bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P5-13-09: Not presented
Authors: Campos-Gomez S , Pacheco-Cuéllar G , Campos-Gomez K , García Garcés M , Valdes Andrade J , Barrera Franco JL
Published: May 2019

This abstract was not presented at the conference.

Citation Format: Campos-Gomez S, Pacheco-Cuéllar G, Campos-Gomez K, García Garcés M, Valdes Andrade J, Barrera Franco JL. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-13-09.
Abstract P5-13-21: The European initiative in breast cancer (ECIBC) - A program to reduce disparities in cancer care by accreditation of all breast centers in Europe
Authors: Mansel RE
Published: May 2019

In order to reduce disparities in breast cancer services in Europe, the European Parliament passed resolutions in 2003 and 2006 calling for all women with breast cancer in Europe to be treated by a multidisciplinary team and called on Member States to establish a network of Certified multidisciplinary breast centres.

In the light of these resolutions the European Commission has tasked the Joint Research Centre (JRC) based in Ispra in Italy to set a programme of work from 2014-2020 to update the European Screening Guidelines and produce standards for an accreditation programme for all European Member States.

The methodology is evidence based and the Ibero American Cochrane group has been recruited to examine the evidence for the key questions concerning quality indicators. The whole pathway for breast cancer treatment is being explored from screening to follow up/survivorship, and only indicators supported by evidence are accepted. Indicators have to be relevant, measurable and feasible and currently 50 indicators have been approved using the Delphi system. Many currently used indicators have failed the test of usability due to lack of precision in measurement (eg cosmetic outcomes, margin assessment), or lack of clear definitions (eg counselling,breast care nurse roles, waiting times, MDT working).

A further problem is the different resources applied to breast services across the wide range of economies in European countries (Western v Eastern Europe), which affects the availability of expensive therapies.

The Indicators will form the basis of the accreditation program which will be published in 2019. The detailed evidence for each indicator will be presented in the poster together with the feedback from the 30+European countries involved.

A pilot of the accreditation program will take place in 2019 to test the feasibility of the audit process in a variety of breast clinic settings.

This project is the most comprehensive attempt to date to produce a robust measurement of breast centers performance based on evidence, and might have global applicability.

Citation Format: Mansel RE. The European initiative in breast cancer (ECIBC) - A program to reduce disparities in cancer care by accreditation of all breast centers in Europe [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-13-21.
Abstract P5-14-03: Patient perspectives on HER2+ breast cancer recurrence: Results from an online patient survey
Authors: Jenkins M
Published: May 2019

Background: The objective of this study was to gather insights from patients with early-stage HER2+ breast cancer regarding fears and knowledge of breast cancer recurrence and approaches to reducing risk of recurrence.

Methods: From Nov. 7-30, 2017, patients with stage I-IIIC HER2+ breast cancer were recruited via postings to Breastcancer.org discussion boards to participate in an online survey comprising 17 questions designed to quantify fears and emotions related to recurrence, identify and characterize knowledge gaps, and understand what patients are willing to tolerate to reduce recurrence risk.

Results: Of 307 respondents, 87% were aged ≥40 years and over half were ≥50 (58%). The majority had completed (48%) or were undergoing (39%) postsurgical treatment. Recurrence was a concern for 93% of patients and was the highest rated concern for 78%; however, most patients (76%) perceived their personal risk of recurrence to be moderate or low. 59% of patients felt they were at least somewhat informed about risk of recurrence; 55% had discussed risk of recurrence with their health care team, with discussions most frequently initiated by the patient (56%) vs the health care team (40%). Oncologists were the primary source of information about risk of recurrence (58%), but patients also frequently sourced information from online content (29%), published research (18%), and Breastcancer.org (15%). Almost all (96%) patients were at least somewhat involved in treatment planning. While 55% of patients would inquire about a new drug if it conferred a 10%-20% reduction in risk of recurrence, 26% required a benefit of ≥50%. For treatments reducing the risk of recurrence, patients were willing to tolerate (in order from most to least willing) hot flashes, fatigue, diarrhea, joint pain, and nausea/vomiting.

Conclusions: While patients with HER2+ breast cancer are highly concerned about recurrence, most feel that their personal risk is moderate. Patients are highly engaged in treatment planning, often initiate discussions about risk of recurrence, and supplement their knowledge with their own research. The threshold to motivate inquiry into a new drug to reduce recurrence risk was <20% for over half of patients. Patients were also frequently willing to tolerate common adverse events.

Citation Format: Jenkins M. Patient perspectives on HER2+ breast cancer recurrence: Results from an online patient survey [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-14-03.
Abstract P5-15-07: Breast surgery – Is routine 'group & save' required? A quality improvement project
Authors: Burrah R , Chicken W , Sathananthan S
Published: May 2019

Introduction

Breast surgery, especially for malignant disease, is not associated with significant blood loss and therefore rarely requires blood transfusions. Pre-operative protocols in our hospital and in most other centers routinely require a blood group screening process (group and save) for elective breast cancer surgery. The process of group and save (G&S) in our hospital requires two blood samples to be drawn with at least 30 minute interval in-between. It takes at least 40 minutes for the samples to get processed and the cost for each test is £2.12. The test is valid for a period of 5 days after which time it needs to be repeated. This process in busy hospitals is clearly time consuming, results in delays and is inconvenient for patients and medical staff.

The aim of this study was to ascertain the number G&S performed and rate of post-operative blood transfusion for patients undergoing surgery for malignant breast disease. This was to establish if mandatory pre-operative G&S is necessary in all cases, and if the number of tests performed can be reduced. The second part of the study was to analyze the outcome after implementation of changes to reduce the number of G&S tests.

Method

Retrospective review of patient records who had surgeries for malignant breast disease from December 2015 to November 2016. Exclusion criteria included benign disease, flap reconstruction and breast surgery combined with another major procedure. Following the initial analysis, it was proposed that only the operating surgeon will request the test and that it will not be routinely requested by the pre-op assessment team. A re-audit was done prospectively to study the outcome of change in practice and close the audit loop.

Results

151 cases were eligible for review. 97.35% (147 patients) had G&S, and the post-operative transfusion rate was 1.32% (2 patients). Following a change in protocol a significant fall in the testing (97.35% to 35.5%) was seen and there were no post-operative blood transfusions in this period.

Conclusion

This simple yet important audit showed that routine G&S did not contribute to the patient management, increased cost of treatment, caused patient inconvenience and consumed hospital personal time. The changes we implemented significantly reduced the frequency of this test and was cost effective to the trust. This study has now been converted into a Quality Improvement Project and through this we will continue to improve the results further. This project has also stimulated an interest in the General Surgery department, and other units are now considering changing their practice based on our results.

Citation Format: Burrah R, Chicken W, Sathananthan S. Breast surgery – Is routine 'group & save' required? A quality improvement project [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-15-07.
Abstract P5-18-09: Performance of Oncotype DX DCIS score across diverse ethnic populations
Authors: Mittar P , Casella S , Bombonati A , Emiloju O , Jablon L , Schultz D , Leighton JC , Solin LJ
Published: May 2019

There is a paucity of data on Oncotype DX DCIS Score and ethnic variation. It has been postulated that there are different molecular features /drivers among different ethnic populations. The Oncotype DX DCIS Score is a genomic test designed to analyze the expression of a group of 12 genes which can quantify 10-year local recurrence risk after surgery. The purpose of this study is to evaluate diverse ethnic patients with DCIS relative to traditional clinical pathologic factors and Oncotype DX DCIS Score

We analyzed consecutive cases of DCIS from 2011-2017 who underwent Oncotype DX DCIS Score testing at a single institution. Eighty-four female patients were divided into 5 groups based on self-reported ethnicity: White (36%), African American (AA) (48%), Asian (8%), Hispanic (4%) and Other (4%). Clinical and traditional pathologic factors were collected including age, nuclear grade (NG), ER/PR status and Oncotype DX DCIS Score. The distribution of NG and Oncotype DX DCIS Score was analyzed across ethnic groups.

The mean age at diagnosis was 63. Overall 99 % of cases were hormone positive. Comparison of White and AA patients revealed a correlation between ethnic group and DCIS Score, with a p value of 0.0087 (Table 1). Similarly, we looked at all five ethnic groups and Oncotype DX DCIS Score and found a p value of 0.022. We evaluated ethnicity with White and AA patients versus NG and obtained a p value of 0.084 (Table 2). In addition, we assessed all five ethnic groups and NG. We obtained a p value of 0.068. No AA patients with DCIS had a high DCIS Score. No patients with low NG DCIS had a high DCIS Score. Analysis of the three factors (NG, ethnicity and DCIS Score) concurrently showed that they are not independent.

In summary, our study provides valuable data on Oncotype DX DCIS Score and NG across a diverse patient population. These data highlight the importance of incorporating both traditional clinical pathologic factors and DCIS Score molecular testing for making treatment decision across different ethnic patient populations.

Table 1.Comparison of DCIS Score and Ethnic GroupEthnic GroupLow DCIS ScoreIntermediate DCIS ScoreHigh DCIS ScoreAA3730White2704p=0.0087

Table 2.Comparison of Nuclear Grade and Ethnic GroupEthnic GroupNuclear Grade 1Nuclear Grade 2Nuclear Grade 3AA17194White1399p=0.084

Citation Format: Mittar P, Casella S, Bombonati A, Emiloju O, Jablon L, Schultz D, Leighton JC, Solin LJ. Performance of Oncotype DX DCIS score across diverse ethnic populations [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-18-09.
Abstract P6-02-14: Not presented
Authors: Xing W , Li Q , Sun G , Cao R , Chen B , Jiang C , Ma L , Wang K
Published: May 2019

This abstract was not presented at the conference.

Citation Format: Xing W, Li Q, Sun G, Cao R, Chen B, Jiang C, Ma L, Wang K. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-02-14.
Abstract P6-02-19: Machine learning based analysis of CT radiomics for the simultaneous indeterminate pulmonary nodules of breast cancer
Authors: Xiao Q , Gu Y , Wu J , Wang Z , Huang Y
Published: May 2019

PURPOSE: To investigate texture features of simultaneous indeterminate pulmonary nodules of breast cancer for predicting their potential metastasis.

METHODS AND MATERIALS: 150 patients with simultaneous breast cancer diagnosed by biopsy and pulmonary nodules (diameter: 5-20mm) detected by preoperative CT were enrolled in this study. After surgery and breast cancer treatment, the patients were followed up for at least half a year or longer by CT to observe the changes of lung nodules, thereby inferring the potential of metastasis. We classify pulmonary nodules into two groups: the reduced or enlarged pulmonary nodules were defined as highly metastasis possibility (Group 1), and long-term stable pulmonary nodules were defined as low metastasis possibility (Group 2). In addition, pathologic proven primary lung cancer in this study (Group 3) was compared with Group 1. Therefore, we carried out a comparative analysis of the texture features between the groups, and additional statistical were used three regression testing to extract texture features. Finally, we construct a machine learning classifier and calculate the accuracy of cross-validation.

RESULTS: We collected 106 features by the texture analysis(TA). There are 18 features with significant differences between Group 1 and the Group 2(p<0.05), and 76 features with significant differences in the Group 1 and Group 3 (p<0.05). We tried to find key features related to pathology in 106 features using three methods: lasso regression, ridge regression and forward stepwise regression. The accuracy in different regressions respectively is 94.5%,94.5%,89.7% using KNN between Group 1 and Group 2. The accuracy in different regressions respectively is 96.2%(KNN),96.2%(Tree),92.3%(Linear Discriminant)in the Group 1 and Group 3.

CONCLUDES: The identified radiomics features have the potential to be used as a biomarker for metastasis prediction of simultaneous indeterminate pulmonary nodules in breast cancer patients, and it may contribute to preoperative treatment and postoperative follow-up planning.

Citation Format: Xiao Q, Gu Y, Wu J, Wang Z, Huang Y. Machine learning based analysis of CT radiomics for the simultaneous indeterminate pulmonary nodules of breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-02-19.
Abstract P6-03-06: Androgen supplementation in patient derived xenografts in androgen receptor positive breast cancer to increase engraftment and growth rate
Authors: Kiver VII , Wulf-Goldenberg A , Jurmeister PS , Schweiger C , Gorea O , Hoffmann J , Denkert C , Keilholz U , Liedtke C , Blohmer J-U
Published: May 2019

Background:

The European fund for regional development (EFRE) supported Precision Oncology and Personalized Therapy Prediction (POP) Project is establishing preclinical models to further the development of personalized therapy options. In the subgroup breast cancer the current goal is to increase the growth and engraftment rates of breast cancer patient derived xenografts (PDX) models.

Methods:

Breast cancer patients of the Department of Gynecology with Breast Center Charité Universitätsmedizin Berlin, Germany are recruited since May 2017. In total 29 tissue samples were collected and included so far.

Treatment naive and treatment refractory patients, tripple negative breast cancer (TNBC), hormone receptor positive (HR+) and Her2 postivie tumors, primary disease, recurrence or metastasis are sampled. Fresh tumor tissue is extracted via surgery or biopsy. The materials are then implanted into female immunodeficient NOG mice. To establish PDX models for HR+ breast cancer the mice received estrogen supplementation.

To increase engraftment and growth rates androgen receptor (AR) testing and subsequently androgen replacement was started since April 2018.

Up to date, 6 new samples have been collected. One HR+ and two TNBC samples tested also positive for AR. These samples are currently in passage 0 (p0) and are now supplied with androgens to increase engraftment and growth rate. One already established AR+ TNBC PDX is being regrown with androgen supplementation to compare growth rates.

Results:

Out of the initial 23 tissue samples ten (six HR+ and four TNBC) have been able to be engrafted into PDX mice.

The TNBC PDX models are one in p1, one in p2, one in p3 and one is being tested with systemic therapy. Engraftment time in p1 were between 19 and 97 days. Growth time to passagable size between 21 and 112 days.

The HR+ PDX models are four in p1 and two in p2. Engraftment time in p1 was between 26 and 123 days. Growth time to passagable size has been achieved in 2 HR+ PDX within 17 to 48 days.

The engraftment/growth rates and times of the androgen supplemented PDX models will be presented.

Conclusion:

Breast cancer growths in humans slowly and this is also the case in the PDX models. To achieve faster growth and higher engraftment rates androgen supplementation in AR+ breast cancer might be an additional enhancive factor.

Citation Format: Kiver VII, Wulf-Goldenberg A, Jurmeister PS, Schweiger C, Gorea O, Hoffmann J, Denkert C, Keilholz U, Liedtke C, Blohmer J-U. Androgen supplementation in patient derived xenografts in androgen receptor positive breast cancer to increase engraftment and growth rate [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-03-06.
Abstract P6-05-06: Estrogen induced miR-489 acts as a negative feedback to confine uncontrolled estrogen signaling and cell proliferation in breast cancer
Authors: Soni M , Patel Y , Shealy R , Chen H
Published: May 2019

Estrogen induced miR-489 acts as a negative feedback to confine uncontrolled estrogen signaling and cell proliferation in breast cancer.

Mithil Soni1,2, Yogin Patel1,2,3, Ryann Shealy1, Hexin Chen1,2,4.

1Dept. of Biological Sciences, University of South Carolina, 2Center for colon cancer research, 3current location, National cancer institute, surgery branch, 4corrosponding author.

Approximately 75% of diagnosed breast cancer tumors are Estrogen receptor positive tumors and are associated with better prognosis due to response to hormonal therapies. However, around 40% of patients relapse after hormonal therapies. Identification of novel molecular targets is necessary to combat such resistant tumors. In the current study, using microarray, qRT-PCR, western blot, luciferase reporter assay and immunofluorescence, we found that miR-489 is an estrogen regulated miRNA that negatively regulates estrogen signaling. Depletion of miR-489 using Anti-miR-489 siRNA or CRISPR-Cas9 significantly increased estrogen induced proliferation, colony formation ability and stem like cell population. Loss of miR-489 also induced estrogen independent proliferation. Mechanistically we found that depletion of miR-489 enhanced nuclear localization of estrogen receptor while restoration of miR-489 increased cytosolic ER and inhibited estrogen induced transcription. Furthermore, we found that miR-489 depletion also increases estrogen independent growth through activation of MAPK and PI3K-AKT pathway. We also observed loss of miR-489 in tamoxifen resistance breast cancer cell line and found increased resistance to tamoxifen upon miR-489 inhibition while miR-489 restoration sensitized Tamoxifen resistant cell lines. Clinical analysis of estrogen receptor positive breast cancer patient showed that ER+ve breast cancers with low miR-489 expression represents aggressive cancers with significant reduction in survival time. In summary, these results indicate potential role of miR-489 as a biomarker to predict aggressiveness of ER+ve breast cancer and response to tamoxifen therapy and can potentially be used as a therapeutic agent to treat or sensitize tamoxifen resistant tumors.

Citation Format: Soni M, Patel Y, Shealy R, Chen H. Estrogen induced miR-489 acts as a negative feedback to confine uncontrolled estrogen signaling and cell proliferation in breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-05-06.
Abstract P6-05-10: MicroRNA-137 inhibits cancer progression by targeting DEL-1 in triple negative breast cancer cells, MDA-MB-231
Authors: Chae YS , Baek DW , Lee IH , Lee SJ , Lee RK , Lee J , Jung J , Park H , Jeong J-H , Kang J , Park J
Published: May 2019

Background: This study aimed to investigate the function of microRNA-137 in Del-1 expression in triple negative breast cancer (TNBC) cells and tissues.

Methods: The Del-1 mRNA and microRNA levels were measured using a qRT-PCR in breast cancer cells (MDA-MB-231, MCF7, SK-BR3, and T-47D) and tissues from 20 patients with TNBC. The effects of miR-137 on cell proliferation, migration, and invasion were determined using MTT, wound healing, and Matrigel Transwell assays.

Results: microRNA-137 (miR-137) levels were remarkably low and Del-1 mRNA expression was higher in MDA-MB-231 cells as compared to other breast cancer cell lines. The luciferase reporter assay revealed that miR-137 binds directly at the 3¢-UTR of Del-1 and that Del-1 expression was downregulated by miR-137 mimics and rescued by its inhibitors. Furthermore, miR-137 inhibited the cell proliferation, migration, and invasion of MDA-MB-231 cells. Moreover, among the 30 TNBC specimens, miR-137 was downregulated (p <0.0001) and the level of Del-1 in plasma was significantly elevated as compared to normal controls (p < 0.0001).

Conclusions: In conclusion, miR-137 regulates Del-1 expression in TNBC via directly binding to the Del-1 gene, and thereby affects cancer progression. This suggests that miR-137 may be a new therapeutic biomarker for patients with TNBC.

Keywords: Del-1, triple negative breast cancer, miR-137, biomarker

Citation Format: Chae YS, Baek DW, Lee IH, Lee SJ, Lee RK, Lee J, Jung J, Park H, Jeong J-H, Kang J, Park J. MicroRNA-137 inhibits cancer progression by targeting DEL-1 in triple negative breast cancer cells, MDA-MB-231 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-05-10.
Abstract P6-05-11: Not presented
Authors: Chu J , Li Y , Fu Z , Tang J , Yin Y
Published: May 2019

This abstract was not presented at the conference.

Citation Format: Chu J, Li Y, Fu Z, Tang J, Yin Y. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-05-11.
Abstract P6-17-35: Withdrawn
Authors: Hamilton EP , Barve M , Bardia A , Beeram M , Edenfield WJ , Noonan A , Tolcher A , Bendell J , Mosher R , Xu J , Hailman E , Burris III H , Soliman HH
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Hamilton EP, Barve M, Bardia A, Beeram M, Edenfield WJ, Noonan A, Tolcher A, Bendell J, Mosher R, Xu J, Hailman E, Burris III H, Soliman HH. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-35.
Abstract P6-20-06: Withdrawn
Authors: Dann S , Chionis J , Eisele K , Zhang Q , Liu C , Yuan J , Miller N , Murray B , Xu M , Solowiej J , Wei P , Weinrich S , Sutton S , Behenna D , Ninkovic S , Hoffman R , Freeman-Cook K , Jessen B , Huser N , Zhang C , Visswanathan R , Boras B , VanArsdale T , White MA
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Dann S, Chionis J, Eisele K, Zhang Q, Liu C, Yuan J, Miller N, Murray B, Xu M, Solowiej J, Wei P, Weinrich S, Sutton S, Behenna D, Ninkovic S, Hoffman R, Freeman-Cook K, Jessen B, Huser N, Zhang C, Visswanathan R, Boras B, VanArsdale T, White MA. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-06.
Abstract P6-20-16: BAT8003, a potent anti-Trop-2 antibody-drug conjugate, for the treatment of triple negative breast cancer
Authors: Tang W , Huang X , Ou Z , Yan H , Gan J , Dong Q , Tan B , Yang Y , Guo Y , Li S , Thomas B , Yu J-C
Published: May 2019

Trophoblast cell surface antigen 2 (Trop-2) is overexpressed on many epithelial carcinomas, yet is expressed at much lower level on normal tissue. Overexpression of Trop-2 has been correlated with poor prognosis in several solid tumors. These two characteristics make Trop-2 a potential drug target. An antibody-drug conjugate (ADC) targeting Trop-2, IMMU-132, has recently been demonstrated to be effective in treating triple negative breast cancer (TNBC) and gastric cancer patients. Here we present a Trop-2 ADC, BAT8003, which contains an uncleavable linker and a maytansine derivative as the payload. An A114C mutation on antibody heavy chain was introduced to BAT8003 for site-specific conjugation, in order to generate a more homogeneous product for a better pharmacokinetics profile. BAT8003 is also completely devoid of fucose modification, to allow for enhanced ADCC effect. We show that BAT8003 is effectively internalized upon binding to Trop-2, and inhibits proliferation of Trop2-overexpressed tumor cells with IC50s of ˜1 nM. In a TNBC (MDA-MB-468 cell) mouse xenograft model, BAT8003 strongly inhibits tumor growth at a dose level as low as 5 mg/kg. BAT8003 also demonstrates potent activity in another TNBC (MX-1 cell) mouse tumor model, in which it shows the same inhibition activity as the naked antibody conjugated heterogeneously with almost two fold payload (DAR 3.5), suggesting the effect caused by site-specific conjugation. We are currently developing BAT8003 for clinical evaluation in TNBC and other cancer indications.

Citation Format: Tang W, Huang X, Ou Z, Yan H, Gan J, Dong Q, Tan B, Yang Y, Guo Y, Li S, Thomas B, Yu J-C. BAT8003, a potent anti-Trop-2 antibody-drug conjugate, for the treatment of triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-16.
Abstract P6-21-02: Withdrawn
Authors: Minichsdorfer C , Bergen E , Steger GG , Pfeiler G , Frantal S , Greil R , Fohler H , Egle D , Balic M , Fitzal F , Wette V , Exner R , Bartsch RA , Gnant M
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Minichsdorfer C, Bergen E, Steger GG, Pfeiler G, Frantal S, Greil R, Fohler H, Egle D, Balic M, Fitzal F, Wette V, Exner R, Bartsch RA, Gnant M. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-21-02.
Abstract P6-21-06: Target N-Ras for degradation by flunarizine to treat basal-like breast cancer
Authors: Zheng Z-Y , Li J , Li F , Zhu Y , Cui K , Wong ST , Chang EC , Liao Y-h
Published: May 2019

Background:Basal-like breast cancer (BLBC) is an aggressive form of breast cancer that are usually triple negative for ER, PR, and HER2. There is no effective targeted therapy for BLBC due to the lack of a druggable driver. Ras GTPases are powerful drivers for tumorigenesis. We have shown that wild type N-Ras, but not K- or H-Ras, is overexpressed in BLBC and driving itsgrowth and transforming activities. However, there is currently no treatment that directly target Ras. This study thus screened existing pharmacologically active and approved compounds for the new ability to induce N-Ras degradation in BLBC.

Methods:Compounds in the LOPAC library were screened by an automated microscopy system for the ability to reduce GFP-N-Ras signals in the cells. Isolated compounds were then examined to identify those that can degrade endogenous N-Ras in BLBC cells without impacting levels of other Ras proteins. Final candidate compounds were further examined to determine by which proteolytic pathway N-Ras is induced to be degraded. The potentials of the identified compound to treat BLBC were assessed by examining cell growth and soft agar colony formation in vitroand tumor growth in vivo.

Results:We identified flunarizine (FLN), previously approved for treating migraine and epilepsy. The FLN-induced N-Ras degradation was not affected by a 26S-proteasome inhibitor. Rather, it was blocked by autophagy inhibitors. Furthermore, N-Ras can be seen co-localized with active autophagosomes upon FLN treatment, suggesting that FLN alters the autophagy pathway to degrade N-Ras. Importantly, FLN treatment recapitulated the effect of N-RASsilencingin vitroby selectively inhibiting the growth of BLBC cells, but not that of breast cancer cells of other subtypes. In addition, in vivoFLN inhibited tumor growth of a BLBC xenograft model.

Conclusion:This proof-of-principle study presents evidence that the autophagy pathway can be coerced by small molecule inhibitors, such as FLN, to degrade Ras as a strategy to treat cancer. FLN has low toxicity and should be further investigated to enrich the toolbox of cancer therapeutics against BLBC.

Citation Format: Zheng Z-Y, Li J, Li F, Zhu Y, Cui K, Wong ST, Chang EC, Liao Y-h. Target N-Ras for degradation by flunarizine to treat basal-like breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-21-06.
Abstract PD6-11: Withdrawn
Authors: Cronin-Fenton DP , Falstie-Jensen AM , Kjaersgaard A , Dupont Jensen J , Lorenzen EL , Reinertsen KV , Dekkers OM , Ewertz M
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Cronin-Fenton DP, Falstie-Jensen AM, Kjaersgaard A, Dupont Jensen J, Lorenzen EL, Reinertsen KV, Dekkers OM, Ewertz M. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD6-11.
Abstract PD8-05: POSNOC - Positive sentinel node: Adjuvant therapy alone versus adjuvant therapy plus clearance or axillary radiotherapy
Authors: Goyal A , Mann B , Thompson AM
Published: May 2019

Background: Role of additional axillary treatment (AxT) (axillary lymph node dissection (ALND) or axillary radiotherapy (ART)) in women with ≤2 macrometastases and undergoing systemic therapy remains unclear. Z11 included both micro and macrometastases (around 40% micrometastases) and showed that ALND may be omitted in women with ≤2 positive nodes undergoing breast conserving surgery (BCS) and receiving whole breast RT. Paradoxically, NCIC MA20, demonstrated improved DFS following the addition of regional RT. 51.8% (949/1832) had 1 or 2 positive nodes. 98.9% (1812/1832) had T1/T2 tumours. A post-Z11 survey shows that most US radiation oncologists treat the undissected axilla in women with macrometastases with ART rather than omitting AxT. Therefore, a confirmatory study is needed to clarify the role of additional AxT in women with ≤2 macrometastases undergoing BCS and other subgroups that were not included in Z11 e.g. mastectomy, microscopic extranodal invasion and sentinel node biopsy (SNB) before neoadjuvant chemotherapy.

Methods: Primary objective is to assess whether for women with ≤2 macrometastases at SNB, systemic therapy alone is non-inferior to systemic therapy plus AxT in terms of axillary recurrence at 5 years. Secondary objectives are arm morbidity assessed by LBCQ and QuickDASH questionnaires; QoL assessed by FACT-B+4 questionnaire; anxiety assessed by STAI; loco-regional recurrence; distant metastasis; time to axillary recurrence; axillary recurrence-free survival; DFS; OS; contralateral breast cancer; non-breast malignancy; and economic evaluation. Eligibility criteria include: ≥18 y, uni or multifocal invasive cancer, T1/T2, 1 or 2 macrometastases, with or without extranodal invasion. Target sample size is 1900 with a projected drop-out and non-compliance with treatment allocation rate of 10%. Primary analysis will be per protocol. The following pre-specified subgroup analyses shall be performed: number of macrometastases (1, 2), age (<50, ≥50), breast surgery (mastectomy, BCS), ER (positive, negative), tumour grade (1 or 2, 3), SN assessment technique (OSNA, non-OSNA), extranodal invasion (present, absent). POSNOC opened to recruitment in July 2014. To date 1100 women have been recruited at 82 sites in the UK and 18 sites in Australia and New Zealand. Clinicaltrials.gov NCT02401685.

Citation Format: Goyal A, Mann B, Thompson AM. POSNOC - Positive sentinel node: Adjuvant therapy alone versus adjuvant therapy plus clearance or axillary radiotherapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD8-05.
Abstract A01: Metastasis suppressors regulate the tumor microenvironment by blocking recruitment of pro-metastatic tumor-associated macrophages
Authors: Rabe Daniel C. , Frankenberger Casey , Bainer Russell , Sankarasharma Devipriya , Chada Kiran , Krausz Thomas , Gilad Yoav , Becker Lev , Rosner Marsha Rich
Published: May 2019

This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR02) of the Conference Proceedings.

Citation Format: Daniel C. Rabe, Casey Frankenberger, Russell Bainer, Devipriya Sankarasharma, Kiran Chada, Thomas Krausz, Yoav Gilad, Lev Becker, Marsha Rich Rosner. Metastasis suppressors regulate the tumor microenvironment by blocking recruitment of pro-metastatic tumor-associated macrophages. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A01.
Abstract A03: Lymphocytes lead to circulating tumor cell death from 4D model seeded with non-metastatic lung cancer cell line
Authors: Mishra Dhruva K. , Juarez Humberto , Thrall Michael J. , Kim Min P.
Published: May 2019

Objective: Mouse lung cancer cell lines 393P and 344SQ are derived from KrasLA1/+ p53R172HΔG mice and have different metastatic potential in immunocompetent mice. 393P cells have local primary tumor growth but do not form metastatic lesions when injected into the subcutaneous space of 129sv mice. However, 344SQ cells form a primary tumor and metastatic lesions when injected into the subcutaneous space. Our aim is to determine if lymphocytes play a role in this differential metastatic lung cancer formation between the two cell lines.

Methods: Both 393P and 344SQ cells were grown in the ex vivo 4D lung cancer model. We determined the amount of primary tumor growth, the number of circulating tumor cells (CTCs), and metastatic lesion formation. The CTCs from the 4D model seeded with either cells were injected into the tail veins of immunocompetent 129sv mice (wt) or immunodeficient mice (nu/nu). We calculated the Kaplan Meier survival curve. Next, we added lymphocytes derived from a 129sv mouse spleen to an ex vivo 4D lung cancer model seeded with 393P or 344SQ and isolated the CTCs. We plated the CTCs on a petri dish and compared the survival of these cells.

Results: Both 393P and 344SQ cells grew in the 4D model. There were no significant differences in the primary tumor growth and circulating tumor cell formation between the two cell lines. There were no significant differences in the number of metastatic lesion formation between the two cell lines (p=0.5). When CTCs from the 4D model seeded with 344SQ were injected into the tail vein of nu/nu mice or wt mice, there were no differences in the survival rates between the two types of mice (p=0.3). However, nu/nu mice that were injected with CTC from the 4D model seeded with 393P were less likely to survive compared to the wt mice (p=0.002). No metastatic lesions formed in the wt mice injected with 393P CTC for 8 months. The CTC from the 4D model seeded with 344SQ and treated with lymphocytes had no significant difference in cell growth when cultured on a petri dish compared to the control group (p=0.9). However, the CTC from the 4D model seeded with 393P treated with lymphocytes had significantly less live cells compared to the control group (p=0.01).

Conclusions: Lymphocytes inhibit metastatic lesion formation in 393P cell lines but not 344SQ cell lines. The ex vivo 4D lung cancer model allows for the identification of the cell type that is responsible for inhibition of metastasis. The model can be used to study the role of different components of a tumor's microenvironment in tumor metastasis.

Citation Format: Dhruva K. Mishra, Humberto Juarez, Michael J. Thrall, Min P. Kim. Lymphocytes lead to circulating tumor cell death from 4D model seeded with non-metastatic lung cancer cell line. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A03.
Abstract A31: A novel 3D osteoblastic niche assay is useful to study the characteristics of bone metastatic cancers
Authors: Lim Seunghwan , Pareek Tej , Palassery Rasmi , Letterio John
Published: May 2019

(Background) Many patients with metastatic cancer (i.e. Prostate, breast, lung, kidney, and melanoma) struggle with skeletal metastases which is frequently causing cancer-related death. Thus, there is an imminent demand for a better understanding of how bone-homing cancers communicate and physically interact with the bone microenvironment. It is known that cancer-stromal cell interaction in bone marrow is a pivotal step in determining bone metastasis and tumor behavior and is seen in the events of competition with HSC for the osteoblastic niche, entering dormant status, and enhanced tumor growth. However, the lack of biologically relevant assay platforms has hampered interrogation of the mechanism of cancer-bone interaction as well as the development of bone-targeted anti-metastatic drugs. (Methods) Here, we present a novel method that can measure the bone-homing ability of cancers by co-culturing 3D osteoblastic niche (3D-ObN) spheroids derived from human mesenchymal stem cells along with reporter cell lines carrying hypoxia response element (HRE)-regulated reporter genes (pGF-HRE4-GFP/SecNLuc). First, the migration ability of metastatic cancers into the 3D-ObN was examined by analyses of O.C.T. frozen section images using confocal microscopy. Next, the metastatic ability of highly metastatic cancers were compared to normal epithelial cells and assessed by using either fluorescent microscopy (IncuCyte) or a luminometer. (Results) The HRE-driven reporter was activated in a 3D-ObN spheroid-specific manner in response to the nature of the hypoxia gradient within the spheroid. While the 3D-ObN provided signals that suppressed cancer cell proliferation, highly metastatic cancer cells displayed higher homing ability in the 3D-ObN assay relative to the normal epithelial cells. Prostate cancer cells expressing putative cancer stem cell markers (CD44/CD133high) showed higher homing ability compared to CD44/CD133low populations. (Conclusion) This assay platform is the first of its kind through the fact that it mimics cancer-osteoblastic niche interactions and allows for quantification of the ability of cancer cells including cancer stem-like cells to invade and anchor in osteoblastic niche. Furthermore, this assay system can be readily amended to an efficient and effective high throughput screening system useful for identifying molecules potentially preventive to critical process of bone metastases.

Citation Format: Seunghwan Lim, Tej Pareek, Rasmi Palassery, John Letterio. A novel 3D osteoblastic niche assay is useful to study the characteristics of bone metastatic cancers. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A31.
Abstract A40: Protein disulfide isomerases in the endoplasmic reticulum promote anchorage-independent growth of breast cancer cells
Authors: Wise Randi , Duhachek-Muggy Sara , Qi Yue , Zolkiewski Michal , Zolkiewska Anna
Published: May 2019

Cancer cells that separate from primary tumors and migrate to metastatic sites are exposed to stress caused by detachment from the extracellular matrix (ECM). Cultured breast cancer cells that survive this stress and are capable of anchorage-independent proliferation form mammospheres. Biological mechanisms responsible for maintaining the mammosphere-growth competence are not fully understood. We hypothesized that mammosphere growth requires elevated ECM secretion, which demands efficient folding quality control in the endoplasmic reticulum (ER). We found that SUM159PT and MCF10DCIS.com breast cancer cells grown as mammospheres had elevated mRNA and protein levels of three protein disulfide isomerases: ERp57, ERp44, and PDI. We also found an increased phosphorylation of eIF2alpha in mammospheres, suggesting that the PERK arm of the unfolded protein response was activated. An inducible knock-down of ERp57 in SUM159PT cells resulted in impaired ability to form mammospheres. Analysis of a publicly available gene expression data for circulating tumor cells (CTCs) revealed that up-regulation of ECM genes and ER folding quality control genes occurred at the time of disease progression and surge in the number of CTCs. These data indicate that breast cancer cell survival and growth under detachment conditions require enhanced assistance of the ER folding machinery in the correct disulfide bond formation.

Citation Format: Randi Wise, Sara Duhachek-Muggy, Yue Qi, Michal Zolkiewski, Anna Zolkiewska. Protein disulfide isomerases in the endoplasmic reticulum promote anchorage-independent growth of breast cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A40.
Abstract A61: A novel image-guided genomics approach to dissect the mechanisms of collective cancer cell invasion
Authors: Konen Jessica , Dwivedi Bhakti , Kowalski Jeanne , Marcus Adam
Published: May 2019

During tumor metastasis, cancer cells invade as a collective pack to navigate the tumor microenvironment. In experimental models, this collective pack is phenotypically heterogenous and contains leader cells which pioneer invasion into the microenvironment and follower cells that immediately attach to and follow the leaders. To dissect the molecular mechanisms underlying this phenotypic heterogeneity, we developed a technique termed spatiotemporal genomic and cellular analysis (SAGA), which uses image-guided genomics to precisely select living, rare cell populations that are maintained within a physiologically relevant environment for downstream genomic and molecular analyses. In this manner, we can select, isolate, and amplify any living cell based upon phenotypic criteria. Using 3-D H1299 lung cancer cell spheroids, we precisely selected as few as 10 leader cells using the SAGA technique and extracted them from the bulk of a multicellular cancer spheroid embedded within a 3-D matrix. These isolated cells were used to create the first leader and follower purified cell cultures. The purified leader cell cultures continually show dynamic invasive patterns over time, while follower cells alone have limited invasive capabilities. Reintroducing limited numbers of leader cells, or even leader cell conditioned media, into follower cell cultures promoted invasion and motility in the follower cells. Genomic analysis comparing leader versus follower cell lines show significant enrichment in cell adhesion and vascular endothelial growth factor (VEGF) signaling pathways in leader cells. This was confirmed by protein analysis showing that leader cells secrete significantly higher levels of VEGF compared to follower cells, and VEGF inhibition abolished leader-follower collective invasion. Overall, our data show that SAGA can precisely select living cells based upon dynamic behaviors for genomic analysis and can amplify rare cell populations for subsequent molecular, cellular, and proteomic analyses. Therefore, this image-guided method has the potential to impact the field of tumor heterogeneity by uncovering genomic signatures of rare yet dynamic subpopulations within a heterogeneous cancer population.

Citation Format: Jessica Konen, Bhakti Dwivedi, Jeanne Kowalski, Adam Marcus. A novel image-guided genomics approach to dissect the mechanisms of collective cancer cell invasion. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A61.
Abstract A65: A novel small-molecule IAP antagonist, AZD5582, draws Mcl-1 down-regulation for induction of apoptosis through targeting of cIAP1 and XIAP in human pancreatic cancer
Authors: Gong Eun-Yeung , Lee Eun Young , Moon Jai-Hee , Shin Jae-Sik , Hong Seung-Woo , Jung Soo-A , Hwang Ih-Yeon , Kim Jeong Hee , Jin Dong-Hoon , Kim Tae Won
Published: May 2019

Inhibitor of apoptosis proteins (IAPs) plays an important role in controlling cancer cell survival. IAPs have therefore attracted considerable attention as potential targets in anticancer therapy. In this study, we investigated the anti-tumor effect of AZD5582, a novel small-molecule IAP inhibitor, in human pancreatic cancer cells. Treating human pancreatic cancer cells with AZD5582 differentially induced apoptosis, dependent on the expression of p-Akt and p-XIAP. Moreover, the knockdown of endogenous Akt or XIAP via RNA interference in pancreatic cancer cells, which are resistant to AZD5582, resulted in increased sensitivity to AZD5582, whereas ectopically expressing Akt or XIAP led to resistance to AZD5582. Additionally, AZD5582 targeted cIAP1 to induce TNF-α-induced apoptosis. More importantly, AZD5582 induced a decrease of Mcl-1 protein, a member of the Bcl-2 family, but not that of Bcl-2 and Bcl-xL. Interestingly, ectopically expressing XIAP and cIAP1 inhibited the AZD5582-induced decrease of Mcl-1 protein, which suggests that AZD5582 elicits Mcl-1 decrease for apoptosis induction by targeting of XIAP and cIAP1. Taken together, these results indicate that sensitivity to AZD5582 is determined by p-Akt-inducible XIAP phosphorylation and by targeting cIAP1. Furthermore, Mcl-1 in pancreatic cancer may act as a potent marker to analyze the therapeutic effects of AZD5582.

Citation Format: Eun-Yeung Gong, Eun Young Lee, Jai-Hee Moon, Jae-Sik Shin, Seung-Woo Hong, Soo-A Jung, Ih-Yeon Hwang, Jeong Hee Kim, Dong-Hoon Jin, Tae Won Kim. A novel small-molecule IAP antagonist, AZD5582, draws Mcl-1 down-regulation for induction of apoptosis through targeting of cIAP1 and XIAP in human pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A65.