bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Table 6 from Analysis of Tumor-Associated AXIN1 Missense Mutations Identifies Variants That Activate β-Catenin Signaling
Authors: Zhang Ruyi , Li Shanshan , Schippers Kelly , Li Yunlong , Eimers Boaz , Lavrijsen Marla , Wang Ling , Cui Guofei , Chen Xin , Peppelenbosch Maikel P. , Lebbink Joyce H.G. , Smits Ron
Published: May 2024

Overview of the interactions at the interface between AXIN1 and APC for the mutated amino acids and their predicted effects
Supplementary Figure 1 from Analysis of Tumor-Associated AXIN1 Missense Mutations Identifies Variants That Activate β-Catenin Signaling
Authors: Zhang Ruyi , Li Shanshan , Schippers Kelly , Li Yunlong , Eimers Boaz , Lavrijsen Marla , Wang Ling , Cui Guofei , Chen Xin , Peppelenbosch Maikel P. , Lebbink Joyce H.G. , Smits Ron
Published: May 2024

Immunofluorescence analysis of β-catenin following Wnt3A addition or transfection with various AXIN1 variants
Supplementary Data1 from Analysis of Tumor-Associated AXIN1 Missense Mutations Identifies Variants That Activate β-Catenin Signaling
Authors: Zhang Ruyi , Li Shanshan , Schippers Kelly , Li Yunlong , Eimers Boaz , Lavrijsen Marla , Wang Ling , Cui Guofei , Chen Xin , Peppelenbosch Maikel P. , Lebbink Joyce H.G. , Smits Ron
Published: May 2024

Original Western blot images
Data from Proteogenomic Characterization Reveals Estrogen Signaling as a Target for Never-Smoker Lung Adenocarcinoma Patients without EGFR or ALK Alterations
Authors: Park Seung-Jin , Ju Shinyeong , Goh Sung-Ho , Yoon Byoung-Ha , Park Jong-Lyul , Kim Jeong-Hwan , Lee Seonjeong , Lee Sang-Jin , Kwon Yumi , Lee Wonyeop , Park Kyung Chan , Lee Geon Kook , Park Seog Yun , Kim Sunshin , Kim Seon-Young , Han Ji-Youn , Lee Cheolju
Published: May 2024

Abstract
Never-smoker lung adenocarcinoma (NSLA) is prevalent in Asian populations, particularly in women. EGFR mutations and anaplastic lymphoma kinase (ALK) fusions are major genetic alterations observed in NSLA, and NSLA with these alterations have been well studied and can be treated with targeted therapies. To provide insights into the molecular profile of NSLA without EGFR and ALK alterations (NENA), we selected 141 NSLA tissues and performed proteogenomic characterization, including whole genome sequencing (WGS), transcriptomic, methylation EPIC array, total proteomic, and phosphoproteomic analyses. Forty patients with NSLA harboring EGFR and ALK alterations and seven patients with NENA with microsatellite instability were excluded. Genome analysis revealed that TP53 (25%), KRAS (22%), and SETD2 (11%) mutations and ROS1 fusions (14%) were the most frequent genetic alterations in NENA patients. Proteogenomic impact analysis revealed that STK11 and ERBB2 somatic mutations had broad effects on cancer-associated genes in NENA. DNA copy number alteration analysis identified 22 prognostic proteins that influenced transcriptomic and proteomic changes. Gene set enrichment analysis revealed estrogen signaling as the key pathway activated in NENA. Increased estrogen signaling was associated with proteogenomic alterations, such as copy number deletions in chromosomes 14 and 21, STK11 mutation, and DNA hypomethylation of LLGL2 and ST14. Finally, saracatinib, an Src inhibitor, was identified as a potential drug for targeting activated estrogen signaling in NENA and was experimentally validated in vitro. Collectively, this study enhanced our understanding of NENA NSLA by elucidating the proteogenomic landscape and proposed saracatinib as a potential treatment for this patient population that lacks effective targeted therapies.
Significance:
The proteogenomic landscape in never-smoker lung cancer without known driver mutations reveals prognostic proteins and enhanced estrogen signaling that can be targeted as a potential therapeutic strategy to improve patient outcomes.
Data from Transfer Learning Reveals Cancer-Associated Fibroblasts Are Associated with Epithelial–Mesenchymal Transition and Inflammation in Cancer Cells in Pancreatic Ductal Adenocarcinoma
Authors: Guinn Samantha , Kinny-Köster Benedict , Tandurella Joseph A. , Mitchell Jacob T. , Sidiropoulos Dimitrios N. , Loth Melanie , Lyman Melissa R. , Pucsek Alexandra B. , Zabransky Daniel J. , Lee Jae W. , Kartalia Emma , Ramani Mili , Seppälä Toni T. , Cherry Christopher , Suri Reecha , Zlomke Haley , Patel Jignasha , He Jin , Wolfgang Christopher L. , Yu Jun , Zheng Lei , Ryan David P. , Ting David T. , Kimmelman Alec , Gupta Anuj , Danilova Ludmila , Elisseeff Jennifer H. , Wood Laura D. , Stein-O'Brien Genevieve , Kagohara Luciane T. , Jaffee Elizabeth M. , Burkhart Richard A. , Fertig Elana J. , Zimmerman Jacquelyn W.
Published: May 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by an immunosuppressive tumor microenvironment enriched with cancer-associated fibroblasts (CAF). This study used a convergence approach to identify tumor cell and CAF interactions through the integration of single-cell data from human tumors with human organoid coculture experiments. Analysis of a comprehensive atlas of PDAC single-cell RNA sequencing data indicated that CAF density is associated with increased inflammation and epithelial–mesenchymal transition (EMT) in epithelial cells. Transfer learning using transcriptional data from patient-derived organoid and CAF cocultures provided in silico validation of CAF induction of inflammatory and EMT epithelial cell states. Further experimental validation in cocultures demonstrated integrin beta 1 (ITGB1) and vascular endothelial factor A (VEGFA) interactions with neuropilin-1 mediating CAF-epithelial cell cross-talk. Together, this study introduces transfer learning from human single-cell data to organoid coculture analyses for experimental validation of discoveries of cell–cell cross-talk and identifies fibroblast-mediated regulation of EMT and inflammation.
Significance:
Adaptation of transfer learning to relate human single-cell RNA sequencing data to organoid-CAF cocultures facilitates discovery of human pancreatic cancer intercellular interactions and uncovers cross-talk between CAFs and tumor cells through VEGFA and ITGB1.
cohort1-47 from Evaluating for Correlations between Specific Metabolites in Patients Receiving First-Line or Second-Line Immunotherapy for Metastatic or Recurrent NSCLC: An Exploratory Study Based on Two Cohorts
Authors: Xu Yanjun , Ding Kaibo , Peng Zhongsheng , Ding Ling , Li Hui , Fan Yun
Published: May 2024

original data
Supplementary Figure S1 from Enhanced Antipediatric Sarcoma Effect of Everolimus with Secukinumab by Targeting IL17A
Authors: Huang Dan , Wu Zhipeng , Wu Zhengyi , Li Nuoya , Hao Liang , Li Kuangfan , Zeng Junquan , Qiu Bingbing , Zhang Shouhua , Yan Jinlong
Published: May 2024

Supplementary Figure S1 shows the humanization status of the PDX model detected by PCR, and HE staining and immunohistochemistry of patient’s RMS tissue and the P3 PDX model.
Synthetic Procedures from Design and Evaluation of ZD06519, a Novel Camptothecin Payload for Antibody Drug Conjugates
Authors: Petersen Mark E. , Brant Michael G. , Lasalle Manuel , Das Samir , Duan Renee , Wong Jodi , Ding Tong , Wu Kaylee J. , Siddappa Dayananda , Fang Chen , Zhang Wen , Wu Alex M. L. , Hirkala-Schaefer Truman , Garnett Graham A. E. , Fung Vincent , Yang Luying , Hernandez Rojas Andrea , Lawn Samuel O. , Barnscher Stuart D. , Rich Jamie R. , Colombo Raffaele
Published: May 2024

Synthesis and characterization of free drugs and drug-linkers
Supplementary Table S2 from Design and Evaluation of ZD06519, a Novel Camptothecin Payload for Antibody Drug Conjugates
Authors: Petersen Mark E. , Brant Michael G. , Lasalle Manuel , Das Samir , Duan Renee , Wong Jodi , Ding Tong , Wu Kaylee J. , Siddappa Dayananda , Fang Chen , Zhang Wen , Wu Alex M. L. , Hirkala-Schaefer Truman , Garnett Graham A. E. , Fung Vincent , Yang Luying , Hernandez Rojas Andrea , Lawn Samuel O. , Barnscher Stuart D. , Rich Jamie R. , Colombo Raffaele
Published: May 2024

Supplementary Table S2 shows the light stability of free drugs
Table S5 from Pharmacological Characterization of SDX-7320/Evexomostat: A Novel Methionine Aminopeptidase Type 2 Inhibitor with Anti-tumor and Anti-metastatic Activity
Authors: Cornelius Peter , Mayes Benjamin A. , Petersen John S. , Turnquist David J. , Dufour Pierre J. , Dannenberg Andrew J. , Shanahan James M. , Carver Bradley J.
Published: May 2024

Detailed information from the x-ray crystallography of SDX-7539 bound to MetAP2 that enabled determination of the co-crystal’s 3D structure.
Table S1 from Pharmacological Characterization of SDX-7320/Evexomostat: A Novel Methionine Aminopeptidase Type 2 Inhibitor with Anti-tumor and Anti-metastatic Activity
Authors: Cornelius Peter , Mayes Benjamin A. , Petersen John S. , Turnquist David J. , Dufour Pierre J. , Dannenberg Andrew J. , Shanahan James M. , Carver Bradley J.
Published: May 2024

Displays the proton and carbon NMR assignments for evexomostat, including chemical shifts, multiplicities and coupling constants, for evexomostat under the experimental conditions shown based on the numbering system presented in Figure S1.
Supplementary Data from Pharmacological Characterization of SDX-7320/Evexomostat: A Novel Methionine Aminopeptidase Type 2 Inhibitor with Anti-tumor and Anti-metastatic Activity
Authors: Cornelius Peter , Mayes Benjamin A. , Petersen John S. , Turnquist David J. , Dufour Pierre J. , Dannenberg Andrew J. , Shanahan James M. , Carver Bradley J.
Published: May 2024

Contains methods and results from additional experiments
Figure S7 from Darolutamide Added to Docetaxel Augments Antitumor Effect in Models of Prostate Cancer through Cell Cycle Arrest at the G1–S Transition
Authors: Buck Stefan A.J. , Van Hemelryk Annelies , de Ridder Corrina , Stuurman Debra , Erkens-Schulze Sigrun , van ’t Geloof Sem , Teubel Wilma J. , Koolen Stijn L.W. , Martens-Uzunova Elena S. , van Royen Martin E. , de Wit Ronald , Mathijssen Ron H.J. , van Weerden Wytske M.
Published: May 2024

Ki-67 staining of PC346C PDX tumor samples.
Ki-67 staining of PC346C PDX tumors after eight days of treatment with darolutamide or vehicle and an i.v. injection of docetaxel or vehicle at day five. (n=4 per group, except for vehicle/vehicle with n=3)
Table S4 from 4′-Ethynyl-2′-Deoxycytidine (EdC) Preferentially Targets Lymphoma and Leukemia Subtypes by Inducing Replicative Stress
Authors: Calbert Marissa L. , Chandramouly Gurushankar , Adams Clare M. , Saez-Ayala Magali , Kent Tatiana , Tyagi Mrityunjay , Ayyadevara V.S.S. Abhinav , Wang Yifan , Krais John J. , Gordon John , Atkins Jessica , Toma Monika M. , Betzi Stéphane , Boghossian Andrew S. , Rees Matthew G. , Ronan Melissa M. , Roth Jennifer A. , Goldman Aaron R. , Gorman Nicole , Mitra Ramkrishna , Childers Wayne E. , Graña Xavier , Skorski Tomasz , Johnson Neil , Hurtz Christian , Morelli Xavier , Eischen Christine M. , Pomerantz Richard T.
Published: May 2024

Individual blood concentrations (ng/mL) and pharmacokinetic parameters for EdC after IP injection.
Figure S7 from 4′-Ethynyl-2′-Deoxycytidine (EdC) Preferentially Targets Lymphoma and Leukemia Subtypes by Inducing Replicative Stress
Authors: Calbert Marissa L. , Chandramouly Gurushankar , Adams Clare M. , Saez-Ayala Magali , Kent Tatiana , Tyagi Mrityunjay , Ayyadevara V.S.S. Abhinav , Wang Yifan , Krais John J. , Gordon John , Atkins Jessica , Toma Monika M. , Betzi Stéphane , Boghossian Andrew S. , Rees Matthew G. , Ronan Melissa M. , Roth Jennifer A. , Goldman Aaron R. , Gorman Nicole , Mitra Ramkrishna , Childers Wayne E. , Graña Xavier , Skorski Tomasz , Johnson Neil , Hurtz Christian , Morelli Xavier , Eischen Christine M. , Pomerantz Richard T.
Published: May 2024

Evaluation of in vitro ADME properties and in vivo pharmacokinetics of EdC.
Figure S5 from 4′-Ethynyl-2′-Deoxycytidine (EdC) Preferentially Targets Lymphoma and Leukemia Subtypes by Inducing Replicative Stress
Authors: Calbert Marissa L. , Chandramouly Gurushankar , Adams Clare M. , Saez-Ayala Magali , Kent Tatiana , Tyagi Mrityunjay , Ayyadevara V.S.S. Abhinav , Wang Yifan , Krais John J. , Gordon John , Atkins Jessica , Toma Monika M. , Betzi Stéphane , Boghossian Andrew S. , Rees Matthew G. , Ronan Melissa M. , Roth Jennifer A. , Goldman Aaron R. , Gorman Nicole , Mitra Ramkrishna , Childers Wayne E. , Graña Xavier , Skorski Tomasz , Johnson Neil , Hurtz Christian , Morelli Xavier , Eischen Christine M. , Pomerantz Richard T.
Published: May 2024

RNA-seq analysis of T-ALL Jurkat and DLBCL SUDHL-10 after 16-hour treatment with 1µM EdC.
Abstract ED07-02: Recent advances in systemic disease
Authors: Loi S.
Published: May 2024

Recent advances in the treatment of HER2 positive breast cancer have focussed on the antibody drug conjugate Trastuzumab Deruxetecan, which is now approved for 2nd line use and beyond. Results show remarkable efficacy in this context, with durable progression free and increased overall survival. Deciphering mechanisms of resistance to T-DXD and ways to overcome this is currently of high clinical interest. In this talk we shall discuss what we know about resistance mechanisms to TDXD

Citation Format: S. Loi. Recent advances in systemic disease [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr ED07-02.
Abstract ED11-02: Surgical controversies in IBC
Authors: Lucci A.
Published: May 2024

In an era of treatment de-escalation, there remain questions regarding the optimal surgical management for patients with inflammatory breast cancer (IBC). For years, the standard surgical approach for patients with IBC has been modified radical mastectomy (MRM) (including complete axillary node dissection as a component of MRM) with delayed breast reconstruction. In the recent past, some authors have proposed the use of breast conserving surgery, sentinel lymph node mapping, skin-sparing mastectomy, and even immediate reconstruction as possibly appropriate procedures for the treatment of patients with IBC. In this educational session, we plan to review the available data to try and reach a conclusion on what surgical procedures appear to provide the best outcomes for patients with IBC.

Citation Format: A. Lucci. Surgical controversies in IBC [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr ED11-02.
Abstract PO1-04-05: Effectiveness and safety of inetetamab + pyrotinib + vinorelbine in ≥second-line treatment of HER2-positive metastatic breast cancer
Authors: Wu Fan , Chen Mulan , Huang Weiwei , Wang Lili , Li Nani , Wu Xiufeng , Chen Xinhua , Hong Yi , Lin Lin , Chen Kan , liu Jian
Published: May 2024

Background: In real-world settings, Patients with HER2-positive metastatic breast cancer (MBC) who cannot receive antibody-drug conjugates (ADCs) as standard second-line therapy due to cost–benefit ratios and who have no preferred options as ≥third-line regimen by NCCN guidelines, require new regimens to meet their clinical needs. This study aims to explore the effectiveness and safety of inetetamab + pyrotinib + vinorelbine for ≥second-line treatment of HER2-positive MBC. Methods: Patients with HER2-positive MBC who received ≥second-line treatment at our hospital from June 2020 to December 2022 were enrolled. Progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR) and adverse reactions were assessed. Patients received inetetamab + pyrotinib + vinorelbine until disease progression or unacceptable toxicity were evaluated every two cycles according to the RECIST 1.1 criteria. Results: 89 patients were included based on the inclusion and exclusion criteria. Among them, 45 patients received second-line treatment who couldn't use T-DM1 or T-DXd, and 44 patients received ≥third-line treatment. The median PFS of the second-line treatment subgroup was 17months, the ORR and CBR were 60.0% and 86.7%, respectively, which were significantly higher than those in the ≥third-line treatment subgroup and numerically superior to T-DM1 as a second-line treatment option. Additionally, the ORR and CBR of patients with baseline brain metastasis who did not receive radiotherapy were 27.3% and 72.7%, respectively. The most common adverse events observed were leukopenia (37.1%), neutropenia (42.7%), anemia (34.8%) and diarrhea (67.4%). The incidence of grade 3-4 leukopenia, neutropenia, anemia and diarrhea were 11.2%, 15.7%, 55.6% and 27.0%, respectively. A total of 8 patients (8.9%) discontinued medication due to adverse reactions. Conclusions: Inetetamab + pyrotinib + vinorelbine demonstrates good efficacy and controllable toxicity as a second-line treatment for HER2-positive MBC. This therapeutic regimen provides a viable alternative option for patients who are unable to receive ADCs as the second-line treatment.

Citation Format: Fan Wu, Mulan Chen, Weiwei Huang, Lili Wang, Nani Li, Xiufeng Wu, Xinhua Chen, Yi Hong, Lin Lin, Kan Chen, Jian liu. Effectiveness and safety of inetetamab + pyrotinib + vinorelbine in ≥second-line treatment of HER2-positive metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-04-05.
Abstract PO1-08-02: Population-based screening of Uruguayan Ashkenazi Jews for recurrent BRCA1 and BRCA2 pathogenic sequence variants
Authors: Castillo Cecilia , Camejo Natalia , Artagaveytia Nora , Brignoni Lucia , Laitman Yael , Cayota Alfonso , Krygier Gabriel , Delgado Lucia , Friedman Eitan
Published: May 2024

In Ashkenazi Jews (AJ) three recurring pathogenic sequence variants (PSVs) are detected in ~2.5% of the general population in the BRCA1 (c.68_69del = 185delAG, c.5266dup = 5382insC), and BRCA2 (c.5946del = 6174delT). Population-based screening for these PSVs in AJ women is part of the health basket in Israel. To assess the feasibility and outcome of BRCA genotyping in the Jewish population of Uruguay, AJ in the greater Montevideo area were recruited using ethically approved protocol and without pretest counseling were genotyped for the three predominant AJ PSVs in the BRCA genes. Independently confirmed PSV carriers were counseled, and genetic testing was offered to additional family members. Overall, 327 participants were enrolled: 312 (95%) female, 261 (80%) had all four grandparents AJ, and 14 (4%) women were breast cancer survivors with a mean age ± standard deviation (SD) 50 ± 11.5 years. The BRCA1 c.68_69del PSV was detected in three cancer free participants (0.92%, CI 95% 0.31-2.6), all with a suggestive family history. No carriers of the other two recurrent PSVs were detected. Online oncogenetic counseling was provided for all carriers. In conclusion, the rate of the BRCA1 c.68_69del PSV was similar with the rate in other AJ communities. AJ population BRCA genotyping screens in Uruguay seem feasible and should be promoted.

Pedigrees of the carrier cases (a-c)

Citation Format: Cecilia Castillo, Natalia Camejo, Nora Artagaveytia, Lucia Brignoni, Yael Laitman, Alfonso Cayota, Gabriel Krygier, Lucia Delgado, Eitan Friedman. Population-based screening of Uruguayan Ashkenazi Jews for recurrent BRCA1 and BRCA2 pathogenic sequence variants [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-08-02.
Abstract PO1-13-11: ZNF689 promotes homologous recombination via NBS1 ubiquitination and its loss confers sensitivity to PARP inhibition in triple-negative breast cancer
Authors: Ge Li-Ping , Wang Zi-Yu , Jin Xi , Jiang Yi-Zhou , Shao Zhi-Ming
Published: May 2024

Background: Triple-negative breast cancer (TNBC) poses significant clinical challenges due to the lack of targeted therapies and poor prognosis. Homologous recombination (HR) deficiency is a defining characteristic of TNBC and renders tumors susceptible to Poly (ADP-ribose) polymerase (PARP) inhibitors. However, not all TNBC patients respond to PARP inhibitors, highlighting the need to identify novel biomarkers to predict therapeutic response and improve treatment strategies. Methods: In this study, we investigated the role of zinc finger protein 689 (ZNF689) in DNA damage response (DDR) and its impact on PARP inhibitor sensitivity in TNBC. Using a comprehensive set of molecular and cellular techniques, including immunoprecipitation, in vitro and in vivo ubiquitination assays, protein expression analysis, and functional assays using TNBC cell lines, patient-derived organoids (PDOs), patient-derived xenograft (PDX) models, and cell line xenograft models, we elucidated the mechanistic role of ZNF689 in HR and PARP inhibitor response. Results: Our findings revealed ZNF689 as a novel player in DDR. ZNF689 is activated by ATM-mediated phosphorylation and recruited to DNA damage sites in an ATM-dependent manner. At the DNA double-strand break sites, ZNF689 collaborates directly with NBS1 to facilitate K63-linked ubiquitination of NBS1 via the E3 ligase SKP2. Furthermore, ZNF689-mediated NBS1 ubiquitination stabilizes the MRE11-RAD50-NBS1 (MRN) complex and feedbacks activation of ATM, therefore accelerating HR repair. Loss of ZNF689 results in HR deficiency, leading to increased sensitivity of TNBC cells to PARP inhibitors in both in vitro and in vivo models. Additionally, the combination of PARP inhibitors and paclitaxel demonstrated potential for improved efficacy in treating ZNF689-deficient TNBC. In our clinical analysis, we observed a positive correlation between ZNF689 expression and the levels of NBS1 and phosphorylated ATM in TNBC patient samples. Importantly, low ZNF689 expression was associated with a favorable response to PARP inhibitors in TNBC patients. Conclusions: Our study highlights the significant role of ZNF689 in HR and its impact on the response to PARP inhibitors in TNBC. These findings suggest ZNF689 as a promising therapeutic target for enhancing the effectiveness of PARP inhibitors in TNBC patients.

Working Modle

Citation Format: Li-Ping Ge, Zi-Yu Wang, Xi Jin, Yi-Zhou Jiang, Zhi-Ming Shao. ZNF689 promotes homologous recombination via NBS1 ubiquitination and its loss confers sensitivity to PARP inhibition in triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-13-11.
Abstract PO1-13-12: Mechanistic Analysis and Potential Therapeutic Implications in Breast Cancer with Fibrotic Focus
Authors: Fang Canbin , Tsang Julia Y. S. , Tse Gary M.K.
Published: May 2024

A fibrotic focus (FF) is a scar-like region that forms in the center of carcinoma due to excessive tumor stroma formation. In our earlier studies, we found FF as an independent poor prognostic factor for breast cancers. However, the underlying mechanisms of how the presence of FF contributed to a poor prognosis are still unknown. To improve our understanding of FF in breast cancer, we have investigated genes associated with FF and their impacts on breast cancer prognosis. Analysis of data from The Cancer Genome Atlas Program (TCGA) indicated that Bone Morphogenetic Protein 8A (BMP8A) was significantly upregulated in breast cancers with FF. To further validate this finding, immunohistochemistry (IHC) on BMP8A was performed on a local cohort of breast cancers (N= 900). Of these samples, 147 (16.3%) were found to be BMP8A positive, and there was a significant association between the presence of FF and high expression of BMP8A (p-value=0.026). We also found that high expression of BMP8A was positively correlated with apocrine phenotype, necrosis, increased Ki67 expression, and triple-negative breast cancer subtype; and most of these are poor prognostic factors for breast cancer. Kaplan-Meier survival estimate analysis revealed that high expression of BMP8A was significantly associated with poor overall survival (p-value=0.035). Gene ontology (GO) analysis showed that "Extracellular matrix organization" was the prominent biological process associated with BMP8A. KEGG pathway analysis suggested that BMP8A was significantly related to "Protein digestion and absorption", "ECM-receptor interaction", and "Focal adhesion" pathways, further validating its correlation with stromal FF. In cellular studies using MCF7 and MDA-MB-231 cell lines, overexpression of BMP8A was found to enhance breast cancer cell proliferation, invasion, and migration. Similar tumor-promoting phenotypes were exhibited when stimulating the cell lines with recombinant human BMP8A. In conclusion, our findings suggested that BMP8A was associated with FF in breast cancer, contributing at least partly to the aggressive features of these cancers. Our findings also provided new insights into the precision treatment and diagnosis of breast cancer. Further exploration of BMP8A as a therapeutic target and prognostic factor may contribute to improved management of breast cancer patients.

Citation Format: Canbin Fang, Julia Y. S. Tsang, Gary M.K. Tse. Mechanistic Analysis and Potential Therapeutic Implications in Breast Cancer with Fibrotic Focus [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-13-12.
Abstract PO1-23-03: Management and risk of upgrade of Atypical Ductal Hyperplasia in the breast – a population-based retrospective cohort analysis
Authors: Wadsten Charlotta , Rask Gunilla
Published: May 2024

Introduction International guidelines recommend open surgery for Atypical Ductal Hyperplasia (ADH) in the breast due to risk of underestimating malignant disease. The aim here was to evaluate the management and risk for upgrade of lesions diagnosed as ADH in percutaneous breast biopsies in two Swedish institutions. Methods All women with a screen-detected or symptomatic ADH diagnosed on percutaneous biopsy between 2013-2022 at Sundsvall and Umeå University Hospitals were included. Women with lesions classified as Breast imaging-reporting and data system (BI-RADS) 5 (highly suspicious) or 6 (confirmed malignancy) were excluded. Data were retrieved from medical records and histopathology reports. Odds ratio (OR) and 95 % confidence intervals (CI) for upgrade to malignant diagnosis after surgery was calculated by logistic regression analysis. Results Altogether, 101 women were included, mean age 56.1 years (range 36-93 years). Most women were selected from the national mammography screening program due to microcalcifications. Biopsies were performed with vacuum-assisted biopsy (VAB)(60.4%) or core-needle biopsy (CNB)(39.6%). Forty-eight women (47.5%) underwent surgery. Presence of a first degree relative with breast cancer (p < 0.001), more extensive microcalcifications (p=0.01), biopsies with ADH bordering DCIS (p=0.01) and CNB as opposed to VAB (p=0.02) increased the likelihood of surgical excision. Among the women undergoing surgery, eleven were upgraded to Ductal Carcinoma in Situ and seven to invasive breast cancer (overall upgrade rate 37.5%). In these women, no variable correlating to risk of upgrade in the surgical specimen was identified. After median 74 months of follow-up (range 4-105 months), one out of 53 women managed conservatively (1.9%) developed subsequent ipsilateral DCIS. Conclusion The upgrade rate to carcinoma was 37.5% after surgery while the estimated 5-year risk of ipsilateral upgrade in women managed conservatively was 1.9%. Acknowledging the short median follow-up time, these results indicate that the selection for non-surgical management in a subset of women was appropriate.

Summary of histopathological results after surgical excision of ADH

Citation Format: Charlotta Wadsten, Gunilla Rask. Management and risk of upgrade of Atypical Ductal Hyperplasia in the breast – a population-based retrospective cohort analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-23-03.
Abstract PO2-12-09: Insomnia, Pain, Anxiety, Distress, Fatigue, and Functional Impairment in Patients with Breast Cancer
Authors: Ruddy Kathryn , Grzegorczyk Veronica , Pachman Deirdre , Mitchell Sandra , Liu Bolun , Smith Deanne , O'Sullivan Ciara , Ehlers Shawna , Herrin Jeph , Rahman Parvez , Cheville Andrea
Published: May 2024

Background: SPPADE symptoms (Sleep disturbance, Pain, Physical function impairment, Anxiety, Depression/distress, and Energy deficits/fatigue) may result from cancer and its treatment. The aim of this analysis was to characterize SPPADE symptoms in patients with breast cancer.

Methods. SPPADE data were drawn from the Enhanced, EHR-facilitated Cancer Symptom Control (E2C2) study, a stepped-wedge pragmatic cluster-randomized trial designed to evaluate a symptom management intervention in routine practice (NCT03892967). Symptom severity was measured on a 0-10 scale via a survey administered by patient portal, in-clinic tablet, or interactive voice response system (by phone) prior to, during, or soon after an outpatient oncology encounter. Scores of 4-6 were categorized as “moderate” and ≥7 as “severe.” In this analysis, only the data from each patient’s initial survey were included.

Results. A total of 9,651 patients with breast cancer completed an initial E2C2 survey between March 2019 and January 2023. The proportion of patients with moderate or severe SPPADE symptoms were as follows: 22% moderate and 10% severe for insomnia; 18% moderate and 7% severe for pain; 17% moderate and 7% severe for anxiety; 15% moderate and 5% severe for emotional distress; 25% moderate and 12% severe for fatigue; and 22% moderate and 8% severe for impaired physical function. Table 1 presents score means and standard deviations by demographic subgroup.

Conclusions. SPPADE symptoms are common in patients with breast cancer. These observations warrant routine implementation of symptom surveillance and management in breast oncology.

Funding acknowledgement: The Improving the Management of symPtoms during And following Cancer Treatment (IMPACT) Consortium is a Cancer Moonshot Research Initiative under the authorization of the 2016 United States 21st Century Cures Act. This research was supported by the National Cancer Institute of the NIH, UM1CA233033 (Mayo Clinic, Rochester, MN).

Insomnia, Pain, Anxiety, Distress, Fatigue, and Functional Impairment in Patients with Breast Cancer

Citation Format: Kathryn Ruddy, Veronica Grzegorczyk, Deirdre Pachman, Sandra Mitchell, Bolun Liu, Deanne Smith, Ciara O'Sullivan, Shawna Ehlers, Jeph Herrin, Parvez Rahman, Andrea Cheville. Insomnia, Pain, Anxiety, Distress, Fatigue, and Functional Impairment in Patients with Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-12-09.
Abstract PO2-15-03: Platelet-to-lymphocyte ratio in patients with metastatic breast cancer treated with eribulin
Authors: Shimada Hiroko , Matsuura Kazuo , Kohyama Shunsuke , Asano Aya , Ohara Masahiro , Ishiguro Hiroshi , Osaki Akihiko , Saeki Toshiaki
Published: May 2024

Eribulin is widely used to treat metastatic breast cancer (BC). Higher neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocyte ratios (PLR) are associated with higher mortality in several cancer types. However, the association between BC prognosis and peripheral immune status remains controversial. We quantified the relative effects of NLR and PLR on survival in patients with recurrent/stage IV BC and evaluated their clinical prognostic value.

This retrospective study included 156 patients with recurrent/stage IV BC who received eribulin monotherapy at Saitama Medical University International Medical Center. We examined clinicopathological features (peripheral blood findings and biochemical liver and kidney function test results) and conducted univariate and multivariate analyses of the overall survival (OS).

The 156 eribulin-treated patients had a median follow-up duration of 18.3 months. Before eribulin treatment, patients with absolute lymphocyte counts (ALC) >1500/uL, NLRs < 3.0, and PLRs < 150 had significantly longer OS than those with lower ALCs, and higher NLR and PLRs (median OS, 25.5 vs. 15.5 months; p< 0.01; 20.3 vs. 13.6 months, P< 0.01; and 29.2 vs. 14.8 months; P< 0.001, respectively). Patients with anemia (hemoglobin < 10 g/dL) or liver dysfunction (albumin-bilirubin grade 2/3) had significantly shorter OS than those without (P< 0.001, respectively). Multivariate analysis revealed low albumin-bilirubin grade (P< 0.001), high hemoglobin (P< 0.01), and low PLR (P< 0.05) as independent factors of longer OS after eribulin administration.

Low PLR, anemia, and liver dysfunction might be factors associated with prolonged OS in patients with recurrent/stage IV BC on eribulin therapy, which could be clinically useful, as their evaluation requires neither new equipment nor invasive testing.

Citation Format: Hiroko Shimada, Kazuo Matsuura, Shunsuke Kohyama, Aya Asano, Masahiro Ohara, Hiroshi Ishiguro, Akihiko Osaki, Toshiaki Saeki. Platelet-to-lymphocyte ratio in patients with metastatic breast cancer treated with eribulin [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-15-03.
Abstract PO2-27-05: Composite biomarkers for the prediction of progression-free survival with CDK4/6 inhibitors in metastatic HR+/HER2- breast cancer
Authors: Witkiewicz Agnieszka , Wang Jianxin , Knudsen Erik , Levine Ellis , O'Connor Tracey
Published: May 2024

CDK4/6 inhibitors are widely used in combination with endocrine therapy in the treatment of HR+/HER2- metastatic breast cancer. Generally the CDK4/6 inhibitors lead to a doubling of progression-free survival (PFS) over single agent endocrine therapy. In spite of a known mechanism of action, biomarkers to define the duration of response to CDK4/6 inhibitors with either aromatase inhibitors (AI) or fulvestrant (FUL) remain lacking. A cohort of over 300 patients receiving standard of care CDK4/6 inhibitor combination therapy for metastatic disease were consented for participation (NCT04526587). The duration of PFS in both AI and FUL treated sub-groups were comparable to that observed in randomized clinical trials. In this cohort progesterone receptor-status (HR 0.70, p=0.0123), visceral disease (HR 1.55, p=0.0013), prior endocrine therapy (HR 2.34, p< 0.001), and type of endocrine therapy (HR 2.16, p< 0.001) were associated with duration of PFS. To develop biomarkers, gene expression analyses was performed on 313 tumor samples representing over 200 individual patients. Focusing on the pre-treatment metastatic biopsy, established signatures associated with prognosis in HR+/HER2- breast cancer were employed to determine association with response to combination therapy in the metastatic setting. Proliferation-associated signatures were associated with shorter PFS. For example, an established RB loss signature was associated with PFS in both AI (HR 1.9, p=0.009) and FUL (HR 2.8, p=0.007) treated patients. Clinically employed signatures (e.g. OncotypeDx and Mammaprint) harbored variable associations with outcomes. Random Survival Forest feature selection was applied to individual and combined prognostic signatures. This approach resulted in a potent classifier for progression-free survival (HR 10, p< 1E-20). To enable applicability to different manifestations of disease, significant clinical pathological variables were incorporated into the model so that there was equivalent performance in AI and FUL treated patients for prediction of PFS. This predictive algorithm was also strongly associated with overall survival (HR 4.6, p=2.7E-8). Ongoing studies are evaluating the algorithms prospectively in NCT04526587.

Citation Format: Agnieszka Witkiewicz, Jianxin Wang, Erik Knudsen, Ellis Levine, Tracey O'Connor. Composite biomarkers for the prediction of progression-free survival with CDK4/6 inhibitors in metastatic HR+/HER2- breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-27-05.
Abstract PO2-27-08: Discovery of glucocorticoid receptor-induced EMT and integrin gene expression and increased cell motility in invasive lobular breast cancer
Authors: Porter Baylee , Frerich Candace , Laine Muriel , Sahoo Sunati , Greene Geoffrey , Lee Jeon , Bennett Lynda , Conzen Suzanne
Published: May 2024

Estrogen receptor (ER)-positive, invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer. Although the five-year stage-matched survival is improved compared to infiltrating ductal carcinoma (IDC), ILC late metastatic recurrences ( >5 years) are more frequent. Understanding the molecular mechanisms of lobular breast cancer’s significantly dormant yet ultimately metastatic phenotype is important to improve clinical outcomes. Our laboratory had previously shown that GR activation in ER+ IDC was associated with decreased cell proliferation, but little is known about GR activity in ER+ ILC. By examining gene expression following GR activation in metastases-derived ER+/GR+ human ILC cell lines, we recently uncovered that GR-activation increases EMT and integrin pathways. Here we show for the first time that in addition to activation of these gene expression pathways, GR activation increases ILC cellular migration in microchannels coated with collagen and fibronectin, consistent with a potential for GR activation to increase ILC metastases. We examined GR expression and activation in SUM44 GR+/GR-, and BCK4 GR+/GR- and MM134 GR+ cell lines and will present data comparing gene GR- mediated expression in the presence of cortisol and clinically relevant GR modulation. Ongoing investigations also include in vivo MIND modeling with GR modulation.

Citation Format: Baylee Porter, Candace Frerich, Muriel Laine, Sunati Sahoo, Geoffrey Greene, Jeon Lee, Lynda Bennett, Suzanne Conzen. Discovery of glucocorticoid receptor-induced EMT and integrin gene expression and increased cell motility in invasive lobular breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-27-08.
Abstract PO2-28-02: ROR1 regulates CREB3L1 via a novel signaling pathway in triple negative breast cancer
Authors: Reed Victoria , Lalu Eric , Peethambaran Bela
Published: May 2024

Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer; it is highly metastatic and incredibly difficult to treat due to its lack of the hormone receptors (estrogen, progesterone, and human epidermal growth factor receptor 2) that are used as therapeutic targets to treat breast cancer patients. TNBC patients are left with limited treatment options besides potent chemotherapy drugs that often leave them with undesirable side effects. My work intends to reveal a novel oncogenic signaling pathway that could be used to specifically target and eliminate TNBC in patients. Our lab is focused on a surface receptor that is found to be highly expressed only in cancerous tissue and during fetal development, Receptor tyrosine kinase-like orphan receptor 1 (ROR1). TNBC patients with high ROR1 expression are found to have poor prognosis and decreased overall survival rate compared to patients with low expression. ROR1 is thought to be a good drug target because it activates various oncogenic pathways such as PI3K/AKT and STAT3 in order to increase TNBC metastasis and chemoresistance. Previous single cell RNA sequencing data showed that TNBC tumors with high ROR1 expression also had reduced expression of cAMP responsive element binding protein 3 like 1 (CREB3L1). Often TNBC patients are found to have low CREB3L1 expression, a transcription factor is thought to play a tumor suppressive role in TNBC by increasing the expression of genes associated with the unfolded protein response (UPR) when ER stress occurs. CREB3L1 silencing in TNBC is due to hypermethylation of its promoter region by DNA methyltransferases (DNMTs). We hypothesize that ROR1 regulates CREB3L1 by influencing DNMT activity. This project aims to reveal the tumor suppressors that are downregulated in TNBC by ROR1 activation.

Citation Format: Victoria Reed, Eric Lalu, Bela Peethambaran. ROR1 regulates CREB3L1 via a novel signaling pathway in triple negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-28-02.
Abstract PO2-28-10: Analysis of whole breast ultrasound image sequence reading time with a new FDA approved automated whole breast ultrasound tomography system for supplemental screening in women with dense breasts
Authors: Yamashita Mary , Mahoney Taylor , Walker Patrick , Larsen Linda Hovanessian
Published: May 2024

Purpose: Ultrasound technology as a supplement to mammography for screening women with dense breasts increases cancer detection. However, automated whole breast ultrasound technologies have been shown to substantially increase radiologist reading time. We conducted a reading validation program to assess how quickly and accurately radiologists could interpret images from a new automated whole breast ultrasound prior to launching a prospective case collection registry. Methods: The study analyzed 500 reading times of bilateral screening breast ultrasounds obtained from SoftVue Automated Whole Breast Ultrasound (SV) (Delphinus Medical) in women with dense breasts. For this proctored reading validation program, 20 bilateral screening ultrasound cases were selected. Thecases included a mix of normal, cysts, benign masses, cancers, and implants. 25 MSQA-trained radiologists with varying experience from 9 institutions across the United States each read the 20 cases. The same hanging protocol was used, beginning with sequences of Wafer and Sound Speed to identify an area of interest, Reflection to determine if the area persists, and then Stiffness Fusion for further confirmation and characterization. The primary outcome was reading time per bilateral ultrasound. Reading times were compared using linear mixed effects models for findings in neither, one, or both breasts and for subgroups of cancer and benign findings. Mean reading time was 3.3± 1.76 minutes (n=498, median 2.9min) per case. Cases that were negative in both breasts tended to have faster read times (2.7min, sd=1.32) compared to those with findings in one breast (3.2min, sd=1.57) or findings in both breasts (3.8min, sd=2.14). Mean read times for cases with clinical findings were within a minute of the mean time for normal cases across all case types. Conclusion Breast image sequences of Wafer, Sound Speed, Reflection, and Stiffness Fusion from SV ultrasound tomography facilitate bilateral ultrasound mean reading times of less than 4 minutes per case. Clinical Significance: SV, used as an adjunct to mammography in screening women with dense breasts, offers the benefits of increased cancer detection with supplemental ultrasound with little increase in radiologist reading time.

Table 1: Analysis of Bilateral SV Read Time Across Types of Case Clinical Findings

Citation Format: Mary Yamashita, Taylor Mahoney, Patrick Walker, Linda Hovanessian Larsen. Analysis of whole breast ultrasound image sequence reading time with a new FDA approved automated whole breast ultrasound tomography system for supplemental screening in women with dense breasts [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-28-10.
Abstract PO2-29-01: POSITIVE PREDICTIVE VALUE FOR THE MALIGNANCY OF MAMMOGRAPHIC ABNORMALITIS IN A ONE-STOP CLINIC MODEL FOR BREAST CANCER IN COLOMBI
Authors: Corredor Kelly , Gil Sara , Agudelo Carlos , Piedrahita Clara , Naranjo Melissa
Published: May 2024

Breast cancer (BC) is the most prevalent malignancy among women in Colombia, with the greatest incidence rate among malignancies. According to available data through the year 2020, the Colombian female population has officially documented 52,025 cases of breast cancer. This variety of cancer has emerged as the leading cause of cancer-related mortality among Colombian women. Currently, it is essential to emphasize the significance of the BI-RADS (Breast Imaging Reporting and Data System) classification as a means of categorizing patients’ risk levels based on criteria for subsequent breast pathology evaluation and diagnosis. We aimed to assess the positive predictive value of BIRADS IV and V in predicting the risk of breast cancer in the Colombian population. From September 2018 to December 2022, consecutive patients referred for breast mammography and suspected of having breast cancer underwent triple assessment of breast tumor and were included in this retrospective study. 27.937 patients were included with breast imaging report and BIRADS classification system 4 and 5. Patients with a previously diagnosed case of breast cancer and a BIRADS score of 1,2 or 3 were excluded. The positive predictive value of categories 4 and 5 was determined using histopathologic results of ultrasound- or stereotactically-guided biopsies as the gold standard. 46% of 21,442 patients had BACAF biopsies, 39% TRUCUT, and 15% stereotactic. Category 4A was found in 12,865 patients (60%) with a 7% positivity rate, 4B in 8,362 (25%) with 20%, and 4C and 5 in 3,216 (15%) with 75%. BIRADS 4 and 5 had a 20% positive predictive value, with 4,371 positive participants (31% under 49 and 69% over 50). Categories 4 - 5 were found to be beneficial for predicting the likelihood of malignancy, with categories 4C and 5 yielding the highest rates of positive results. Comparable to previous research, the PPV for malignancy in the present investigation was comparable.

Citation Format: Kelly Corredor, Sara Gil, Carlos Agudelo, Clara Piedrahita, Melissa Naranjo. POSITIVE PREDICTIVE VALUE FOR THE MALIGNANCY OF MAMMOGRAPHIC ABNORMALITIS IN A ONE-STOP CLINIC MODEL FOR BREAST CANCER IN COLOMBI [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-29-01.