bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P4-11-21: Plasma cytokine levels in breast cancer-related lymphedema patients
Authors: Vang Anna R , Shaitelman Simona F , Sevick-Muraca Eva M , Wen-yaw Chan , Rasmussen John C , DeSnyder Sarah D , Aldrich Melissa B 
Published: March 2022

Abstract
Background: Breast cancer-related lymphedema (BCRL) is encountered by approximately 40% of breast cancer survivors. BCRL drastically affects quality of life, as the arm, breast, and trunk swelling, together with pain, depression, and cellulitis risk can make everyday functions difficult or impossible. Objective: To identify plasma biomarkers that can suggest targeted pharmacological treatments for breast cancer survivors who develop lymphedema (LE). Methods: In a prospective, ongoing, longitudinal clinical study (NCT02949726), peripheral blood, perometric arm volumes, and near-infrared fluorescence lymphatic images/videos (NIRF-LI) for the first 33 enrolled advanced breast cancer patients were collected pre-mastectomy/breast-conserving surgery with ALND, four weeks postoperatively, at the end of radiation therapy (RT), and at 6 months post-RT. 29 cytokines were measured at each time point using a MILLIPLEX MAP human cytokine/chemokine magnetic bead panel from isolated blood plasma. Cytokine levels in subjects with &gt;5% perometric arm swelling at 6 months post-regional nodal RT were analyzed and compared to those with &lt;5% perometric arm swelling at 6 months post-regional nodal RT. Additionally, subjects who exhibited LE-associated dermal backflow, identified by cloudy fluid masses, instead of linear vessels, with NIRF-LI, at 6 months post-regional nodal RT were compared to those without backflow at 6 months post-regional nodal RT. GraphPad/Prism 9 non-parametric Mann-Whitney t-test was used to compute the p-values of each cytokine. P-values less than 0.05 were deemed significant. Results: Out of the 33 subjects, 7 developed &gt;5% perometric arm swelling 6 months post-regional nodal RT and 15 developed dermal backflow 6 months post-regional nodal RT. Of the 15 subjects that developed backflow, 7 also had &gt;5% perometric arm swelling. G-CSF, GM-CSF, IL-10, IL-12p40, and IL-1R-alpha were found to be significantly higher in subjects with &gt;5% perometric arm swelling at 6 months post-RT than in subjects with &lt;5% perometric arm swelling while IL-1beta was identified to be significantly lower in subjects with backflow at 6 months post-regional nodal RT than those without backflow at 6 months post-regional nodal RT. Conclusions: G-CSF, GM-CSF, IL-10, IL-12p40, IL-1Ralpha, and IL-1beta are candidate biomarkers for detecting and directing pharmacological treatment for lymphedema in breast cancer survivors.
Citation Format: Anna R Vang, Simona F Shaitelman, Eva M Sevick-Muraca, Chan Wen-yaw, John C Rasmussen, Sarah D DeSnyder, Melissa B Aldrich. Plasma cytokine levels in breast cancer-related lymphedema patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-11-21.
Abstract P5-01-05: Transcriptional signature of metastatic triple negative breast cancer in humanized mice
Authors: Yu Chun I , Wu Te-Chia , Menghi Francesca , George Joshy , Kim Kyung In , Marches Florentina , Liu Edison T , Banchereau Jacques , Palucka Karolina 
Published: March 2022

Abstract
Triple-negative breast cancer (TNBC) is a particularly aggressive form of breast cancer with high risk of recurrence and approximately 22% rate of five-year survival when the disease becomes metastatic. Thus, understanding of mechanisms supporting metastatic colonization of distant organs is of critical importance for the development of new therapies and possibly improved outcomes. Syngeneic mouse models suggest the role of innate immune cells, particularly neutrophils, in support of metastatic dissemination of TNBC. However, it is not possible to study human cancer in immunocompetent mice. Furthermore, organoids or other 3D tissue models do not allow investigations of distant organs colonization with metastatic TNBC tumors. Here, we used humanized mice and patient-derived xenograft (PDX) from treatment naïve primary TNBC tumors to investigate the mechanisms that promote metastasis. NSG mice with transgenic expression of human hematopoietic cytokines SCF/GM-CSF/IL-3 were engrafted with human CD34+ hematopoietic progenitor cells (HPCs) to generate humanized (h)NSG-SGM3 mice. All PDX tumors grew after orthotopic implantation at week 8-12. The presence of distant metastasis was determined by macroscopic evaluation of distant organs and further confirmed by E-cadherin and cytokeratin 19 expression using polychromatic immunofluorescence on frozen tissue section. Among ten PDX tumors tested, four did not develop metastasis, four developed only lung metastasis and two developed multi-organ metastases (lung and liver). We find that different TNBC PDX tumors have different metastatic potential. Their metastatic potential is linked with differences in cellular composition and transcriptional signatures at the level of the primary tumor. Interferon Response signature is enriched in primary TNBC PDXs with metastatic potential, while non-metastatic primary tumors display a TNF signature as well as allograft rejection signature. Furthermore, liver metastases were enriched in myeloid transcripts. Thus, our model enables mechanistic and pre-clinical studies of human TNBC metastasis.
Citation Format: Chun I Yu, Te-Chia Wu, Francesca Menghi, Joshy George, Kyung In Kim, Florentina Marches, Edison T Liu, Jacques Banchereau, Karolina Palucka. Transcriptional signature of metastatic triple negative breast cancer in humanized mice [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-01-05.
Abstract P5-06-13: Second-harmonic generation imaging reveals neoadjuvant chemotherapy-induced changes in breast tumor collagen
Authors: Brown Edward , Desa Danielle , Brown Robert M , Brown Edward B , Hill Robert L , Turner Bradley M 
Published: March 2022

Abstract
Breast cancer is the most common invasive cancer in women, with most deaths attributed to metastases. Neoadjuvant chemotherapy (NACT) may be prescribed prior to surgical removal of the tumor for subsets of breast cancer patients but can have diverse undesired and off-target effects including increased appearance of the ‘tumor microenvironment of metastasis’ or TMEMs, image-based multicellular signatures which are prognostic of metastasis. In this study we explored whether NACT alters other image-based prognostic/predictive signatures, specifically second-harmonic generation (SHG) directionality, which is indicative of collagen fiber internal structure, as well as the disorganization in collagen fiber alignment. This was performed in paired biopsy/excision samples from 22 patients with HER2 overexpressing invasive ductal carcinoma as well as 22 patients with triple negative breast cancer (TNBC). We found that collagen fiber internal structure, measured using the SHG forward-to-backward-scattered ratio (F/B), is altered in the bulk of the tumor in both tumor types (p = 0.015 and 0.038, respectively), but not the adjacent tumor-stroma interface (p = 0.54 and 0.92, respectively), where F/B is prognostic of metastatic outcome. Overall disorganization in collagen fiber alignment was not significantly changed by NACT in HER2 overexpressing disease (p = 0.41) but was decreased in TNBC (p = 0.0051). These results suggest that NACT alters the collagenous extracellular matrix in diverse ways, with implications for the use of F/B and collagen fiber alignment as prognostic and predictive tools.
Citation Format: Edward Brown, Danielle Desa, Robert M Brown, Edward B Brown, Robert L Hill, Bradley M Turner. Second-harmonic generation imaging reveals neoadjuvant chemotherapy-induced changes in breast tumor collagen [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-06-13.
Abstract P5-07-07: Mapping clonal evolution and tumor heterogeneity by whole exome sequencing of tissue and plasma circulating tumor DNA in metastatic breast cancer
Authors: Kavan Stephanie , Kruse Torben A , Andersen Lars , Larsen Martin , Hildebrandt Malene G , Jylling Anne-Marie Bak , Ewertz Marianne , Vogsen Marianne , Thomassen Mads 
Published: March 2022

Abstract
Tumor heterogeneity in breast cancer tumors is widely recognized but evolution of the breast cancer genome is complex and not yet understood. Characterizing the evolutionary landscape of breast tumors can provide biological understanding of tumor progression and metastasis may be important for directing effective treatments. We performed copy number profiling and mutation detection based on whole exome sequencing of primary tumors, lymph node and distant metastasis as well as on plasma circulating tumor DNA from twelve metastatic breast cancer patients. Preliminary data shows diverse patterns of tumor evolution. Although linear evolution with late dissemination of metastatic cells was common, parallel evolution with early dissemination from primary tumor to distant sites was evident in some cases. Comparing tissue biopsies with plasma samples, we could detect variants mirroring primary tumor and/or metastasis, depending on the time span between the progression steps. The genomic discordance between the different stages of tumor evolution in these patients not only emphasizes the importance of molecular profiling of metastatic tissue but also the possibilities of liquid biopsies for real-time tracking of tumor clonal evolution.
Citation Format: Stephanie Kavan, Torben A Kruse, Lars Andersen, Martin Larsen, Malene G Hildebrandt, Anne-Marie Bak Jylling, Marianne Ewertz, Marianne Vogsen, Mads Thomassen. Mapping clonal evolution and tumor heterogeneity by whole exome sequencing of tissue and plasma circulating tumor DNA in metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-07-07.
Abstract P5-08-08: C/EBPβ antagonist peptide, ST101, as a novel therapeutic for breast cancer
Authors: Rotolo Jim , Koester Mark , Ramirez Rick , Leong Siok , Ghamsari Lila , Gallagher Erin , Darvishi Emad , Merutka Gene , Kappel Barry 
Published: March 2022

Abstract
CCAAT/Enhancer Binding Protein Beta (C/EBPβ) is an oncogenic transcription factor that is active in many cancers, where it drives the expression of factors that promote tumor survival and proliferation. In breast cancer, increased C/EBPβ expression is associated with a metastatic phenotype, high tumor grade and an overall poor prognosis (Zahnow, 2009). C/EBPβ forms dimers via leucine zipper domain interactions that are required for its transcriptional activity . ST101 is a novel peptide antagonist of C/EBPβ currently being evaluated in a Phase 1/2 clinical study in patients with advanced unresectable and metastatic solid tumors. ST101 binds to the C/EBPβ leucine zipper domain and antagonizes it’s dimerization, resulting in increased C/EBPβ proteosomal degredation and significantly decreased target gene transactivation. Here, we describe the non-clinical anti-tumor activity of ST101 against breast cancer. In vitro studies in 4T1-luc triple-negative (TNBC) and MCF7 HRPOS BC cells demonstrate ST101 dose-dependent cytotoxicity (EC50 of 4.8 and 2.1 µM, respectively), accompanied by significant impact on C/EBPβ-mediated gene expression as determined by qPCR analysis. In contrast, normal human mammary epithelial cells were not sensitive to ST101 (EC50 &gt;100 µM). In HR-negative BC and TNBC tumoroids in vitro, ST101 exposure resulted in a dose-dependent reduction in proliferation and viability, with EC50 values of 18.56 and 15.32 µM, respectively. In vivo experiments indicate significant anti-tumor activity. In a MCF7 subcutaneous xenograft model, 25 mg/kg ST101 resulted in tumor growth delay and a significant decrease in tumor volume (p&lt;0.001 vs. controls). In a 4T1-luc orthotopic model, ST101 resulted in dose-dependent tumor growth inhibition, and tumor regression following 25 mg/kg ST101 (p&lt;0.001 vs. controls). These data emphasize the potential of ST101 as a potent peptide therapeutic for HRPOS and triple-negative BC.
Citation Format: Jim Rotolo, Mark Koester, Rick Ramirez, Siok Leong, Lila Ghamsari, Erin Gallagher, Emad Darvishi, Gene Merutka, Barry Kappel. C/EBPβ antagonist peptide, ST101, as a novel therapeutic for breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-08-08.
Abstract P5-12-12: The role of a cancer testis-antigen in regulating tumor growth and oncogenic pathways in triple-negative breast cancer
Authors: Sedano Melina J , Harrison Alana L , le Ine , Gadad Shrikanth S 
Published: March 2022

Abstract
Breast cancer is the second leading cause of cancer mortality in women after lung cancer; however, it is the primary cause of death among Hispanic women. About 10-20% of breast cancers are basal (triple-negative) subtype at the time of diagnosis, and they do not respond well to treatment regimens due to a lack of specific targets. Triple-negative breast cancer is a deadly and very aggressive tumor type associated with poor prognosis compared to other molecular subtypes of breast cancer, especially among Hispanic women. Thus, identifying novel molecules with prognostic and therapeutic value is critical to treat this ever-evolving disease. Numerous studies suggest that genes transcribed from chromosome X (X-linked genes) are implicated in cancers. The expression of these genes is tightly regulated and restricted to immune-privileged organs; however, many of them escape regulation and become aberrantly expressed in tumors.Interestingly, our genomic analysis suggests that several newly annotated X-linked genes are cancer testis-antigens (CT genes) that are highly antigenic and are located at regions previously considered to be gene deserts in the human genome. To date, very minimal is known about their expression and role in triple-negative breast cancer. In this regard, we used an integrated genomic approach to identify testis-tissue-specific genes that are differentially expressed in triple-negative breast cancer. Further, we identified a highly immunogenic cancer-testis gene by incorporating cutting-edge technology-driven (Global Run-On Sequencing) gene expression analysis. Mechanistically, by using cell-, mouse-based, and genomic approaches, we have found that candidate CT gene modulates gene expression, immune response, and tumor growth in triple-negative breast cancer. Hence, it has the potential to change the way triple-negative breast cancer is diagnosed and treated. S.S.G. is supported by a First-time Faculty Recruitment Award from the Cancer Prevention and Research Institute of Texas (CPRIT; RR170020). S.S.G. is also supported by a grant from Lizanell and Colbert Coldwell foundation.
Citation Format: Melina J Sedano, Alana L Harrison, Ine le, Shrikanth S Gadad. The role of a cancer testis-antigen in regulating tumor growth and oncogenic pathways in triple-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-12-12.
Abstract P5-12-13: Exploring the impact of the tumor microenvironment on nuclear morphometry: Lessons learned for sensitivity to cytotoxic treatment
Authors: Chhetri Apekshya 
Published: March 2022

Abstract
Globally, breast cancer remains the leading cause of death in females. While systemic therapy for breast cancer may work effectively in the early phases, for more than 10% of primary and 50% of metastatic cases, the disease eventually progresses, resisting treatments. To overcome this issue, recognizing markers of resistance as early as possible is critical. Microenvironmental factors influence tumors, and increased stiffness of the extracellular matrix (ECM) is associated with cancer progression. Additionally, neighboring cells such as non-neoplastic epithelial cells(that may constitute an important portion of the tumor microenvironment -TME) are suspected to affect tumors, but details on their impact are lacking. Here, we asked whether the response to increased ECM stiffness differed depending on the degree of aggressiveness of triple negative breast cancers (TNBC) and the presence of the non-neoplastic epithelium. We investigated two morphometric parameters, nuclear circularity and area (used in cancer pathology), and tumors’ sensitivity to cisplatin to assess tumor aggressiveness- with TNBC cultured at normal (770 Pa) and increased (2000 and 3300 Pa) collagen I stiffness. Reduced nuclear circularity and increased heterogeneity for this parameter in the cancer cell population resulted from higher matrix stiffness and were associated with decreased sensitivity to the cytotoxic drug, cisplatin, notably in the more invasive cancer type. Interestingly, the impact of stiffness increase was reduced by the conditioned medium from the non-neoplastic cells. These findings warrant further investigations to identify whether changes in nuclear circularity that illustrate a global nuclear reorganization affect gene expression profiles linked to cell survival.
Citation Format: Apekshya Chhetri. Exploring the impact of the tumor microenvironment on nuclear morphometry: Lessons learned for sensitivity to cytotoxic treatment [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-12-13.
Abstract P5-13-31: Pik3ca mutations and myc amplification are associated with pathological complete response in human epidermal growth factor receptor 2-positive breast cancer patients receiving pyrotinib combined with trastuzumab neoadjuvant treatment
Authors: Shi Qiyun , Xuhong Juncheng , Ge Jia , Liu Feng , Lan Yang , Zhang Yi , Tao Luo , BIan Xiuwu , Qi Xiaowei , Jiang Jun 
Published: March 2022

Abstract
Background: Our previous study reported a good efficacy and safety of pyrotinib combined with trastuzumab neoadjuvant treatment in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients. We further explored the potential biomarkers for the efficacy of pyrotinib combined with trastuzumab neoadjuvant treatment in HER2-positive breast cancer patients. Methods:To date, a total of 162 patients with early-stage breast cancer were enrolled for the neoadjuvant pyrotinib combined with trastuzumab treatment clinical trial (ChiCTR1900022293). By the method of 425 genes next-generation sequencing (NGS), the genomic characteristics of them were evaluated for the potential correlation with postoperative pathological complete response (pCR). Results:. Among the cohort of 162 cases, a total of 43 patients have completed the whole therapy as well as final surgery and acquired qualified sequencing analysis report, and 25 of them achieved total pCR. The most frequently mutated driver genes were TP53 (80%), PIK3CA (46%), ERBB2 (10%), NF1 (8%), NBN (8%), ATRX (8%), respectively. In terms of somatic copy number alterations, the most frequent alterations are gain or amplification of ERBB2 (66%), MYC (24%), CKD12 (14%), CCND1 (12%) and ZNF217 (12%), respectively. The median tumor mutation burden (TMB) was 4.76 mut/Mb (0.00-29.61). Compared with pCR populations, non-pCR populations had higher median TMB but not statistically significant (5.29 vs 3.85 mut/Mb, P=0.141). In addition, the pCR rate of patients with wild-type PIK3CA is significantly higher than that of patients with mutated PIK3CA (80.0% vs 27.8%, P = 0.001), and those with amplified MYC are more likely to achieve pCR (22.2% vs 67.6%, P = 0.023). Conclusions:Preliminary results suggested that HER2-positive breast cancer patients with activating mutations in PIK3CA and amplified MYC are less likely to benefit from pyrotinib combined with trastuzumab neoadjuvant therapy, which need larger sample size to validate.
Citation Format: Qiyun Shi, Juncheng Xuhong, Jia Ge, Feng Liu, Yang Lan, Yi Zhang, Luo Tao, Xiuwu BIan, Xiaowei Qi, Jun Jiang. Pik3ca mutations and myc amplification are associated with pathological complete response in human epidermal growth factor receptor 2-positive breast cancer patients receiving pyrotinib combined with trastuzumab neoadjuvant treatment [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-31.
Abstract P5-17-06: P38 kinase as a therapeutic target to reverse an immune suppressive tumor microenvironment in metastatic breast cancer
Authors: Rajan Priyanka , Zonneville Justin , Colligan Sean , Abrams Scott , Bakin Andrei 
Published: March 2022

Abstract
The immune suppressive tumor microenvironment (TME) in metastatic breast cancer (MBC) limits the benefits of immunotherapy with immune checkpoint inhibitors (ICIs). In particular, the primary TME drives the expansion and recruitment of immune suppressive myeloid cell populations, such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Treatments targeting these populations can potentially improve the efficacy of ICI therapy. To that end, our published and new findings have revealed that the p38 Mitogen-Activated Protein Kinase (MAPK) contributes to the expansion and mobilization of TAMs and MDSCs. Further, we found that pharmacological blockade of p38 decreased metastasis and increased the levels of CD8+ T cells while decreasing TAMs in the primary TME. Depletion of PMN-MDSCs, a major MDSC subset, was accompanied by reduced TAM infiltration and phenocopied the anti-metastatic effects of p38 blockade. Next, we explored the impact of p38 blockade on the composition and functionality of the immune populations in the primary TME by using single-cell RNA-sequencing. We found that p38 blockade increased levels of Irf8+ monocytic populations, indicating a decrease in immune-suppressive properties of the TME. Notably, p38 blockade increased the expression of factors related to the activation of CD8+ cytotoxic T lymphocytes, i.e., Jchain, Icos, and Cd137. Thus, our data indicate that p38 blockade alters the immune landscape within the primary TME and favors an antitumor immune response. Our data also suggest that the p38 kinase controls the production of tumor-derived factors (TDFs) which facilitate the recruitment of those pro-tumor myeloid populations. Thus, we explored this p38-TDF-myeloid axis by using trans-well migration assays. We tested the migration of the monocyte-like cell line RAW 264.7 in response to tumor-conditioned media prepared from tumor cells treated with or without the p38 inhibitor, Ralimetinib. Our data showed that the migration of RAW 264.7 cells was significantly diminished towards the conditioned media from tumor cells treated with the p38 inhibitor or from tumor cells with a genetic inactivation of p38α by CRISPR/Cas9 compared to the corresponding controls. Altogether, our studies demonstrate that p38 kinase is a potential therapeutic target, which reshapes the immune suppressive contexture of TME in MBC to improve antitumor immunity.
Citation Format: Priyanka Rajan, Justin Zonneville, Sean Colligan, Scott Abrams, Andrei Bakin. P38 kinase as a therapeutic target to reverse an immune suppressive tumor microenvironment in metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-17-06.