bluuebunny/crossref_metadata_2025 huggingface dataset:
Table S7 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 results from each behavioural measurement conducted in rats to assess potential CNS toxicity of SDX-7320.
Figure S6 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

Variance in the expression of genes between control and SDX-7320-treated tumor samples is displayed in this graph.
Figure S9 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

Western blot of p27, PSA and AR in LNCaP cells after treatment as indicated for 24 hours. GAPDH was used as loading control.
Figure S8 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

Combination of docetaxel and darolutamide in C4-2B4 and LNCaP.
Dose-response curve with mean normalized viability (+/- SEM) of two (A-B) or three (C-D) separate experiments with technical triplicates. Curves were interpolated by non-linear regression analysis and used to determine absolute IC50 value.
Figure S6 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

Darolutamide and docetaxel pharmacokinetics in PC346C bearing mice, related to Figure 2A-C.
A: Mean systemic darolutamide concentrations in PC346C bearing mice treated with darolutamide, with or without docetaxel (n=8 and n=9 per group, respectively) directly after oral darolutamide administration at treatment initiation (start), 2 weeks or 4 weeks after treatment initiation and at time of mouse sacrifice (end).
B: Mean systemic docetaxel concentrations in PC346C bearing mice treated with docetaxel, with or without darolutamide (n=8 per group) directly after i.v. docetaxel administration.
Figure 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

Sequential steps and intermediates for synthesis of EdC (compound 13).
Data from A Review of Recent Advances in the Molecular Mechanisms Underlying Brain Metastasis in Lung Cancer
Authors: Guan Chao , Zhang Xiaoye , Yu Li
Published: May 2024

Abstract
Brain metastasis from lung cancer is a prevalent mode of treatment failure associated with a poor prognosis. The incidence of brain metastasis has recently shown a dramatic increase. The early detection and risk stratification of lung cancer–related brain metastasis would be highly advantageous for patients. However, our current knowledge and comprehension of the underlying mechanisms driving brain metastasis in lung cancer pose significant challenges. This review summarizes the mechanisms underlying brain metastasis, focusing on the intricate interplay between lung cancer–derived tumor cells and the unique characteristics of the brain, recent advancements in the identification of driver genes, concomitant genes, epigenetic features, including miRNAs and long noncoding RNAs, as well as the molecular characterization of brain metastasis originating from other organs, which may further enhance risk stratification and facilitate precise treatment strategies.
Data from Differential Distribution of the DNA-PKcs Inhibitor Peposertib Selectively Radiosensitizes Patient-derived Melanoma Brain Metastasis Xenografts
Authors: Ji Jianxiang , 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 The Antipsychotic Drug Penfluridol Inhibits N-Linked Glycoprotein Processing and Enhances T-cell–Mediated Tumor Immunity
Authors: Xu Wenlong , Wang Yuqi , Zhang Na , Lin Xiaofeng , Zhu Di , Shen Cheng , Wang Xiaobo , Li Haiyang , Xue Jinjiang , Yu Qian , Lu Xinyi , Zhou Lu , He Qingli , Tang Zhijun , He Shaodan , Fan Jianjun , Pan Jianbo , Tang Jiangjiang , Jiang Wei , Ye Mingliang , Lu Fanghui , Li Zengxia , Dang Yongjun
Published: May 2024

Abstract
Aberrant N-linked glycosylation is a prominent feature of cancers. Perturbance of oligosaccharide structure on cell surfaces directly affects key processes in tumor development and progression. In spite of the critical role played by N-linked glycans in tumor biology, the discovery of small molecules that specifically disturbs the N-linked glycans is still under investigation. To identify more saccharide-structure-perturbing compounds, a repurposed drug screen by using a library consisting of 1530 FDA-approved drugs was performed. Interestingly, an antipsychotic drug, penfluridol, was identified as being able to decrease cell surface wheat germ agglutinin staining. In the presence of penfluridol, cell membrane glycoproteins programmed death-ligand 1 (PD-L1) shifted to a lower molecular weight. Further studies demonstrated that penfluridol treatment caused an accumulation of high-mannose oligosaccharides, especially Man5–7GlcNAc2 glycan structures. Mechanistically, this effect is due to direct targeting of MAN1A1 mannosidase, a Golgi enzyme involved in N-glycan maturation. Moreover, we found that altered glycosylation of PD-L1 caused by penfluridol disrupted interactions between programmed cell death protein 1 and PD-L1, resulting in activation of T-cell tumor immunity. In a mouse xenograft and glioma model, penfluridol enhanced the antitumor effect of the anti–PD-L1 antibody in vivo. Overall, these findings revealed an important biological activity of the antipsychotic drug penfluridol as an inhibitor of glycan processing and proposed a repurposed use of penfluridol in antitumor therapy through activation of T-cell immunity.
Data 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

Abstract
Anticancer nucleosides are effective against solid tumors and hematologic malignancies, but typically are prone to nucleoside metabolism resistance mechanisms. Using a nucleoside-specific multiplexed high-throughput screening approach, we discovered 4′-ethynyl-2′-deoxycytidine (EdC) as a third-generation anticancer nucleoside prodrug with preferential activity against diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL). EdC requires deoxycytidine kinase (DCK) phosphorylation for its activity and induces replication fork arrest and accumulation of cells in S-phase, indicating it acts as a chain terminator. A 2.1Å cocrystal structure of DCK bound to EdC and UDP reveals how the rigid 4′-alkyne of EdC fits within the active site of DCK. Remarkably, EdC was resistant to cytidine deamination and SAMHD1 metabolism mechanisms and exhibited higher potency against ALL compared with FDA-approved nelarabine. Finally, EdC was highly effective against DLBCL tumors and B-ALL in vivo. These data characterize EdC as a preclinical nucleoside prodrug candidate for DLBCL and ALL.
Abstract ED02-02: The Challenges of Lobular Carcinoma
Authors: King T.
Published: May 2024

Infiltrating lobular carcinoma (ILC) and lobular carcinoma in situ (LCIS) were first described in the1940s by two Memorial Hospital pathologists, Foote and Stewart. They were most intrigued by the infiltrative appearance of these lobular cancers which they described as demonstrating large numbers of isolated, loose or dyscohesive cells of rather uniform size but of varying shape. We now recognize that this dyscohesive growth pattern is the result of loss of a functional e-cadherin protein; a distinguishing feature between ILC and invasive ductal carcinoma (IDC). Several studies comparing clinical features and outcomes between ILC and IDC have generated consistent findings. Lobular cancers are more likely to be ER+, larger, lower grade, less likely to be detected on MMG and more likely to have positive margins at breast conserving surgery (BCS), or to require mastectomy. Yet importantly, if BCS is successful, local recurrence and rates of contralateral breast cancer are equal for ILC and IDC. Although lobular cancers represents only 5-15% of all breast cancer, numerically, if ILC was an independent cancer in women, it would rank as the 6th most common cancer in women. Notably the incidence of ILC rose sharply in the late 80s throughout the 90s, and it has become clear that there is a strong relationship between ILC and hormone replacement therapy. Perhaps the “strongest” risk factor for ILC, is LCIS. Classic LCIS is an incidental finding – there are no pathnogmonic features on breast imaging or gross examination of tissue. On microscopic examination it is often multicentric and bilateral. Although originally considered a precursor to ILC and treated with mastectomy, over the years it was realized that rates of ipsilateral cancer in women who were not treated for LCIS were lower than expected and were quite similar to rates of contralateral breast cancer – and this combined with the fact that only 50% of the cancers were of the lobular phenotype led to a movement to consider LCIS as a high risk lesion. Contemporary data continue to support this management approach as rates of cancer development in women with a diagnosis of LCIS are consistently reported at 1-2% per year and the risk is conferred bilaterally, with a slightly higher representation of ILC in the ipsilateral breast. In this presentation we will review areas of clinical controversy, including the use of MRI, the safety of breast conservation, the role of neoadjuvant chemotherapy and the utility of genomic assays in patients with ILC.

Citation Format: T. King. The Challenges of Lobular Carcinoma [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 ED02-02.
Abstract ED08-02: Next generation therapeutics in hormone positive breast cancer: balancing efficacy and tolerability
Authors: Mayer E.
Published: May 2024

The past several years have brought a wealth of new and emerging novel agents for the management of both early and advanced hormone repcetor positive breast cancer, including inhibitors of PIK3CA, mTOR, AKT, CDK4/6, PARP, as well as oral SERDs. These agents have significantly improved survival outcomes for many patients, but progress may come at the cost of specific and sometimes challeging side effects, whcih may threaten the ability to keep a patient on a therapy that is providing benefit. We will review a spectrum of agents, the expected side effect profiles, and strategies to mitigate toxicity and maximize therapeutic index.

Citation Format: E. Mayer. Next generation therapeutics in hormone positive breast cancer: balancing efficacy and tolerability [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 ED08-02.
Abstract ED09-01: Emerging approaches to targeting pathways using precision medicine in breast cancer
Authors: Radovich M.
Published: May 2024

The past few decades have yielded significant strides forward in the pursuit to extend survival for patients with breast cancer. Much of this success is directly attributed to breakthroughs in the development of targeted therapies intersecting advances in genomic medicine. Despite these achievements, challenges remain, and targeted therapeutic development is still evolving rapidly to offset them. The focus of this educational session is centered around reviewing the latest in targeted therapeutic advancements and precision medicine. Recent advances have centered on novel selective estrogen receptor degraders (SERDs) for advanced ESR1-mutated or endocrine-resistant disease. Antibody-drug conjugates (ADCs) continued to make gains, targeting HER2-positive/low advanced cancers as well as an expanded indications for TROP2-targeted ADCs. New ADCs are also on the horizon leveraging new cell surface targets. Emerging are forward-looking cell-surface methodologies that harness bispecific antibodies and T-cell engagers. Various strategies combining established targeted immunotherapies such as PD-1 and PD-L1 with additional therapies continue. Attempts to target the frequently mutated PI3K pathway have yielded some success, but clinical exploration continues using new approaches that utilize mutation specific inhibitors. Second generation PARP inhibitors have emerged recently and are being explored in a variety of indications with promising early results. Finally, understanding treatment resistance in particular with the use of longitudinal liquid biopsies is fueling further target discovery. Altogether, development in precision medicine is advancing rapidly with advanced genomics, novel targets, and cutting-edge drug modalities.

Citation Format: M. Radovich. Emerging approaches to targeting pathways using precision medicine in 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 ED09-01.
Abstract ED10-02: Identifying Collateral Vulnerabilities in the AKT pathway for Therapeutic Benefit
Authors: Toker A.
Published: May 2024

The PI 3-kinase (PI3K) and AKT signaling pathway plays a critical role in regulating all aspects of normal cellular physiology, and is also frequently deregulated in human pathophysiologies, most evidently in cancer and diabetes. Three AKT isoforms exist in humans encoded by distinct genes (AKT1, AKT2, AKT3), and although originally thought to function redundantly, many studies have shown that AKT isoforms have non-overlapping and unique roles in both normal physiology and disease. Similarly, genetic lesions in the PIK3CA and AKT oncogenes have been described, and many of the genes that contribute to PI3K/AKT pathway activation and also signal termination have been found to be altered in human cancers. Numerous drugs that inhibit PI3K as well AKT have been developed for therapeutic use in patients, and many of these are being evaluated in late-stage clinical trials. During the seminar, I will review the major mechanisms that contribute to AKT hyperactivation in cancer. Genetic lesions in the PI3K/AKT pathway in human cancers will also be discussed, as well as efforts to target this pathway therapeutically, including our recent efforts aimed at developing new AKT degrader compounds. I will further present new studies using CRISPR-based genome wide synthetic lethal screens to identify genes that synergize with PI3K and AKT pathway inhibition to induce a cytotoxic response in TNBC addicted to pathway hyperactivation. I will present studies on genes and mechanisms that represent collateral vulnerabilities to pathway inhibition and our efforts at designing combination therapy strategies for cancer patients with genetic aberrations in the PI3K and AKT pathway.

Citation Format: A. Toker. Identifying Collateral Vulnerabilities in the AKT pathway for Therapeutic Benefit [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 ED10-02.
Abstract PO1-08-03: Using Telehealth to Establish a High Risk Cancer Prevention Clinic over a large Geographic Area
Authors: Purcell Maricel , Reading Teresa , Lee Ginger , Tittensor Jennifer , VanMeter Margaret
Published: May 2024

There are health disparities in breast cancer screening based on urban, rural or frontier geographic designations. For instance, in Utah, the percentage of women who had no mammography in the last two years was 33.5% for urban, 33.8% for rural and 40.4% for frontier designations. Rural women are also diagnosed with breast cancer at later stages. Diagnosing breast cancer at earlier stages leads to improved survival, more affordable care, less toxic treatments, better quality of life and less time away from home and work.

We are presenting the innovative use of telehealth to establish a High Risk Cancer Prevention Clinic to effectively reach a large geographic area and mitigate obstacles to accessing care. The clinic's mission is to identify and care for individuals with increased cancer risk due to familial, genetic and/or high risk lesions. This initiative provides centralized comprehensive evaluation, counseling and screening planning as well as referral for risk-reducing interventions closer to home. With a collaborative approach involving surgical and medical oncology, genetics, radiology and women's health specialists, the teleclinic has successfully served 280 patients since Spring 2022. Recently our health care system has increased significantly in geographic reach due to mergers with other health systems. We think this teleclinic is nimble enough and easily scalable to accommodate caring for increased numbers of patients needing this service.

Citation Format: Maricel Purcell, Teresa Reading, Ginger Lee, Jennifer Tittensor, Margaret VanMeter. Using Telehealth to Establish a High Risk Cancer Prevention Clinic over a large Geographic Area [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 PO1-08-03.
Abstract PO1-08-09: Drynaria fortunie, a nutritional herb for prevention in triple negative breast cancer
Authors: TELANG Nitin , Nair Hareesh , Wong George
Published: May 2024

Study Rationale: The triple negative breast cancer (TNBC) lacks the expression of hormone and growth factor receptors and responds only to anthracycline/taxol-based conventional chemotherapy. Major therapeutic limitations include systemic toxicity and acquired resistance to chemo-therapeutics. Relatively non-toxic nutritional herbs from traditional Chinese medicine (TCM) may represent testable alternatives against TNBC. These herbs effectively target multiple signaling pathways (Yang et al: J. Ethno-pharmacology 264: 113249, 2021). Growth inhibitory efficacy of nutritional herbs in a cellular model for TNBC is associated with downregulation of RB, RAS, PI3K and AKT signaling pathways (Telang et al: Pharmaceuticals 14: 1318, 2021). Drynaria fortunie (DF) is a nutritional herb that is used in many TCM herbal formulations. The present study is designed to examine the effects of DF in a cellular model for TNBC and to identify mechanistic leads for its efficacy. Experimental Model, herbal extract and biomarkers: Estrogen receptor negative, progesterone receptor negative and human epidermal growth factor receptor-2 negative MDA-MB-231 human breast cancer cell line represented a cellular model for TNBC. Non-fractionated aqueous extract from the bark of DF represented the test agent. Cell cycle progression, RB signaling and caspase 3/7 activity represented quantitative end point biomarkers. Study Outcome: Treatment with DF at cytostatic concentrations induced S phase arrest and inhibited RB signaling via downregulated expression of cyclin E, CDK2, pRB and E2F1. DF treatment also induced caspase 3/7 activity, a marker for cellular apoptosis. Collectively, these data provide potential mechanistic leads for anti-proliferative and pro-apoptotic effects of DF in the present model. Conclusion: Present data validate a mechanism-driven experimental approach to prioritize efficacious nutritional herbs as testable alternatives for prevention/therapy of TNBC.

Citation Format: Nitin TELANG, Hareesh Nair, George Wong. Drynaria fortunie, a nutritional herb for prevention 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 PO1-08-09.
Abstract PO1-16-03: GDP-mannose enhances the efficacy of PARP inhibitors and immunotherapy in triple-negative breast cancer
Authors: Xiao Yi , Ding Jiahan , Jiang Yi-Zhou , Shao Zhi-Ming , Di Genhong , Yang Fan , Song Xiaoqing
Published: May 2024

Background: Triple-negative breast cancer (TNBC) patients with high HRD scores benefit from poly (ADP-ribose) polymerase (PARP) inhibitors, while those with low HRD scores still lack therapeutic options. Homologous recombination deficiency (HRD) induction is an effective strategy to broaden the indications of PARP inhibitors. Metabolic reprogramming is a critical feature of TNBC. In this study, we aimed to explore novel metabolic biomarkers for HRD and new strategy for sensitizing PARP inhibitors. Methods: We utilized TNBC metabolomics to systematically evaluate metabolites that were correlated with HRD. A crucial metabolite, GDP-mannose (GDP-M), that impedes homologous recombination repair (HR) and sensitizes PARP inhibitors was identified and functionally validated. We further explored the detailed mechanism and proposed a potential treatment strategy utilizing GDP-M for TNBC in preclinical models. Results: Systematic metabolomic analysis revealed that GDP-mannose (GDP-M) was significantly enriched in basal-like tumors with HRD. GDP-M promoted cisplatin-induced DNA double-strand breaks by inducing HRD. Mechanistically, the low expression of the upstream enzyme GMPPA led to the endogenous upregulation of GDP-M, which further promoted the ubiquitin-mediated degradation of BRCA2 to inhibit HR. GMPPA expression and GDP-M could serve as predictive biomarkers for HRD and the response to PARP inhibitors. Therapeutically, we validated that the combination of GDP-M and PARP inhibitors synergistically inhibit tumor growth in multiple preclinical models. Moreover, GDP-M supplementation plus PARP inhibition activated STING-dependent antitumor immunity and further augmented the efficacy of anti-PD-1 antibodies. Conclusions: GDP-M promotes the degradation of BRCA2 and thus enhances the sensitivity of PARP inhibitors in TNBC. The combination of GDP-M, PARP inhibitors and anti-PD-1 immunotherapy may be a potential treatment strategy for HRD-low TNBC.

Citation Format: Yi Xiao, Jiahan Ding, Yi-Zhou Jiang, Zhi-Ming Shao, Genhong Di, Fan Yang, Xiaoqing Song. GDP-mannose enhances the efficacy of PARP inhibitors and immunotherapy 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 PO1-16-03.
Abstract PO1-17-03: Real-world evidence of Trastuzumab biosimilars in HER2-positive breast cancer: Evaluating utilization, efficacy, and safety in Taiwan
Authors: Lo Yi-Hung , Tzeng Yen-Dun
Published: May 2024

Purpose

Biosimilars have emerged as a promising alternative to reference biologic products for the treatment of cancers and immunological diseases. With regard to breast cancer, trastuzumab, a reference monoclonal antibody biologic, has been the standard of care for early and advanced HER2-positive breast cancer since 1998. Trastuzumab biosimilars, which provide comparable efficacy at a lower cost, have the potential to reduce financial burden on patients and healthcare systems and improve patient access to HER2-targeted therapy. This study aimed to evaluate the utilization, efficacy, and safety of trastuzumab biosimilars in HER2-positive breast cancer patients at Kaohsiung Veterans General Hospital. Methods

A total of 113 HER2-positive breast cancer patients were enrolled between February 2020 and December 2022 and treated with trastuzumab biosimilars (OGIVRI®, trastuzumab-dkst). Of these, 44 were in the neoadjuvant group, 27 in the adjuvant group, and 42 in the metastatic group. Clinical outcomes were evaluated, including pathological complete response (pCR) rate in the neoadjuvant group, objective response rate (ORR) and clinical benefit rate (CBR) in the metastatic group, and safety profile in all groups. Results

In the neoadjuvant group, 18 out of 44 evaluable patients achieved pathological complete response after surgery, resulting in a pCR rate of 40.90%. In the metastatic group , the ORR was 57.14% and the CBR was 90.47%. Furthermore, in the metastatic group, treatment with dual blockade using biosimilars resulted in an better ORR of 62.96%. No adverse events of cardiac toxicity were reported in any group. In the adjuvant group, longer follow-up is needed to assess efficacy. Conclusions

Our real-world experience suggests that trastuzumab biosimilars are a safe and cost-effective alternative to reference trastuzumab in the treatment of HER2-positive breast cancer. Biosimilar trastuzumab demonstrated efficacy in the neoadjuvant setting, while dual blockade with biosimilars resulted in better disease control in the metastatic setting. Further follow-up is necessary to evaluate the efficacy of trastuzumab biosimilars in the adjuvant setting.

Citation Format: Yi-Hung Lo, Yen-Dun Tzeng. Real-world evidence of Trastuzumab biosimilars in HER2-positive breast cancer: Evaluating utilization, efficacy, and safety in Taiwan [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 PO1-17-03.
Abstract PO1-24-02: Enhancement of TGF-β Receptor Inhibitor Efficacy through CD44 Suppression in Claudin-low Breast Cancer
Authors: Matsunuma Ryoichi , Imada Sae , Sato Shoko , Hayami Ryosuke , Tsuneizumi Michiko
Published: May 2024

Introduction:

Claudin-low breast cancer is mostly classified as triple-negative breast cancer and is known to possess cancer stem cell properties with high expression of epithelial-to-mesenchymal transition (EMT) markers. However, specific therapeutic targets for this subtype have not yet been identified. While reports suggest that inhibition of EMT using EMT inhibitors can suppress cell and tumor proliferation, monotherapy may not be sufficient. The expression of CD44, a surface marker of cancer stem cells, has been reported to be involved in multiple signaling pathways, promoting cancer growth and invasion. In this study, we focus on CD44 and the TGF-β receptor, which is involved in EMT, to investigate the effect of inhibiting TGF-β receptor through CD44 inhibition in Claudin-low breast cancer and validate its potential as an effective treatment.

Methods:

SUM159 and MDA-MB-231 cell lines were used as Claudin-low breast cancer cell models. CD44 knockdown cells were established to examine the effects of TGF-β receptor inhibition and downstream signaling.

Results:

CD44 knockdown did not affect the expression of TGF-β receptor. Both SUM159 and MDA-MB-231 cells showed comparable cell growth inhibition through CD44 knockdown and TGF-β receptor inhibition, with enhanced effects observed in CD44 knockdown cells in response to TGF-β receptor inhibition. Furthermore, CD44 knockdown combined with TGF-β receptor inhibition significantly reduced the expression of Smad2/3.

Conclusion:

In Claudin-low breast cancer cells, CD44 knockdown enhances the effectiveness of TGF-β receptor inhibition and significantly influences the expression level of Smad2/3.

Citation Format: Ryoichi Matsunuma, Sae Imada, Shoko Sato, Ryosuke Hayami, Michiko Tsuneizumi. Enhancement of TGF-β Receptor Inhibitor Efficacy through CD44 Suppression in Claudin-low 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 PO1-24-02.
Abstract PO2-01-10: 21-Gene Recurrence Score Index (ONCOTYPE DX) as a predictive biomarker for neoadjuvant chemotherapy response and outcome in patients with HR+HER2- breast cancer
Authors: Cudós Ariadna Gasol , Murillo Serafin Morales , Der-Abrain Noemí Tuset , Villellas Felip Vilardell , Cid Laura Arbones , Olivé Jordi Melé , Morales Carles Canosa
Published: May 2024

Background: Hormone receptor positive (HR+), HER2- early stage breast cancer (EBC) has shown lower response to neoadjuvant chemotherapy (NCT) compared with other clinicopathologic subtypes. ONCOTYPE DX may help inform systemic treatment decisions for EBC and predicting likelihood of pathological complete response (pCR) or chemosensitivity. We analyze the pathologic response according ONCOTYPE RS and their prognostic value.

Methods: We included a serie of 139 consecutive patients with high clinical risk factor with criteria to received NCT than have performed an ONCOTYPE DX test previous to start NCT. The median age was 51 years with 65 patients (47%) less than 50 years. Median initial tumoral size was 25 mm (9-97), T1: 35%, T2: 51% and T3: 14%. 70 patients (50%) have initial axillary node involvement. Median ONCOTYPE DX score was 29 (12 – 76) , RS < 25 in 36% and RS < 30 in 54%. Complete pathologic response (pCR) was found in 35 patients (25%), and by RCB was: RCB:0 23%, RCB-1 18%, RCB-2 24% and RCB-3 34%.

Results: pCR score was correlated with ONCOTYPE DX (pearson : p:0,001) , patients with ONCOTYPE RS score superior to 30 has a total of 37% of pCR in contrast to a 14% in patients with ONCOTYPE RS score less than 30. Median follow-up was 32 months (5 -100). The rate of recurrence was similar independently the ONCOTYPE RS score (12% < 30 ; 15% >30) , but patients with ONCOTYPE RS < 30 with achieve pCR had better prognostic compared to patients that not achieve pCR (0% vs 14%). Patients with ONCOTYPE RS > 30 tumors that had a pCR the recurrence rate was 8% compared to 20% in patients with non pCR.

Conclusions: These data suggest ONCOTYPE DX predicts pCR in HR+HER2- BC patients, especially in patients with a RS superior to 30 with an high rate of pCR of 37%. Patients with ONCOTYPE DX less than 30 that achieved pCR had the better outcomes and patients with ONCOTYPE DX superior to 30 that not achieved pCR had the worst outcomes with a total of 20% of recurrence. ONCOTYPE DX predicts the possibility of achieve a pCR and patients with a high ONCOTYPE DX RS score with residual disease have a high recurrence despite receiving treatment with chemotherapy, which requires a better adjuvant treatment, possibly with CDK 4/6 cyclin inhibitors.

Citation Format: Ariadna Gasol Cudós, Serafin Morales Murillo, Noemí Tuset Der-Abrain, Felip Vilardell Villellas, Laura Arbones Cid, Jordi Melé Olivé, Carles Canosa Morales. 21-Gene Recurrence Score Index (ONCOTYPE DX) as a predictive biomarker for neoadjuvant chemotherapy response and outcome in patients with 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 PO2-01-10.
Abstract PO2-05-06: Palbociclib in advanced hormone receptor positive breast cancer: A real world study in South America
Authors: SÁNCHEZ Cesar , Samtani Suraj , Gómez Henry , Falcon-Lizaraso Silvia , Muñoz René , Soria Tannia
Published: May 2024

BACKGROUND: First-line combined endocrine therapy is the standard of care for hormone receptor-positive (HR+) human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC). Palbociclib, in combination with aromatase inhibitors or fulvestrant, is a treatment option for HR+/HER2-negative ABC patients. We aimed to analyze the real-world experience of palbociclib in this setting in South America.

METHODS: Real-world study collecting sociodemographic and clinical data from women with ABC treated with palbociclib in centers from Chile (n = 40), Perú (n = 61), and Ecuador (n = 10). Treatment efficacy and safety were analyzed.

RESULTS: The median age was 54 years (range: 28 – 83), and 81.1% of women had received previous treatment: adjuvant therapy (20.0%), ABC treatment (31.1%), or both (48.9%). The median duration of palbociclib treatment was 14 months (range: 1 – 57), with differences among countries (longer in Perú; p = 0.009). The dose was reduced in 28.2% of women and only 6.5% returned to the previous one. Most women (97.3%) received combined endocrine therapy, letrozole (48.1%) or fulvestrant (44.4%), with differences between countries (p < 0.001). Palbociclib was usually the first-line therapy in Ecuador (60.0%) and Perú (80.3%), and the third line in Chile (37.5%). Considering all women, it was the first- or second-line therapy for 52.3% and 20.7% of them, respectively. The overall response rate was 34.2% and progressive disease was significantly lower in patients receiving first-line palbociclib (25.9 vs. 66.0%, p < 0.001). The disease-free survival was longer than 12 months in 67.2% of patients treated with first-line palbociclib. Regarding safety, 38.7% of women had any relevant adverse event (AE) during the treatment, most frequently neutropenia (39.5%), diarrhea (9.3%), and elevated transaminase levels (4.7%). The number of patients who developed any relevant AE was lower among the first-line treated patients (19.0% vs. 60.4%, p< 0.001).

CONCLUSION: The study reflects differences among countries in routine palbociclib use. But considering all data, palbociclib has confirmed its efficacy and safety, supporting its use in HR+/HER2-negative patients, especially as a first-line therapy.

Citation Format: Cesar SÁNCHEZ, Suraj Samtani, Henry Gómez, Silvia Falcon-Lizaraso, René Muñoz, Tannia Soria. Palbociclib in advanced hormone receptor positive breast cancer: A real world study in South America [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 PO2-05-06.
Abstract PO2-06-05: Neutrophil-to-lymphocyte ratio (NLR) Predict the Outcome Significance for Primary Tumor Surgery in Patients with De novo stage Ⅳ Breast Cancer
Authors: Sugihara Rie , Toh Uhi , Watanabe Hidetaka , Katagiri Yuriko , Matsushima Shuntaro , Mina Okabe , Takao Yuko , Iwakuma Nobutaka , Fujita Fumihiko
Published: May 2024

[Background] Although several prospective randomized trials have not shown a statistically significant difference in overall survival(OS),and quality-of-life(QOL) for the primary tumor surgery(PTS) of De novo stageⅣ breast cancer(BC), but more recent studies showed that could prolong OS in selected cases. This study respectively evaluated the value of neutrophil-to-lymphocyte ratio(NLR) as a biomarker for predicting the benefit of PTS in patients(pts) with stageⅣ BC.

[Method] The clinical outcome and associated prognostic factors of pts with De novo stageⅣ BC were investigated. The decision of surgery option for primary tumor was shared with pts and determined by treating physicians according to the clinical symptoms. Laboratory blood examinations were performed before and after surgery or each treatment courses. The kinetics of peripheral blood lymph cell counts, NLR etc. were analyzed simultaneously.

[Result] A total of 141 pts with stageⅣ BC were treated and enrolled from January 2004 to December 2022. 61 pts (Surgery group: SG) received and 80 pts (Non surgery group: NSG) not received PTS. The biological subtypes of primary BC included that 76 HR+(Luminal), 13 HR+Her2+(Luminal Her2), 29 Her2+ and 21 triple negative, respectively. The median PFS of SG and NSG were 88 ms and 30.3 ms, the median OS were 100.1 ms and 31.8 ms, respectively. Pts of SG who had high NLR ( >3) before the surgery showed a significant worse OS (p= < 0.0001)( Fig.1). And pts who responded to the systemic therapies prior to PTS for longer than 8.1 months showed a better OS(p=0.044). In contrast, pts of NSG who had a low ALC(≦1500/μL) at 6 months(p=0.026) and 1 year(p=0.007) after systemic therapies, and high NLR( >3) at 1 year(p=0001) had worse prognosis.

[Summary] Our results suggested that pts with De novo stageⅣ BC who responded to the systemic therapies prior to PTS longer than 8.1 months, and who had a preoperative low NLR(≦3) might be benefit to PTS after the systemic therapies. And peripheral blood NLR before surgery may be a predictive marker for the indication of PTS in those pts. Further larger scale prospective studies are warranted.

Citation Format: Rie Sugihara, Uhi Toh, Hidetaka Watanabe, Yuriko Katagiri, Shuntaro Matsushima, Okabe Mina, Yuko Takao, Nobutaka Iwakuma, Fumihiko Fujita. Neutrophil-to-lymphocyte ratio (NLR) Predict the Outcome Significance for Primary Tumor Surgery in Patients with De novo stage Ⅳ 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 PO2-06-05.
Abstract PO2-08-10: Effect of 6 months of bazedoxifene + conjugated estrogens on body composition and insulin resistance
Authors: Fabian Carol , Zelenchuk Adrian , Powers Kandy , Kreutzjans Amy , Pittman Krystal , Hendry Bill , Altman Christy , Giles Erin , Cook Katherine L. , Hursting Stephen , Kimler Bruce
Published: May 2024

Menopause transition is often marked by an acceleration of visceral fat accumulation. Excess visceral fat is associated with insulin resistance and increased risk for breast cancer as well as heart disease and diabetes. We measured change in body composition (via iDXA), fasting insulin and glucose as part of an ongoing, Phase IIB trial (NCT04821141) of 6 months of bazedoxifene (BZA) + conjugated estrogen (CE) vs control with primary endpoints of change in mammographic density and breast tissue Ki-67. Participants are women ages 45-60 with vasomotor symptoms at increased risk for development of breast cancer. Methods: Visceral and total fat, lean, and total mass, were measured with iDXA (GE CoreScan™). Fasting plasma was assayed same day as drawn for total insulin using a chemiluminescence assay and glucose using a hexokinase method. Values generated were used to calculate HOMA IR (as a measure of insulin resistance) using the formula insulin µl/ml x glucose mg/dl/405. HOMA %S was calculated as 1/HOMA IR X100 as a measure of insulin sensitivity. Optimal HOMA IR is considered as ≤1; HOMA IR >1.5 is considered abnormal with >2.0 as evidence of insulin resistance. Optimal HOMA %S is 100%. Results: 24 women (12 BZA+CE, 12 Control) have completed baseline and 6-month body composition and insulin resistance assessments. Women randomized to BZA+CE were more likely to experience reduction in insulin resistance and improved insulin sensitivity despite a small weight gain over the initial 6 months. 7/12 randomized to BZA+CE had ≥15% reduction in HOMA IR vs only 2/12 controls. Three participants had HOMA IR >2 at baseline. Of these, one was randomized to BZA+CE and had a normal HOMA IR value at 6 months. The remaining two women were in the control group and saw no improvement in HOMA IR at 6 months. In addition, one woman randomized to control with normal HOMA-IR at baseline had HOMA IR > 2 at 6 months. Next Steps: The improvements in insulin resistance parameters with BZA+CE are similar to those observed in our rodent studies, supporting this combination as promising for use in breast cancer risk reduction in women with vasomotor symptoms at high-risk for metabolic disease.

Citation Format: Carol Fabian, Adrian Zelenchuk, Kandy Powers, Amy Kreutzjans, Krystal Pittman, Bill Hendry, Christy Altman, Erin Giles, Katherine L. Cook, Stephen Hursting, Bruce Kimler. Effect of 6 months of bazedoxifene + conjugated estrogens on body composition and insulin resistance [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 PO2-08-10.
Abstract PO2-10-06: The Rising Burden of Contraception Requirements in Breast Cancer Clinical Trials: Time for Change?
Authors: Chiodi Camila , Hamid Munzir , Weadick Catherine , Hennessy Maeve , Martin-Quesada Ana , Kenny Louise , Lambertini Matteo , Luis Ines Vaz , O'Reilly Seamus
Published: May 2024

Background: Breast cancer clinical trials often involve therapies with potentially deleterious effects on the fetus and the baby in the event of pregnancy or breastfeeding. Consequently, eligibility criteria include contraceptive requirements for both the patient and their partner. Patient feedback on the burden of requirements in clinical trials prompted an evaluation of changes in contraceptive requirements in breast cancer clinical trials over the past two decades.

Methods: Breast cancer ClinicalTrials.gov trials protocols over three periods of enrollment were reviewed: 01/01/2001 - 01/01/2002, 01/01/2011 - 01/01/2012, and 01/01/2021 - 01/01/2022. Inclusion criteria: 1. Interventional studies including (neo)adjuvant or palliative systemic therapy, 2. Premenopausal female patients. Data, including the required number, types, and duration of contraceptive strategies, treatment regimen, and study design, were collated. A descriptive analysis by time period was performed.

Results: 305 studies were included from the three periods: 63 (2001), 127 (2011), and 115 (2021). Of these, contraception requirements were specified in ClinicalTrial.gov protocol information in 4, 61, and 71 CT for 2001, 2011, and 2021, respectively, limiting our analyses in the two later periods. Complete data is available in Table 1.

Conclusions: Our data demonstrates a time trend towards more stringent contraception requirements in breast cancer clinical trials inclusion criteria. The impact of contraception burden on enrollment, patient compliance, and investigator insight warrants further assessment.

Citation Format: Camila Chiodi, Munzir Hamid, Catherine Weadick, Maeve Hennessy, Ana Martin-Quesada, Louise Kenny, Matteo Lambertini, Ines Vaz Luis, Seamus O'Reilly. The Rising Burden of Contraception Requirements in Breast Cancer Clinical Trials: Time for Change? [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 PO2-10-06.
Abstract PO2-12-11: Ocular Toxicity of Tamoxifen in Patients with Breast Cancer
Authors: Alhouz Husain , Azmeh Arwa , Saifo Maher
Published: May 2024

Background: The latest recommendations in breast cancer treatment protocols with tamoxifen indicate that it should be used from five to 10 years. It depends mainly on the cumulative dose of the drug in the body. Despite its multiplicity, the various studies conducted on this subject did not reach conclusive results. Objectives: This research aims to study retinopathy associated with hormonal treatment of breast cancer using tamoxifen. Methods: A cross-sectional study was conducted at Al-Mouwasat University Hospital on a sample of 130 eyes according to (G-Power) with a statistical power of 95%. The participants were briefed on the research and consented on the ethical considerations. Then, the patients who entered the study were interrogated, clinically examined, and were asked about their medical history, the time of breast cancer diagnosis along with the details about the treatment protocols they underwent or currently undergoing. The refractive errors were measured with an automatic refractive device, then they were examined on the slit lamp to investigate the refractory media, then the corrected and uncorrected visual acuity were taken. Finally, after ensuring that the inclusion criteria were met and excluding those who fulfil one or more of the exclusion criteria, optical coherence tomography was performed using SD-OCT technique to measure and review the retinal thickness map in circles of 1-3-6 mm, respectively, to notice possible changes on it. Results: We found that the use of tamoxifen irrespective to cumulative dose leads to increase in the macula thickness values in the upper and lower sectors within the 3 mm circle, and to significant decrease in the macula thickness values in the upper and lower sectors within the 6 mm circle, in addition to decrease in nasal sector thickness within the circles of 3 and 6 mm. Conclusion: We conclude that the difference between people treated with tamoxifen and those not treated with it is not limited to the occurrence of crystals deposition in the macular area or the presence of a cavity in the central macula (with or without typical cystic macular edema), but rather to existence of macula thickness differences unrelated to the cumulative dose of the drug, whether by increase or decrease in thickness of the upper, lower and nasal segments.

Citation Format: Husain Alhouz, Arwa Azmeh, Maher Saifo. Ocular Toxicity of Tamoxifen 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 PO2-12-11.