bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P2-24-02: Analyzing susceptibility to macrophage-activating immunotherapy bexmarilimab in breast cancer by using patient-derived tumor explants
Authors: Rannikko Jenna H. , Virtakoivu Reetta , Takeda Akira , Boström Pia , Koskivuo Ilkka , Bono Petri , Hollmén Maija 
Published: March 2023

Abstract
The immunosuppressive tumor microenvironment governed by tumor-associated macrophages (TAMs) remains a major obstacle to effective cancer immunotherapy. A novel humanized antibody bexmarilimab, targeting the scavenger receptor Clever-1 on TAMs, has shown clinical benefit in ~40% of patients with late-stage ER+ breast cancer (MATINS; NCT03733990). To increase response rates, a comprehensive understanding on how TAM phenotype and the tumor immune landscape affect bexmarilimab-induced immune activation is needed. Single-cell RNA sequencing analysis of breast tumor macrophages shows high phenotypic variation across pathological subtypes and Clever-1 mRNA (STAB1) expression on various immunosuppressive IL4I1+ and TREM2+ monocyte-derived TAMs. STAB1 expressing macrophages were located in both lymphocyte rich and excluded areas in the tumor stroma based on digital spatial profiling with GeoMx. Due to this diversity, we studied bexmarilimab mode-of-action in breast cancer patient-derived tumor explant cultures (PDEC) by RNA sequencing and cytokine profiling. Our results show that bexmarilimab induced TNFα and CXCL10 secretion in 30-40% of the treated explants. In depth analysis of the responsive PDECs revealed a lower baseline expression of interferon responsive genes in their tumor microenvironment. Correspondingly, in vitro assays with primary human macrophages showed that chronic IFNγ priming abolished bexmarilimab-induced immune activation, suggesting potential use of bexmarilimab in patients with immunologically cold breast tumors.
Citation Format: Jenna H. Rannikko, Reetta Virtakoivu, Akira Takeda, Pia Boström, Ilkka Koskivuo, Petri Bono, Maija Hollmén. Analyzing susceptibility to macrophage-activating immunotherapy bexmarilimab in breast cancer by using patient-derived tumor explants [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-24-02.
Abstract P2-24-05: TAVO412 - A Novel Trispecific cMet x EGFR x VEGF Antibody for Triple Negative Breast Cancer
Authors: Chiu Mark 
Published: March 2023

Abstract
Novel Multispecific Antibody with Superior Activity in TNBC INTRO: TNBC (Triple Negative Breast Cancer) has a diverse etiology and high unmet need. We created a novel multispecific antibody with unique 2:1:1 ratio of EGFR:cMet:VEGF binding arms with excellent activity against TNBC. METHOD: Multiple in vitro EGFR & cMet signaling pathway inhibition, proliferation inhibition, and ADCC, ADCP, and CDC were conducted. Various in vivo studies using the TNBC cell lines (MDA-MB-468, MDA-MB-231, HCC70, BT20) with diverse levels of EGFR and cMet receptor density levels were tested. RESULTS: Strong tumor growth inhibition was found in multiple TNBC animal models (56% tumor growth inhibition (TGI) in BT20, 26% TGI in HCC70, 62% TGI in MDA-MB-231). Tavo412 demonstrated better activity than comparator molecules in several in vivo models using lung, gastric, and pancreatic cancer cell lines (data not shown). A one month GLP toxicity study in cynomolgus monkeys has been completed with well-expected tolerability and pharmacokinetic profiles. Besides shutting down three important cancer pathways, TAVO412 showed high potency because it also has strong EGFR and VEGF binding at pH 6 in the tumor microenvironment. Moreover, Tavo412 has exemplary Fc effector function engaging the innate immune responses that include ADCC, ADCP, and CDC. There is also a synergistic tumor growth inhibition in the presence of a standard of care molecule such as doxorubicin (61% in HCC70 with TAVO412 + doxorubicin, 66% TGI in BT20 with TAVO412 + doxorubicin, 71% TGI in MDA-MB-231 with TAVO412 + doxorubicin). In addition, gastric, pancreatic, and lung cancer in vivo models showed excellent TGI profiles. CONCLUSIONS: Tavo412 has the potential activity to be a superior multispecific antibody to treat patients with triple negative breast cancer. Phase 1 clinical testing in patients is anticipated in early 2023.
Citation Format: Mark Chiu. TAVO412 - A Novel Trispecific cMet x EGFR x VEGF Antibody for Triple Negative Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-24-05.
Abstract P2-25-04: Granzyme B expression in tumor microenvironment as a biomarker for prognosis of triple-negative breast cancer
Authors: Mizoguchi Kimihisa , Nakamura Masafumi 
Published: March 2023

Abstract
Background: Many analyzes on tumor microenvironment has made it clear that tumor infiltrating lymphocytes (TILs) plays an important role in treating cancers with high tumor mutation burden such as triple-negative breast cancer (TNBC). We reported that the relationship between TILs and PD-L1 expression (Oncotarget 2017) and revealed that high-TILs/positive-PD-L1 expression population in TNBC was associated with better prognosis. However, its molecular mechanism is still unclear. Meanwhile, it was well-known that activated T-cells work as antitumor lymphocytes by enhancing the apoptosis by granzyme B (GZMB) and perforin, and then production of cytokines such as INFγ. We focused on GZMB and examined the function of activated T-cells. Patients and Methods: This study included 230 patients with primary TNBC who underwent resection without neoadjuvant chemotherapy at our three hospitals between January 2004 and December 2014. The immunohistochemistry (IHC) scoring for GZMB expression on TILs was defined as 1 or 5%. PD-L1 positivity was defined as ≥ 10 Combined Positive Score (CPS) based on tumor and immune cells staining positive for PD-L1. Results: Of the 230 TNBC, GZMB on TILs was expressed as more than 1% and 5% positive in 181 (79%) and 50 (22%) tumors, respectively, and PD-L1 and CD8 on TILs was expressed as positive in 99 (43%) and 127 (55%) tumors, respectively. GZMB expression (more than 5%) was significantly correlated with PD-L1 expression (P=0.0048) and CD8 expression (P=0.0156). There was no significant difference in recurrence free survival (RFS) and overall survival (OS) regardless of CD8 or PD-L1expression level. Meanwhile, the patients with GZMB-positive tumors had a longer OS, compared to the patients with GZMB-negative tumors (P = 0.0155 in RFS and P = 0.0202 in OS) when PD-L1 expression on TILs was high, but not when it was low. Conclusion: OS was significantly longer among patients with high GZMB expressing TNBC. These results may validate the significance of GZMB as a biomarker for various immunotherapies in TNBC.
Citation Format: Kimihisa Mizoguchi, Masafumi Nakamura. Granzyme B expression in tumor microenvironment as a biomarker for prognosis of triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-25-04.
Abstract P2-26-21: The Principal Factors Associated with Engraftment Success of Patient-Derived Xenograft of Breast Cancer
Authors: Lee Jongwon , Lee Uk , Lee Hee Jin , Gong Gyungyub 
Published: March 2023

Abstract
Background: Patient-derived xenografts (PDXs) are increasingly used in cancer research as tools for studying cancer biology and personalized immunotherapy response. However, a comprehensive evaluation of patient-derived breast cancer xenograft generation rates in various settings is understudied. Methods: We conducted a prospective study of breast cancer patients treated with surgery to generate PDXs. PDXs were characterized by molecular subtypes, specific diagnostic entities, modified Bloom-Richardson system nuclear and histologic grades, treatment with neoadjuvant chemotherapy (NAC), Miller Payne grade, residual caner burden class, invasive tumor size, lymphovascular invasion status, number of positive lymph nodes, and the percentage of tumor infiltrating lymphocytes in the implanted tumors. Results: Three hundred and seventy-two (157 post-chemotherapy, 215 chemo-naïve) patient-derived tumors were implanted and 63 PDXs were established (17.0%). PDX engraftment was higher in the patients with higher nuclear and histologic grades using the modified Bloom-Richardson system (27.6% vs. 3.2%, p = 0.003) and triple negative breast cancer (TNBC) than in those with hormone receptor-positive cancer (36.4% vs. 3.2%, p = 0.02). Tumors from patients who received NAC (30.0% vs. 7.4%, p = 0.05) were also close to being statistically significant for successful PDX generation. Conclusions: PDXs can be established from clinically aggressive breast cancers, especially in patients with high nuclear and histologic grade TNBC treated with NAC. The prediction of engraftment success using these factors would establish cost-effective immunotherapy trials employing PDXs.
Citation Format: Jongwon Lee, Uk Lee, Hee Jin Lee, Gyungyub Gong. The Principal Factors Associated with Engraftment Success of Patient-Derived Xenograft of Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-26-21.
Abstract P3-03-29: SMARTphone-Based Cardiovascular Risk Reduction in Breast Cancer Patients [SMART-BREAST]: A Randomized Controlled Trial
Authors: Murphy Alexandra C. , Farouque Omar , Koshy Anoop N. , Yeo Belinda , Dick Ron , Nadurata Voltaire , Roccisano Laura , Reid Christopher , Yudi Matias 
Published: March 2023

Abstract
Introduction Breast cancer survivors are at greater risk for cardiovascular-related mortality compared to women without breast cancer. Accordingly, attention to reducing the risk of cardiovascular disease must be a priority in the long-term management of these patients. Objective To assess the efficacy of a smartphone-based model of care for exercise promotion, cardiovascular risk reduction and psychological wellbeing in women undergoing treatment for breast cancer. Methods Female patients with breast cancer across four tertiary Australian hospitals were screened for inclusion in this randomized controlled trial. Patients were randomized to standard care (SC), with or without an adjunctive smartphone application ‘BreastMate’ (SP) at time of diagnosis. The primary endpoint was change in exercise capacity, measured by the change in six-minute walk test (6MWT) distance at 12-months when compared to baseline, between groups. Secondary endpoints included changes in cardiovascular risk factors, psychological wellbeing, and major adverse cardiovascular events (MACE). Results Of the 103 patients recruited, complete follow-up data was available in 80 (77.7%) patients (age 60±12 years, SP=41, SC=39). At 12-months follow-up, the SP group had a statistically and clinically significant improvement in 6MWT distance (Median Δ46 (IQR 28 to 63) metres vs. Δ8 (-10 to 35) metres; p&lt; 0.001). Compared to SC, patients in the SP group had a greater reduction in systolic blood pressure (Δ-5.1 (-10 to 0) vs 0 (-10 to 7) mmHg; p=0.03) and waist circumference (Δ-1 (-4 to 0) vs 0 (-1.5 to 1) centimetres; p=0.003) as well as a greater improvement in vitality as measured by the sf-36 questionnaire (48.1 ± 18.4 to 63.3±19.2 vs 48.3 ± 24.2 to 59.6±18.8; p=0.04). There was no significant difference in cholesterol levels, diabetes control, smoking cessation or incidence of MACE between groups (p-value for all=NS). Conclusion In patients with breast cancer, a smartphone-based cardiovascular risk reduction program, as an adjunct to standard care, improved exercise capacity, systolic blood pressure, waist circumference and patient-reported vitality at 12-months. This innovative model of care could be implemented to improve the cardiovascular risk profile of breast cancer survivors. Australia and New Zealand Clinical Trials Registry (ANZCTR12620000007932).
Citation Format: Alexandra C. Murphy, Omar Farouque, Anoop N. Koshy, Belinda Yeo, Ron Dick, Voltaire Nadurata, Laura Roccisano, Christopher Reid, Matias Yudi. SMARTphone-Based Cardiovascular Risk Reduction in Breast Cancer Patients [SMART-BREAST]: A Randomized Controlled Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-03-29.
Abstract P3-05-57: Lymphatico-venous communications and rhythmic, respiratory pressure changes influence the incidence of metastatic disease at presentation in solid tumours
Authors: Badwe Rajendra , Joshi Shalaka , Hawaldar Rohini , Chaubal Rohan , Bhattacharjee Atanu , Vanmali Vaibhav , Nair Nita S. , Gupta Sudeep 
Published: March 2023

Abstract
Background-
Dissemination of cancer cells and their colonization at distant sites (metastases) is the primary cause of death in patients with solid tumors. Despite of popular theories of cancer metastases, there are several lacunae in our understanding of extent of Metastatic Disease at Presentation (MDP). The aim of this study was to evaluate if organ sites could be grouped together based on the available knowledge extent of lympho-vascular communication (LVC) and probable respiratory pressure changes they undergo and whether this correlated with incidence of MDP.
Methods-
We analyzed a prospectively maintained database of patients with solid tumors presenting between January and December 2017 at our tertiary care cancer center. The tumors were hypothetically divided into four regions (R) depending on extent of LVC and respiratory pressure changes. All patients had clinico-radiological staging after pathological confirmation of cancer. The hypothetical region grouping R1-R4 was independently evaluated by unsupervised k-means clustering. The incidence of MDP was compared in subgroups defined by primary tumor stage, anatomical region, histology, gender, and age using logistic regression.
Results-
Of 17,467 patients included with median age 54 years, 6714 (38.4%) had MDP. The incidence of M1 disease in R1 vs R2 vs R3 vs R4 regions, older (&gt;50 years) vs younger
Conclusion-
Primary anatomical regions defined by LVC and respiratory pressure changes; primary tumor histology (type and grade) and male gender are significant determinants of MDP in solid tumors.
Region grouping of solid organs based on extent of lymphaticovenous communications and rhythmic respiratory pressure changes and % MDP
Citation Format: Rajendra Badwe, Shalaka Joshi, Rohini Hawaldar, Rohan Chaubal, Atanu Bhattacharjee, Vaibhav Vanmali, Nita S. Nair, Sudeep Gupta. Lymphatico-venous communications and rhythmic, respiratory pressure changes influence the incidence of metastatic disease at presentation in solid tumours [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-57.
Abstract P3-07-20: Treatment of 4T1 Breast Cancer with Liposome-Encapsulated AdAPT-001, a TGF-beta Trap Encoded Oncolytic Adenovirus Currently in a Phase 1/2 Anticancer Trial
Authors: Reid Tony , Kummel Andrew , Caroen Scott , Shah Jaimin , Oronsky Bryan , Larson Christopher 
Published: March 2023

Abstract
Adenoviral vectors have been used extensively for gene therapy. However, efficient infection of cells requires expression of the coxsackie-adenoviral receptor (CAR). Many tumor cells lack adequate expression of CAR and, hence, are not good targets for adenoviral based vectors. We have developed a unique nanoparticle (Epi-039) that can be used to efficiently introduce adenoviral vectors into tumor cells that have low or no CAR expression. We used the CAR-negative 4T1 mammary carcinoma model system, which represents a typical triple-negative breast cancer cell line (ER−, PR−, HER2−) and which is refractory to adenoviral infection to demonstrate effective transduction of an encapsulated oncolytic adenovirus. The adenovirus that was used is called AdAPT-001. This armed oncolytic virus, which is currently in a phase I/II clinical trial called BETA PRIME for the treatment of refractory cancers, expresses a TGFb receptor trap to neutralize the immunosuppressive cytokine, TGF beta. Overexpression of TGF-beta positively correlates with metastasis in breast carcinoma and thus confers a poorer prognosis. In this study, the unique Epi-039 nanoparticle carrying AdAPT-001 not only significantly enhanced the transduction efficiency of AdAPT-001 but also protected it from neutralization by natural antibodies in human whole blood. Accordingly, we demonstrate a significant increase (P value= 0.0029) in the expression of green fluorescent protein (GFP) in CAR-negative 4T1 cells infected with the encapsulated AdAPT-001 adenovirus but not the unencapsulated AdAPT-001 adenovirus. Additional in vivo studies using nanoparticle encapsulated adenoviral vectors including AdAPT-001 to treat breast cancer are underway for rapid translation to the clinic.
Citation Format: Tony Reid, Andrew Kummel, Scott Caroen, Jaimin Shah, Bryan Oronsky, Christopher Larson. Treatment of 4T1 Breast Cancer with Liposome-Encapsulated AdAPT-001, a TGF-beta Trap Encoded Oncolytic Adenovirus Currently in a Phase 1/2 Anticancer Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-20.
Abstract P3-08-09: Development and molecular characterization of hard-to-treat breast cancer pre-clinical models to enhance precision medicine
Authors: Kuasne Hellen , fortier Anne-Marie , Busque Sandrine , Mathien Simon , Savage Paul , Ramirez Constanza Martinez , Monast Anie , Soleinova Margarita , Omeroglu Atilla , Asselah Jamil , Bouganim Nathaniel , Meterissian Sarkis , Basik Mark , Park Morag 
Published: March 2023

Abstract
Invasive breast carcinoma is a combination of heterogeneous diseases with distinct molecular and clinical features. Some subsets of breast cancer present major clinical challenges, including triple-negative, metastatic/recurrent disease and rare breast histologies. Previously, we developed a unique resource of 37 hard-to-treat breast cancer patient-derived xenografts (PDX). This set included mainly triple negative breast cancer (TNBC) patients that presented poor response to neoadjuvant chemotherapies (Savage et al. 2020 - PMID: 32546838). PDXs accurately reproduce the molecular heterogeneity of the primary tumors and show that multi-drug chemoresistance was retained upon xenotransplantation. Here, we present the characterization of PDX 3-dimensional cultures organoids (8) and PDX derived epithelial cell lines (11). Using single-cell RNAseq we showed that an organoid cultured for several passages (P8) maintained the heterogeneity of the matched PDX. Although in different proportions, all cancer cell populations found in the PDX were retained in matched organoids supporting that organoids are suitable models that recapitulates the tumor heterogeneity and are therefore a suitable model for drug screening. Among our new PDXs models (30), we have developed four PDXs from rare metaplastic breast cancers (MpBC), an aggressive subtype of breast cancer that present the poorest response to standard of care chemotherapy. We also developed one male breast cancer PDX with matched organoid. Omic analysis on our pre-clinical models and patient primary tumor and metastasis will inform development of therapeutic opportunities. This molecular information will guide selection of compounds that will be validated using our high throughput organoid drug screening pipeline. This will allow rapid screens of thousands of approved drugs, enhancing drug repurposing with potential for rapid clinical translation. The combined use of 3D tumor organoids and PDXs, is an important opportunity poised to transform identification of new therapeutic options for hard-to-treat lethal breast cancers.
Citation Format: Hellen Kuasne, Anne-Marie fortier, Sandrine Busque, Simon Mathien, Paul Savage, Constanza Martinez Ramirez, Anie Monast, Margarita Soleinova, Atilla Omeroglu, Jamil Asselah, Nathaniel Bouganim, Sarkis Meterissian, Mark Basik, Morag Park. Development and molecular characterization of hard-to-treat breast cancer pre-clinical models to enhance precision medicine [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-08-09.
Abstract P3-09-02: Pateint Derived Breast Cancer Organoids as a Model for Testing Personalized Therapies
Authors: Wajih Nadeem , Erali Richard , Forsythe Steven , Soker Shay , Votanopoulos Konstantinos 
Published: March 2023

Abstract
Introduction: Breast cancer is one of the most frequently diagnosed cancer in women with a high mortality rate. More than 20 different subtypes of breast cancer are identified. Advancement in patient-derived organoid technology makes it possible to preserve cellular, structural, and tissue microenvironment which mimics the tissue in vivo. Method: We developed patient derived breast organoids both from normal and cancer biopsies recapitulate the structure of breast tissue. Breast biopsies were enzymatically digested to yield a single cell suspension. About 1 × 105 cells were encapsulated in a specialized hydrogel mixture. Immune enhanced breast tumor organoids (iTOs) included 2 × 105 patient matched PMBCs. Results: Histological analyses of the breast organoids shows the characteristics of the breast tissue with well-defined acini in H&E. In tumor organoids acini were somewhat perturbed compared to normal breast organoids. Immuno-fluorescence staining shows the expression of breast biomarkers including EGF receptor 2 (HER2), Progesterone receptor (PR), Estrogen receptor (ER). Zona occludin 1 and 2 and keratin 19 expression in luminal cells and expression of Keratin 14 and P63 in basal cells suggested correct polarization in the organoids. Immunofluorescence staining of (iTOs), with T cell markers including CD3, CD4, and CD8 indicated that immune cells remained viable in the iTOs. Drug responses to Doxorubicin, Paclitaxel and a combination of Doxorubicin-Paclitaxel showed significant inhibition of cell growth in normal and tumor organoids (p&lt; 0.04, n=11) except for Paclitaxel failed to inhibit tumor cell growth. However, immunotherapy with nivolumab (anti PD-1) showed no significant effect on cell growth. Conclusions: Pateint Derived Breast cancer organoids recapitulate the histological features of breast tissue in culture and response to chemotherapies. In the future, patient-derived tumor organoids can provide a platform for personalized medicine.
Citation Format: Nadeem Wajih, Richard Erali, Steven Forsythe, Shay Soker, Konstantinos Votanopoulos. Pateint Derived Breast Cancer Organoids as a Model for Testing Personalized Therapies [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-09-02.