bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P5-06-24: Validation of the Johns Hopkins oncotype DX recurrence score estimator
Authors: Millado Kristen , Fogg Louis , Ghai Ritu , Cobleigh Melody 
Published: March 2020

Abstract
Objective
Oncotype DX (ODX) is a 21-gene assay used to predict the benefit of adjuvant chemotherapy in hormone receptor-positive, HER2-negative, lymph node-negative breast cancer. However, the test is expensive and the incremental contribution of this assay to routinely available clinicopathological information and how to integrate that information to best inform clinical decision making is unknown. Several models have been developed to predict whether there are cases in which a clinician or patient could opt to forgo ODX because the outcome of the test might be predicted with a high degree of accuracy using routinely available measures. One such model was developed and validated at Johns Hopkins University. Here we used their recurrence score estimator to learn whether we could safely adopt the calculator for use at our institution to improve resource utilization.
Methods
An IRB-approved prospective database was created in 2010 for patients seen by a single medical oncologist at Rush University Medical Center and for whom oncotype DX was performed. From this database, patients were identified with HR+, HER2-negative, node-negative breast cancer and for whom age at diagnosis, tumor size, grade and Ki-67 were known. These data were entered into the Johns Hopkins breast cancer recurrence score estimator (http://www.breastrecurrenceestimator.onc.jhmi.edu). This model categorizes patients with a recurrence score (RS) of less than or equal to 25 as low risk and those with a score of greater than 25 as high risk.
Results
There were 189 patients. The mean age, tumor size, ER%, PR% and Ki-67% were 58 years old, 1.5 cm, 88%, 44% and 15% respectively. 14% had a RS greater than 25. The estimator assigned 65 patients to low risk, 59 of whom had a low RS and 6 with a high RS. The estimator assigned 4 patients to high risk, all of whom had a high RS.
Conclusions
The Johns Hopkins recurrence score estimator assigned 69 patients to low or high risk with 91.3% accuracy. Future analysis of a larger sample size is needed to optimize the accuracy of this estimator nationally. It may also be beneficial to separately analyze patients aged 50 or younger with an ODX score between 16 and 25 who had chemotherapy benefit in the TAILORx study in order to improve the utility of this risk estimator.
Citation Format: Kristen Millado, Louis Fogg, Ritu Ghai, Melody Cobleigh. Validation of the Johns Hopkins oncotype DX recurrence score estimator [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-24.
Abstract P5-08-11: Applying risk-based follow-up strategies on the Dutch breast cancer population: Consequences for care and costs
Authors: Draeger Teresa , Voelkel Vinzenz , Groothuis-Oudshoorn Catharina GM , Lavric Miha , Veltman Jeroen , Dassen Anneriet , Boersma Lisbeth J. , Witteveen Annemieke , Sonke Gabe S. , Koffijberg Hendrik , Siesling Sabine 
Published: March 2020

Abstract
Purpose: An important aim of follow-up after primary breast cancer treatment is early detection of locoregional recurrences (LRR) to improve survival. This study proposes and simulates two personalized follow-up schemes based on LRR risk predictions provided by the INFLUENCE-nomogram (a time-dependent prognostic model for breast cancer-LRR) and quantifies their possible follow-up efficiency. Methods: Patients with early breast cancer who received surgery with curative intent between 2003 and 2008 were selected from the Netherlands Cancer Registry. The INFLUENCE-nomogram was used to estimate five annual LRR risks for every patient. Applying two thresholds, defined according to (a) Youden’s J-statistic, and (b) a pre-defined follow-up sensitivity of 95%, these risk estimations served as basis to decide when to schedule follow-up visits; thus, two personalized follow-up schemes were simulated. The number of potentially saved follow-up visits and corresponding cost savings for each follow-up scheme were compared to the current Dutch breast cancer guideline on a training and testing cohort. Results: Using LRR risk predictions for 30,379 Dutch breast cancer patients from 2003 to 2006 (training cohort), two thresholds were calculated. The threshold according to Youden’s approach yielded a follow-up sensitivity of 62.5% and a potential saving of 62.1% of follow-up visits and 24.8 M €. When the threshold corresponding to 95% follow-up sensitivity is used, 17.0% of follow-up visits and 7.0 M € could be saved. Similar results were obtained by applying these thresholds to the testing cohort of 11,462 patients from 2007 to 2008. Conclusion: Personalized follow-up schemes based on the INFLUENCE-nomogram’s individual risk estimations for breast cancer-LRR could decrease the number of follow-up visits if one accepts a limited risk of delayed LRR detection.
Citation Format: Teresa Draeger, Vinzenz Voelkel, Catharina GM Groothuis-Oudshoorn, Miha Lavric, Jeroen Veltman, Anneriet Dassen, Lisbeth J. Boersma, Annemieke Witteveen, Gabe S. Sonke, Hendrik Koffijberg, Sabine Siesling. Applying risk-based follow-up strategies on the Dutch breast cancer population: Consequences for care and costs [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-08-11.
Abstract P5-11-03: Practice patterns and outcomes of post progression treatment after CDK 4/6 inhibitors
Authors: Clifton Katherine Keaney , Raghavendra Akshara Singareeka , Yi Min , Litton Jennifer , Tripathy Debu , Karuturi Meghan 
Published: March 2020

Abstract
Background: CDK 4/6 inhibitors have become frontline treatment for patients (pts) with advanced hormone receptor (HR) positive breast cancer. There is limited data regarding post-progression outcomes in pts receiving CDK 4/6 inhibitors as standard of care. In this study, we analyzed treatment patterns and clinical outcomes of post-progression treatment in pts with advanced HR positive breast cancer after receiving CDK 4/6 inhibitors. Methods: Pts with metastatic breast cancer receiving CDK 4/6 inhibitors who received treatment after progression were identified from a cohort of pts at MDACC. Pts receiving CDK 4/6 inhibitors in a clinical trial were excluded. Clinical and demographic data as well as progression-free survival (PFS) was collected. Data was analyzed using Fischer's exact test for categorized variables and T test/Wilcoxon rank-sum test for continuous variables. PFS was analyzed using the Kaplan Meier method. Results: 206 pts who met eligibility criteria were included. Median age at metastatic diagnosis was 56 years-old and the majority of pts were white (n=160, 77.7%) with a pre- treatment performance status of 0 (n=168, 81.6%). The largest fraction of pts (n=98, 47.6%) received a chemotherapy agent following progression on a CDK 4/6 inhibitor while 19.4% (n=40) received endocrine therapy, 21.8% (n=45) received a biologic, 6.3% (N=13) received a different CDK 4/6 inhibitor and 4.9% (n=10) received an investigational therapy. The majority of pts who progressed on a subsequent agent had visceral progression (n=193, 93.7%). The median time to progression on an agent after CDK 4/6 inhibitor was 122 days. There was no statically significant difference in time to progression after CDK 4/6 inhibitor between pts receiving different classes of therapies, including CDK 4/6 inhibitors and investigational therapies (p=0.3). Conclusion: Pts in our cohort were more likely to receive chemotherapy following progression on a CDK 4/6 inhibitor. Reassuringly, there was no significant difference between time to progression on different agents. As CDK 4/6 inhibitors become frontline therapy for HR positive metastatic breast cancer, it is important to evaluate the sequencing of therapies as well as outcomes on subsequent agents.
Citation Format: Katherine Keaney Clifton, Akshara Singareeka Raghavendra, Min Yi, Jennifer Litton, Debu Tripathy, Meghan Karuturi. Practice patterns and outcomes of post progression treatment after CDK 4/6 inhibitors [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-03.
Abstract P5-11-16: The efficacy and safety of selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors in hormone receptor-positive (HR+), human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer (ABC): A systematic review and meta-analysis
Authors: Jing Li , Fangmeng Fu , Liuwen Yu , Meng Huang , Yuxiang Lin , Qian Mei , Jinxing Lv , Chuan Wang 
Published: March 2020

Abstract
Background Breakthrough progress has been made in Cyclin-Dependent kinase 4 and 6 (CDK4/6) inhibitors when combined with endocrine therapy (ET) for hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). Surprisingly, the overall survival (OS) advantage of ribociclib was reported in the MONALEESE-7 trial. This study was conducted to further evaluate the efficacy and safety of CDK4/6 inhibitors for HR+/HER2- ABC. MethodWe searched PUBMUD, MEDLINE, EMBASE et al to identify relevant randomized controlled trials that compared CDK4/6 inhibitors plus ET to ET alone in HR+/HER2- ABC. We extracted the hazard ratios (HRs) for progression-free survival (PFS) and OS, and risk ratios (RRs) for objective response rate (ORR), clinical benefit rate (CBR), adverse events (AEs). Statistical analysis was performed with random-effects model. Heterogeneity was assessed by I2 statistic. Result Eight trials and 4,580 patients were included in this meta-analysis. Both PFS (HR=0.54, 95% confidence interval [CI]: 0.50-0.59, p&lt;0.00001) and OS (HR=0.79, 95% CI: 0.67-0.93, p=0.004) were significantly improved with CDK4/6 inhibitors for HR+/HER2- ABC. Similarly, the benefit was also manifested in ORR (RR=1.47, 95%CI: 1.30-1.67, p&lt;0.00001) and CBR (RR=1.20, 95%CI: 1.12-1.30, p&lt;0.00001). The improvement of PFS were observed in the combined treatment group, as both first-line (HR=0.56) and second-line therapy (HR=0.53), and irrespective of menopausal statue, the presence of visceral metastasis, previous treatment with chemotherapy, their race or age. Nevertheless, more toxicity profiles were observed with CDK4/6 inhibitors. The most common Grade 3-4 AEs is neutropenia (RR 31.95). Conclusion Substantial advantages of PFS and OS was observed for CDK4/6 inhibitors in HR+/HER2- ABC. Furthermore, the benefit of PFS was across all subgroups. Though associated with an increasing occurrence of AEs, most of which are reversable, manageable and acceptable. Therefore, CDK4/6 inhibitors could be recommended as the preferred options for HR+/HER2- ABC.
Citation Format: Li Jing, Fu Fangmeng, Yu Liuwen, Huang Meng, Lin Yuxiang, Mei Qian, Lv Jinxing, Wang Chuan. The efficacy and safety of selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors in hormone receptor-positive (HR+), human epidermal growth factor receptor-2 negative (HER2-) advanced breast cancer (ABC): A systematic review and meta-analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-16.
Abstract P6-03-04: Microenvironment-induced epigenetic reprogramming imposes drug-tolerant states in breast cancer cells
Authors: Jokela Tiina A , Schones Dustin , LaBarge Mark A 
Published: March 2020

Abstract
Development of resistance to breast cancer (BC) therapy is frustratingly common. Multiple mechanisms of resistance have been identified including selection of genetic resistance, redundant signaling, and others. More recently, rare cancer cells were shown to be sporadically reprogrammed by the presence of anti-cancer drugs into transiently resistant states, then to expand later after cessation of therapy. We have demonstrated that the physical character and composition of tumor microenvironment (ME) components are determinants of BC cell drug resistance, however, the mechanism by which this phenomenon occurs is unclear. We hypothesize that epigenetic reprogramming is not rare or sporadic, indeed, that specific tumor ME components impose epigenetic states that beget the expression of gene clusters that put cancer cells into drug-tolerant states. Our current pharmacopeia targets cancer cells, not their ME. Some tumor ME components, e.g. extracellular matrices (ECM), have half-lives that span years, and growth factors with typically short half-lives can be stabilized by direct association with ECM. Thus, a ME-imposed drug tolerance mechanism would explain how resistance can arise rapidly, in multiple locations, without the need for genetic selection. Because ME-cell interactions lead to activation of specific pathways, based on canonical receptor-ligand models, we should be able to circumvent ME-imposed drug tolerance by addition of molecules that alter ME-induced signaling. Clusters of genes that are activated in multidrug resistant breast cancer cells identified potential markers of drug tolerance. ME-drivers of the drug tolerance markers were identified in high-throughput cell-based screens with the MicroEnvironment MicroArray (MEMA) platform. BC cells were exposed in parallel to over 1000 unique combinatorial MEs, which were chosen to mimic normal mammary gland, and luminal or basal BC tumor MEs. Single-cell resolution analysis revealed MEs that induce and maintain drug-tolerance markers. Longer-term functional experiments validated that the identified MEs also increased BC cells drug tolerance. Chromatin accessibility profiling with ATAC-sequencing demonstrated that BC cells cultured in those drug-tolerance inducing MEs exhibit chromatin opening in promoter regions of genes linked to epithelial plasticity (e.g. Axl, SNAI2, Vimentin, TWIST1) within 24h of exposure. These results support the concept that specific MEs drive drug-tolerant cellular phenotypes and suggest a novel interventional avenue for preventing acquired therapy resistance.
Citation Format: Tiina A Jokela, Dustin Schones, Mark A LaBarge. Microenvironment-induced epigenetic reprogramming imposes drug-tolerant states in breast cancer cells [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-03-04.
Abstract P6-03-15: MCL-1 confers oncogenic role in breast cancer through modulating drug resistance and cancer stemness by targeting MRP1
Authors: Zhang Yuzhu , Huang Junyan , Bie Fengjie , Ren Liping , Chen Qianjun 
Published: March 2020

Abstract
Background: Breast cancer is the most common malignant tumor and the leading killer in women. Chemotherapy is one of the most important treatments for breast cancer. However, development of chemotherapy resistance is the main reason for 20-30% of breast cancer patients getting metastasis and leading to death. MCL-1, the anti-apoptotic protein, is not clarified in conforing chemotherapy resistance of Breast cancer. This work is mainly to prove that MCL-1 is the role of chemotherapy resistance and stemness of Breast cancer.Methods: We used large gene panels to detect pathological sections of tumors in drug-resistant and sensitive patients. We validated protein profiling by IHC in a larger cohort of samples. We performed the function of MCL-1 by knockdown and overexpression in vitro and in vivo. Luciferase assay and CHIP assay were used to prove the regulatory network between MCL-1 and MRP1.Result: Here, we find that MCL-1 is highly expressed in drug-resistant breast cancer tissues than sensitive. Functional studies reveal that MCL-1 plays important role in drug resistant by regulating apoptosis in breast cancer cells. We identity that knockdown of MCL-1 enhances sensitivity and reduces stem cell of breast cancer in vitro and in vivo, while overexpression has the opposite effect. Furthermore, by down and up regulation MCL-1, we show that MCL-1 regulates the expression of MRP1 (ABCC1) in breast cancer cells. Finally, we demonstrate that MCL-1 regulates ABCC1 expression through binding to its specific promoter region and promoting its transcription levels.Conclusion: Our work highlight the role of MCL-1 in chemoresistance and stemness, suggesting it could be used as a new clinical marker for breast cancer with drug resistance.Keyword:MCL-1, Breast cancer, chemoresistance, stemness, MRP1. Funding: Guangdong Natural Science Foundation No. 2017A030313719;Foundation Project of Guangzhou University of Traditional Chinese Medicine, No. XKP2019002.
Citation Format: Yuzhu Zhang, Junyan Huang, Fengjie Bie, Liping Ren, Qianjun Chen. MCL-1 confers oncogenic role in breast cancer through modulating drug resistance and cancer stemness by targeting MRP1 [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-03-15.
Abstract P6-04-08: Mismatch repair defects induce metastasis of ER+ breast cancer
Authors: Khanal Sujita , Jimenez Athena , Haricharan Svasti 
Published: March 2020

Abstract
Estrogen receptor (ER) positive breast cancer is a leading cause of cancer-related death among women globally. Metastasis and endocrine treatment resistance are the two principal causes of death from ER+ breast cancer. There are few available targeted therapeutics for metastatic, endocrine treatment resistant disease other than CDK4/6 inhibitors. However, CDK4/6 inhibitors only work in a subset of patients and markers that can identify these patients have not yet been discovered. Considering cost and toxicity associated with chronic use of these inhibitors, it is critical to identify (a) biomarkers of response (b) combinatorial approaches to enhance efficacy. To achieve these goals, we need to understand the biology underlying endocrine treatment resistance and CDK4/6 inhibitor response. We recently identified loss of the MutL complex of mismatch repair (MLH1 and PMS2), as a cause of endocrine treatment resistance in 5-10% of women with primary (non-metastasized) ER+ breast cancer. We also demonstrated that primary ER+ breast cancer cells defective in these genes lacked ATM/Chk2 activation and were, therefore, sensitized to CDK4/6 inhibitors.
Here, we present data demonstrating that MutL loss induces metastasis of ER+ breast cancer cells, which can be prevented/treated using ATM/Chk2 activators in combination with CDK4/6 inhibitors. We observed increased migration and invasion in three independent cell line models of MutL loss when treated with endocrine therapies in vitro, and increased lung colonization in vivo. We observe a similar phenotype in a PDX model of MutL defective ER+ disease. We also demonstrate significant inhibition of metastatic phenotypes upon administration of a combination of CDK4/6 inhibitors and ATM/Chk2 activators.
Alternative targeted therapies that are effective against metastatic ER+ breast cancer remain elusive, and lethality associated with this diagnosis remains high. Current standard care comprises of endocrine treatment administered with CDK4/6 inhibitors. Even when effective, this combination is costly and associated with side effects as it requires chronic administration to maintain stable disease. The results of this study suggest that (a) MutL loss can be a predictor of increased risk for metastatic disease (b) MutL defective ER+ breast cancer has increased sensitivity to CDK4/6 inhibitors (c) combinatorial use of ATM/Chk2 activators with CDK4/6 inhibitors could significantly benefit ER+ breast cancer patients with defective MutL. These potential outcomes could greatly improve quality of life and decrease cancer-related death in thousands of women every year.
Citation Format: Sujita Khanal, Athena Jimenez, Svasti Haricharan. Mismatch repair defects induce metastasis of ER+ breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-04-08.
Abstract P6-05-08: Progesterone receptor membrane component 1 controls cellular proliferation and plays a key role in the molecular circuitry of both ER positive and triple negative breast cancers
Authors: Pedroza Diego A , Bencomo Alejandra , Galvez Adriana , Subramani Ramadevi , Rajamanickam Venkatesh , Lakshmanaswamy Rajkumar 
Published: March 2020

Abstract
Introduction: Increased expression of progesterone receptor membrane component 1 (PGRMC1), has been linked to breast cancer cell proliferation and tumor growth via epidermal growth factor receptor (EGFR) dependent interaction. As estrogen receptor positive breast cancers receive endocrine therapy and triple negative breast cancers (TNBC) rely on chemotherapeutic agents and or small molecule inhibitors. PGRMC1 could be a potential therapeutic target for both estrogen receptor positive and TNBCs, however its mechanism of action remains elusive. We, aim to understand the signaling mechanism behind PGRMC1 and its potential as viable target for the treatment of breast cancers. Materials and Methods: A panel of non-malignant and malignant breast cell lines were cultured and screened for PGRMC1 expression. PGRMC1 overexpressing breast cancer cell lines were treated with AG-205 (PGRMC1 inhibitor) and PGRMC1 targeting siRNAs. MTS, qRT-PCR, Western blot, immunofluorescence, flow cytometry assays and phospho explorer antibody array analysis were performed. Results: Increased PGRMC1 mRNA and protein levels were observed in estrogen receptor positive ZR-75-1 and TNBC MDA-MB-468 cells, these results were validated and compared to online RNA-seq based gene expression analysis of breast cell lines and breast tumor data sets. Data from online databases also demonstrated PGRMC1 overexpression in multiple breast cancer subtypes (Luminal, Basal B and Basal A). Immunohistochemistry demonstrated strong staining for PGRMC1 in human breast cancer tissue compared to normal tissue. Both AG-205 treatment and PGRMC1 silencing decreased cell proliferation, induced cell cycle arrest at the G0/G1 phase, promoted apoptosis and reduced the capability of the cells to migrate and invade. Phospho-specific antibody array data demonstrated overall downregulation of the EGFR/PI3K/AKT signaling mechanisms following AG-205 and PGRMC1 silencing. Alteration in the expression of key markers of cell proliferation, apoptosis and cell cycle revealed that PGRMC1 inhibition decreases breast cancer proliferation. Conclusion: Our data demonstrate that PGRMC1 plays a prominent role in regulating breast cancer growth and progression by altering the EGFR/PI3K/AKT signaling mechanisms.
Citation Format: Diego A Pedroza, Alejandra Bencomo, Adriana Galvez, Ramadevi Subramani, Venkatesh Rajamanickam, Rajkumar Lakshmanaswamy. Progesterone receptor membrane component 1 controls cellular proliferation and plays a key role in the molecular circuitry of both ER positive and triple negative breast cancers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-05-08.