bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P5-10-04: Metformin mediated upregulation of microRNA-193 triggers apoptosis by decreasing fatty acid synthase
Authors: Cochrane DR , Wahdan-Alaswad RS , Edgerton SM , Terrell KL , Spoelstra NS , Thor AD , Anderson SM , Richer JK 
Published: August 2014

Abstract
Background: We have previously shown that the anti-diabetic drug metformin kills triple negative (TN) breast cancer cells lines via apoptosis, at lower IC50 than luminal and HER2 subtypes (presented at ENDO, manuscript in preparation). Metformin reportedly shows greater efficacy against stem cells than differentiated cells, reducing mammosphere formation in in non-adherent culture. Fatty acid synthase (FASN) is an enzyme critical for de novo fatty acid synthesis that is overexpressed in breast cancer.
Hypothesis: We hypothesized that miRNAs might be involved in the ability of metformin to preferentially kill TN cell lines at a lower IC50 than luminal A lines.
Methods: TN and luminal A (LA) breast cancer cell lines (MDA-468, HCC70 and MCF7, T47D, respectively) were used to study the effects of 10mM metformin action in vitro, at physiological and hyperglycemic culture conditions. Affymetrix chips Human Gene 1.1 and the miRNA 2.0 were utilized to profile gene and miRNA expression at 6 and 24 hrs. Mimics and lentiviral expression vectors were utilized to manipulate miRNA expression and a luciferase reporter was used to confirm miR-193 direct targeting of the FASN 3′ UTR.
Results: miR-193 is significantly higher in untreated LA as compared to TN cells. MiR-193 increases 2–4 fold within 6 hrs of metformin treatment in both TN, but not LA cell lines. A predicted target of miR-193, fatty acid synthase (FASN), is decreased by 8 fold following 24 hrs 10mM metformin treatment of the TN breast cancer cells. miR-193 directly targets FASN via a binding site in the 3′ UTR, downregulating gene expression. Restoration of miR-193 to TN lines, causes a dramatic decrease in FASN protein in a dose dependent fashion.
Conclusions and future directions: Metformin stimulates an increase in mature miR-193, which mediates the dramatic downregulation of FASN. This occurs coincident with apoptotic cell death. It remains to be determined if FASN is the only relevant direct target of miR-193 in TN cell lines. The addition of exogenous non-targetable FASN, lacking its 3′ UTR, will demonstrate whether this pathway is a primary mechanism of metformin action in TN cells. Future studies will investigate the ability of metformin to inhibit FASN in non-adherent mammosphere (stem cell-like) subpopulations, the role of fatty acid metabolism in mammosphere maintenance and anoikis resistance.
Supported by Komen Breast Cancer Foundation Grants KG100575 (ADT, JKR, SME, NSS) and KG090415 (JKR, DRC)
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-10-04.
Abstract P5-10-14: MicroRNAs as biomarkers and therapeutic adjuvants for the prognosis and treatment of drug-resistant breast cancers
Authors: Chang Y-F , Panneerdoss S , Zoghi B , Pertsemlidis A , Rao M 
Published: August 2014

Abstract
Intrinsic and acquired resistance to antineoplastic agents continues to be a major clinical impediment to successful treatment of cancer in general, and breast cancer in particular. For example, about 40% of ER-positive breast tumors fail to respond to tamoxifen therapy, and of those that initially respond many will eventually develop resistance. Similarly, taxanes used as a first-line chemotherapy agent will have a response rate of 50%, which comes down to 20–30% in second- or third-line chemotherapy; nearly half of the treated subjects do not respond to it and suffer side effects. These facts underscore the importance of understanding the mechanism of resistance, which is crucial for better management of breast cancer. Unfortunately, in spite of extensive inquiry in this field, little is known about the key molecules/signaling pathways that regulate this phenomenon. Recently, we have discovered that small non-coding RNAs, i.e. microRNA (miRNAs), may play a critical role in mediating drug resistance in breast cancers. We have identified miRNAs that are differentially expressed between chemoresistant and sensitive breast cancer cells. Specifically, we have combined a high-throughput screening platform with a library of chemically synthesized inhibitors for all known human miRNAs and identified specific miRNA that selectively sensitize/de-sensitize drug-resistant breast cancer cells to either tamoxifen or trastuzumab (herceptin), drugs that are commonly used as a first line treatment for ER-positive and Her2-positive breast cancers, respectively. Interestingly, we identified 10 and 12 miRNA inhibitors that sensitized resistant cells to tamoxifen and trastuzumab, respectively. Interestingly, expression of cognate miRNA/s that sensitize resistant tumors to drug-induced cell death in our screen was found to be lower in relapsed (drug resistant) metastatic breast cancer patients compared to normal matched control. In addition to tumor tissues, the levels of sensitizer miRNA/s in the blood sera of relapsed metastatic breast cancer patients was found to be dramatically lower than that of normal healthy individual. These findings are significant as it suggests that miRNAs can be efficiently detected in blood serum and therefore, can be used as a potential biomarker for predicting treatment outcomes. In addition, miRNAs may provide novel therapeutic tools for the treatment of drug-resistant breast cancers.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-10-14.
Abstract P5-13-02: Decision making from multidisciplinary team meetings to bedside: factors predicting for physicians' and breast cancer patients' acceptance of clinical trials proposed by MTMs
Authors: Deneuve J , Mazouni C , Arnedos M , Prenois F , Saghatchian M , André F , Bourrgier C , Delaloge S 
Published: August 2014

Abstract
Background: In University hospitals or Comprehensive Cancer Centers (CCC), breast cancer (BC) patients have a theoretically large access to clinical trials as part of the management and treatment of their localized or advanced disease. Though, most patients are not proposed inclusion into suitable trials or studies or do not accept them. We aimed at determining the factors that influence physicians and patient's choice to respectively propose or enter clinical trials for which the patients were considered eligible by MTM.
Methods: Patients who were considered eligible for a clinical trial by a BC-specific multidisciplinary team meeting (MTM) assessing their cases were prospectively registered during a 6 months period. The complete files of these patients were prospectively registered following initial written proposal by the MTM. The 27 clinical trials proposed were classified in 5 categories: cognitive studies, imaging, radiation therapy, diagnostic/prognostic biology, or interventional therapeutic studies. Detailed analysis of factors predicting physician's proposal and patient's final inclusion was conducted. Candidate factors were age, socio-demographic characteristics, PS, type of clinician, time intervals, stage of disease, type of disease, type of study, single vs multiple study proposal.
Results: MTM proposed 547 inclusions into clinical trials for 397 patients between March 3rd and Sept 21st, 2011. 267 pts were considered eligible for 1 trial, 100 for 2, 25 for 3, 4 for 4 and 1 for 5 trials; 211 for cognitive studies, 13 for imaging, 71 for radiation therapy, 136 for diagnostic/prognostic biology, 116 for interventional therapeutic studies. Upon referral physician's visit, the trial was only proposed in 39.3% and pts were finally included in 29.1% of the cases. Reasons for non inclusion were patients' refusal in only 5–11%, but absence of proposal by physician in 45–81%, according to the types of studies. The only factor predicting both proposal by the referral physician's and final inclusion into trials was type of study (both p &lt; 0.001). Diagnostic/prognostic biology trials were proposed in 71%, while interventional therapeutic and cognitive studies were only respectively proposed in 35 and 19% of the cases. The factors predicting non-inclusion upon physicians' proposal were professional status (p = 0.03) and type of study (p = 0.0007). The highest inclusion rates were among retired pts and those with executive work (84 and 76% respectively).
Conclusion: The main reason for non inclusion into clinical trials remains absence of physicians' proposal, while professional status and type of study influence both the physicians' and the patients' decision. Educative measures dedicated mostly to treating physicians might be proposed.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-13-02.
Abstract P5-14-06: Analysis of test-therapy concordance for biomarkers uPA and PAI-1 in primary breast cancer in clinical hospital routine: Results of a prospective multi-center study at Certified Breast Cancers in Germany
Authors: Jacobs VR , Augustin D , Wischnik A , Kiechle M , Hoess C , Steinkohl O , Rack B , Kapitza T , Krase P 
Published: August 2014

Abstract
Objective: Biomarkers uPA and PAI-1 are guideline recommended by ASCO, USA, and AGO, Germany, to be used in primary breast cancer to avoid unnecessary CTX in medium risk recurrence patients [G2, N−, HR+, Her2neu−, &gt;35 years]. For quality assurance of uPA/PAI-1 testing an analysis of test-therapy concordance was performed.
Methods: Prospective, non-interventional, multi-center study over two years among six Certified Breast Centers in Germany to analyze application of uPA/PAI-1 and use of the result in consecutive decision making in Tumor Board decision and actual therapy in the clinical setting for AOK Bayern-insured patients. Concordance and discordance rates of uPA/PAI-1 testing in daily clinical setting were calculated and individual reasons for decision making analyzed.
Results: Among n=93 uPA/PAI-1 tests evaluated n=42/93 (45.2%) were uPA+PAI-1 negative and n=51/93 (54.8%) uPA and/or PAI-1 positive. In the group of uPA+PAI-1 negative test result in n=35/42 (83.3%) CTX was avoided and and in n=7/42 (16.7%) CTX performed. In the group of uPA and/or PAI-1 positive test result in n=26/51 (51.0%) CTX was performed and in n=25/51 (49.0%) not. Concordance of uPA/PAI-1 test result vs. consecutive therapy was (35+26)/93=65.6% and discordance of uPA/PAI-1 test-therapy (7+25)/93 = 34.4%. However, discordance of uPA/PAI-1 test result vs. Tumor Board recommendation was only n=21/93 (22.6%). As reasons for discordance a variety of influencing and/or interference factors were indentified, affecting use of test and test results or even changing therapy decision, e.g. individual therapy decision by physician, parallel use of competitive biomarkers, study participation, missing CTX therapy option in advance (like advanced age), wrong target group, timing of uPA/PAI-1 test too early, test result in contradiction of physicians' expectations (expected negative result) and rejection of CTX recommended by patients despite uPA/PAI-1 test-proven benefit.
Conclusions: Individual process optimization of uPA/PAI-1 test indication, performance and result assessment could improve quality of care, reduce costs and lead to an improved application of uPA/PAI-1 test results as well as more stringency and consistency of test-therapy decisions in daily clinical setting.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-14-06.
Abstract P5-18-05: Interim Results from a Phase 1b/2a Study of Trastuzumab Emtansine and Docetaxel, With and Without Pertuzumab, in Patients With HER2-Positive Locally Advanced or Metastatic Breast Cancer
Authors: Martin M , García-Sáenz JÁ , Dewar JA , Albanell J , Limentani SA , Strasak A , Patre M , Branle F , Fumoleau P 
Published: August 2014

Abstract
Introduction: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprising trastuzumab, a stable linker, and DM1 (a microtubule inhibitor). In 2 randomized trials in patients (pts) with HER2-positive metastatic breast cancer (MBC), T-DM1 significantly prolonged progression-free survival (PFS) compared with standard therapy (Hurvitz, ESMO 2011; Blackwell, ASCO 2012). The combination of T-DM1 and docetaxel (D) or pertuzumab (P) has shown enhanced antitumor activity in preclinical models of HER2-positive BC (Lewis Phillips, AACR 2008; Fields, AACR 2010).
Methods: This phase 1b/2a dose-escalation study examines the safety, tolerability, efficacy, and pharmacokinetics (PK) of T-DM1 (starting dose 2.4 mg/kg every 3 weeks [q3w]) combined with D (starting dose 75 mg/m2 q3w) in pts with MBC, and T-DM1 with D±P (840 mg loading dose, then 420 mg q3w) in pts with newly diagnosed locally advanced BC (LABC; clinical stage IIa-IIIc). The maximum tolerated dose (MTD) for T-DM1+D is established in pts with MBC and used as the starting dose for feasibility of T-DM1+D±P (up to 6 cycles) in pts with LABC. Eligibility criteria include HER2-positive MBC (locally assessed) or LABC (centrally confirmed). This interim report includes data from pts who completed at least 1 treatment cycle in phase 1b.
Results: During MBC feasibility, 21 pts were enrolled; median age was 47.0 years (yr; range, 33–70); median number of prior lines of MBC therapy was 2 (range, 0–10). Four pts experienced 6 DLTs (Table 1). The MTD was T-DM1 3.6 mg/kg q3w + D 60 mg/m2 q3w. Common grade (G) 3/4 adverse events (AEs): neutropenia (81%), leukopenia (52%), and thrombocytopenia (29%). ORR was 76.2% (16/21); median PFS was 11.8 months (range, 1.6–26.9). In LABC feasibility, 18 pts were enrolled; median age was 49.5 yr (range, 34–74). Four pts experienced 4 DLTs (Table 2). The MTD for T-DM1+D was 3.6 mg/kg q3w + 75 mg/m2 q3w; MTD for T-DM1+D+P was 3.6 mg/kg q3w + 75 mg/m2 q3w + 840 mg (with G-CSF primary prophylaxis). Common G3/4 AEs: T-DM1+D, neutropenia (2/9; 22%), increased alanine aminotransferase (ALT; 2/9; 22%), thrombocytopenia (TCP; 1/9; 11%); T-DM1+D+P, neutropenia (5/9; 56%), TCP (2/9; 22%), increased ALT (2/9; 22%), and cytolytic hepatitis (1/9; 11%). With 9 pts enrolled in the T-DM1+D LABC cohorts and 8 pts currently evaluable, pCR rate (ypT0N0) is 87.5%.

Conclusions: Full-dose T-DM1 can be safely combined with D in pts with MBC, and with D±P in pts with LABC. G-CSF is needed with higher doses of D. Pathological assessment for all LABC patients and PK analyses will be available for the full presentation.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-05.
Abstract P5-18-11: Pharmacokinetics and exposure-efficacy relationship of trastuzumab emtansine in EMILIA, a phase 3 study of trastuzumab emtansine vs capecitabine and lapatinib in HER2-positive locally advanced or metastatic breast cancer
Authors: Wang B , Jin J , Wada R , Fang L , Saad O , Olsen S , Althaus B , Swain S , Untch M , Girish S 
Published: August 2014

Abstract
Background: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate composed of trastuzumab (T), the cytotoxic agent DM1, and a stable thioether linker; it is being evaluated for the treatment (tx) of HER2-positive cancer. EMILIA is a randomized, multicenter, open-label phase 3 study assessing the efficacy and safety of T-DM1 vs capecitabine (X) and lapatinib (L) in pts with HER2-positive locally advanced or metastatic breast cancer (MBC) previously treated with T and a taxane. We report the pharmacokinetics (PK) of T-DM1 in EMILIA and compare these data with historical data of single-agent T-DM1. The effects of T-DM1 exposure on efficacy outcomes in EMILIA are also reported.
Methods: In EMILIA, pts were randomized 1:1 to receive T-DM1 3.6 mg/kg q3w (n = 495) or X + L (n = 496) in 21-day cycles. At least 1 PK sample was collected from 350 pts in the T-DM1 arm; 307 of these had adequate PK profiles for the estimation of ≥1 PK parameter in cycle 1. PK parameters were estimated by noncompartmental analysis for serum T-DM1, serum total T (conjugated and unconjugated T), and plasma DM1. A logistic regression model was used to evaluate the relationship between T-DM1 exposure (ie, T-DM1 AUC and DM1 Cmax) and objective response rates (ORR). Analyses of progression-free survival (PFS) and overall survival (OS), stratified by T-DM1 exposure, were conducted. Cox regression was used to evaluate the effect of T-DM1 exposure and other potential covariates on PFS and OS.
Results: The PK parameters for T-DM1, total T, and DM1 in EMILIA and other studies of single-agent T-DM1 are summarized in Table 1. The PK parameters appear similar regardless of prior tx for MBC. No significant differences in mean serum T-DM1 AUC (P = 0.091) or plasma DM1 Cmax (P = 0.812) were observed between responders and non-responders following T-DM1 tx. Furthermore, variability in T-DM1 AUC and DM1 Cmax does not appear to affect the probability of response to therapy (P = 0.23 for T-DM1 AUC and P = 0.74 for DM1 Cmax). Based on Cox proportional hazards analysis, no significant exposure-efficacy relationship was observed between T-DM1 AUC (P = 0.23 for PFS and p = 0.53 for OS) or DM1 Cmax (P = 0.96 for PFS and P = 0.34 for OS) and PFS or OS, respectively.

Conclusions: T-DM1 PK data in EMILIA pts were similar to those observed in previous phase 2 studies, which include pts who have and have not received prior therapy for MBC. Variation in T-DM1 exposure among pts who received T-DM1 3.6 mg/kg q3w had no significant impact on ORR, PFS, or OS. Detailed analyses will be presented.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-11.
Abstract P5-20-03: A phase 2, double-blind, randomized, placebo-controlled, dose-finding study of sotatercept for the treatment of patients with chemotherapy-induced anemia and metastatic breast cancer.
Authors: Auerbach M , Osborne CRC , Klesczewski K , Laadem A , Sherman ML , Bianca R 
Published: August 2014

Abstract
Background: Sotatercept is a recombinant activin receptor IIA (ActRIIA) ligand trap and is comprised of the extracellular domain of ActRIIA linked to the Fc domain of human IgG1 (ActRIIA-IgG1). Results of preclinical and early clinical studies provide evidence that sotatercept increases the concentration of hemoglobin (Hb) in blood and may constitute a novel treatment for chemotherapy-induced anemia (CIA), a condition that results in significant morbidity.
Methods: This study evaluated the safety of, and hematopoietic response to, sotatercept in patients with CIA and metastatic breast cancer (MBC). Response was defined as increase in Hb ≥1 g/dL for ≥28 consecutive days during treatment or ≤2 months following the last dose, in the absence of red blood cell (RBC) transfusion or treatment with an erythropoiesis stimulating agent (ESA). If RBC transfusion or treatment with an ESA was required, no Hb measurements within 28 days of the RBC transfusion or administration of ESA were used to determine the Hb response. Subjects were randomized to subcutaneous injection of sotatercept (0.1, 0.3, or 0.5 mg/kg) or placebo and were treated on day 1 of each of four 28-day cycles.
Results: Thirty (30) subjects were enrolled and treated (5 placebo, 25 sotatercept). Increases in mean Hb in the 0.3 and 0.5 mg/kg groups were greater than in 0.1 mg/kg and placebo groups. Increases peaked approximately 15 days following treatment and declined over the remaining interval between treatments. Among 23 subjects with confirmed CIA and administered ≥1 dose and followed for ≥57 days (per-protocol analysis), 5/18 (28%) administered sotatercept responded (0/5 [0%] at 0.1 mg/kg; 3/9 [33%] at 0.3 mg/kg; 2/4 [50%] at 0.5 mg/kg) vs 1/5 [20%] administered placebo. Among 13 nonresponders administered sotatercept, 5 (39%) experienced ≥1 dose interruption/reduction, as per protocol, due to elevated Hb. The incidence of adverse events (AEs) was consistent with that reported in patients with MBC. No dose-limiting or dose-related toxicity was observed.
Conclusions: Sotatercept demonstrated dose-dependent hematopoietic activity in subjects with CIA and MBC. The safety findings were generally consistent with the known safety profile of sotatercept. These data suggest that a greater dose of sotatercept or a dose interval &lt;28 days might result in a more sustained, and greater rate of, hematopoietic response.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-03.
Abstract P5-20-08: Phase II trial of ixabepilone (Ixa) and dasatinib (D) for treatment of metastatic breast cancer (MBC)
Authors: Schwartzberg LS , Tauer KW , Schnell FM , Hermann R , Rubin P , Christianson D , Weinstein P , Epperson A , Walker M 
Published: August 2014

Abstract
Background: Ixa is a novel semi-synthetic epothilone microtubule blocking agent with activity in taxane and anthracycline-resistant MBC. D is a potent small molecule tyrosine kinase inhibitor with substantial activity against SRC family non-receptor kinases, known to play multiple roles in promoting tumor growth and metastases. D inhibits cellular SRC autophosphorylation in cell lines that highly express SRC and inhibits in vivo activation in a broad array of tumors in nude mice. Ixa and D have synergistic effects in preclinical models suggesting this strategy would be of clinical benefit as combination therapy. A phase I trial of the combination determined the maximally tolerated doses of ixabepilone at 20 mg/m2 weekly and dasatinib 100 mg po daily with objective responses seen. Neutropenia was the dose limiting toxicity.
Methods: Multicenter single arm phase II trial. Eligibility: Measurable or evaluable disease by RECIST 1.0, ECOG PS 0–2, HER2− or HER2 refractory, no CYP 3A4 inducers or inhibitors, no H2 blockers or PPIs, no pleural/pericardial effusion, exposure to 1 or 2 prior lines of chemotherapy in the metastatic setting, peripheral neuropathy ≤ grade 1. The primary endpoint was progression-free survival (PFS). Assessment for response was performed every 8 weeks. The treatment schedule was D at 100 mg po daily starting day 1, and Ixa 20 mg/m2 Day 1, 8, 15 every 28 days (1 cycle).
Results: The study met its accrual goal with 50 patients (pts) enrolled on the phase II dosing, including six from the phase I portion. As of May 21, 2012, 47 pts are evaluable. The median age was 55 (range, 34–70), 19 African-American, 46 ECOG PS 0–1, median number of metastatic sites, three. Forty pts had prior taxanes, 24 prior anthracyclines. Median PFS was 6.0 months (95% CI, 2.9–8.0), achieving pre-specified value of interest for further study of the combination. The overall unconfirmed response rate was 14.9% with a clinical benefit rate (CR+PR + stable at 24 weeks) of 25.5%. Six pts continued D monotherapy after eight cycles of Ixa + D. All-grade adverse events (AEs) occurring in &gt;15% of pts included anemia (45%), neutropenia (32%), nausea (51%), vomiting (32%) diarrhea (51%), fatigue (53%), anorexia (25%) dysgeusia (32%), headache (28%), peripheral neuropathy (34%) cough (28%) alopecia (21%) and hypokalemia (19%). Grade 3/4 adverse events occurred in 30 patients, with only four experiencing grade 4 AEs, three neutropenia and one chest pain. No grade 3/4 febrile neutropenia occurred. Grade 3 AEs of interest included two pts with peripheral neuropathy and 1 with pleural effusion.
Conclusions: The combination of Ixabepilone weekly + Dasatinib orally daily is an active and well tolerated regimen in pretreated MBC with manageable toxicity. Updated results will be reported.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-08.