bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P1-13-11: YES1 is a targetable vulnerability for improving taxane response in triple-negative breast cancer
Authors: Ingles Natasha , Piemonte Katrina , Singh Salendra , Weber-Bonk Kristen , Keri Ruth 
Published: March 2023

Abstract
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Due to the lack of receptor expression, there are limited targeted therapies available for TNBC. As a result, TNBC patients are primarily treated with chemotherapies such as taxanes. Although TNBCs initially regress in response to taxane treatment, resistance is common. One mechanism of taxol unresponsiveness/resistance is an increase in chromosomal instability (CIN). Increased CIN can confer survival advantages to cancer cells and increase their aggressiveness. However, CIN levels can be leveraged using drugs that inhibit proteins important for chromosomal stability. Combining CIN-inducing drugs, such as taxanes, can improve treatment efficacy or re-sensitize tumor cells to certain drugs by shifting cells towards a state of maladaptive CIN that is incompatible with cell viability. We have found that the non-receptor SRC family kinase YES1 is crucial for chromosomal stability. YES1 is important for cell division, motility, adhesion, and survival in both normal and TNBC cells. Since taxol and YES1 silencing independently increase chromosomal instability, I hypothesized that combining a YES1 inhibitor (YES1i) with taxanes would shift cells toward an irreversible state of maladaptive CIN, decreasing their survival. I found that YES1 mRNA and protein are upregulated in taxane-resistant cells and that YES1 protein expression correlates with the paclitaxel IC50 in a panel of TNBC cell lines, suggesting that YES1 may drive taxane resistance. Furthermore, I found that a selective YES1 inhibitor (CH6953755) synergizes with paclitaxel and improves taxane response in both in vitro and in vivo TNBC models. In addition, the combination of YES1i and paclitaxel treatment increases phenotypes associated with chromosomal instability more than either drug alone. These data suggest that YES1 inhibition in combination with taxanes represents an innovative and novel drug treatment regimen that improves TNBC patient outcomes.
Citation Format: Natasha Ingles, Katrina Piemonte, Salendra Singh, Kristen Weber-Bonk, Ruth Keri. YES1 is a targetable vulnerability for improving taxane response in triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-13-11.
Abstract P2-11-07: Association of PIK3CA mutations with efficacy in HER2-positive first-line metastatic breast cancer: a meta-analysis
Authors: Swain Sandra , Cortés Javier , Xu Binghe , Lambertini Chiara , Essioux Laurent , Knott Adam , Restuccia Eleonora , Madjar Katrin , De Haas Sanne Lysbet 
Published: March 2023

Abstract
BACKGROUND: PIK3CA mutations have been shown to be associated with poor prognosis in HER2-positive breast cancer (BC). We combined data from three completed Phase III Roche-sponsored randomized trials of HER2-targeted therapy for the first-line treatment of HER2-positive metastatic BC (MBC); this allowed for exploration of the prognostic impact of PIK3CA mutations observed in the three individual trials across subgroups of interest.
METHODS: Data from CLEOPATRA (pertuzumab + trastuzumab + docetaxel [PHD] vs. placebo [Pla] + HD; NCT00567190; N = 808), MARIANNE (HD vs. ado-trastuzumab emtansine [K] + Pla vs. K + P; NCT01120184; N = 1095), and PUFFIN (PHD vs. Pla + HD; NCT02896855; N = 243) were included. An individual patient data (IPD) meta-analysis was performed to test the association between PIK3CA mutation status in tumor tissue (mutated vs. wild type [WT]) and efficacy (progression-free and overall survival [PFS/OS]) in different biomarker and clinical subgroups. Confounder adjustment was conducted for age, Eastern Cooperative Oncology Group Performance Status, body mass index, treatment, disease type, and number of metastases (all at baseline). “Study” was included as a random effect in the IPD meta-analysis model to account for variability between studies.
A landmark analysis was conducted on fast and non-fast progressors (cutoff of &gt;137 days [i.e., after six chemotherapy cycles]) from CLEOPATRA and PUFFIN only, since they include the current standard-of-care regimens (PHD), by using Day 137 as the landmark time with separate Cox proportional hazards models.
RESULTS: PIK3CA mutation data were available for 1905/2146 patients (89%; ~80% from primary tissue); mutation prevalence was 27% (n = 521). PIK3CA-mutated vs. WT in association with PFS in pooled treatment arms is shown in the table. OS data were consistent.
CONCLUSIONS: PIK3CA mutations were associated with a worse prognosis across subgroups of interest, including in fast and non-fast progressors, in the two PHD-containing studies as compared with the overall ITT population.
Table: PIK3CA-mutated vs. WT in association with PFS in pooled treatment arms
Citation Format: Sandra Swain, Javier Cortés, Binghe Xu, Chiara Lambertini, Laurent Essioux, Adam Knott, Eleonora Restuccia, Katrin Madjar, Sanne Lysbet De Haas. Association of PIK3CA mutations with efficacy in HER2-positive first-line metastatic breast cancer: a meta-analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-07.
Abstract P2-11-09: Association of 21-gene recurrence score with overall survival in phase 3 TAILORx trial
Authors: Yang Sherry X. , Yu John , Wang Molin 
Published: March 2023

Abstract
Background: The 21-gene recurrence score (RS) assay is a prognostic measurement originally established for distant recurrence in estrogen receptor-positive and node-negative breast cancer. Retrospective studies and the Trial Assigning Individualized Options for Treatment (TAILORx; ClinicalTrials.gov NCT00310180) validated its significance besides testing chemotherapy benefit in patients with midrange RS (11-25). However, unclarity remains as to whether RS has comparable prognostic value for overall survival (OS) in the TAILORx trial population. Methods: Association between the recurrence scores (midrange or high-range 26-100 vs. low-range 0-10) and OS was evaluated in all eligible patients with clinicopathological and treatment information by multivariable Cox proportional hazards regression model including RS, tumor size, tumor grades, chemotherapy, endocrine regimens, surgery type, progesterone receptor and demographics. We also evaluated the association between RS and invasive disease-free survival (DFS), recurrence-free interval (RFI) or distant recurrence-free interval (dRFI) by multivariable Cox analysis. Results: Median follow-up was 95.5 (range 0.1 to 138.6) months for OS, 89.6 months (range 0 to 134.8) for DFS, 87.7 (range 0 to 134.8) months for RFI or 87.6 (range 0-134.8) months for dRFI. Compared with low score group, midrange and high-range scores were associated with RFI and dRFI, respectively (P≤0.01 each). However, midrange score was neither associated with OS (adjusted HR 1.15; 95% CI 0.87-1.52; P=0.33) nor associated with DFS (HR 1.16; 95% CI 0.97-1.38; P=0.11). High-range score was associated with DFS (HR 1.58; 95% CI 1.21-2.06; P&lt; 0.01) and had a trend towards association with OS (HR 1.44; 95% CI 0.95-2.19; P=0.08). Conclusions: The data indicate that the recurrence scores provide independent prognosis for breast cancer recurrence at both distant and locoregional sites and for distant recurrence, respectively. High-range score is prognostic of disease-free survival, with the midrange score showing marginal association. Midrange and high-range recurrence scores do not provide independent prognostic information for overall survival in hormone receptor-positive, HER2-negative, node-negative breast cancer in the TAILORx trial population.
Citation Format: Sherry X. Yang, John Yu, Molin Wang. Association of 21-gene recurrence score with overall survival in phase 3 TAILORx trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-09.
Abstract P2-14-09: Sensory Evaluation of Nipple-Areolar Complex after Nipple-Sparing Mastectomy: A Comparison of Incision Approaches
Authors: Kook Yoonwon , Jang Ji Soo , Baek Seung Ho , Bae Soong June , Ahn Sung Gwe , Jeong Joon 
Published: March 2023

Abstract
Background: Since nipple-sparing mastectomy (NSM) has been widely practiced, majority of previous studies have evaluated the effects of Nipple-areolar complex (NAC) preservation on body image adjustment. However, few have evaluated NAC sensation after NSM in a large sample size. This study aims to assess NAC sensation after NSM and compare the results according to different incisional approaches; specifically, inframammary fold (IMF) and peri-areolar.
Methods: Post NSM patients from Oct 2019 to Nov 2021 have been recruited prospectively. A total of 115 patients (IMF 69 and peri-areolar 36) were evaluated for NAC sensory at various time points during follow up within 1.5 to 4 years after surgery. NAC sensation was scored by pin-prick test in a scale of 0 to 2 (0: no sensation, 1: dull sensation, 2: sharp sensation), divided in 5 areas of the NAC and summed up to a total of 10.
Results: In all patients, a median of the pin-prick test total score on NAC was 3 (0-10). Pin-prick test of NAC showed numerically higher NAC sensory score in the IMF incision than in the peri-areolar group without a statistical significance (IMF: Median 4 Mean 3.83 ± 3.04, Peri-areolar Median 2 Mean 2.69 ± 3.64, p=0.062). When sensory scores were evaluated depending on NAC zones (A: Nipple, B: Upper outer, C: Upper inner, D: Lower outer, E: Lower inner) the IMF incision group showed better outcomes in zone B (p=0.015) and E (p=0.043). Simple linear regression analysis showed the possibility of incisional approach, diabetes mellitus (DM) history, previous radiotherapy of ipsilateral breast, post mastectomy radiotherapy (PMRT), adjuvant chemotherapy, tumor to nipple distance and laterality influencing NAC sensory with p&lt; 0.2. When these factors were taken to multiple linear regression analysis, DM history (p=0.045), previous radiotherapy (p=0.001), postop radiotherapy (p=0.001), and adjuvant chemotherapy (p=0.001).
Conclusion: NAC sensory deteriorated postoperatively in general. Scores of NAC sensation were numerically higher in the patients with IMF incision, although the difference was not statistically significant. NAC sensation was negatively affected by DM history, previous ipsilateral breast radiotherapy and post-NSM treatments such as chemotherapy and PMRT. While incision type may improve aesthetic outcomes, additional efforts are necessary to ameliorate the post-NSM NAC desensitization.
Table 1. Patient characteristics
Table 2. Linear regression analysis for clinical factors affecting NAC sensory
Citation Format: Yoonwon Kook, Ji Soo Jang, Seung Ho Baek, Soong June Bae, Sung Gwe Ahn, Joon Jeong. Sensory Evaluation of Nipple-Areolar Complex after Nipple-Sparing Mastectomy: A Comparison of Incision Approaches [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-14-09.
Abstract P2-16-02: TXNIP-dependent tumor suppressive pathways in breast cancer growth and progression
Authors: Singh Jasvinder , sah Bindeshwar , Liu Liang 
Published: March 2023

Abstract
Thioredoxin-interacting protein (TXNIP) plays a critical role in glucose metabolism and redox signaling through negatively regulating thioredoxin activity. Over the past decade, TXNIP has emerged as a novel tumor suppressor in various cancer models. In search of the molecular targets mediating the anticancer effect of an epigenetic drug UNC0642, we found TXNIP to be consistently upregulated by UNC0642, which was coupled with significant suppression of MDA-MB-231 breast cancer cell proliferation in vitro and tumor growth in vivo. TXNIP knockdown increased MDA-MB-231 cell proliferation and in vivo tumor growth and metastasis. In contrast, TXNIP-reconstitution in TXNIP-deficient HCC1954 breast cancer cells suppressed cell proliferation and migration that is coupled with increases in reactive oxygen species, strongly supporting TXNIP’s potent antitumor function. TXNIP-reconstitution also decreased mitochondrial respiration and glycolysis in HCC-1954 cells as determined by using the Agilent Seahorse XF Cell Energy assays. To understand the molecular targets through which TXNIP exerted its antitumor activity, we performed co-immunoprecipitation studies and proteomic analyses to identify TXNIP-interacting proteins in UNC0642-treated MDA-MB-231 cells. Besides thioredoxin, we identified peroxiredoxin-6 (PRDX6), another modulator of cellular redox signaling, as a major TXNIP-interacting protein. While Prdx6-knockout mice develop normally, PRDX6 is frequently upregulated in breast cancer patients that is significantly associated with aggressive tumor subtypes and poor overall survival. The mechanism underlying the role of PRDX6 in breast oncogenesis remains elusive. Our findings suggest that TXNIP might exert its antitumor activity through binding and inhibiting PRDX6 activity in breast cancer cells to alter ROS signaling, thus providing novel therapeutic targets and potential prognostic biomarkers for breast cancer patients.
Citation Format: Jasvinder Singh, Bindeshwar sah, Liang Liu. TXNIP-dependent tumor suppressive pathways in breast cancer growth and progression [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-16-02.
Abstract P2-18-01: Matched Single-Cell RNA-seq and Single-Cell ATAC-seq of Male Breast Cancers Nominate Salient Cancer-Specific Enhancers
Authors: Wisniewska Kamila , Kim Hyunsoo , Regner Matthew J. , Spanheimer Philip , Franco Hector L. 
Published: March 2023

Abstract
Although male breast cancer accounts for less than 1% of all breast cancer cases, overall survival is worse for men compared to women. This is due, in part, to the older age of patients at the time of diagnosis and the increased presence of comorbidities in the male population. While male breast cancer presents with similarities to certain female breast cancers, the paucity of data available on male breast cancer makes it difficult to establish targeted therapies, and to date, most male breast cancers are treated according to the standards in place for female breast cancer. Thus, investigating the transcriptional and epigenetic landscape of male breast cancer with improved resolution is crucial for understanding the tumor heterogeneity of this rare cancer type and can lead to the discovery of new therapeutic targets. In this study, we present matched transcriptional (scRNA-seq) and epigenetic (scATAC-seq) profiles of two male breast cancer tumors at single-cell resolution. Using scRNA-seq, we determine differentially expressed genes between male and female breast cancer tumors, specifically in the malignant cell populations, and highlight several genes that may have therapeutic implications within male breast cancer. We then leverage the scATAC-seq data to link variation in chromatin accessibility to changes in gene expression and show that certain highly expressed genes in the tumor-epithelial cells of male breast tumors are linked to highly active enhancer elements that drive their expression. Finally, we examine transcription factor motifs in the tumor-epithelial regulatory regions of male breast cancer tumors to further investigate the regulatory logic of these cell types. Overall, this dataset exposes clinically relevant regulatory networks in male breast tumors, providing a useful resource to the field of breast oncology that expands on the current knowledge of male breast cancer genetics.
Citation Format: Kamila Wisniewska, Hyunsoo Kim, Matthew J. Regner, Philip Spanheimer, Hector L. Franco. Matched Single-Cell RNA-seq and Single-Cell ATAC-seq of Male Breast Cancers Nominate Salient Cancer-Specific Enhancers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-18-01.
Abstract P2-20-11: Progesterone impacts the growth and immune cell infiltration of murine mammary gland tumors
Authors: Werner Lauryn R , Helm Dominika E. , Tinoco Julio , Chowanec Eilidh I , Holloran Sean M , Hastings Richard C , Wei Junping , Lei Gangjun , Yang Xiao-Yi , Markiewicz Mary A , Chalise Prabhakar , Balko Justin , Hartman Zachary C , Hagan Christy R 
Published: March 2023

Abstract
Clinical studies have linked usage of progestins (synthetic progesterone) to breast cancer risk. However, little is understood regarding the role of native progesterone (P4), signaling through the progesterone receptor (PR), in breast tumor formation. Recently, we demonstrated that P4 treatment or PR overexpression can drive changes in immune cell populations in the murine mammary gland and that PR overexpression leads to increased development of mammary gland tumors in mice. Given these findings, we sought to investigate whether P4 impacts tumor growth and immune cell infiltration of mammary gland tumors. We utilized syngeneic mammary gland tumor models to evaluate the effect of P4 on PR+ mammary gland tumor growth, which revealed that P4 promoted tumor growth and impacted immune cell infiltration of PR+ mammary gland tumors. Of note, numbers of tumor-infiltrating dendritic cells were decreased and exhausted T cells and regulatory T cells were increased with P4 treatment in PR+ tumors. To determine if anti-progestin therapies could reverse the growth-promoting effect of P4 on mammary gland tumors, mice bearing PR+ mammary gland tumors were treated with the anti-progestin onapristone. Onapristone treatment led to significantly decreased tumor volumes in two syngeneic mammary gland tumor models and reversed the effect that P4 had on tumor-infiltrating regulatory T cells. To determine if inhibition of tumor growth by onapristone was immunologically mediated, SCID mice bearing PR+ mammary gland tumors were treated with onapristone. Results revealed a decreased ability of onapristone to inhibit tumor growth in SCID mice compared to immunocompetent mice, suggesting that inhibition of tumor growth is, in part, immunologically mediated. These findings offer a novel mechanism of P4-driven mammary gland tumor development and provide rationale in investigating the usage of anti-progestin therapies to promote immune-mediated elimination of mammary gland tumors.
Citation Format: Lauryn R Werner, Dominika E. Helm, Julio Tinoco, Eilidh I Chowanec, Sean M Holloran, Richard C Hastings, Junping Wei, Gangjun Lei, Xiao-Yi Yang, Mary A Markiewicz, Prabhakar Chalise, Justin Balko, Zachary C Hartman, Christy R Hagan. Progesterone impacts the growth and immune cell infiltration of murine mammary gland tumors [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-20-11.
Abstract P2-23-19: Interrogating multicellular signaling in breast cancer using a bio-orthogonal chemistry-based proteomics platform
Authors: Krajina Brad A. , Yamamoto Ami , Cheung Kevin J. , Madasu Samuel 
Published: March 2023

Abstract
Tumors are multicellular ecosystems that communicate through the exchange of extracellular signaling molecules. In breast cancer, this multicellular communication can enable tumor cells to cooperate in a range of contexts, including tumor invasion and the outgrowth of distal metastases. Illuminating the mechanisms by which tumor cells communicate may reveal new therapies. To this end, three-dimensional tumor organoid models have emerged as versatile platforms for modeling multicellular behavior ex vivo. However, organoid culture typically requires the use of poorly defined, animal-derived extracellular matrices, such as Matrigel. These exogenous matrices contain thousands of proteins that dominate over and conceal cell-secreted factors in conventional proteomics approaches. Revealing low abundance cell-secreted factors from this complex exogenous background presents a formidable challenge. To surmount this challenge, we develop a new method to isolate the pericellular proteome in 3D organotypic culture models. This technology harnesses biorthogonal click chemistry to bypass exogenous factors, infiltrate intercellular spaces, and retrieve the endogenous intercellular proteome. This approach requires no genetic manipulation, requires only 1 million cells, and can be adapted to diverse organotypic models. These capabilities enable isolation of intercellular signaling factors in models that yield precious amounts of material and that can sustain only limited manipulation ex vivo, which we demonstrate using organoids established from patient-derived xenografts. To establish the generalizability of our approach, we apply this technology to a panel of breast cancer and small-cell lung cancer organoid models. Furthermore, we demonstrate that this method can be readily adapted to different extracellular matrix environments that are widely employed in organoid research, including basement membrane matrices and collagen gels. Taken together, our results establish this technology as a scalable and generalizable platform that may open opportunities for researchers investigating diverse questions in organoid models of cancer. Moving forward, we are leveraging these capabilities to investigate changes in the intercellular proteome that emerge after the acquisition of therapy resistance. We hope to uncover new mechanisms of collective signaling that may be targeted to overcome therapy resistance.
Citation Format: Brad A. Krajina, Ami Yamamoto, Kevin J. Cheung, Samuel Madasu. Interrogating multicellular signaling in breast cancer using a bio-orthogonal chemistry-based proteomics platform [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-23-19.