bluuebunny/crossref_metadata_2025 huggingface dataset:
Figure S4 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

Expression of the AR and its splice variants.
GAPDH normalized expression of full length (A) and alternatively spliced AR (B) mRNA. In PC2416-DEC tumors, AR full length expression is 2.5 times higher compared to PC346C tumors, while AR splice variants have a 1.4 to 3.4 times higher expression in PC2416-DEC tumors compared to PC346C. Data adapted from Van Hemelryk et al. (13)
Table S1 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

Mechanism of action of compounds identified in PRISM screen as top hits with similar efficacy and sensitivity profile as EdC.
Supplementary Methods 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

Additional methods for PRISM screen and EdC synthesis.
Figure S8 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

Additional in vivo data.
Figure S6 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

Additional EdC metabolism data.
Figure 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

EdC sensitivity correlates with sensitivity to replication stress-inducing compounds.
Figure S3 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

Mutation-based sensitivity patterns and correlation analysis of CRISPR knock-out with EdC sensitivity.
Supplementary Table S1 from Simvastatin Overcomes Resistance to Tyrosine Kinase Inhibitors in Patient-derived, Oncogene-driven Lung Adenocarcinoma Models
Authors: Ma Weijie , Wei Sixi , Li Qianping , Zeng Jie , Xiao Wenwu , Zhou Chihong , Yoneda Ken Y. , Zeki Amir A. , Li Tianhong
Published: May 2024

Supplementary Table S1
Supplementary Fig S5 from Simvastatin Overcomes Resistance to Tyrosine Kinase Inhibitors in Patient-derived, Oncogene-driven Lung Adenocarcinoma Models
Authors: Ma Weijie , Wei Sixi , Li Qianping , Zeng Jie , Xiao Wenwu , Zhou Chihong , Yoneda Ken Y. , Zeki Amir A. , Li Tianhong
Published: May 2024

Supplemental Fig S5
Supplementary Fig S4 from Simvastatin Overcomes Resistance to Tyrosine Kinase Inhibitors in Patient-derived, Oncogene-driven Lung Adenocarcinoma Models
Authors: Ma Weijie , Wei Sixi , Li Qianping , Zeng Jie , Xiao Wenwu , Zhou Chihong , Yoneda Ken Y. , Zeki Amir A. , Li Tianhong
Published: May 2024

Supplemental Fig S4
Supplementary Fig S3 from Simvastatin Overcomes Resistance to Tyrosine Kinase Inhibitors in Patient-derived, Oncogene-driven Lung Adenocarcinoma Models
Authors: Ma Weijie , Wei Sixi , Li Qianping , Zeng Jie , Xiao Wenwu , Zhou Chihong , Yoneda Ken Y. , Zeki Amir A. , Li Tianhong
Published: May 2024

Supplemental Fig S3
Supplementary Fig S2 from Simvastatin Overcomes Resistance to Tyrosine Kinase Inhibitors in Patient-derived, Oncogene-driven Lung Adenocarcinoma Models
Authors: Ma Weijie , Wei Sixi , Li Qianping , Zeng Jie , Xiao Wenwu , Zhou Chihong , Yoneda Ken Y. , Zeki Amir A. , Li Tianhong
Published: May 2024

Supplemental Fig S2
Supplementary Fig S1 from Simvastatin Overcomes Resistance to Tyrosine Kinase Inhibitors in Patient-derived, Oncogene-driven Lung Adenocarcinoma Models
Authors: Ma Weijie , Wei Sixi , Li Qianping , Zeng Jie , Xiao Wenwu , Zhou Chihong , Yoneda Ken Y. , Zeki Amir A. , Li Tianhong
Published: May 2024

Supplemental Fig S1
Data 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

Abstract
In this study, we explored the therapeutic potential of everolimus, an mTOR inhibitor, in a patient-derived xenograft (PDX) of rhabdomyosarcoma, the most prevalent malignant pediatric sarcoma. In addition, rhabdoid tumor cell line A-204 and Ewings sarcoma cell line A-673 were cultured to assess the in vitro effect of everolimus. Furthermore, the cell-derived xenograft (CDX) of A-673 was established and treated with everolimus in vivo. IHC and Western blotting were performed to detect the expressions of pertinent proteins. Results showed that everolimus intervention had limited inhibitory effect on PDX tumor growth compared with cyclophosphamide. Nevertheless, everolimus treatment significantly influenced the phosphorylation levels of S6 kinase beta 1 (S6K1) and eIF4E-binding protein 1 (p-4E-BP1), resulting in the inhibition of angiogenesis in vitro and in vivo. Interestingly, everolimus led to an upregulation in the level of IL17A in sarcoma cells. Notably, when secukinumab, a mAb of IL17A, was combined with everolimus, it synergistically enhanced the inhibitory effect of everolimus on sarcoma cell proliferation in vitro and on the growth of PDX or CDX xenograft tumors in vivo. Importantly, this combination therapy did not affect the mTOR signaling. These results indicate that everolimus exerts an antipediatric sarcoma effect by inhibiting mTOR signal. However, everolimus induces sarcoma cells to produce IL17A, which promotes tumor cell survival and counteracts its antipediatric sarcoma effect. The combination of secukinumab effectively eliminates the effects of IL17A, thereby improving the therapeutic efficacy of everolimus in the context of pediatric sarcomas.
Data 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

Abstract
Immune checkpoint inhibitors (ICI) have displayed impressive clinical efficacy in the context of non–small cell lung cancer (NSCLC). However, most patients do not achieve long-term survival. Minimally invasive collected samples are attracting significant interest as new fields of biomarker study, and metabolomics is one of these growing fields. We concentrated on the augmented value of the metabolomic profile in differentiating long-term survival from short-term survival in patients with NSCLC subjected to ICIs. We prospectively recruited 97 patients with stage IV NSCLC who were treated with anti–PD-1 inhibitor, including patients treated with monoimmunotherapy as second-line treatment (Cohort 1), and patients treated with combination immunotherapy as first-line treatment (Cohort 2). Each cohort was divided into long-term and short-term survival groups. All blood samples were collected before beginning immunotherapy. Serum metabolomic profiling was performed by UHPLC-Q-TOF MS analysis. Pareto-scaled principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis were performed. In Cohort 1, the mPFS and mOS of long-survival patients are 27.05 and NR months, respectively, and those of short-survival patients are 2.79 and 10.59 months. In Cohort 2, the mPFS and mOS of long-survival patients are 27.35 and NR months, respectively, and those of short-survival patients are 3.77 and 12.17 months. A total of 41 unique metabolites in Cohort 1 and 47 in Cohort 2 were screened. In Cohorts 1 and 2, there are 6 differential metabolites each that are significantly associated with both progression-free survival and overall survival. The AUC values for all groups ranged from 0.73 to 0.95. In cohort 1, the top 3 enriched KEGG pathways, as determined through significant different metabolic pathway analysis, were primary bile acid biosynthesis, African trypanosomiasis, and choline metabolism in cancer. In Cohort 2, the top 3 enriched KEGG pathways were the citrate cycle (TCA cycle), PPAR signaling pathway, and primary bile acid biosynthesis. The primary bile acid synthesis pathway had significant differences in the long-term and short-term survival groups in both Cohorts 1 and 2. Our study suggests that peripheral blood metabolomic analysis is critical for identifying metabolic biomarkers and pathways responsible for the patients with NSCLC treated with ICIs.
Data from Differential Distribution of the DNA-PKcs Inhibitor Peposertib Selectively Radiosensitizes Patient-derived Melanoma Brain Metastasis Xenografts
Authors: Ji Jianxiong , Dragojevic Sonja , Callaghan Cameron M. , Smith Emily J. , Talele Surabhi , Zhang Wenjuan , Connors Margaret A. , Mladek Ann C. , Hu Zeng , Bakken Katrina K. , Sarkaria Paige P. , Carlson Brett L. , Burgenske Danielle M. , Decker Paul A. , Rashid Mohammad Abdur , Jang Mi-hyeon , Gupta Shiv K. , Eckel-Passow Jeanette E. , Elmquist William F. , Sarkaria Jann N.
Published: May 2024

Abstract
Radioresistance of melanoma brain metastases limits the clinical utility of conventionally fractionated brain radiation in this disease, and strategies to improve radiation response could have significant clinical impact. The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is critical for repair of radiation-induced DNA damage, and inhibitors of this kinase can have potent effects on radiation sensitivity. In this study, the radiosensitizing effects of the DNA-PKcs inhibitor peposertib were evaluated in patient-derived xenografts of melanoma brain metastases (M12, M15, M27). In clonogenic survival assays, peposertib augmented radiation-induced killing of M12 cells at concentrations ≥100 nmol/L, and a minimum of 16 hours exposure allowed maximal sensitization. This information was integrated with pharmacokinetic modeling to define an optimal dosing regimen for peposertib of 125 mpk dosed just prior to and 7 hours after irradiation. Using this drug dosing regimen in combination with 2.5 Gy × 5 fractions of radiation, significant prolongation in median survival was observed in M12-eGFP (104%; P = 0.0015) and M15 (50%; P = 0.03), while more limited effects were seen in M27 (16%, P = 0.04). These data support the concept of developing peposertib as a radiosensitizer for brain metastases and provide a paradigm for integrating in vitro and pharmacokinetic data to define an optimal radiosensitizing regimen for potent DNA repair inhibitors.
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

Abstract
Methionine aminopeptidase type 2 (METAP2) is a ubiquitous, evolutionarily conserved metalloprotease fundamental to protein biosynthesis which catalyzes removal of the N-terminal methionine residue from nascent polypeptides. METAP2 is an attractive target for cancer therapeutics based upon its over-expression in multiple human cancers, the importance of METAP2-specific substrates whose biological activity may be altered following METAP2 inhibition, and additionally, that METAP2 was identified as the target for the anti-angiogenic natural product, fumagillin. Irreversible inhibition of METAP2 using fumagillin analogues has established the anti-angiogenic and anti-tumor characteristics of these derivatives; however, their full clinical potential has not been realized due to a combination of poor drug-like properties and dose-limiting central nervous system (CNS) toxicity. This report describes the physicochemical and pharmacological characterization of SDX-7320 (evexomostat), a polymer–drug conjugate of the novel METAP2 inhibitor (METAP2i) SDX-7539. In vitro binding, enzyme, and cell-based assays demonstrated that SDX-7539 is a potent and selective METAP2 inhibitor. In utilizing a high molecular weight, water-soluble polymer to conjugate the novel fumagillol-derived, cathepsin-released, METAP2i SDX-7539, limitations observed with prior generation, small molecule fumagillol derivatives were ameliorated including reduced CNS exposure of the METAP2i, and prolonged half-life enabling convenient administration. Multiple xenograft and syngeneic cancer models were utilized to demonstrate the anti-tumor and anti-metastatic profile of SDX-7320. Unlike polymer–drug conjugates in general, reductions in small molecule–equivalent efficacious doses following polymer conjugation were observed. SDX-7320 has completed a phase I clinical safety study in patients with late-stage cancer and is currently being evaluated in multiple phase Ib/II clinical studies in patients with advanced solid tumors.
Data 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

Abstract
Resistance to taxane chemotherapy is frequently observed in metastatic prostate cancer. The androgen receptor (AR) is a major driver of prostate cancer and a key regulator of the G1–S cell-cycle checkpoint, promoting cancer cell proliferation by irreversible passage to the S-phase. We hypothesized that AR signaling inhibitor (ARSi) darolutamide in combination with docetaxel could augment antitumor effect by impeding the proliferation of taxane-resistant cancer cells. We monitored cell viability in organoids, tumor volume, and PSA secretion in patient-derived xenografts (PDX) and analyzed cell cycle and signaling pathway alterations. Combination treatment increased antitumor effect in androgen-sensitive, AR-positive prostate cancer organoids and PDXs. Equally beneficial effects of darolutamide added to docetaxel were observed in a castration-resistant model, progressive on docetaxel, enzalutamide, and cabazitaxel. In vitro studies showed that docetaxel treatment with simultaneous darolutamide resulted in a reduction of cells entering the S-phase in contrast to only docetaxel. Molecular analysis in the prostate cancer cell line LNCaP revealed an upregulation of cyclin-dependent kinase inhibitor p21, supporting blockade of S-phase entry and cell proliferation. Our results provide a preclinical support for combining taxanes and darolutamide as a multimodal treatment strategy in patients with metastatic prostate cancer progressive on ARSi and taxane chemotherapy.
Data from Simvastatin Overcomes Resistance to Tyrosine Kinase Inhibitors in Patient-derived, Oncogene-driven Lung Adenocarcinoma Models
Authors: Ma Weijie , Wei Sixi , Li Qianping , Zeng Jie , Xiao Wenwu , Zhou Chihong , Yoneda Ken Y. , Zeki Amir A. , Li Tianhong
Published: May 2024

Abstract
There is an unmet clinical need to develop novel strategies to overcome resistance to tyrosine kinase inhibitors (TKI) in patients with oncogene-driven lung adenocarcinoma (LUAD). The objective of this study was to determine whether simvastatin could overcome TKI resistance using the in vitro and in vivo LUAD models. Human LUAD cell lines, tumor cells, and patient-derived xenograft (PDX) models from TKI-resistant LUAD were treated with simvastatin, either alone or in combination with a matched TKI. Tumor growth inhibition was measured by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and expression of molecular targets was assessed by immunoblots. Tumors were assessed by histopathology, IHC stain, immunoblots, and RNA sequencing. We found that simvastatin had a potent antitumor effect in tested LUAD cell lines and PDX tumors, regardless of tumor genotypes. Simvastatin and TKI combination did not have antagonistic cytotoxicity in these LUAD models. In an osimertinib-resistant LUAD PDX model, simvastatin and osimertinib combination resulted in a greater reduction in tumor volume than simvastatin alone (P < 0.001). Immunoblots and IHC stain also confirmed that simvastatin inhibited TKI targets. In addition to inhibiting 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, RNA sequencing and Western blots identified the proliferation, migration, and invasion-related genes (such as PI3K/Akt/mTOR, YAP/TAZ, focal adhesion, extracellular matrix receptor), proteasome-related genes, and integrin (α3β1, αvβ3) signaling pathways as the significantly downregulated targets in these PDX tumors treated with simvastatin and a TKI. The addition of simvastatin is a safe approach to overcome acquired resistance to TKIs in several oncogene-driven LUAD models, which deserve further investigation.
Abstract ED04-02: Combination endocrine therapy following progression on first-line therapy
Authors: O'Regan R.
Published: May 2024

Assessing genomic status is critical to make treatment decisions in patients who have experienced disease progression following a CDK 4/6 inhibition with endocrine therapy. Three trials have evaluated CDK 4/6 inhibition with endocrine therapy through progression and show that switching CDK 4/6 inhibitor results in modest efficacy while continuing the same CDK 4/6 inhibitor is not effective. The optimal therapy for patients whose tumors have a PI3-kinase mutation is alpelisib and fulvestrant. Other PIK3-ca inhibitors have not shown efficacy to date. Everolimus with endocrine therapy is an effective second line approach. Emerging data demonstrate efficacy of AKT inhibition with endocrine therapy. Several other agents are in clinical development.

Citation Format: R. O'Regan. Combination endocrine therapy following progression on first-line therapy [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 ED04-02.
Abstract ED11-03: Approaches to radiation therapy for inflammatory breast cancer
Authors: Bellon J.
Published: May 2024

Inflammatory breasst cancer ((BC) is an uncommon and highly agressive form of breast cancer, with a predilection for both distant metastases and local regional recurrence. In this talk we will review challenges in radiation therapy planning and execution unique to IBC. These include staging studies and photographs to define the full extent of disease prior to systemic therapy, as well as current thoughts on dose and fractionation. We will also discuss pros and cons of local therapy in patients with metastatic disease, as well as ongoing research studying ways to optimize local regional control with concurrent systemic therapy and radiation.

Citation Format: J. Bellon. Approaches to radiation therapy for inflammatory 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 ED11-03.
Abstract PO1-04-13: CARDIAC-STAR: Prevalence of Cardiovascular Comorbidities in Hormone Receptor Positive Human Epidermal Growth Factor Negative metaStatic breasT cAnceR
Authors: Dent Susan , Guha Avirup , Moore Heather , McCaleb Rachael , Arias Irene , Stergiopoulos Stella , Li Benjamin , Makari Doris , Fradley Michael
Published: May 2024

BACKGROUND: Baseline cardiovascular (CV) comorbidities can impact treatment decisions for patients (pts) with metastatic breast cancer (mBC). There is limited data on the prevalence of CV comorbidities at the time of hormone receptor positive human epidermal growth factor negative (HR+/HER2-) mBC diagnosis. The primary objective of this study is to describe the prevalence of pre-existing CV comorbidities in women and men with newly diagnosed HR+/HER2- mBC. A secondary objective is to describe the first documented cancer treatment for patients with or without CV comorbidities. METHODS: Women and men ≥18 years of age with newly diagnosed HR+/HER2- mBC from 01/2016 to 12/2021 were included in this retrospective, observational study using the Merative™ Marketscan® Commercial and Medicare Databases which is nationally representative. Evidence of mBC was defined as having two or more claims containing one or more diagnosis code for BC at least 30 days apart and at least two secondary malignancy diagnosis codes. Previously published claims-based algorithms were used to identify the HR+/HER2- molecular subtype. The index date is defined as the date of first mBC diagnosis. Patients had a 1-year pre-index period for observation of CV comorbidities and a 6-month post-index period for first documented cancer treatmen RESULTS: We identified 5,452 pts with HR+/HER2- mBC, 99% of whom were female, with a median age of 58 years (yrs) (IQR 13), and 83% having a health plan from an employer; i.e., are still employed. At mBC diagnosis, 3,335 pts (61.2%) had at least one pre-existing CV comorbidity (see Table). The most reported CV comorbidities were hypertension (50.7%), hyperlipidemia (33.7%), and diabetes (19.2%). The median age of pts with or without a CV comorbidity was 61 and 52 yrs, respectively; 16.2% with CV comorbidities were ≥75 yrs. Additional data, including first documented treatment, will be presented at the meeting. CONCLUSIONS: The prevalence of CV comorbidities in pts with HR+/HER2- mBC is often underrecognized. In this analysis, more than half of pts had at least one CV comorbidity by mBC diagnosis. CV comorbidities may impact treatment decisions in the HR+/HER2- mBC population, particularly in older pts.

Table

Citation Format: Susan Dent, Avirup Guha, Heather Moore, Rachael McCaleb, Irene Arias, Stella Stergiopoulos, Benjamin Li, Doris Makari, Michael Fradley. CARDIAC-STAR: Prevalence of Cardiovascular Comorbidities in Hormone Receptor Positive Human Epidermal Growth Factor Negative 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 PO1-04-13.
Abstract PO1-11-02: Reporting of Post-protocol Therapies in Metastatic Breast Cancer Registration Clinical Trials: A Systematic Review
Authors: Shachar Shlomit , Korzets Yasmin , Shepshelovich Daniel , Zlotchover Noa , Amir Eitan , Tibau Ariadna , Goldvaser Hadar
Published: May 2024

BACKGROUND As the treatment for metastatic breast cancer (MBC) often includes sequential lines of therapy, data on post-protocol treatment in clinical trials are valuable in the assessment of long-term outcome. The objective of this study was to assess the reported data on post-protocol therapy in clinical trials supporting US Food and Drug Administration (FDA) approval of drugs for MBC.

METHODS We identified all initial and subsequent published trials supporting FDA approved indications for MBC between 1/2000-2/2023.

Collected data included study design, patient characteristics and whether reporting on post-protocol therapy was available. Differences in study design and population between studies with and without data on post-protocol therapy were evaluated.

FINDINGS A total of 41 indications for MBC were identified. Supporting studies comprised 20,152 patients. Data were evaluated from 241 publications or abstracts. Reporting of post progression therapy was available for 21 (51%) indications. Of these, post-progression therapy data were often partial and the appropriateness of the therapy could not be evaluated. At the time of FDA approval, data on overall survival (OS) were reported only in 17 (41%) studies. Of these, in 8 studies OS was significantly improved, in 7 studies OS was not improved and 2 studies were single arm. Differences between studies with and without data on post progression therapy are presented in the Table. Studies with OS as their primary endpoints were associated with significantly higher reporting of post-protocol therapy, while studies with both OS and progression free survival (PFS) as their primary endpoint had low reporting rate. There were no other statistically significant differences. Reporting post-protocol therapy has not changed over time with reported data in 50% and 52% studies between 2000-2010 and 2011-2023, respectively.

CONCLUSIONS Data on post progression therapy in trials supporting FDA approval of drugs for MBC are available in fewer than half of indications. Reported data are often partial and may not include sequential therapies consistent with standard of care. As subsequent lines of therapy may have a crucial role in patients' outcome, post protocol reporting should be included in the regulatory submission and be made available publicly.

Differences between studies with and without data on post progression therapy

Citation Format: Shlomit Shachar, Yasmin Korzets, Daniel Shepshelovich, Noa Zlotchover, Eitan Amir, Ariadna Tibau, Hadar Goldvaser. Reporting of Post-protocol Therapies in Metastatic Breast Cancer Registration Clinical Trials: A Systematic Review [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 PO1-11-02.
Abstract PO1-12-07: Denosumab vs. Pamidronate in the Management of Osteolytic Bone Metastases Secondary to Breast Cancer, a Multi-Institutional Analysis
Authors: Bradley Megan , Nichols Mabry , Miles Brittany
Published: May 2024

Breast cancer is one of the most common cancers in women and is associated with poor outcomes due to the metastatic potential of high-grade tumors. One common site of breast cancer metastasis is to the bone, leading to serious adverse effects such as bone pain, bone fracture, and spinal cord compression. Denosumab, a monoclonal antibody against the receptor activator of nuclear factor kappa-b (RANK) ligand (RANKL), and Pamidronate, a bisphosphonate, are two pharmacologic agents offered for the treatment of these adverse complications. The goal of this study was to conduct a retrospective cohort analysis across multiple institutions to compare the efficacy of Denosumab vs. Pamidronate in the management of osteolytic bone metastases secondary to breast cancer by evaluating the risk of adverse events. TriNetX, an online network that provides access to anonymized medical records for more than 108 million patients in 72 large healthcare organizations, was used in this study. Two cohorts, consisting of 847 patients with a diagnosis of bone metastases and breast cancer, were created and subsequently matched for age, race, gender, and ethnicity. One cohort was given Denosumab while the other was given Pamidronate, and each cohort was excluded from receiving the other medication. The occurrence of pathologic fracture in each arm, spinal cord compression, and overall five-year survival rate was measured and analyzed. The results of this study showed that Denosumab had a statistically insignificant risk reduction in both pathological fracture (2.7% vs. 2.8%, p = 0.88) and spinal cord compression (2.6% vs. 2.7%, p = 0.88) and a statistically insignificant difference in the overall five-year survival rate (45.5% vs. 52.4%, p = 0.78) when compared to Pamidronate. As a result, additional factors such as financial cost, route of administration, dosing schedule, and potential adverse side effects should be discussed with each individual who requires pharmacological therapy for bone metastases secondary to breast cancer.

Citation Format: Megan Bradley, Mabry Nichols, Brittany Miles. Denosumab vs. Pamidronate in the Management of Osteolytic Bone Metastases Secondary to Breast Cancer, a Multi-Institutional 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 PO1-12-07.
Abstract PO1-13-06: Androgen Receptor Isoform V7 (AR-V7): A Promising Biomarker for Prognosticating Breast Cancer Aggressiveness
Authors: Srivastava Tryambak Pratap , Talukdar Joyeeta , Verma Rohit Kumar , Karmakar Subhradip
Published: May 2024

Androgen Receptor (AR) is an emerging endocrine therapy target in Breast Cancer (BrCa) with up to 80% expression in clinical cases. AR-V7 is a constitutively activated splice variant of AR having a truncated ligand-binding domain (LBD). This confers ligand-independent transcriptional activity to AR-V7 and makes it susceptible to nonsteroidal antiandrogens such as Bicalutamide or Enzalutamide which target the LBD of AR. Higher levels of AR-V7 in metastatic prostate cancer leads to therapeutic resistance and enhanced metastasis. We assessed AR-full length (AR-FL) and AR-V7 expression in BrCa cell lines of different molecular subtypes. This was extended for a clinical correlation of AR-FL and AR-V7 in validated treatment naïve BrCa patients undergoing surgical intervention at a tertiary care hospital in India. Transcriptomic and proteomic analysis was performed using qRT-PCR and Western Blotting. Immunocytochemistry and immunohistochemistry were used to examine protein expression and localisation in cells and tissues. AR-FL and AR-V7 were variably expressed in cell lines which got elevated with Dihydrotestosterone (DHT) treatment. Cell lines stimulated with Bicalutamide or Enzalutamide showed significant downregulation in AR-FL expression. From a cohort of 82 clinical cases, more than 50% originated from the urban setting, post-menopausal stage, and in the age groups of 61 to 70 years. ER, PR, HER2, and AR were positive in 65%, 55%, 24%, and 67% respectively. We were able to correlate aggressive clinical traits and higher pathological grades with increased expression of AR-V7 in the AR-positive BrCa fraction. This was consistent with the cell line-based preclinical research. This study affiliates AR-V7 as an important prognostic biomarker for predicting breast cancer aggressiveness. It can serve as a screening marker of poor clinical outcomes and aid in appropriate therapeutic intervention. These outcomes, however, seek extensive prospective validation.

Citation Format: Tryambak Pratap Srivastava, Joyeeta Talukdar, Rohit Kumar Verma, Subhradip Karmakar. Androgen Receptor Isoform V7 (AR-V7): A Promising Biomarker for Prognosticating Breast Cancer Aggressiveness [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 PO1-13-06.
Abstract PO1-16-09: Does T1c-2N0-1M0 triple negative breast cancer derive a benefit from neoadjuvant chemotherapy?
Authors: Zhang Jie , Yu Yushuai , Chen Weiwei , Fu Wenfen , Chen Ruiliang , Yi Jialu , Song Chuangui
Published: May 2024

Objective: Although neoadjuvant chemotherapy (NCT) is a standard approach for operable triple negative breast cancer (TNBC), the potential risks brought by it should also be noticed. Is the expanding indication of NCT to T1cN0M0 population appropriate? We conducted an investigation to compare the long-term survival of small tumor TNBC between NCT and adjuvant chemotherapy (ACT). Methods: For this propensity-matched analysis, we used data from SEER database. We enrolled 1183 cases with NCT and 2550 cases with ACT who are AJCC clinical T1c-T2 N0-N1, diagnosed with TNBC, from 2016 to 2017. The propensity score matching was utilized to minimize baseline characteristics bias. Based on the Cox proportional hazard regression model, we calculated hazard ratios (HR) with 95% confidence intervals (CIs). Results: Multivariate analysis in matched patients showed that NCT had no significant survival benefit compared with ACT in T1c-2N0-1M0 TNBC patients. Stratified analyses by T stage and N stage demonstrated NCT mainly presented a survival advantage in patients with N1 stage. Further investigation found that NCT didn’t improve BCSS (HR=0.472; 95% CI: 0.135-1.647; p=0.239) and OS (HR=0.392; 95% CI: 0.147-1.047; p=0.062) for patients with T1cN0M0 TNBC; however, for patients with T2N1M0 TNBC, it was associated with improved OS (HR=1.951; 95% CI: 1.003-3.797; p=0.049). Conclusion: In our study, we did not find any profit brought by NCT in the stage I and stage IIa cohorts, but even more unfavorable outcomes appeared in the T1cN0M0 cohort. Therefore, whether the candidates of NCT should be extended to T1cN0M0 still need to be cautious.

Treatment effect on breast cancer-specific survival (BCSS) and overall survival (OS) by subgroup.

Citation Format: Jie Zhang, Yushuai Yu, Weiwei Chen, Wenfen Fu, Ruiliang Chen, Jialu Yi, Chuangui Song. Does T1c-2N0-1M0 triple negative breast cancer derive a benefit from neoadjuvant chemotherapy? [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 PO1-16-09.
Abstract PO1-20-10: Wernicke Encephalopathy Syndrome in Metastatic Breast Cancer – A Diagnostic Dilemma or An Underdiagnosed Entity
Authors: Patel Archit , Roy Arya Mariam , Alberico Ronald , Gandhi Shipra
Published: May 2024

Wernicke encephalopathy (WE) is an acute medical syndrome that manifests as a clinical triad of encephalopathy, gait ataxia, and oculomotor dysfunction, requiring urgent treatment. Early recognition and treatment can prevent severe neurological morbidity and the chronic neurological consequence of WE, known as Korsakoff syndrome. Thiamine (vitamin B1) deficiency is the root cause of WE, which can occur due to several underlying conditions, including chronic alcoholism, hyperemesis of pregnancy, malnutrition, prolonged fasting, and malignancy. In cases of malignancy, WE is often undiagnosed or misdiagnosed because the presenting symptoms can be confused with several other complications of malignancy. We present the case of a 47-year-old woman with no significant medical history who was diagnosed with triple negative metastatic breast cancer and admitted to the hospital with confusion, memory loss, and progressive lower extremity weakness. During her breast cancer treatments, she experienced significant nausea and vomiting, leading to a prolonged state of nutritional imbalance. Patient underwent extensive infectious and neurological workup for encephalopathy including lumbar puncture which was negative for leptomeningeal disease or infection. MRI brain did not show any new metastatic lesions however revealed enhancement of mammillary bodies bilaterally. Mammillary body enhancement can be seen in WE but not always present on imaging. She was treated for WE with high dose of thiamine infusion for five days, resulting in an improvement of her neurological symptoms.

Diagnosing WE in cancer patients is challenging, as there are various factors to consider, such as cerebral metastasis, infection, chemotherapy treatment, and electrolyte imbalances, that can cause neurological symptoms. Cancer patients are at high risk for development of WE due to chemotherapy or whole brain radiation induced nausea and vomiting that can lead to chronic malnutrition. The typical triad of symptoms is not present in many cases and presenting symptoms can be nonspecific which makes the diagnosis challenging. As a result, WE is often underdiagnosed in such patients, making it essential to educate the physician community about this acute neurological manifestation that can be easily treated. A high index of suspicion is necessary for early recognition, and prompt treatment can prevent Korsakoff syndrome, thereby enhancing the overall quality of life of patients with malignancy.

Citation Format: Archit Patel, Arya Mariam Roy, Ronald Alberico, Shipra Gandhi. Wernicke Encephalopathy Syndrome in Metastatic Breast Cancer – A Diagnostic Dilemma or An Underdiagnosed Entity [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 PO1-20-10.
Abstract PO1-22-06: Pre-operative radiotherapy followed by mastectomy and breast reconstruction – a systematic review of oncological and reconstructive outcomes
Authors: Ho Ken , Ward Joseph , Ike Chiugo , Thiruchelvam Paul , Khan Aadil , Leff Daniel
Published: May 2024

Background Pre-operative radiotherapy (PRT) followed by mastectomy and autologous breast reconstruction for locally advanced breast cancer has the potential to reduce the deleterious impact of radiotherapy on the reconstructed breast and expedite treatment without impact on oncologic control. The PRADA feasibility study (Lancet Oncol 2022; 23: 682-90) has previously demonstrated the technique is technically feasible and safe in modern breast oncology practice, however, there is a clear necessity for longer term outcome data to precisely determine clinical efficacy. In order to understand and appraise this evidence gap, we performed a systematic review focused on oncologic and reconstructive outcomes of PRT followed by mastectomy and breast reconstruction. Methods A prospectively registered search (PROSPERO ID: CRD42023349524) of Medline (Ovid), EMBASE (Ovid), EMCARE (Ovid) and CINAHL (EBSCO) databases was performed in August 2022 for studies reporting NART prior to mastectomy and breast reconstruction. Oncological and aesthetic outcomes were extracted with risk of bias (ROBINS-I) and methodological quality assessed (STROBE checklist) for each study. Results Twenty one published articles (18 papers and 3 abstracts) were identified reporting the outcomes of 1,126 patients with median follow-up between 19.0-212.4 months. Seventeen studies were non randomised single-centre cohort studies (12 retrospective and 5 prospective). Patients received neoadjuvant chemotherapy in 18 studies. The majority of studies were of low methodological quality and at serious risk of bias. Rates of locoregional recurrence and overall survival ranged between 0-21.7% and 79.8%-98.3% respectively. Rates of flap loss or necrosis ranged from 0-12.0%. Rates of revisional procedures ranged between 0-35.3%. Patient-reported outcomes were reported in 8 studies and were mostly ‘good’ or ‘excellent’. Conclusion The published literature described a heterogeneity of outcome for patients undergoing NART prior to mastectomy and breast reconstruction. This reflects a large number of small retrospective single-centre cohort studies of low methodological quality at risk of bias. There is a clear need for a prospective randomised controlled trial appraising the outcomes of PRT in the context of autologous breast reconstruction.

Citation Format: Ken Ho, Joseph Ward, Chiugo Ike, Paul Thiruchelvam, Aadil Khan, Daniel Leff. Pre-operative radiotherapy followed by mastectomy and breast reconstruction – a systematic review of oncological and reconstructive outcomes [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 PO1-22-06.
Abstract PO1-22-10: Long term outcomes of breast cancer patients with local recurrence after mastectomy undergoing immediate breast reconstruction: A retrospective multi-institutional study of 4153 cases
Authors: Ogiya Akiko , Nagura Naomi , Shimo Ayaka , Nogi Hiroko , Narui Kazutaka , Seki Hirohito , Mori Hiroki , Sasada Shinsuke , Ishitobi Makoto , Kondo Naoto , Yamauchi Chikako , Akazawa Kohei , Shien Tadahiko
Published: May 2024

Background: The number of breast cancer patients in Japan undergoing immediate breast reconstruction (IBR) has increased and the postoperative follow-up period has been extended. This study was conducted to clarify the clinical aspects of and factors associated with local recurrence (LR) after IBR. Methods: This was a multicenter study which included 4153 early breast cancer patients who underwent IBR. Clinicopathological characteristics were examined and factors potentially contributing to LR were analyzed. Risk factors for LR were examined separately for non-invasive and invasive breast cancers. Results: The median follow-up period was 75 months. The 7-year LR rates were 2.1% and 4.3% for non-invasive and invasive cancers, respectively (p < 0.001). The proportions of LR detected by palpation, subjective symptoms, and ultrasonography were 40.0%, 27.3%, and 25.9%, respectively. Overall, 75.7% of LR were solitary, and 92.7% of these cases had no further recurrences during the observational period. Multivariate analysis of LR for invasive cancer showed that skin-sparing mastectomy (SSM) or nipple-sparing mastectomy (NSM), the presence of lymphovascular invasion, cancer at the surgical margin, and not receiving radiation therapy were factors related to LR. The 7-year overall survival rates of the patients with LR and non-LR of invasive cancers were 92.5% and 97.3%, respectively, (p=0.002). Conclusions: The rate of LR after IBR was acceptably low and IBR can thus be performed safely for early breast cancer patients. Invasive cancer, SSM/NSM, lymphovascular invasion, and/or cancer at the surgical margin should prompt awareness of the possibility of LR.

Citation Format: Akiko Ogiya, Naomi Nagura, Ayaka Shimo, Hiroko Nogi, Kazutaka Narui, Hirohito Seki, Hiroki Mori, Shinsuke Sasada, Makoto Ishitobi, Naoto Kondo, Chikako Yamauchi, Kohei Akazawa, Tadahiko Shien. Long term outcomes of breast cancer patients with local recurrence after mastectomy undergoing immediate breast reconstruction: A retrospective multi-institutional study of 4153 cases [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 PO1-22-10.
Abstract PO1-23-05: Exploratory clinical trial of preoperative non-invasive localization before surgery in breast cancer patients using augmented reality technology
Authors: Lee Minah , Lee Jun Woo , Lim Woosung , Woo Joohyun , Kim Hyun-Goo , Paek Se Hyun , Park SangHui , Kim Ji Min , Chung Jin , Lee Jee Eun , Kim Jeoung Hyun
Published: May 2024

Purpose: A single-center, randomized, prospective exploratory clinical trial to assess the clinical efficacy of augmented reality(AR)-based breast cancer localization medical imaging solution in patients with breast cancer Methods: This prospective exploratory clinical trial enrolled 20 women who were diagnosed with invasive breast cancer between the ages of 19 and 70, had a single lesion or multifocal lesion with a lesion size of 5mm or more and 30mm or less, had no metastasis to other organs, and had not received prior chemotherapy. All patients underwent mammography, ultrasound, CT, and MRI for preoperative assessment. Patients were randomly assigned to US-guided skin marking (control) and SKIA-breast (AR localization) groups of 10 each. Result: Two surgeons performed breast-conserving surgery on twenty patients. Pathologic evaluation of all patients confirmed negative margins. Two independent pathologists evaluated marginal distance, and neither the two reader's estimates (R1, 6.20±4.37 vs. 5.04±3.47, p=0.519; R2, 5.10±4.31 vs. 4.10±2.38, p= 0.970) nor the two reader's average values (5.65±4.19 vs. 4.57±2.84, p= 0.509) showed any difference between the two groups. In comparing the tumor plane area ratio, there was no statistically significant difference between the two groups for the two readers (R1, 15.90±9.52 vs. 19.38±14.05, p=0.525; R2, 15.32±9.48 vs. 20.83±12.85, p=0.290) and the two reader's mean values (15.56±9.11 vs. 20.09±13.38, p=0.388). Based on the two surgeons' responses, convenience, safety, satisfaction, and reusability were all superior in the AR localization group (p=0.000). Conclusion: AR localization is an acceptable alternative to US-guided skin marking with no significant differences in surgical outcomes.

Citation Format: Minah Lee, Jun Woo Lee, Woosung Lim, Joohyun Woo, Hyun-Goo Kim, Se Hyun Paek, SangHui Park, Ji Min Kim, Jin Chung, Jee Eun Lee, Jeoung Hyun Kim. Exploratory clinical trial of preoperative non-invasive localization before surgery in breast cancer patients using augmented reality technology [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 PO1-23-05.