bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reversal of Lactate and PD-1–mediated Macrophage Immunosuppression Controls Growth of PTEN/p53-deficient Prostate Cancer
Authors: Chaudagar Kiranj , Hieromnimon Hanna M. , Khurana Rimpi , Labadie Brian , Hirz Taghreed , Mei Shenglin , Hasan Raisa , Shafran Jordan , Kelley Anne , Apostolov Eva , Al-Eryani Ghamdan , Harvey Kate , Rameshbabu Srikrishnan , Loyd Mayme , Bynoe Kaela , Drovetsky Catherine , Solanki Ani , Markiewicz Erica , Zamora Marta , Fan Xiaobing , Schürer Stephan , Swarbrick Alex , Sykes David B. , Patnaik Akash 
Published: March 2023

Abstract

Purpose:
Phosphatase and tensin homolog (PTEN) loss of function occurs in approximately 50% of patients with metastatic castrate-resistant prostate cancer (mCRPC), and is associated with poor prognosis and responsiveness to standard-of-care therapies and immune checkpoint inhibitors. While PTEN loss of function hyperactivates PI3K signaling, combinatorial PI3K/AKT pathway and androgen deprivation therapy (ADT) has demonstrated limited anticancer efficacy in clinical trials. Here, we aimed to elucidate mechanism(s) of resistance to ADT/PI3K-AKT axis blockade, and to develop rational combinatorial strategies to effectively treat this molecular subset of mCRPC.

Experimental Design:
Prostate-specific PTEN/p53-deficient genetically engineered mice (GEM) with established 150–200 mm3 tumors, as assessed by ultrasound, were treated with either ADT (degarelix), PI3K inhibitor (copanlisib), or anti–PD-1 antibody (aPD-1), as single agents or their combinations, and tumors were monitored by MRI and harvested for immune, transcriptomic, and proteomic profiling, or ex vivo co-culture studies. Single-cell RNA sequencing on human mCRPC samples was performed using 10X Genomics platform.

Results:
Coclinical trials in PTEN/p53-deficient GEM revealed that recruitment of PD-1–expressing tumor-associated macrophages (TAM) thwarts ADT/PI3Ki combination–induced tumor control. The addition of aPD-1 to ADT/PI3Ki combination led to TAM-dependent approximately 3-fold increase in anticancer responses. Mechanistically, decreased lactate production from PI3Ki-treated tumor cells suppressed histone lactylation within TAM, resulting in their anticancer phagocytic activation, which was augmented by ADT/aPD-1 treatment and abrogated by feedback activation of Wnt/β-catenin pathway. Single-cell RNA-sequencing analysis in mCRPC patient biopsy samples revealed a direct correlation between high glycolytic activity and TAM phagocytosis suppression.

Conclusions:
Immunometabolic strategies that reverse lactate and PD-1–mediated TAM immunosuppression, in combination with ADT, warrant further investigation in patients with PTEN-deficient mCRPC.
Interplay Between Extracellular Matrix Remodeling and Angiogenesis in Tumor Ecosystem
Authors: Siddhartha Rohit , Garg Minal 
Published: March 2023

AbstractStudying the complex mechanisms of tumorigenesis and examining the interactions of neoplastic cells within tumor ecosystem are critical to explore the possibility of effective cancer treatment modalities. Dynamic tumor ecosystem is constantly evolving and is composed of tumor cells, extracellular matrix (ECM), secreted factors, and stromal cancer-associated fibroblasts (CAF), pericytes, endothelial cells (EC), adipocytes, and immune cells. ECM remodeling by synthesis, contraction, and/or proteolytic degradation of ECM components and release of matrix-sequestered growth factors create a microenvironment that promotes EC proliferation, migration, and angiogenesis. Stromal CAFs release multiple angiogenic cues (angiogenic growth factors, cytokines, and proteolytic enzymes) which interact with ECM proteins, thus contribute to enhance proangiogenic/promigratory properties and support aggressive tumor growth.Targeting angiogenesis brings about vascular changes including reduced adherence junction proteins, basement membrane and pericyte coverage, and increased leakiness. This facilitates ECM remodeling, metastatic colonization and chemoresistance. Owing to significant role of denser and stiffer ECM in inducing chemoresistance, direct or indirect targeting of ECM components is being reported as major axis of anticancer treatment. Exploring the agents targeting angiogenesis and ECM in a context specific manner may lead to reduced tumor burden by promoting conventional therapeutic effectiveness and overcoming the hurdles of therapy resistance.
Abstract ED1-2: How to incorporate PROs into clinical care
Authors: Fayanju Oluwadamilola (Lola) 
Published: March 2023

Abstract
Patient-reported outcomes (PROs) are self-reported assessments of health status that come from the patient’s perspective. Communicated without interpretation by a physician, PROs can enhance shared-decision making. When administered in multi-lingual, level-appropriate, and culturally aware formats, PROs can be used to address the individual and collective health status of potentially vulnerable groups including children, older adults, those with disabilities, and those from racial/ethnic minority backgrounds thereby providing an opportunity not only to address the needs of individuals but also identify potential disparities across groups. In her talk, Dr. Fayanju will provide strategies to facilitate incorporation of PROs into routine patient care and describe the benefits and potential challenges associated with doing so.
Citation Format: Oluwadamilola (Lola) Fayanju. How to incorporate PROs into clinical care [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 ED1-2.
Abstract ED3-3A: Mechanisms of resistance
Authors: Ellisen Leif 
Published: March 2023

Abstract
Antibody Drug Conjugates (ADCs) are emerging as promising therapeutics for all subtypes of breast cancer. ADCs are composed of a monoclonal antibody directed against a tumor-expressed antibody, conjugated via a variety of linker chemistries to a cytotoxic or other tumor-active payload. Tumor-selective drug delivery via ADCs has the potential to substantially improve the therapeutic window and efficacy for a variety of therapeutic agents. Indeed, recent clinical data have demonstrated significant improvements in overall survival with the use of single-agent ADCs across the spectrum of advanced breast cancer. However, both de novo and acquired resistance to ADCs is common, and may involve a diverse array of potential mechanisms that reflect the complexity of ADC action. These include alteration or downregulation of the ADC target, deregulation of intracellular trafficking or endolysosomal processing of the internalized ADC, and a variety of payload-specific mechanisms of resistance such as induction of drug efflux or activation of cell survival pathways. Which mechanism(s) dominates in a given setting may depend on both ADC-specific and tumor-specific factors. For example, linker design is likely to have a major influence on potential ADC resistance: ADCs with a non-cleavable linker (e.g. trastuzumab emtansine) are dependent upon fusion with acidified lysosomes for degradation and payload release, and attenuated acidification has been demonstrated pre-clinically as a resistance mechanism. In contrast, ADCs with a cleavable peptide linker (e.g. trastuzumab deruxtecan) may not require lysosomal processing for payload release. Furthermore, highly genetically unstable tumors may simultaneously generate multiple types of resistance mechanisms. We recently demonstrated the emergence of distinct acquired resistance mutations to sacituzumab govitecan, involving the ADC antibody target (TROP2) and the payload target (topoisomerase 1), within different metastatic lesions of an individual patient. General strategies to overcome ADC resistance include the sequential use of multiple ADCs, and/or the up-front use of select combination therapies incorporating ADCs. Clearly, the success of these approaches will require a more thorough evaluation and understanding of resistance mechanisms as they occur in patients. Fortunately, the relative success of ADCs for breast cancer treatment to date is spurring the identification of new targets, approaches for linker design, and a wide diversity of payloads that will be instrumental for efforts to overcome resistance.
Citation Format: Leif Ellisen. Mechanisms of resistance [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 ED3-3A.
Abstract ED6-1: Contralateral mastectomy in patients with germline mutations
Authors: Yao Katharine 
Published: March 2023

Abstract
The educational session titled "Contralateral mastectomy in patients with germline mutations" will cover contralateral mastectomy in affected gene carriers. The session will first cover trends in contralateral mastectomy in germline mutation carriers and the impact of genetic testing on contralateral mastectomy utilization. Second, the session will review guidelines on contralateral mastectomy for gene carriers. Literature on potential beneficial impacts of contralateral mastectomy for gene carriers will be reviewed. Impact to contralateral risk, survival outcomes and patient quality of life will be examined. Lastly, the session will review new surgical approaches for prophylactic mastectomy and protocols to reduce pain and enhance recovery after mastectomy.
Citation Format: Katharine Yao. Contralateral mastectomy in patients with germline mutations [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 ED6-1.
Abstract ED7-4: Beyond the lab: Clinical implications
Authors: Curtis Christina 
Published: March 2023

Abstract
During this talk, I will review the ever expanding repertoire of single cell and spatially resolved profiling techniques which enable the interrogation breast cancer pathlogy, immuno-biology and treatment response at unprecedented resolution. I will outline considerations for throughput, plex and resolution across different methods before providing several case studies in their application. As one example, I will outline the use of multi-omic single cell profiling and spatial proteomic profiling to characterize changes throughout the course of neoadjuvant Her2-targeted therapy and leading to the identification of candidate predictive biomarkers. I will go on to discuss translational and potential clinical applications of these techniques.
Citation Format: Christina Curtis. Beyond the lab: Clinical implications [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 ED7-4.
Abstract ED8-1: Overview of the current state of the art – what patients and oncologists need to know
Authors: Jimenez Rachel 
Published: March 2023

Abstract
While radiation therapy plays a significant role in the treatment of breast cancer for many patients, the nuances of modern day radiation therapy are often poorly understood by both patients and referring providers. Radiation therapy techniques to reduce toxicity and improve treatment accuracy have rapidly evolved in the past decade. This session will introduce non-radiation oncologists to recent innovations that allow increased personalization of treatment based on anatomical variations. Methods to improve patient positioning will be discussed. Frequently utilized dosimetric techniques for breast radiotherapy will be described and compared, including Volumetric Modulated Arc Therapy (VMAT), Intensity Modulated Radiation Therapy (IMRT), and 3D conformal planning. New methods for patient monitoring during treatment and the purpose of respiratory gating will be reviewed. Finally, the impact of surgical therapies on radiation planning and delivery will also be examined. Attendees should leave the session having a greater understanding of the current available options for radiotherapy and rationale for the choice of treatment technique.
Citation Format: Rachel Jimenez. Overview of the current state of the art – what patients and oncologists need to know [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 ED8-1.
Abstract GS1-06: Evaluation of the Breast Cancer Index in premenopausal women with early-stage HR+ breast cancer in the SOFT trial
Authors: O’Regan Ruth , Zhang Yi , Fleming Gini F. , Francis Prudence , Kammler Roswitha , Viale Giuseppe , Láng István , Ezquerra Meritxell Bellet , Bonnefoi Hervé R. , Loi Sherene , Colleoni Marco , Schnabel Catherine A. , Treuner Kai , Regan Meredith 
Published: March 2023

Abstract
Background: The landmark Suppression of Ovarian Function Trial (SOFT) in premenopausal breast cancer patients revealed that the addition of ovarian function suppression (OFS) to adjuvant endocrine therapy with either tamoxifen (T+OFS) or exemestane (E+OFS) reduces the risk of recurrence compared with adjuvant tamoxifen alone. The benefit from the addition of OFS was most clinically meaningful for patients at higher clinico-pathologic risk of recurrence. There are no biomarkers to aid decision-making about intensification of endocrine therapy with OFS and its resultant toxicities. The Breast Cancer Index (BCI) is a gene expression–based signature that stratifies patients based on the risk of overall (0-10 years) and late (post-5 years) distant recurrence (DR) and predicts the likelihood of benefit from extended endocrine therapy in early stage HR+ breast cancer. The purpose of this study is to assess BCI’s prognostic and predictive ability in premenopausal women randomly assigned to 5-years treatment with E+OFS or T+OFS vs T alone in the SOFT trial.
Methods: All available FFPE tumor samples from the SOFT trial (n=1718 of 3047) were included in the study. BCI testing was performed blinded to clinical characteristics, treatment and outcome. Median follow-up was 13 years. Primary endpoint was breast cancer-free interval (BCFI). Secondary endpoints were distant recurrence-free interval (DRFI) and disease-free survival (DFS). Kaplan-Meier analysis and Cox proportional hazards regression models, stratified by prior chemotherapy and lymph node status, were used to evaluate the predictive performance of BCI (H/I) status (High vs Low), and secondarily H/I as a continuous score. Hypothesis testing for interaction was performed by stratified log-rank tests.
Results: Tumor samples from 1687 (98%) patients (30.4% &lt; 40 years, 64.1% T1, 50.1% G2, 65.8% N0, 85.5%% HER2-, 53.3% received prior chemotherapy) were successful in BCI testing and included in the final analysis. Patient characteristics in the translational cohort are representative of the parent SOFT trial. 42.4% of patients’ tumors had H/I-High status. Prognostic and predictive analyses are ongoing and will be presented at the meeting.
Citation Format: Ruth O’Regan, Yi Zhang, Gini F. Fleming, Prudence Francis, Roswitha Kammler, Giuseppe Viale, István Láng, Meritxell Bellet Ezquerra, Hervé R. Bonnefoi, Sherene Loi, Marco Colleoni, Catherine A. Schnabel, Kai Treuner, Meredith Regan. Evaluation of the Breast Cancer Index in premenopausal women with early-stage HR+ breast cancer in the SOFT 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 GS1-06.
Abstract GS5-12: Hypofractionated Radiotherapy in patients with Breast Cancer (HRBC): Acute toxicity data of a phase III randomized study
Authors: Yadav Budhi Singh , Dahiya Divya , Gupta Manish 
Published: March 2023

Abstract
Background HRBC is a phase III randomized open label study of adjuvant radiotherapy in patients with breast cancer. In this study we compared a 3 weeks radiation schedule with 2 weeks. Materials and methods Patients with breast cancer, stage I-III, post mastectomy or after breast conservative surgery who needed adjuvant locoregional radiotherapy were randomized to 34Gy in 10 fractions over 2 weeks (study arm) or 35Gy in 15 fractions over 3 weeks to the chest wall and 40Gy/15#/3wks to breast and supraclavicular fossa (control arm). Boost dose when indicated was 8Gy/2# in both the arms. Patients were planned on simulator with 2 tangential fields to breast/chest wall and incident supraclavicular fossa field. Acute toxicity was assessed using a RTOG grading system. Assessment was carried out weekly during radiotherapy and at 4 weeks after treatment by the physician. Cosmetic outcome was assessed using Harvard/NSABP/RTOG scale. The toxicity between the two arms was compared using Fisher’s exact test. The trial was approved by institutional ethics committee. This trial is registered with ClinicalTrials.gov, number NCT04075058. Results This study included 1121 patients. Median follow up was 35 months (range 6-84 months). Mean age was 48 year (range 24-80 years). The patient characteristics were comparable between the two arms except for more mastectomies in the 3 week arm and more node positive patients in the 2 week arm. There were more oestrogen receptor positive tumors in the 3 week arm. Acute skin toxicities were comparable between the two arms. Grade 2 and 3 skin toxicity was 98(17%) and 82(15%); and 16(3%) and 10(2%) in the 3 week and 2 week arm (p=0.15), respectively. Cosmetic outcome was significantly better in 2 week arm 94% as compared to 90% in the 3 week arm (p=0.016). Conclusion The two radiation schedules were comparable in terms of acute skin toxicity. Cosmetic outcome was better in the 2 week schedule.
Citation Format: Budhi Singh Yadav, Divya Dahiya, Manish Gupta. Hypofractionated Radiotherapy in patients with Breast Cancer (HRBC): Acute toxicity data of a phase III randomized study [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 GS5-12.
Abstract P1-05-26: A blood-based lipid panel for personalized risk assessment of breast cancer
Authors: Fahrmann Johannes , Irajizad Ehsan , Vykoukal Jody , Barrera Angelica Gutierrez , Dennison Jennifer , Wu Ranran , Arun Banu K. , Brewster Abenaa , Hanash Samir 
Published: March 2023

Abstract
Background: The metabolic syndrome characterized in part by obesity, hyperinsulinemia, and insulin resistance is associated with increased risk of breast cancer. However there remains a need to establish a circulating biomarker metabolic profile indicative of increased risk of breast cancer. In the current study, we performed a comprehensive metabolomics screen to identify biomarkers indicative of increased risk of breast cancer. Methods: Unbiased metabolomics profiling was conducted on an initial Development Set of plasmas collected from 353 newly-diagnosed breast cancer cases and 141 controls. A deep learning neural network with 3 layers each containing 32 nodes based on 11 individual lipids corresponding to discrete lipid subclasses was built for risk prediction of breast cancer. The model was validated in an independent Test Set consisting of 79 breast cancer cases and 163 controls. Using a nested case:control matched design, we evaluated the performance of the model among body mass index (BMI) strata (≥ 30 or &lt; 30kg/m2). Results: An 11-marker lipid biomarker panel encompassing lipid subclasses with known pro-inflammatory and tumor promoting roles yielded an AUC of 0.75 (95% CI: 0.70-0.79) for distinguishing breast cancer cases from controls in the Development Set. Predictive performance of the lipid panel was comparable when stratifying cases into hormone-receptor (HR) positive, HER2-positive/HR negative, and triple-negative breast cancer subtypes. The biomarker panel had an AUC of 0.74 (95% CI: 0.68-0.81) in the independent Test Set. The predictive performance of the panel was most pronounced among obese subjects (BMI ≥ 30) with an AUC of 0.81 (95% CI: 0.71-0.91) in the Test Set. Conclusions: The lipid-based biomarker panel has utility for identifying women with ‘metabolic obesity’ who are at increased risk of breast cancer and would benefit from tailored screening.
Citation Format: Johannes Fahrmann, Ehsan Irajizad, Jody Vykoukal, Angelica Gutierrez Barrera, Jennifer Dennison, Ranran Wu, Banu K. Arun, Abenaa Brewster, Samir Hanash. A blood-based lipid panel for personalized risk assessment of 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 P1-05-26.
Abstract P1-10-07: Role of postmastectomy radiation therapy in breast cancer patients according to pathologic nodal status after neoadjuvant chemotherapy
Authors: Kim Dowook , Kim Jin Ho , Kim In Ah , Chang Ji Hyun , Shin Kyung Hwan 
Published: March 2023

Abstract
Purpose: The role of post-mastectomy radiation therapy (PMRT) in breast cancer patients after neoadjuvant chemotherapy (NAC) is highly controversial. This study aimed to evaluate the impact of PMRT according to pathologic nodal status. Methods and Materials: We retrospectively reviewed 682 patients with clinical stage II-III breast cancer who underwent NAC and mastectomy from 2013 to 2017. Of total, 596 (87.4%) received PMRT and 86 (12.6%) did not. We investigated the relationship amongst locoregional recurrence-free survival (LRRFS), disease-free survival (DFS), overall survival (OS), and various prognostic factors. Subgroup analyses to identify the patients who may benefit from PMRT were also performed. Results: The median follow-up duration was 67 months. In ypN+ patients (n = 368, 51.2%), PMRT showed significant benefit for LRRFS, DFS, and OS (all p &lt; 0.001). Based on multivariate analysis, histologic grade (HG) III (hazard ratio [HR] = 3.67, p = 0.002), lymphovascular invasion (LVI) (HR = 2.38, p = 0.045), and ypN2-3 (HR = 2.37, p = 0.02) were identified as significant risk factors for poor LRRFS. In ypN1 patients with more than two factors among (i) luminal subtype (ii) HG I-II and (iii) absence of LVI, PMRT showed no significant difference in LRRFS (p = 0.18). In ypN0 patients (n = 351, 48.8%), PMRT was not significantly associated with LRRFS, DFS, and OS. However, PMRT showed better LRRFS in triple-negative breast cancer (TNBC) subtype (p = 0.04). Conclusion: PMRT had a high impact on treatment outcomes in patients with residual lymph nodes following NAC and mastectomy. Among the ypN0 patients, PMRT may be beneficial only in the TNBC subtype.
Citation Format: Dowook Kim, Jin Ho Kim, In Ah Kim, Ji Hyun Chang, Kyung Hwan Shin. Role of postmastectomy radiation therapy in breast cancer patients according to pathologic nodal status after neoadjuvant chemotherapy [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 P1-10-07.