bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract OT1-03-08: A multicenter, phase I/II trial of anastrozole, palbociclib, trastuzumab and pertuzumab in HR-positive, Her2-positive metastatic breast cancer
Authors: Cascetta KP , Poulikakos P , Shapiro C , Fasano J , Bhardwaj A , Irie H , Goel A , Klein P , Adams S , Kalinsky K , Vahdat L , Ru M , Tiersten A 
Published: February 2018

Abstract
Background: Overexpression or amplification of HER2 occurs in approximately 15 – 20% of patients and about half of these tumors are hormone receptor (HR) positive. Studies suggest that this 10% of all breast cancer cases may derive less benefit from endocrine therapy than those with HR positive disease without HER2 overexpression. The use of aromatase inhibitors in the metastatic setting is well established while significant improvement in overall survival has been established with the use of trastuzumab or pertuzumab in HER2-overexpressing tumors. To date, no studies have examined the combination of endocrine therapy, palbociclib, and dual HER2 therapy with pertuzumab and trastuzumab in this patient population.
Trial Design: Multicenter, Phase I/II Trial of Anastrozole, Palbociclib, Trastuzumab and Pertuzumab in HR-positive, Her2-positive Metastatic Breast Cancer.
Eligibility Criteria: Stage IV hormone receptor positive, HER2 positive breast cancer patients.
Specific Aims: Phase I: To determine the maximum dose tolerated of palbociclib. Phase II: To determine the clinical benefit rate (CBR) of treatment with anastrozole, palbociclib, trastuzumab, and pertuzumab in HR+, HER2+ metastatic breast cancer patients. Exploratory: Examine potential biomarkers of response to palbociclib including cyclin D1 expression levels, phosphorylated retinoblastoma expression and p16 levels. RNA sequencing will be used to assess for other predictors of response in an unbiased manner to see if there is correlation with inhibition of Ki-67 and phosphorylated retinoblastoma expression as well as evaluate for potential mechanisms of resistance.
Statistical Methods: This study will evaluate the maximum tolerated dose (MTD) of the Anastrozole, Palbociclib, Trastuzumab and Pertuzumab. If ≥ 33 % of patients experience a dose limiting toxicity (DLT) at any dose level, the dose level below that level will be considered the MTD. Or, if the highest level has been reached and &lt; 33% of patients have experienced DLT, that will be considered the MTD. Once the MTD is reached, we will assess the clinical benefit rate using a Simon's II stage design among a maximum 30 patients.
Accrual: Maximum of 36 subjects.
Citation Format: Cascetta KP, Poulikakos P, Shapiro C, Fasano J, Bhardwaj A, Irie H, Goel A, Klein P, Adams S, Kalinsky K, Vahdat L, Ru M, Tiersten A. A multicenter, phase I/II trial of anastrozole, palbociclib, trastuzumab and pertuzumab in HR-positive, Her2-positive metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-03-08.
Abstract OT1-04-02: Mifepristone treatment for breast cancer patients expressing levels of progesterone receptor isoform A (PRA) higher than those of isoform B (PRB)
Authors: Liguori M , Lanari C , Gass H , Rojas P , Elia A , Martinez Vazquez P , Burruchaga J , Gonzalez P , Caillet Bois I , Ventura C , San Martin G , Castets A , Lovisi S , Acosta Haab G , Lamb C , Fabris V , Novaro V , Molinolo A 
Published: February 2018

Abstract
Seventy percent of breast cancers express estrogen (ER) and progesterone receptors (PR) and respond to antiestrogen therapies. Emerging evidence from experimental studies and human epidemiology, points to a relevant role for progestins in breast carcinogenesis and cancer growth. Others and we have proposed that there is a role for antiprogestins in the therapeutic armamentarium, but the challenge remains to identify which patients would benefit from targeting the PR in addition to ER. Preclinical data indicates that antiprogestins block cell proliferation and increase apoptosis only in ER+ breast cancers expressing levels of PRA higher than those of PRB. The aim of this study is to evaluate the therapeutic effects of Mifepristone (MFP) on breast cancer patients selected by their PRA/PRB isoform ratio, for 14 days in between core biopsy and surgery (MIPRA trial ClinicalTrials.gov Identifier: NCT02651844). Methods: This is an open label, interventional with single group assignment study. We perform core biopsies on menopausal patients with clinically palpable breast cancers larger than 1.5 cm to confirm diagnosis. We will assess the PRA/PRB ratio by western blotting in frozen samples and total PR in formalin-fixed samples by immunohistochemistry (IHC). Twenty eligible PR+ patients (PR &gt; 50 %) with PRA/PRB ≥1.5 who have signed consent forms, and meet the inclusion criteria will be recruited. Patients will be treated for 14 days with MFP p.o 200 mg. Surgery will be performed on day 15. Samples will be frozen for molecular studies or fixed for IHC. The primary outcome is the evaluation of Ki-67 staining pre- and post treatment. Secondary outcomes include comparatively expression of proliferation/apoptosis/PR signaling markers in core and surgical biopsy samples. Other pre-specified outcomes include molecular profiling, study of liquid biopsies, mammography, and ultrasound studies. Wilcoxon signed rank test will be used to evaluate differences in biomarker expression between core biopsy and surgical samples of each patient.
Citation Format: Liguori M, Lanari C, Gass H, Rojas P, Elia A, Martinez Vazquez P, Burruchaga J, Gonzalez P, Caillet Bois I, Ventura C, San Martin G, Castets A, Lovisi S, Acosta Haab G, Lamb C, Fabris V, Novaro V, Molinolo A. Mifepristone treatment for breast cancer patients expressing levels of progesterone receptor isoform A (PRA) higher than those of isoform B (PRB) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-04-02.
Abstract OT1-05-01: A phase I/II, single arm, non-randomized study of ribociclib (LEE011), a CDK 4/6 inhibitor, in combination with bicalutamide, an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer
Authors: Santa-Maria CA , Rampurwala M , Wisinski K , Toppmeyer D , O'Regan R 
Published: February 2018

Abstract
Background: Triple negative breast cancer (TNBC) is a heterogeneous disease encompassing distinct intrinsic molecular subtypes, including a luminal androgen receptor (AR) subtype, characteristically dependent on AR signaling. The AR is expressed in more than 50% of TNBCs. Bicalutamide is an oral, non-steroidal, AR antagonist, which has been studied in metastatic TNBC with a clinical benefit rate of 19% at 24 weeks. In preclinical models, cyclin dependant kinase (CDK) 4/6 inhibition has been shown to restore sensitivity to AR inhibition, and may thus be an important resistance mechanism. Ribociclib is an orally bioavailable, highly specific CDK4/6 inhibitor that induces cell cycle arrest, already approved in endocrine receptor positive breast cancers. We hypothesize that inhibition of CDK inhibition can enhance the activity of anti-androgen therapy in TNBC that express AR.
Methods: We designed a phase I/II, single arm, non-randomized, open label study of the combination of bicalutamide with ribociclib in women with advanced AR-positive TNBC. The primary objective of the phase I component is to determine the maximum tolerated dose of the combination, and of the phase II component to assess the clinical benefit rate at 16 weeks. Secondary objectives include progression free and overall survival, objective response rates, and safety and tolerability. Exploratory objectives will be to assess AR quantification, localization and splice variants in circulating tumor cells, as well as quantification of pan and phospho proteins of Rb. Eligible patients must have measurable metastatic or unresectable AR-positive TNBC and have had no more than 1 line of systemic therapy for metastatic disease. The phase I study will be conducted using a 3+3 dose escalation schema, 12 to 18 patients are expected to enroll. The phase II component will utilize a Simon's two stage design, enrolling 24 patients for the first stage. At least 5 subjects must have clinical benefit by 16 weeks to proceed onto the second stage, which would enroll an additional 22 subjects for a total of 46 patients. The study will be powered to detect a clinical benefit rate of 40% with a power of 80% and a type I error rate of 10%. Contact dmusapatika@hoosiercancer.org for more information about the study.
Citation Format: Santa-Maria CA, Rampurwala M, Wisinski K, Toppmeyer D, O'Regan R. A phase I/II, single arm, non-randomized study of ribociclib (LEE011), a CDK 4/6 inhibitor, in combination with bicalutamide, an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-05-01.
Abstract P1-01-17: Characterization of novel ESR1 (c.749T&gt;C; p.Met250Thr) mutation in enhancing cellular invasiveness of breast cancer
Authors: Liao N , Zhang G-C , Wang Y , Cao L , Li K , Ren C-Y , Wen L-Z , Shi Y , Zhu W , Chen X 
Published: February 2018

Abstract
Emerging evidence has revealed that the mutations in estrogen receptor alpha (ERα) gene (ESR1) is frequently observed in ER+ metastatic breast cancer, and is associated with the aggressively invasive and metastatic phenotype in advanced breast cancer due to the resistance of endocrine therapy. In our previous study, we have identified three novel mutations of ESR1, including ESR1 G74R, D230H and M250T, in the untreated patients with early breast cancer. However, the functional roles for these novel mutations in the cellular biology of breast cancer remain to be elucidated. In this study, we described the molecular mechanism underlying potential roles for the novel mutation ESR1 p.Met250Thr (c.749T&gt;C) in regulating the cellular invasiveness of breast cancer. Firstly, we found, as compared with wild-type (WT) HA-ESR1, forced expression of HA-ESR1 M250T enhanced the invasive capacity of breast cancer MCF-7 cells by using Transwell assay. Moreover, we found that the levels of miR-190 were significantly up-regulated in the MCF-7 (HA-ESR1 M250T) cells, and further verified that miR-190 played an important role in ESR1 M250T-mediated induction of cellular invasiveness by using specific shRNA to knock down miR-190 levels in MCF-7 (HA-ESR1 M250T) cells. Further bioinformatics analysis showed that there were several half Estrogen Response Elements (EREs) in the promoter region of Talin-2, as the host gene of miR-190. Talin-2-driven luciferase reporter assay indicated ESR1 M250T resulted in a higher increase in the luciferase activity than ESR1 WT. Chromatin-immunoprecipitation (ChIP) assay identified a higher binding ability with Talin-2 promoter for ESR1 M250T than ESR1 WT. Collectively, our mechanistic study revealed that the ESR1 M250T mutation, located in the DNA-binding domain, increased the invasive capacity of breast cancer cells via the transcriptional induction of Talin-2 and miR-190. The potential role for ESR1 M250T in affecting the efficacy of endocrine therapy has been under the investigation in our laboratory, and the result from which will help us better elucidate the clinical relevance for novel ESR1 mutations in affecting the sensitivity of endocrine therapy.
This study was supported in part by National Natural Science Foundation of China (8160111571) and Guangdong Natural Science Foundation (2016A030313768).
Citation Format: Liao N, Zhang G-C, Wang Y, Cao L, Li K, Ren C-Y, Wen L-Z, Shi Y, Zhu W, Chen X. Characterization of novel ESR1 (c.749T&gt;C; p.Met250Thr) mutation in enhancing cellular invasiveness of breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-01-17.
Abstract P1-02-05: The effect of obesity and metabolic factors on genomic assays for risk of recurrence
Authors: Soliman H , Treece T , Audeh W ,   IMPACt Investigators Group I
Published: February 2018

Abstract
Background: Obesity and other factors contributing to metabolic syndrome (MS) have become increasingly prolific in today's population. They are also known risk factors or comorbidities in many disease states including breast cancer (BC). While obesity and MS are known to increase the risk of developing BC, the effect on the risk of distant recurrence is uncertain. This substudy evaluated the relationship of BMI, blood pressure, cholesterol, triglyceride, diabetic status, and MS on the risk of recurrence in early BC patients. Methods: The effect of these metabolic factors on MammaPrint (MP) and Oncotype DX (ODX) risk of recurrence assays was compared. Additionally, gene expression analysis was performed to elucidate the differences between obese patients who were MP high risk (HR) vs. low risk (LR), and MP HR patients who were obese vs. not-obese. This subanalysis included patients from the PROMIS (n=198) and IMPACt (n=382) studies for whom metabolic characteristics were captured with informed consent. From the IMPACt study, 98 patients also reported ODX results (RS range 0-69). Results: By BMI, 1% of patients were classified as underweight (BMI &lt;18.5), 22% normal (18.5≤ BMI &lt;25), 31% overweight (25≤ BMI &lt;30), and 46% as obese (BMI ≥30). To be classified as having MS, the patient had to exhibit any 3 of the 5 metabolic factors. In the full cohort, having MS was significantly associated with ethnicity (p &lt; 0.05) and menopausal status (p &lt; 0.001), but not histopathological tumor type, histological grade, tumor stage, or lymph node status (p &gt; 0.05). 36% (207/580) of patients were considered as having MS in the full cohort, similarly 36% (35/98) had MS in the ODX subset. Of the patients with MS, MP classified 52% (108/207) as HR. For the subset of ER-positive patients with an ODX result, ODX classified the 11% (4/35) as HR whereas MP classified 57% (20/35) of the same patients as HR. Conclusions: Patients with obesity as measured by BMI and with MS were more frequently classified as HR by MP, in contrast to ODX which classified nearly all patients as intermediate or LR, confirming previous findings by Robinson, et. al (SABCS 2012 and 2014). Understanding the biological foundation of how obesity and metabolic factors affect risk of recurrence in breast cancer will improve both the treatment and care of patients.
Citation Format: Soliman H, Treece T, Audeh W, IMPACt Investigators Group I. The effect of obesity and metabolic factors on genomic assays for risk of recurrence [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-02-05.
Abstract P1-03-10: Breast tumour kinase and its role in mTOR signalling
Authors: Harvey A , Foster H , Thorpe M , Karteris E 
Published: February 2018

Abstract
Background: The development of distal metastases and the acquisition of resistance to chemotherapeutic agents are one of the leading causes of cancer related death in breast cancer patients. There is both a scientific and clinical need to understand the alterations in cellular signalling pathways that could contribute to chemotherapeutic resistance in breast cancer, thereby identifying novel targets for therapy. The intracellular tyrosine kinase Brk/PTK6 enhances coupling of ErbB signalling to PI3K/Akt and we hypothesise that Brk plays a role in chemo-resistance and activation of downstream effectors such as mTOR.
Methods: The protein and activation levels of mTOR pathway components and expression levels of Brk, in both Taxol-sensitive and resistant breast cancer cells, were examined by western blotting and immunofluorescence. Brk transfected cells were treated with BEZ-235 for 72 hours and relative cell numbers determine by MTT assay. Immunoprecipitation studies were carried out on lysates from T47D cells, transfected to express FLAG-tagged Brk, with ANTI-FLAGM2 agarose beads. Sequence alignment was done using the NCBI BLAST Tool.
Results: We found that mTOR signalling was up-regulated in the Taxol-resistant cell line compared to parental Taxol-sensitive cells. This up-regulation was also accompanied by increased Brk levels. Transfection of a Brk-negative breast cancer cell line, MDA-MB-468 with wild-type Brk resulted in increased levels of both mTOR and, to a lesser extent, the downstream signalling component GβL at the protein level compared to cells transfected with vector only. Levels of the mTOR inhibitor DEPTOR were also decreased in response to Brk expression and mTOR co-precipitated in FLAG-Brk pull downs using FLAG M2 beads.
The Taxol resistant cells also showed altered responses to the mTOR inhibitor RAD-001/everolimus. Interestingly, sequence alignment revealed that there are common amino acid motifs between Brk and the mTOR regulatory molecule DEPTOR.
Conclusions: These data implicate Brk in up-regulating mTOR expression and indicate that Brk may influence mTOR signalling in the development of Taxol resistance. It is possible that Brk could substitute for DEPTOR in mTOR complexes providing a mechanism for elevated mTOR signalling in many breast cancers.
Citation Format: Harvey A, Foster H, Thorpe M, Karteris E. Breast tumour kinase and its role in mTOR signalling [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-03-10.
Abstract P1-04-01: A novel oncolytic herpes simplex virus, GD116, has enhanced antitumour efficacy in human breast cancer
Authors: Cheng L , Wang J , Liu R 
Published: February 2018

Abstract
Background: Oncolytic herpes simplex virus-1 (oHSV-1) vectors are promising new therapeutic agents for cancer. For the nuerovirulence of ICP34.5 protein, the encoding gene named γ34.5 is deleted in all oHSV-1 mutants currently in clinical trials. However, the deletion of γ34.5 also promotes the interferon-induced shutoff of virual protein synthesis, and attenuates the virus replication in cancer cells at the same time. Previous studies reported that the carboxyl-terminus of MyD116/GADD34 was homologous to that of γ34.5 gene; hence, it might substitute for γ34.5 gene to enhance the replication and cytotoxicity of the virus. Objective: To reconstruct a novel oHSV-1 mutant named GD116 by inserting γ34.5-MyD116 chimeric gene into G47Δ genome, and to investigate whether the carboxyl-terminus of murine MyD116 can enhance the antitumour efficacy of GD116 on human breast cancer cell line in vitro and in vivo. Methods: Using G47Δ genome and bacterial artificial chromesome (BAC) as the backbone, the GD116 virus expressing γ34.5-MyD116 was reconstructed via Cre/loxp and FLP/FRT recombinase systems. A GD-empty virus mutant containing only the CMV sequence was also constructed as a control at the same time. Then, the replication and cytotoxicity of these two virus mutants in MDA-MB-231 humanbreast cancer cell line was evaluated in vitro. Meanwhile, the subcutaneous tumor model was also generated by injecting MDA-MB-231 cells into the right flank of BALB/c mice. Then, the antitumor efficacy of GD116 on breast cancer in vivo was evaluated by intratumoral injection. Results: Compared with GD-empty, GD116 possessed an enhanced replication capability and oncolytic efficacy in MDA-MB-231 cell line. On the fifth day after infection with GD116 at MOIs of 0.1 and 0.3, 35.0% and 50.2% of MDA-MB-231 cells were killed respectively, which were higher than that with GD-empty (24.3% and 37.8%). Additionally, GD116 exhibited enhanced antitumor efficacy on subcutaneous tumor xenografts of human breast cancer cells in vivo compared with GD-empty. On day 21 after treatment, the average tumor volume of mice was 585.5 mm3, 289.0 mm3 and 121.9 mm3 in Control, GD-empty and GD116 group respectively. Conclusion: Our findings indicate that the carboxyl-terminus of the murine MyD116 can substitute for the corresponding domain of the γ34.5 gene in oHSV-1 to promote the replication of the virus in infected cancer cells; and the mutant GD116 armed with γ34.5-MyD116 chimaera has enhanced oncolytic effect on MDA-MB-231 breast cancer cells in vitro and in vivo.
Citation Format: Cheng L, Wang J, Liu R. A novel oncolytic herpes simplex virus, GD116, has enhanced antitumour efficacy in human breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-04-01.
Abstract P1-07-35: Adipokine receptor CAP1 expression as predictor of survival outcome among breast cancer patients
Authors: Rosendahl AH , Bergqvist M , Kimbung S , Borgquist S 
Published: February 2018

Abstract
Background: Obesity is a challenging health concern in breast cancer. Not only are obese women at higher risk of breast cancer, but if diagnosed with the disease, obesity is also impairing the prognosis of a breast cancer. Understanding the underlying biology behind these associations are key to improve survival rates in breast cancer. In obesity, the more abundant, activated adipose tissue may lead to insulin resistance and secretion of soluble mediators that may contribute to impaired breast cancer outcomes observed among obese women. The adipokine resistin is implied to be an important link between obesity and insulin resistance, and to be elevated among breast cancer patients. Yet, the expression of the newly identified resistin receptor CAP1 and its impact on breast cancer prognosis is poorly understood.
Purpose: To evaluate the impact by the adipokine receptor CAP1 tumor expression on breast cancer outcomes.
Experimental Design: CAP1 mRNA expression was explored among 1,881 primary breast tumors. Associations between CAP1 expression, categorized into tertiles, and survival outcomes were estimated using the Kaplan-Meier method and log-rank test, and by multivariable Cox regression models providing adjusted hazard ratios (HRadj) with 95% confidence intervals (CI). Independent biological network interaction analyzes were conducted in a subset of 1,105 invasive breast carcinomas within The Cancer Genome Atlas (TCGA) project.
Results: CAP1 was linked to poor tumor characteristics with higher CAP1 expression found among estrogen receptor (ER)-negative tumors, relative to ER-positive tumors, as well as with increasing tumor grade (P=0.025). High CAP1 tumor expression was further associated with shorter overall survival (HRadj 1.54; 95% CI, 1.11-2.13) and relapse-free survival (HRadj 1.47; 95% CI, 1.10-1.96), compared with low or intermediate CAP1 expression, particularly among ER-positive tumors or lymph node positive tumors. Additionally, CAP1 was identified in complex with genes involved in growth promoting and cell motility processes.
Conclusion: These results highlight the potential role of the resistin receptor CAP1 regarding breast cancer outcomes. Further investigations are needed to elucidate the biological and clinical implication of the resistin-CAP1 link in obesity-associated breast cancer.
Citation Format: Rosendahl AH, Bergqvist M, Kimbung S, Borgquist S. Adipokine receptor CAP1 expression as predictor of survival outcome among breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-07-35.