals (OS and DFS). Results: After a mean follow-up of 81 months, 5-years OS and DFS in global population were 49.7% and 22.7%, respectively. No clinicopathologic preoperative factor was found to be predictive for OS or DFS. HGPs were analyzed in a first set of 21 patients. All patients showed some rHGP component. Of these, 11 were pure rHGP (52.4%), 4 dominant-rHGP (19%) and 6 dominant-dHGP (28.6%). Five-years postoperative OS and DFS were of 19.4 and 18.2% in pure rHGP, as compared with 64.8 and 33.3% in patients with some dHGP component (p = 0.089). Conclusions: rHGP appears as the main phenotype of BCLM. First analyzes suggest that surgery for BCLM with pure rHGP is associated with a worse oncological outcome as compared to BCLM with a dHGP component.
Low-dose metronomic chemotherapy (LDMC) as an efficient treatment option in metastatic breast cancer: Results of an exploratory case-control study.
Authors: Battista Marco Johannes , Schnatz Carola , Almstedt Katrin , Brenner Walburgis , Heimes Anne-Sophie , Nezi-Cahn Sandra , Schwab Roxana , Hasenburg Annette , Schmidt Marcus , Krajnak Slavomir 
Published: May 2019

e12578 Background: There is a growing importance of low-dose metronomic chemotherapy (LDMC) in metastatic breast cancer (MBC). In this retrospective case-control-analysis we compared the efficacy of LDMC and conventional chemotherapy in MBC. Methods: Each LDMC patient receiving oral cyclophosphamide (CTX) (50 mg daily) and methotrexate (MTX) (2.5 mg every other day) was matched with two patients who received conventional chemotherapy. Age, number of chemotherapy lines and metastatic lesions as well as hormone receptor (HR) status were considered as matching criteria. Primary endpoint was disease control rate greater than 24 weeks (DCR). Secondary endpoints were DCR in subgroups (number of chemotherapy lines, number of different metastatic lesions and HR status), progression-free survival (PFS) and duration of response (DoR). Results: A total of 35 cases and 70 controls entered the study. 31% patients with LDMC and 26% patients with conventional chemotherapy showed DCR (p = 0.644). Among younger patients DCR was 41% in LDMC vs. 30% in the control group (p = 0.534). In addition, DCR was achieved in 35% vs. 27% patients with ≤ 2 chemotherapy lines (p = 0.560) and in 36% vs. 20% patients with ≤ 2 different metastatic lesions (p = 0.168), respectively. In the triple negative group 30% LDMC vs. 5% control patients showed DCR (p = 0.095). PFS was 12.0 vs. 13.5 weeks (p = 0.415), DoR was 26.5 vs. 20.5 weeks (p = 0.628), respectively. Conclusions: In this retrospective case-control study we demonstrated a similar efficacy of LDMC compared to conventional chemotherapy in the treatment of MBC. Moreover, no significant differences were found in the subgroups studied. Therefore, the concept of LDMC may also be a treatment option in both younger and non-heavily pre-treated MBC patients who do not need rapid remission.
Patterns of mutation enrichment in metastatic triple-negative breast cancer.
Authors: Saravia Cesar H. , Flores Claudio J. , Schwarz Luis Jesus , Bravo Leny , Zavaleta Jenny , Araujo Jhajaira M , Neciosup Silvia P. , Pinto Joseph A. 
Published: May 2019

e12596 Background: Triple-Negative breast cancer (TNBC) is a group of heterogeneous tumors with aggressive biology. The purpose of this research was to evaluate enrichment patterns of genomic alterations in metastatic TNBC (mTNBC). Methods: We retrieved genomic data (mutations and copy number variation) from 550 primaries TNBC (pTNBC) from the projects METABRIC and TCGA and 58 mTNBC from the projects “Mutational Profile of Metastatic Breast Cancers” and “The metastatic Breast Cancer Project”. Differences in the proportions of mutations between primary vs. metastatic tumors were evaluated by the Chisquare test and the percentage of enrichment in mTNBC was estimated. Pvalues were adjusted for multiple testing with the Benjamini-Hochberg method with and a FDR < 0.05. In addition we conducted an analysis of the hallmarks of cancers enriched in mTNBC. Results: In total, mutations in eight genes were significantly enriched in mTNBC after correcting for multiple testing. These genes included TTN, HMCN1, RELN, PKHD1L1, DMD, FRAS1 and RYR3. In the other hand, only amplification of RPS6KB2 was enriched in mTNBC. Deletions were enriched more frequently in the genes TET1, RHOA, EPHA5, SET, KCNJ5, ABCG4, NKX3-1, SDHB, IGF2, BRCA1, among others. The hallmark of “genetic instability and mutation” was over represented while the hallmark “activating immune destruction” was the least represented between the enriched genetic alterations in mTNBC. Conclusions: Despite the study limitations, we identified that deletions are the aberrations more commonly enriched in mTNBC while some biological processes could be targetable in order to improve the therapeutic opportunities in TNBC.