bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiplexed Imaging Mass Cytometry Analysis Characterizes the Vascular Niche in Pancreatic Cancer
Authors: Sussman Jonathan H. , Kim Nathalia , Kemp Samantha B. , Traum Daniel , Katsuda Takeshi , Kahn Benjamin M. , Xu Jason , Kim Il-Kyu , Eskandarian Cody , Delman Devora , Beatty Gregory L. , Kaestner Klaus H. , Simpson Amber L. , Stanger Ben Z. 
Published: May 2024

Abstract
Oncogenesis and progression of pancreatic ductal adenocarcinoma (PDAC) are driven by complex interactions between the neoplastic component and the tumor microenvironment, which includes immune, stromal, and parenchymal cells. In particular, most PDACs are characterized by a hypovascular and hypoxic environment that alters tumor cell behavior and limits the efficacy of chemotherapy and immunotherapy. Characterization of the spatial features of the vascular niche could advance our understanding of inter- and intratumoral heterogeneity in PDAC. In this study, we investigated the vascular microenvironment of PDAC by applying imaging mass cytometry using a 26-antibody panel on 35 regions of interest across 9 patients, capturing more than 140,000 single cells. The approach distinguished major cell types, including multiple populations of lymphoid and myeloid cells, endocrine cells, ductal cells, stromal cells, and endothelial cells. Evaluation of cellular neighborhoods identified 10 distinct spatial domains, including multiple immune and tumor-enriched environments as well as the vascular niche. Focused analysis revealed differential interactions between immune populations and the vasculature and identified distinct spatial domains wherein tumor cell proliferation occurs. Importantly, the vascular niche was closely associated with a population of CD44-expressing macrophages enriched for a proangiogenic gene signature. Taken together, this study provides insights into the spatial heterogeneity of PDAC and suggests a role for CD44-expressing macrophages in shaping the vascular niche.
Significance: Imaging mass cytometry revealed that pancreatic ductal cancers are composed of 10 distinct cellular neighborhoods, including a vascular niche enriched for macrophages expressing high levels of CD44 and a proangiogenic gene signature.
Minimal Residual Disease using a Plasma-Only Circulating Tumor DNA Assay to Predict Recurrence of Metastatic Colorectal Cancer Following Curative Intent Treatment
Authors: Parikh Aparna R. , Chee Bryant H. , Tsai Jill , Rich Thereasa A. , Price Kristin S. , Patel Sonia A. , Zhang Li , Ibrahim Faaiz , Esquivel Mikaela , Van Seventer Emily E. , Jarnagin Joy X. , Raymond Victoria M. , Corvera Carlos U. , Hirose Kenzo , Nakakura Eric K. , Corcoran Ryan B. , Van Loon Katherine , Atreya Chloe E. 
Published: May 2024

Abstract

Purpose:
Minimal residual disease (MRD) detection can identify the recurrence in patients with colorectal cancer (CRC) following definitive treatment. We evaluated a plasma-only MRD assay to predict recurrence and survival in patients with metastatic CRC who underwent curative intent procedures (surgery and/or radiotherapy), with or without (neo)adjuvant chemotherapy. The primary objective of this study was to assess the correlation of postprocedure tumor cell–free DNA detection status with radiographic disease recurrence.

Experimental Design:
Preprocedure and postprocedure longitudinal samples were collected from 53 patients and analyzed with a multiomic MRD assay detecting circulating tumor DNA (ctDNA) from genomic and epigenomic signals. Preprocedure and postprocedure ctDNA detection correlated with recurrence-free and overall survival (OS).

Results:
From 52 patients, 230/233 samples were successfully analyzed. At the time of data cutoff, 36 (69.2%) patients recurred with median follow-up of 31 months. Detectable ctDNA was observed in 19/42 patients (45.2%) with ctDNA analyzed 3 weeks postprocedure. ctDNA detection 3 weeks postprocedure was associated with shorter median recurrence-free survival (RFS; HR, 5.27; 95% CI, 2.31–12.0; P &lt; 0.0001) and OS (HR, 12.83; 95% CI, 3.6–45.9; P &lt; 0.0001). Preprocedure ctDNA detection status was not associated with RFS but was associated with improved OS (HR, 4.65; 95% CI, 1.4–15.2; P = 0.0111). Undetectable ctDNA preprocedure had notable long-term OS, &gt;90% 3 years postprocedure.

Conclusions:
In this cohort of oligometastatic CRC, detection of ctDNA preprocedure or postprocedure was associated with inferior outcomes even after accounting for known prognostic clinicopathologic variables. This suggests ctDNA may enhance current risk stratification methods helping the evaluation of novel treatments and surveillance strategies toward improving patient outcomes.
The Vedotin Antibody–Drug Conjugate Payload Drives Platform-Based Nonclinical Safety and Pharmacokinetic Profiles
Authors: Neff-LaFord Haley D. , Carratt Sarah A. , Carosino Christopher , Everds Nancy , Cardinal Kristen A. , Duniho Steven , Schutten Melissa M. , Frantz Christopher , Zuch de Zafra Christina , Harstad Eric B. 
Published: May 2024

Abstract
Nonclinical safety and pharmacokinetic data for monomethyl auristatin E (MMAE) and 14 vedotin antibody–drug conjugates (ADC) were evaluated to determine patterns of toxicity, consistency of pharmacokinetic results, and species differences between rats and monkeys. Most nonclinical toxicities were antigen-independent, common across ADCs, and included hematologic, lymphoid, and reproductive toxicity related to MMAE pharmacology. Hematologic toxicity was the dose-limiting toxicity (DLT) or predominant toxicity for the majority of vedotin ADCs in both species. Tissue expression of the targeted antigen of an ADC rarely correlated with DLT; only two ADCs had antigen-dependent skin DLTs. For two additional ADCs, antigen-dependent delivery of MMAE in the bone marrow may have exacerbated the antigen-independent hematologic DLT. The highest tolerated doses and pharmacokinetics were similar within a given species, with rats tolerating higher doses than monkeys. Studies longer than 1 month in duration detected the same or fewer toxicities than 1-month studies and had no additional findings that affected the human risk assessment. These data support opportunities to streamline ADC toxicity assessments without compromising human starting dose selection or target organ identification.
Abstract ED01-01: Optimizing endocrine therapy in premenopausal women
Authors: Stearns V. 
Published: May 2024

Abstract
Premenopausal women with early-stage hormone receptor (HR)-positive breast cancer are candidates for adjuvant endocrine therapy and have several treatment options. The clinical team should assess an individual woman’s risk of recurrence, estimate benefits from specific endocrine manipulations, and consider co-morbidities, adverse event profile and host factors. Risk stratification strategies including clinic-pathologic features, genomic assays and composite scores can guide recommendations regarding type and duration of endocrine therapy, in particular in node-negative disease. Adjuvant tamoxifen for 5 to 10 years significantly reduces breast cancer recurrence and death. Premenopausal women who are at high risk of recurrence benefit from ovarian function suppression (OFS) with tamoxifen or an aromatase inhibitor for 5 years. Those include women with high-risk clinico-pathological features and younger age, and for whom chemotherapy is commonly recommended. There are currently no available data regarding the use of extended OFS beyond 5 years. Newer data support the addition of CDK 4/6 inhibitors to endocrine therapy in women with high-risk disease. Endocrine therpay is associated with frequent bothersome and few significant side effects that can negatively impact quality of life and adherence to treatment. Clinicians must carefully weigh the benefits associated with specific endocrine therapies, and possible short- and long-term side effects to individualize therapy, and to consider interventions to enhance adherence.
Citation Format: V. Stearns. Optimizing endocrine therapy in premenopausal women [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 ED01-01.
Abstract ED07-03: Novel Systemic Therapy Strategies for HER2+ Brain Metastases
Authors: Sammons S. 
Published: May 2024

Abstract
More than 1/3 of patients with HER2+ metastatic breast cancer will develop brain metastases. Local therapies such as resection or radiation therapy continue to play a pivotal role in brain metastases treatment. However, receipt of HER2-directed systemic therapies lead to significant survival advances for both stable and active brain metastases and are integral to optimal outcomes. We will review clinical goals for stable and active brain metastases. In the last few years, novel early line systemic therapy regimens have improved outcomes for HER2+ brain metastases which will be reviewed. We will review evolving evidence that Antibody Drug Conjugates targeting HER2 have robust intracranial activity. We will review exciting HER2 directed tyrosine kinase inhibitors and combinations.
Citation Format: S. Sammons. Novel Systemic Therapy Strategies for HER2+ Brain Metastases [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr ED07-03.
Abstract PO1-04-06: Exposure-response analyses of sacituzumab govitecan efficacy and safety in patients with metastatic breast cancer
Authors: Singh Indrajeet , Sathe Abhishek , Diderichsen Paul , Witjes Han , Van Schanke Arne , Maringwa John , Verret Wendy , Girish Sandhya , Othman Ahmed 
Published: May 2024

Abstract
Background: Sacituzumab govitecan (SG) is an antibody-drug conjugate that is composed of an anti Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolysable CL2A linker. SG (10 mg/kg on D1 and D8 of every 21D cycle) is approved for patients (pts) with metastatic triple-negative breast cancer (mTNBC) who received ≥2 prior systemic therapies (≥1 in the metastatic setting). The relationship between exposure of SG, free SN-38, and total antibody (tAB) following SG administration and its efficacy and safety were evaluated in pts with HR+/HER2‒ metastatic breast cancer (mBC) and all pts with mBC (mTNBC or HR+/HER2‒ mBC), respectively. Methods: Available exposure and efficacy outcomes from HR+/HER2‒ mBC pts from phase 3 study TROPiCS-02 (n=260) and safety outcomes from mBC pts in phase 1/2 study IMMU-132-01, phase 3 study ASCENT and TROPiCS-02 (total n=569) were analyzed. Exposure-response (ER) models were developed to characterize the relationship between exposure and efficacy (complete response [CR], overall response rate [ORR], clinical benefit rate [CBR], overall survival [OS] and progression-free survival [PFS]) and safety (adverse events [AEs] of vomiting, diarrhea, hypersensitivity reactions, nausea, neutropenia, febrile neutropenia, time to first dose reduction and first dose delay) endpoints. Exposure metrics of SG, free SN-38, and tAB were evaluated as predictors and effect of clinically relevant covariates was characterized within the modeling framework. Results: Average SG-related serum exposures over the duration of treatment (until the event) were associated with significantly increased efficacy (probability of CR, ORR, CBR and longer OS and PFS) and safety events (probability of any grade AE). Neutropenia was the only AE where the increase in exposure was significantly associated with the increased probability of Grade ≥3 and Grade 4 events. Baseline Trop-2 expression level was not correlated with assessed efficacy and safety endpoints. Conclusions: Within the exposure range achieved with the 10 mg/kg regimen, higher exposure values were associated with a higher probability of achieving better efficacy. The 10 mg/kg SG dose achieved an acceptable balance between efficacy and safety which supports the appropriateness of this regimen in pts with HR+/HER2‒ mBC.
Citation Format: Indrajeet Singh, Abhishek Sathe, Paul Diderichsen, Han Witjes, Arne Van Schanke, John Maringwa, Wendy Verret, Sandhya Girish, Ahmed Othman. Exposure-response analyses of sacituzumab govitecan efficacy and safety in patients with 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 PO1-04-06.
Abstract PO1-14-03: Discovery of proliferation essential gene signature and ACTL6A as potential biomarker for predicting prognosis and neoadjuvant therapy response in triple-positive breast cancer
Authors: Li Xiaofen , Fu Wenfen , Luo Shiping , Zhang Jie , Wang Qingshui , Song Chuangui 
Published: May 2024

Abstract
Background: Based on the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), a special subtype of breast cancer which expresses all three receptors can be distinguished, namely triple-positive breast cancer (TPBC). TPBC patients has a higher risk of recurrence and lower survival rate compared to other luminal breast cancers. However, there are few studies on predicting molecules of prognosis and treatment response for TPBC. Methods: Proliferation essential genes (PEGs) were identified using CRISPR-Cas9 dataset of DepMap. The expression profiles and clinical data of TPBC were obtained from the TCGA database, GEO datasets and our center cohort. To develop a TPBC-PEG prognostic signature, cox regression and Lasso (Least absolute shrinkage and selection operator) regression analysis were applied. Functional analysis was performed using Gene Set Enrichment analysis. Finally, the relationship between candidate genes and neoadjuvant therapy (NAT) sensitivity was explored using real-time qPCR (RT-qPCR) and immunohistochemistry (IHC) based on clinical samples. Results: Among 900 TPBC-PEGs, 437 genes showed significant differential expression between TPBC and normal tissues. Subsequently, we identified 3 prognostic PEGs (ACTL6A, CCT2, TARS) and used them to construct a PEG signature. Patients with high PEG signature scores exhibited worse overall survival and lower sensitivity to NAT compared to those with low PEG signature scores. RT-qPCR indicated that in patients who lacked sensitivity to NAT, ACTL6A and CCT2 were significantly upregulated. The IHC results showed that ACTL6A protein was highly expressed in the NAT-insensitive group and non-pathological complete response patients. Conclusion: In this study, we developed an efficient PEG prognostic model that can predict the outcome for TPBC. Furthermore, we found that the expression of ACTL6A is associated with neoadjuvant therapy sensitivity in TPBC patients and can serve as an important factor in predicting patient prognosis and drug sensitivity.
Figure 3. Construction and validation of a PEG signature for TPBC patients.
Figure 6. The predictive value of ACTL6A on NAT efficacy and its correlation with clinical characteristics.
Citation Format: Xiaofen Li, Wenfen Fu, Shiping Luo, Jie Zhang, Qingshui Wang, Chuangui Song. Discovery of proliferation essential gene signature and ACTL6A as potential biomarker for predicting prognosis and neoadjuvant therapy response in triple-positive 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 PO1-14-03.
Abstract PO1-25-07: Obesity, breast cancer, and adipose-derived mesenchymal stem/stromal cells: The complex cross-signaling in the tumor microenvironment
Authors: Ritter Andreas , Solbach Christine , Yuan Juping 
Published: May 2024

Abstract
Objective:
Breast cancer is the most frequently diagnosed cancer and a common cause of cancer related death in women. The breast cancer microenvironment (TME) is mainly composed of adipose tissue, consisting of adipocytes, adipose-derived mesenchymal stem/stromal cells (bASCs) and immune cells. Interestingly, it is well recognized that obesity, as indicated by increased body mass index (BMI≥30), is associated with an enhanced risk of more aggressive breast cancer (BC) as well as reduced patient survival. Therefore, we asked how BC affects the biological functionality of bASC, how obesity fuels this process, and on the other hand how these cells influence BC cells.
Methods:
Multiple molecular biological approaches as transcriptomic profiling and diverse functional assays were conducted to characterize at least 5 lean and obese patients derived bASCs samples near the TME (lean/obese-aT) or distant (lean/obese-dT). Afterwards, these cells were used to investigate the interaction with BC cells in 2-dimensional and 3-dimensional cell culture experiments. Moreover, immunohistological analyses were conducted in 16 lean and 16 obese breast cancer patients (grade 3-4).
Results:
The TME shifts bASCs towards cancer supporting phenotypes into an inflammatory cancer-associated phenotype, whereas ob-aT bASCs are prone to be cancer-educated into a myofibroblastic phenotype with a significant deregulated gene expression, cytokine/chemokine secretion, and reduced differentiation capacity. In corroberation, these BMI dependent de-differentiation processes could be confirmed in breast cancer tissue. Moreover, the cell-cell interaction of BC cells with aT-bASCs increased their proliferation, motility, and chemoresistance.
Conclusions:
The study found multiple pathways deregulated in bASCs associated with tumor promoting effects. Additionally, it revealed the role of aT-bASCs in promoting breast cancer progression on a functional and molecular level.
Citation Format: Andreas Ritter, Christine Solbach, Juping Yuan. Obesity, breast cancer, and adipose-derived mesenchymal stem/stromal cells: The complex cross-signaling in the tumor microenvironment [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 PO1-25-07.
Abstract PO2-08-04: Unraveling alterations in the pre-neoplastic breast microenvironment of BRCA1/2 mutation carriers using spatial transcriptomics
Authors: Karaayvaz Mihriban , Caputo Anthony , Vipparthi Kavya , Bazeley Peter , Downs-Kelly Erinn , McIntire Patrick , Ni Ying , Hu Bo , Keri Ruth 
Published: May 2024

Abstract
Breast cancer is the most common cancer in females, affecting one in every eight women and accounting for the majority of cancer-related deaths in women worldwide. Germline mutations in the BRCA1 and BRCA2 genes are significant risk factors for specific subtypes of breast cancer. BRCA1 mutations are associated with basal-like breast cancers, whereas BRCA2 mutations are associated with luminal-like disease. There are currently few chemoprevention strategies available for BRCA1/2 mutation carriers, and irreversible prophylactic mastectomy is the primary option. Designing chemo-preventive strategies requires an in-depth understanding of the physiological processes underlying tumor initiation. Here, we employ spatial transcriptomics to investigate defects in mammary epithelial cell differentiation accompanied by distinct microenvironmental alterations in preneoplastic breast tissues from BRCA1/2 mutation carriers and normal breast tissues from non-carrier controls. We uncovered spatially defined receptor-ligand interactions in these tissues for the investigation of autocrine and paracrine signaling. We discovered that β1-integrin-mediated autocrine signaling in BRCA2-deficient mammary epithelial cells differs from BRCA1-deficient mammary epithelial cells. In addition, we found that the epithelial-to-stromal paracrine signaling in the breast tissues of BRCA1/2 mutation carriers is greater than in control tissues. More integrin-ligand pairs were differentially correlated in BRCA1/2-mutant breast tissues than non-carrier breast tissues with more integrin receptor-expressing stromal cells. These results reveal alterations in the communication between mammary epithelial cells and the microenvironment in BRCA1 and BRCA2 mutation carriers, laying the foundation for designing innovative breast cancer chemo-prevention strategies for high-risk patients.
Citation Format: Mihriban Karaayvaz, Anthony Caputo, Kavya Vipparthi, Peter Bazeley, Erinn Downs-Kelly, Patrick McIntire, Ying Ni, Bo Hu, Ruth Keri. Unraveling alterations in the pre-neoplastic breast microenvironment of BRCA1/2 mutation carriers using spatial transcriptomics [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 PO2-08-04.
Abstract PO2-08-06: Metformin may improve the outcome of patients with breast cancer and type 2 diabetes mellitus through the effect of tumor immune microenvironment
Authors: Shiba Satomi , Harao Michiko , Ogihara Kasumi , Fukuda Takayo , Sakuragi Masako , Joji Kitayama , Sata Naohiro 
Published: May 2024

Abstract
Metformin, an anti-diabetic drug, is known to have anti-tumor effects. We examined the outcome of 177 patients with type 2 diabetes mellitus (T2DM) who received surgery for breast cancer. Among them, 49 patients were treated with drugs including metformin. In those patients, recurrence in distant organs was less frequent and postoperative disease-free survival (DFS) tended to be better than those without metformin intake. In patients who received preoperative systemic therapy (PST), rate of pathological complete response (pCR) was significantly more frequent in patients with metformin treatment (p &lt; 0.05). Multiplex immunohistochemical staining of resected tumors revealed that the density of tumor associated macrophages (TAM), especially of CD68(+)CD163(+) M2-type TAM, was significantly lower in tumors with metformin treatment. In contrast, the rate of CD8(+) phenotype in CD3(+) tumor infiltrating lymphocytes (TILs) was significantly higher in metformin group. The results suggest that metformin can change the immune microenvironment from pro-tumorigenic to anti-tumorigenic status, which leads to the favorable outcome of the patients with breast cancer and T2DM.
Citation Format: Satomi Shiba, Michiko Harao, Kasumi Ogihara, Takayo Fukuda, Masako Sakuragi, Kitayama Joji, Naohiro Sata. Metformin may improve the outcome of patients with breast cancer and type 2 diabetes mellitus through the effect of tumor immune microenvironment [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 PO2-08-06.