bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical value of CTC in predicting the efficacy of treatment in breast cancer.
Authors: Zhou Yidong 
Published: May 2019

e12104 Background: Circulating tumor cells (CTCs) have proven to be underlying surrogate markers for several cancers. We aimed to investigate the diagnostic, predictive, and prognostic value of tCTCs using a four-CTC marker (CK19, surviving, Her2 and MUC1) real-time quantitative PCR (RT-PCR) assay in patients with breast cancer. Methods: In a previous study, we established a multimarker RT-PCR platform to detect and quantify CTC in colorectal cancer. By choosing four mRNA markers (CK-19/surviving/Her2/Muc1), we quantified CTC in the peripheral blood of 90 early operable breast cancer patients, 40 patients who had undergone surgery and received 6 cycles of follow-up of neoadjuvant chemotherapy, and 30 healthy volunteers. For early operable breast cancer patients, the CTC status at preoperative and postoperative time points was monitored. For the other 40 patients undergoing systemic adjuvant chemotherapy, the CTC status at six or more different time points was monitored. Results: CTCs were detected in 81% (73/90) of patients with early operable breast cancer. After surgery, 67.1% (49/73) of the patients switched to negative status. 36 out of 40 (90%) patients who received systemic adjuvant chemotherapy were CTC-positive. During follow-up, 31 out of 36 (86%,) patients became CTC-negative after 4 chemotherapy cycles. Among these 36 patients, four patients had relapsed within one year, and one had died. Three out of four relapsed patients, including the deceased one, switched into high CTC-positive status before diagnosed recurrence. Conclusions: The decrease of the levels of these CTC mRNA markers after surgery indicates that these CTC markers could be used as an indirect evaluation of tumor burden. The level of CTC mRNA markers could also help to evaluate therapeutic efficacy and disease progression.
NOTCH3 expression in metastatic TNBC cells.
Authors: D'Assoro Antonino Bonaventura 
Published: May 2019

e12123 Background: Onset of metastases involves a complex multistep biological process termed the invasion-metastasis cascade, which include dissemination of cancer cells from the primary tumor to secondary organs. NOTCH signaling plays a critical role in promoting Triple Negative Breast Cancer (TNBC) metastasis. Although all four NOTCH receptors show oncogenic properties, the unique role of each of these receptors in the sequential stepwise events that typify the invasion-metastasis cascade remains elusive. Methods: We established unique TNBC cells (TNBC-M14, -M25 and –M40), isolated from patient-derived brain metastasis xenografts (PD-BMXs). NOTCH3 genetic targeting was achieved using Lenti-vector shRNAs. Immunoblot analysis was used to assess NOTCH3 expression. ALDH1 activity was measured using the ALDEFLUOR Kit. To assess self-renewal capacity and resistance to docetaxel-based chemotherapy, TNBC cells were cultured under non-adherent conditions to form mammospheres (MPS). A publicly clinical database ( http://kmplot.com ) was employed to analyze NOTCH3 expression in a selected cohort of 107 lymph- node+ TNBC patients. Results: TNBC-M14, -M25 and -M40 MPS showed NOTCH3 overexpression and higher ALDH1 activity compared to MDA-MB 231 MPS used as control. To investigate the causative role of NOTCH3 in inducing ALDH1 activity, self-renewal capacity and chemoresistance, we infected TNBC MPS with Lenti-vector shRNAs targeting NOTCH3. NOTCH3 geneting targeting induced a significant reduction of ALDH1 activity compared to TNBC MPS infected with scrambled Lenti-shRNAs. NOTCH3 geneting targeting significantly impaired MPS formation and restored sensitivity to docetaxel. The correlation between aberrant NOTCH3 expression and poor outcome in patients with advanced TNBC was validated in a publicly clinical database. Conclusions: These findings provide a compelling preclinical rationale for the design of novel clinical trials that will selectively target NOTCH3 to restore chemosensitivity and to improve the progression-free survival of TNBC patients that lack FDA-approved targeted therapies.
Estrogen receptor (ER) status and survival outcomes in HER2 positive (+) metastatic breast cancer (mBC).
Authors: DeSouza Karen , Zammit Rosa-Rita , Haire Anna , Sinha Rajesh , Simcock Richard , Moss Charlotte Hannah , Mera Anca , Mansi Janine , Karapanagiotou Eleni , Sawyer Elinor , Patel Gargi Surendra 
Published: May 2019

e12503 Background: The oncological management of HER2+ mBC is complicated by the development of resistance to HER2-directed therapies (HER2-DTs). This project analyses real-world clinical data to determine disease response patterns that may guide treatment sequencing decisions. Methods: This collaborative project analysed HER2+ mBC datasets held by the Sussex Cancer Centre and Guy’s Cancer Centre, UK. The datasets were generated by reviewing clinical notes, radiology and e-prescribing records to collect clinical data on patients diagnosed with HER2+ mBC between 01/01/2013 – 30/09/2018. Results: 138 patients with a median age of 59 years (30 - 89 years) were diagnosed with HER2+ mBC during this time period: 88 were ER+ (63.7%) and 50 were ER- (36.3%); the median OS is 41.1 mos. (range 0.7 - 62 mos.). Patients with HER2+ mBC were more likely to present with visceral metastases (68.1%, n = 94). A poorer median OS was identified in patients with ER+ HER2+ mBC (35.5 mos.) vs ER- HER2+ mBC (MNR). A benefit to median OS was observed with first line treatment using Docetaxel/Trastuzumab/Pertuzumab (THP) compared to other HER2-DTs ((54.5 mos. (n = 76) vs 26.7 mos. (n = 40)) 65.2% (n = 90) were previously treated for early breast cancer (EBC), evenly distributed across the 2 groups ER+ (64.7%, n = 57) vs ER- (66%, n = 33). 53.7% (n = 50) received trastuzumab with neo-adjuvant/adjuvant therapy (NACT/ACT). Patients previously treated for EBC demonstrated a poorer median OS (34 mos.) when compared to patients with de-novo mBC (MNR). When treated for EBC, ER+ disease was less likely to have a pathological complete response (pCR) with NACT (ER+ 22.2% (n = 4/18) vs ER- 50% (n = 5/10)). PFS data in response to an array of prescribed systemic therapies will be presented. Conclusions: Though, HER2 signalling is considered the dominant signalling pathway in HER2+ breast cancer, pre-clinical research indicates that the ER pathway represents an important escape mechanism influencing the development of resistance. Lack of efficacy (pCR) to NACT in ER+HER2+ EBC may translate to poorer outcomes (OS) when these patients develop MBC. Earlier targeting of the ER pathway in conjunction with HER2-DTs may contribute to improving patient outcomes.
HD201: Analytical biocomparability and clinical trial progression of trastuzumab.
Authors: hii Jocelyn , Pivot Xavier , Park Lisa Soyeon , Kim Michael , Feyaerts Peggy , Chan Kuo Wei , Lee Jeong-Hyeon , Ang Felicia 
Published: May 2019

e12505 Background: Trastuzumab, an approved prescription drug by EMA and FDA under the name Herceptin has become the key treatment in patients with HER2 positive breast cancer. HD201, developed and owned by Prestige Biopharma Pte Ltd is a biosimilar product to Herceptin (Trastuzumab). The development of HD201 from analytical biocomparability to clinical trial progression are demonstrated. Methods: Analytical biocomparability in terms of physicochemical (primary, higher order structure, glycan profiles, molecular and charge variants) and biological properties (inclusive of binding to Fcγ receptors and neonatal receptor) between HD201 and EU and US-Herceptin were compared. The first human study of HD201 (clinical phase I) was designed to assess the pharmacokinetic (PK) equivalence between HD201 and EU-Herceptin. In this randomised, blinded, single-dose comparative PK study, randomised healthy human subjects were subjected to a single 6 mg/kg IV dose of HD201 and EU-Herceptin following by PK and safety evaluations. Following this, a randomised, double-blind, parallel group, equivalence, multicentre clinical phase III trial (TROIKA) was designed to compare the efficacy, safety, and pharmacokinetics of HD201 to EU-Herceptin in 500 patients with HER2+ early breast cancer. Each group of patients (250 patients) were administered with either HD201 or EU-Herceptin once every 3 weeks up to 8 cycles in combination of a neoadjuvant chemotherapy comprising of docetazel followed by an anthracycline-containing regimen. Results: HD201 shows equivalent in physicochemical and biological properties compared to EU- and US-Herceptin. Clinical phase I study demonstrated that HD201 is safe and well tolerated with comparable PK profiles as EU-Herceptin after single dose administration to healthy male adults (Pivot et al., 2018). Analysis of sub study from clinical phase III has demonstrated comparable results with EU- Herceptin in terms of patient demographic, clinical response, safety and pharmacokinetic profile. Conclusions: HD201 is demonstrated to be equivalent in analytical biocomparability and in clinical response, safety and PK profile to Herceptin in human study. Additional data for Pharmacokinetic from Troika trial will be reported in Asco meeting. Clinical trial information: 2012-000805-56.
Tumor pathological and immunological changes in HER2+ metastatic breast cancer (MBC) following trastuzumab combined with expanded and activated autologous natural killer (NK) cell infusion.
Authors: Yadav Kritika , Shimasaki Noriko , Ow Samuel Guan Wei , Wong Andrea Li Ann , Lim Joline Si Jing , Koe Priscillia , Koh Liang Piu , Tan Lip Kun , Goh Boon C. , Campana Dario , Lee Soo-Chin 
Published: May 2019

e12511 Background: A central mechanism for the anti-tumor activity of Trastuzumab, a HER2 monoclonal antibody, against HER2+ tumors is induction of antibody dependent cell cytotoxicity (ADCC) mediated by NK cells. We are conducting a first-in-human trial of Trastuzumab followed by infusion of expanded, activated autologous NK cells in refractory HER2+ MBC (ClinicalTrials.gov: NCT02030561) to test the hypothesis that NK cell infusions will augment Trastuzumab-mediated ADCC and increase immune cell infiltration in tumor. Pre- and post-infusion tumor biopsies were obtained in a subset of patients to determine degree of NK cell infiltration in tumor and histopathological and immunological effects after infusion. Methods: HER2+ MBC patients underwent apheresis to harvest NK cells for ex vivo expansion and activation. NK cells (107/kg), expressing high levels of the antibody receptor CD16, were infused 24 hours post-Trastuzumab. Histology analysis and immunohistochemistry with CD56, CD3, CD20 and cleaved caspase-3 to identify NK, T, B, and apoptotic cells respectively, was performed in pre- and post-infusion biopsies. Studies of CD4 and CD8 to further classify T cell infiltrates, and CD16 to assess NK cell functionality are underway. Results: Analysis of 7 paired tumor biopsies collected before and 7-14 days after NK cell infusion showed absolute increase in lymphocyte infiltration (mean cell count/5 HPF: 204 vs 265 in pre- vs post- biopsy, p = 0.109). Most infiltrating lymphocytes were CD3+ T cells (74.28±12.72% vs 80 ±10% in pre vs post) and CD56+ NK cell number in the immune infiltrate were increased post infusion (mean cell count/5 HPF: 4.57±3.46 vs 20.57±13.83 in pre vs post; p = 0.009). Increased tumor apoptosis was observed post NK cell infusion (mean apoptotic cell count/5 HPF: 3.14±2.48 vs 5.86±6.72 in pre vs post, p = 0.27). Conclusions: Histopathology analysis of tumors from HER2+ MBC patients demonstrated significant increase in NK and T cells in tumor following Trastuzumab and NK cell infusion, suggesting that this combination might also augment recruitment of T lymphocytes into tumor, further enhancing anti-tumor activity. Clinical trial information: NCT02030561.
Impact of mastectomy in women with stage IV HER2+ breast cancer.
Authors: Babar Arslan , Covut Fahrettin , Kewan Tariq Zuheir , Rahman Shafia , Grobmyer Stephen R. , Montero Alberto J. 
Published: May 2019

e12515 Background: Women with stage IV HER2+ breast cancer typically have longer overall survival (OS) compared to other breast cancer subsets due to the effectiveness of dual anti HER-2 antibody therapy. The role of mastectomy remains controversial. Methods: We reviewed patients who were diagnosed with stage IV HER2+ breast cancer between 2/2015 and 12/2017 at Cleveland Clinic. Overall survival (OS) was estimated by the Kaplan-Meier method, and compared by the log-rank test. Univariable and multivariable analysis were performed using Cox regression to identify predictors of OS. Results: We identified 47 patients, with a median age of 58 (range: 22 – 87). Twenty-eight (60%) and 14 (30%) patients had ER+ and PR+ disease, respectively. Four patients had brain metastasis at time of stage IV diagnosis. All patients received systemic therapy. 17 (36%) patients underwent mastectomy after diagnosis of stage IV breast cancer,. Of the 30 (64%) patients who did not undergo mastectomy, 24 (80%), 2 (7%), and 4 (13%) were treated with both chemotherapy and HER2-directed therapy, chemotherapy alone, and HER2-directed therapy alone, respectively. Breast radiotherapy was performed on 9 (53%) and 8 (27%) patients in mastectomy and no mastectomy cohorts, respectively. Median follow-up time was 22 months . The two-year OS for mastectomy and no mastectomy cohorts were 94% (95% CI: 83 – 100) and 50% (95% CI: 33 – 76), respectively (p=0.009). On univariable analysis, only mastectomy vs no mastectomy (HR: 0.18, 95% CI: 0.04 – 0.80, p=0.025) predicted OS. On multivariable analysis, mastectomy vs no mastectomy has remained to be statistically significant predictor of OS (HR: 0.08, 95% CI: 0.01 – 0.66, p=0.019), whereas age, chemotherapy, HER2-directed therapy, and breast radiation were not independent predictors of improved OS (p>0.05). Conclusions: In our cohort, mastectomy was an independent predictor of longer OS in women with stage IV HER2+ breast cancer.
Real-world effectiveness of ribociclib + aromatase inhibitor, or endocrine monotherapy, or chemotherapy as first-line treatment in postmenopausal women with HR-positive, HER2-negative locally advanced or metastatic breast cancer: Baseline data from the RIBANNA study.
Authors: Wöckel Achim , Decker Thomas , Fasching Peter A. , Jackisch Christian , Luftner Diana , Marme Frederik , Reimer Toralf , Roos Christian 
Published: May 2019

e12520 Background: Ribociclib, a selective CDK4/6 inhibitor, in combination with an aromatase inhibitor (AI) is approved for the treatment of HR+/HER2- advanced breast cancer (aBC) (locally advanced or metastatic). Real-world evidence for the effectiveness, safety and tolerability of ribociclib + AI in routine clinical practice is needed to support its use. Methods: RIBANNA (CLEE011ADE03) is a non-interventional study running in Germany since October 2017 involving up to 3020 postmenopausal patients receiving ribociclib + AI, endocrine monotherapy (ET), or chemotherapy (CT) as first-line treatment for HR+/HER2- aBC, prescribed in line with German guidelines. Data are collected from clinical practice in all three cohorts. Further lines of treatment are documented to examine outcomes of sequential therapy. Results: 461 patients enrolled to October 9, 2018 (Table). First-line mean daily ribociclib dose was 382 mg including and 540 mg excluding dose interruptions; mean duration of exposure to ribociclib: 128 days. Ribociclib was given in combination with anastrozole (8%), exemestane (7%), and letrozole (83%); ET comprised a selective estrogen receptor degrader (25%), nonsteroidal AI (64%), steroidal AI (5%), and a selective estrogen receptor modulator (7%); CT included taxane-based monotherapy (30%) or combination therapy (27%), anthracycline-based combination therapy (5%), other monotherapy (23%) or other combination therapy (13%). Conclusions: Population characteristics from the RIBANNA study show a diverse group of patients from a real-world setting of ribociclib treatment. Baseline demographics and characteristics. Clinical trial information: CLEE011ADE03. [Table: see text]
Real-world evidence evaluating continuation of CDK4/6 inhibitors beyond first progression in hormone receptor-positive (HR+) metastatic breast cancer.
Authors: Eziokwu Akaolisa Samuel , Varella Leticia , Kruse Megan Lynn , Jia Xuefei , Moore Halle C. F. , Budd George Thomas , Abraham Jame , Montero Alberto J. 
Published: May 2019

e12538 Background: CDK inhibitors (CDKi), in combination with aromatase inhibitors (AI), are approved for the treatment of hormone receptor positive (HR+) Her2 negative metastatic breast cancer (MBC). The effectiveness of continuing CDKi beyond first disease progression is not known. This study evaluated real world evidence and assessed the impact of continuation of CDKi beyond first disease progression in combination with endocrine therapy. Methods: This is a retrospective, single institution review of HR+ MBC patients treated with CDKi from 2015-2018 who continued CDKi after initial progression. The primary outcome was progression-free survival (PFS) beyond first disease progression, as assessed by the clinician based on radiological and/or clinical criteria. Overall survival (OS) – defined as date of initial CDKi treatment to date of death or last follow up – was a secondary outcome. Results: 30 women with HR+/HER2- MBC, median age 47.5 years (range: 31 – 81), sequentially continued on CDKi beyond first progression were identified from a database of patients treated with Palbociclib. Median and average follow up times on CDKi were 27.18 and 24.53 months, respectively. Initial endocrine/CDKi regimen received included: palbociclib (PA)/letrozole (LTZ) [67%], PA/fulvestrant (FULV) [23%], and PA/other AI [10%]. Prescribed combinations beyond 1st progression were: PA/FULV [56.7%], PA/LTZ [16.7%], and PA/other AI [20%], abemaciclib plus LTZ or FULV [6%]. As of 1/31/2019, 25 patients (83.3%) were still alive, and 19 (63%) had undergone a second progression on CDKi. The estimated median PFS for the entire duration while on CDKi was 23.5 months (95% CI 12.8 – 27.8), of which 11.8 months (95% CI 5.34 – 13.13) was the median PFS beyond first progression. The estimated median OS was 45.4 months. Conclusions: Among a small cohort of HR+ MBC patients, in a non-clinical trial setting, continuation of palbociclib plus endocrine therapy beyond first progression was associated with a median PFS of approximately 11 months. Formal clinical evaluation of continuation of CDK inhibitor plus endocrine therapy beyond first progression is warranted.
New docetaxel-peptide conjugate for the treatment of sortilin-positive triple-negative breast cancer.
Authors: Demeule Michel , Annabi Borhane , Currie Jean-Christophe , Larocque Alain , Charfi Cyndia , Béliveau Richard 
Published: May 2019

e12556 Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease which still lacks defined molecular biomarkers. In the last decade, targeting of specific gene/protein molecular signature of tumors emerged among the best anticancer strategies. Recently, increased expression of the Sortilin (SORT1) receptor has been reported in TNBC patients. Given SORT1 functions in protein internalization, sorting and trafficking, we developed a new peptide-anticancer drug conjugation platform to target SORT1-positive breast cancer by linking Docetaxel to a peptide (KA-peptide) that specifically targets SORT1. Methods: MDA-MB-231 cells were used as a TNBC cell model for in vitro and in vivo xenograft (CD1 nude mice) assays. Cell migration was assessed using the xCELLigence real-time system, whereas MTT assay was used for cell proliferation analysis. Apoptosis biomarkers expression was assessed by immunoblotting. Results: In MDA-MB-231, the Docetaxel-KA-peptide conjugate (DoceKA) exerted potent anti-proliferative and anti-migratory activities in vitro. DoceKA triggered faster and higher cell death mechanisms than did free Docetaxel alone. The apoptotic and anti-migratory effects were reversed by the SORT1 ligands Neurotensin and Progranulin, and upon siRNA-mediated silencing of SORT1. DoceKA altered microtubules polymerization and triggered the down-regulation of IL-6, Survivin, Bcl-xL and mutant p53 pro-survival biomarkers. In vivo, DoceKA exhibited a greater tumor regression capacity with a prolonged survival in a murine MDA-MB-231 xenograft tumor model than did Docetaxel. Conclusions: Collectively, we demonstrate that DoceKA is specifically internalized through a receptor-mediated mechanism. Such property allows for targeting SORT1-positive breast cancers, and makes DoceKA a promising novel therapy for the treatment of TNBC.
High-throughput screening (HTS) of natural products with triple-negative breast cancer (TNBC) organoids.
Authors: Sun Zhijian , Zhang Bailin 
Published: May 2019

e12558 Background: Breast cancer is one of the most malignant diseases threatening the health of our society. Triple negative breast cancer (TNBC) is an aggressive histological subtype representing 15–20% of all breast cancers. Comparing with other breast cancer subtypes, TNBC is characterized with limited treatment options and a worse clinical outcome. Resistance to chemotherapies is common for TNBC. Therefore, continuously developing new anti-cancer drugs is of great importance for TNBC. Nature products a source of medicinal leads, but lacking suitable pre-clinical models, which could faithfully reflect in vivo tumor property, prevents these compounds from further characterizing. Now cancer organoids, as a new in vitro 3-D culture technique, were demonstrated to largely retain the biological characteristics of tumors from patients, and potentially served as an ideal platform for drug sensitivity test. Methods: Here we set up system to efficiently establish breast cancer organoids from clinical patients and further test the sensitivity of these organoids to various nature products. Results: A total of 29 TNBC organoid models were established with fresh biopsy or surgery tumor tissues from TNBC patients. Estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) in TNBC PDOs were evaluated with qPCR, western blot, Immunohistochemistry (IHC). A high-throughput cell viability assay was established for identifying lead compounds from a unique collection of 969 natural products. Primary hits were serial diluted and further evaluated for IC50 and percentage of inhibition. Preliminary mechanism of action (MOA) studies was performed with gene reporter assays, western blot and qPCR. Interestingly, organoids derived from paclitaxel resistant TNBC patients also show less sensitivity to paclitaxel in vitro, which indicated a high clinical relevance. Conclusions: Triple negative breast cancer organoid, as a good pre-clinical model largely containing tumor in vivo property, provides an ideal platform for new drug discovery and inhibitor screening. Moreover, serving as in vitro replacements for breast cancer, organoid models make it possible to test drug sensitivity for individual patient to achieve precise and personalize medication.