bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P3-04-10: Utility of the orally bioavailable selective estrogen receptor degrader AZD9496 in ESR1 mutant preclinical models of estrogen receptor positive breast cancer
Authors: Morrow CJ , Lawson M , Ladd B , de Almeida C , James N , Curwen JO , Hanson L , Bell K , Goeppert A , Fisher D , Gangl E , De Savi C , Scott JS , D'Cruz C , Klinowska T , Weir HM 
Published: March 2017

Abstract
Approximately 70% of breast cancers express estrogen receptor alpha (ERα) and anti-hormonal therapies which either block the production of estrogen (e.g. anastrozole) or directly block ERα function (e.g. tamoxifen) remain the mainstay of treatment for these patients. While these therapies are highly effective resistance can occur. A common resistance mechanism to anti-hormonal agents is the mutation of ESR1, the gene that encodes ERα, which leads to ligand independent activity. Evidence is emerging that the selective estrogen receptor degrader (SERD) fulvestrant is effective in patients with ESR1 mutations. However, given the low bioavailability of fulvestrant and the still detectable levels of ER in clinical samples after treatment with fulvestrant it is hypothesised that SERDs with improved pharmacokinetic properties which are able to drive greater degradation of ERα may provide additional clinical benefit. We have previously described the discovery and characterisation of the orally bioavailable SERD AZD9496, which is currently in phase I clinical trials in ER+ breast cancer patients. Here we report the preclinical activity of AZD9496 in cell line and patient derived xenograft models expressing clinically relevant ESR1 mutations. We have engineered MCF-7 cells to express Y537S ESR1 which confers the ability to proliferate in the absence of estradiol, consistent with ligand independent activation of ER signalling. AZD9496 is able to inhibit proliferation of these cells and downregulate progesterone receptor protein expression at low nanomolar concentrations. Furthermore, when MCF-7 Y537S ESR1 cells are implanted as xenografts they grow in the absence of exogenous estradiol, are as sensitive to AZD9496 as parental MCF7 xenografts and demonstrate downregulation of ER dependent biomarkers. AZD9496 also has anti-tumour and pharmacodynamic efficacy in patient derived xenograft models expressing D538G ESR1. Taken together, these data strengthen the body of data suggesting that SERDs may be active in patients with tumours containing ESR1 mutations and supports the inclusion of this patient population in AZD9496 clinical trials.
Citation Format: Morrow CJ, Lawson M, Ladd B, de Almeida C, James N, Curwen JO, Hanson L, Bell K, Goeppert A, Fisher D, Gangl E, De Savi C, Scott JS, D'Cruz C, Klinowska T, Weir HM. Utility of the orally bioavailable selective estrogen receptor degrader AZD9496 in ESR1 mutant preclinical models of estrogen receptor positive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-10.
Abstract P3-04-21: Androgen receptor in tamoxifen-resistant breast cancer is affected by SUMO
Authors: Bahnassy S , Kumar S , Ren J , Frutiz G , Karami S , Bawa-Khalfe T 
Published: March 2017

Abstract
Resistance to tamoxifen is a major problem in treating women with estrogen receptor-positive (ERa+) breast cancer (BCa). Previous studies report elevated levels of the androgen receptor (AR) in tamoxifen-resistant (TamR) human mammary tumors. Inversely, in vitro overexpression of AR in ERa+-MCF-7 cells potentiates growth in the presence of tamoxifen. AR is a target for small ubiquitin like modifiers (SUMO) posttranslational modification (PTM). Prostate cancer (PCa) studies, show that SUMO-PTMs can have diverse effects on AR transcriptional activity, by modifying the AR itself or its co-regulators. SUMOylation regulates the AR's interaction with chromatin and modulates its function in a gene selective manner. Although SUMO-1 inhibited the AR transcriptional activity, SUMO-3 strongly enhanced the transactivation of AR in LNCaP cells but negatively affected the AR transcriptional activity in primary prostate epithelial cells. On the other hand, SUMO modifications and its subsequent effects on the AR in breast tumors and in particular TamR-BCa is unknown. Our objective is to understand how SUMO-PTMs affect AR activity in TamR-BCa. Others report that high Ubc9, a SUMO E2 conjugating enzyme, correlates with with aggressive phenotypes of BCa and that PIAS3, a SUMO E3 ligase, expression increases in breast tumors. Consistently, we now report that global SUMO2/3-conjugation is enhanced while the full-length SUMO protease SENP7 (SENP7L) is reduced in TamR-BCa cells. Collectively, these observations would suggest reduced SUMO dynamics in TamR-BCa as compared to tamoxifen-sensitive (TamS) BCa cells. Unlike PCa cells that favor unmodified over SUMOylated AR, we report that AR SUMOylation is potentiated in TamR-BCa cells. Functionally, SUMOylation of AR augments its chromatin binding and enhances its transcriptional activity. Our results suggest that the level of unmodified to SUMOylated AR is dramatically altered with onset of TamR and drives a functionally distinct population of AR in TamR versus TamS BCa. Consistently these biochemical reactions that define protein diversity could have a major impact on drug resistance in BCa.
Citation Format: Bahnassy S, Kumar S, Ren J, Frutiz G, Karami S, Bawa-Khalfe T. Androgen receptor in tamoxifen-resistant breast cancer is affected by SUMO [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-21.
Abstract P3-04-24: Identification of preclinical mechanisms driving acquired resistance to selective ERa degraders (SERDs), CDK4/6 inhibitors, or to combinations of both agents
Authors: O'Brien T , Xiao Y , Ong C , Daemen A , Friedman L 
Published: March 2017

Abstract
Estrogen positive (ER+) breast cancer accounts for the majority of all breast cancers and standard practice is treatment with endocrine therapy. Recently a series of CDK4/6 inhibitors have emerged that can be effectively combined with estrogen modulators to treat ER+ breast cancer patients. The most advanced of these compounds, palbociclib, is now approved in the US in combination with letrozole or fulvestrant. Even though these combinations are effective, invariably patients will relapse. Our understanding of the mechanisms of acquired resistance to CDK4/6 inhibitors is still relatively nascent, and it is not known whether acquired resistance to combination treatments (e.g. palbociclib with fulvestrant) will be the same as mechanisms for the individual single agents. Additionally, it is not known if tumors that no longer respond to one combination regimen will remain sensitive to other standard of care treatments.
To pre-clinically address these questions we generated cell lines that have acquired resistance to three Selective Estrogen Receptor Degraders (SERDs) and to two CDK4/6 inhibitors, palbociclib and abemaciclib. Additionally, we also generated cells with acquired resistance to the combination of fulvestrant and palbociclib. Characterization of cells resistant to each of these treatments will be presented. Initial data indicate that MCF7 cells with acquired resistance to SERDs have increased PI3K signaling and MEK/ERK signaling and have increased sensitivity to inhibitors of these pathways when treated with single agents. These cells are also more sensitive to palbociclib relative to parental cells. All 11 clones with acquired resistance to abemaciclib lose Retinoblastoma (Rb) expression and 20/24 palbociclib-resistant clones lose Rb expression, indicating the importance of Rb to CDK4/6 inhibitor activity. Interestingly, palbociclib resistant clones have decreased sensitivity to fulvestrant and to PI3K inhibitors, and investigation is under way to determine if that relates to slower doubling times for the clones.
Detailed characterization of resistant clones reveals a surprisingly complex interaction between ERa and CDK4/6 signaling, and further results, including acquired resistance to drug combinations, will be presented. These preclinical studies may inform biomarkers of sensitivity and resistance to endocrine agents and CDK4/6 inhibitors.
Citation Format: O'Brien T, Xiao Y, Ong C, Daemen A, Friedman L. Identification of preclinical mechanisms driving acquired resistance to selective ERa degraders (SERDs), CDK4/6 inhibitors, or to combinations of both agents [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-24.
Abstract P3-05-09: Glucocorticoid receptor modulation affects ER+ breast cancer cell proliferation
Authors: Tonsing-Carter E , Bowie KR , West DC , Harkless RV , Hernandez KM , Conzen SD 
Published: March 2017

Abstract
Early-stage ER+ breast cancer with high tumor glucocorticoid receptor (GR) expression is associated with improved long term relapse-free survival compared to tumors with low GR expression. In addition, activation of GR inhibits estradiol-mediated ER+ BC cell proliferation. This finding led us to hypothesize that GR and ER engage in nuclear receptor cross-talk to affect pro-proliferative gene expression, thus contributing to a better outcome in ER+/GR+ BC patients. To better understand the mechanisms by which ER/GR co-activation contributes to this more indolent phenotype, we performed ChIP-sequencing and gene expression analyses in ER+/GR+ BC cell lines (MCF-7 and T47D).
We found that co-activation of ER and GR led to decreased ER+ BC cell proliferation in vitro. Furthermore, following co-activation of ER/GR, there was decreased gene expression of key cell cycle genes (e.g. CDK6, CDK2 and CCNE1) compared to ER-activation alone. Studies are underway to determine if this decrease in gene expression is associated with less CDK activity as well as a slowing of cell cycle progression.
We also wanted to know if GR activation with a pure agonist versus a mixed GR modulator was required for decreasing ER-mediated cell proliferation. Based on our previous work (DC West et al. MCR 2016), we hypothesized that ligand-mediated GR activation could be working by preventing access of ER to regulatory regions of pro-proliferative genes rather than causing direct GR agonist-mediated gene expression. To examine this question, we used a GR modulator, mifepristone (expected to alter ER-mediated gene expression indirectly). Indeed we found that a GR modulator also reduced ER-mediated cell proliferation. We are currently testing the mechanisms by which GR modulators affect estradiol-mediated cell cycle gene expression.
Taken together, these studies suggest that modulation of GR activity could be an effective approach to decrease ER+ tumor cell proliferation. Xenograft studies are underway to examine whether the addition of GR modulation to tamoxifen will improve tumor shrinkage compared to tamoxifen alone.
Citation Format: Tonsing-Carter E, Bowie KR, West DC, Harkless RV, Hernandez KM, Conzen SD. Glucocorticoid receptor modulation affects ER+ breast cancer cell proliferation [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-05-09.
Abstract P3-06-07: Combination of doxorubicin with S1P signaling modulator FTY720 significantly suppressed obesity-associated breast cancer
Authors: Katsuta E , Takabe K 
Published: March 2017

Abstract
Background:
Obesity is one of the biggest health issues in the US. It has been shown that obesity-associated breast cancer is more aggressive with poor prognosis, which is partly explained by the low-grade inflammation caused by obesity. Recently we have published that sphingosine-1-phosphate (S1P), a signaling lipid mediator, link inflammation and cancer in colitis-associated colon cancer model. We hypothesized that addition of S1P modulator that block S1P signaling thus suppress the effect of obesity-mediated inflammation should enhance anti-cancer effect of doxorubicin, which is a typical anti-cancer drug for breast cancer used as a standard of care.
Methods:
Female B6.cg-Lepob (OB/OB) mice fed with high fat diet for 2 weeks prior to implantation of cancer cells were used as an obesity model, and litter mate control mice fed with normal diet were used as a control. 1 x 106 murine mammary adenocarcinoma E0771 cells were inoculated into #2 rt. fat pads as previously described (Katsuta et al JSR 2016). 9 days after inoculation, both OB/OB and control mice were randomized into 4 groups in each group; vehicle, Doxorubicin, FTY720 and Combination of Doxorubicin and FTY720. Doxorubicin was administrated by i.p. injection at a dose of 5 mg/kg on Day 0 and 3. FTY720 was administered everyday by gavage at a dose of 1 mg/kg during the entire course. Tumor growths were measured daily by caliper measurements. Tumor weights were measured on 21 days after cell inoculation.
Results:
The body weight of obesity model was significantly heavier than control mice at the time of cancer cell inoculation (44.1 g vs 19.4 g; p &lt; 0.001). In non-treatment group, tumor weight in obesity group was significant heavier than control mice[KT1] (1232 mg vs 966 mg; p = 0.049), which is consistent with the dogma that obesity worsen cancer progression. As expected, tumor weight in non-treatment group is heavier than any treatment group, and that in combination treatment of doxorubicin and FTY720 is lightest in both of obesity group and control group. Interestingly, tumor reduction rate in obesity group compared with non-treatment group is significant greater than control group (Doxorubicin: 83% vs 19%, p = 0.001; FTY720: 80% vs 46%, p = 0.027, Doxorubicin + FTY720: 93% vs 64%, p = 0.011). Over 15 % weight loss were seen in obesity doxorubicin group and obesity combination treatment group.
Conclusion:
Modification of S1P signaling by FTY720 was shown to enhance the effect of doxorubicin particularly in obese mice, which implicate a novel approach to treat obesity-associated breast cancer.
Citation Format: Katsuta E, Takabe K. Combination of doxorubicin with S1P signaling modulator FTY720 significantly suppressed obesity-associated breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-06-07.
Abstract P3-09-04: Beyond CHEK2 in breast cancer: Search for additional moderately penetrant risk gene variants by analyzing the oligogenic disease course in CHEK2 mutation carriers
Authors: Pohl E , Richters L , Hauke J , Ernst C , Kröber S , Niederacher D , Arnold N , Ramser J , Groß E , Gehrig A , Schmidt G , Dutrannoy V , Kast K , Hahnen E , Schmutzler R 
Published: March 2017

Abstract
This abstract was not presented at the symposium.
Abstract P3-12-04: Is 6 hour monitoring for administration related reactions after first administration of subcutaneous trastuzumab necessary? A single institution audit
Authors: Karmali S , Hughes N , Galiauskas R , Cook J , Murphy K , Bird BR , Murphy CG 
Published: March 2017

Abstract
Background: Subcutaneous (sc) trastuzumab has demonstrated non-inferiority to intravenous (iv) trastuzumab and is preferred by patients and providers. Serious administration related reactions (ARRs) such as hypotension, respiratory distress etc. were not reported in the pivotal HannaH study. However, the summary of product characteristics (SPC) advises that patients should be observed for ARRs for 6 hours post the first injection (and 2 hours post subsequent injections), similar to the iv formulation.
Methods: We conducted an audit of patients commencing sc trastuzumab at our institution. Medical notes of each patient were reviewed to record adverse events reported on the day of first administration or at the subsequent visit. In addition all patients were interviewed by telephone and questioned regarding adverse events with first or subsequent injections.
Results: 39 patients were identified, 32 had received prior iv trastuzumab. Patients received a mean of 12 injections. In total patients received 470 sc trastuzumab injections, associated with a recommended 1,096 hours of observation as per SPC. 3 injections (0.6%) were associated with ARRs within 24 hours, all on the first cycle. 2 patients (5%) experienced injection site reactions immediately post injection and 1 patient had injection site pain during the injection. 1 patient experienced pyrexia and dry cough 24 hours post injection and was hospitalized for respiratory tract infection. No patient experienced a reaction between 2 and 6 hours post first injection. There were no serious ARRs.
Conclusions: ARRs related to sc trastuzumab are usually immediate, mild and self-limiting. Observing patients for 6 hours post first injection and 2 hours post subsequent injections represents an inefficient use of healthcare resources.
Citation Format: Karmali S, Hughes N, Galiauskas R, Cook J, Murphy K, Bird BR, Murphy CG. Is 6 hour monitoring for administration related reactions after first administration of subcutaneous trastuzumab necessary? A single institution audit [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-12-04.
Abstract P3-13-21: Primary surgery in inflammatory breast cancer
Authors: Muzaffar M , Vohra N , Wong J 
Published: March 2017

Abstract
Background: Inflammatory Breast Cancer (IBC) is a rare but very aggressive variant of breast cancer accounting for around 1-5% of all breast cancer cases. Current standard of care is multimodality therapy with preoperative chemotherapy followed by modified radical mastectomy and adjuvant radiotherapy.
Method and Material: We searched the Surveillance Epidemiology and End results Registry to identify female patients diagnosed with Stage III IBC between 1988-2013.We performed descriptive and univariate analyses of the patients with IBC. Variables assessed included patient age, race/ethnicity, histologic subtype, tumor grade, hormone receptor status, surgery type.
Results: We identified 11604 women with IBC from SEER database diagnosed between 1988-2013.The median age was 57 yrs., 80 % ( 9273) of patients were white,14.4 % ( 1667) blacks, and around 73% had nodal involvement. 32.4 % (3756) patients were diagnosed with IBC between 1988-2000, while 67.6 % ( 7848) between 2001-2013.We excluded patients with missing primary surgery information with 7586 patients remaining for analysis. The median age in this final cohort was 56yrs, 80.4 % ( 6097) patients were white, and 13.7 % (1044) were black. The predominant tumor type was invasive ductal carcinoma, majority of the patients had grade 3 tumor 59.4 % ( 4504), grade2 in 23.2 % ( 1757),47.1% were estrogen receptor (ER)positive,43% were ER negative,53% were progesterone receptor negative, and 7% had HER 2 positive tumor. In this cohort 6.4 % (487) patients underwent partial mastectomy and 93.6 % (7099) underwent mastectomy. In the cohort undergoing breast conservation, 15% were during 1988-2000 and 84.4% during years 2001-2013 (p value=0.06).
Surgery in non-metastatic inflammatory Breast CancerType of Surgery1988-20002001-2013p-valuePartial Mastectomy76 (6.7%)1140(93.3%)0.06Mastectomy411 (6.9%)5959(93.1%)
The median survival was 46 months among patients diagnosed between 1988-2000 and 61 months for 2001-2013 time period(p&lt;0.0001).The median survival in patients undergoing partial mastectomy was 42 months versus 48 months among patients undergoing mastectomy (p=0.0001).
Discussion: IBC continues to be an aggressive breast cancer subtype, but survival has improved over last decade. The utility of partial mastectomy has increased in the last decade compared to 1988-2000. Mastectomy still remains the standard surgical option, but with more effective systemic therapeutic agents, better tumor responses are noted especially in Her 2 positive and triple negative IBC. Partial Mastectomy may be a viable option for patients achieving complete clinical response.
Citation Format: Muzaffar M, Vohra N, Wong J. Primary surgery in inflammatory breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-13-21.
Abstract P3-13-26: Deep Infrared Imaging to identify venous impairment after breast cancer surgery
Authors: Belgrado J-P , Vandermeeren L , Vankerckhove S , Valsamis J-B , Feipel V , Rooze M , Moraine J-J , Hertens D , Carly B , Liebens F 
Published: March 2017

Abstract
This abstract was not presented at the symposium.
Abstract P3-13-27: Early detection of secondary lymphedema after cancer treatments
Authors: Belgrado J-P , Vandermeeren L , Vankerckhove S , Valsamis J-B , Carly B , Hertens D , Jeanjot I , Beier B , Etbaz S , De Coster C , Liebens F 
Published: March 2017

Abstract
This abstract was not presented at the symposium.
Abstract P3-17-05: Claudin-4 expression is associated with disease free survival in breast carcinoma in situ: Mean follow up of 8.2 years
Authors: Duarte GM , Almeida NR , Tocchet F , Espinola J , Pinto T , Barreto CT , Pinto GA , Soares FA , Marshall P , Paiva GR 
Published: March 2017

Abstract
Introduction: Claudins are tight junction molecules that have been associated with breast cancer prognosis. The claudin-low intrinsic subtype of invasive carcinoma was recently described and associated with high grade carcinoma, low junction molecules expression and worse response to chemotherapy. However, it is not known whether the expression of claudins may provide clues as to carcinoma in situ prognosis. The aim of study was evaluate the association between claudin–4 expression and disease-free survival and histologic type of local recurrence in carcinoma in situ after longer follow up.
Methods: A tissue microarray (TMA) block was constructed from 137 pure carcinoma in situ paraffin blocks sampled from patients treated from 1999 to 2009. The TMA was submitted to immunohistochemical staining for claudin-4. A claudin-4 score calculated based on percentage and intensity of expression, categorized samples as: claudin-4-low or claudin–4-high. Clinical data, treatment data, local recurrence data and survival of each patient were reanalyzed from medical records. Kaplan-Meier curves, log-rank and Wilcoxon tests were used to analyze disease-free survival; qui-square and Fisher test were employed to compare others variables; a significance level of 5 % was used.
Results: Claudin-4 expression was evaluated in 86 samples, 88.4% were claudin-4-high and 11.6% claudin-4-low. Mean follow up was 8.2 years ( and local recurrence rate was 10.5 %. There was significant difference in the disease-free survival between claudin-4-high and claudin-4-low (4.9 x 1.9 respectively, p= 0.02); however there was no difference between both in histologic type of recurrence, invasive or in situ (p=0.44).
Conclusion: In our samples, claudin-4-high expression in carcinoma in situ was more frequent than low expression. Our data showed that claudin-4-low expression had a worse prognosis in carcinomas in situ (inferior disease-free survival) but it was similar to claudin-4-high in histologic type of local recurrence.
Citation Format: Duarte GM, Almeida NR, Tocchet F, Espinola J, Pinto T, Barreto CT, Pinto GA, Soares FA, Marshall P, Paiva GR. Claudin-4 expression is associated with disease free survival in breast carcinoma in situ: Mean follow up of 8.2 years [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-17-05.
Abstract P4-01-05: In vivo, intraoperative margin detection utilizing the Lumicell margin assessment system
Authors: Rai U , Tang R , Plichta JK , Rice-Stitt T , Gadd MA , Specht MC , Strasfeld DS , Ferrer JM , Brachtel EF , Smith BL 
Published: March 2017

Abstract
This abstract was withdrawn by the authors.