tbuckley/cabot-search huggingface dataset:
Abstract PO2-25-01: Tumor Derived Chitinase-3 like 1 Induces Neutrophil Extracellular Traps that Promote T cell Exclusion and Resistance to Immunotherapies in Breast Cancer
Authors: Tarek Taifour, Sherif Samer Attalla, Dongmei Zuo, Yu Gu, Virginie Sanguin-Gendreau, Hailey Dall-Proud, Emilie Solymoss, Tung Bui, Hellen Kuasne, Vasilios Papavasiliou, Chun Geun Lee, Suchitra Kamle, Peter Siegel, Jack Elias, Morag Park, William Muller
Journal: Cancer Research (2024)

Abstract Breast cancer remains the most prevalent cancer and a major cause of mortality affecting women worldwide. Chemotherapy along with radiation and surgery have long been the standard of care for breast cancer patients. However, devastating side effects, resistance to treatments and relapse are major concerns for patients and physicians. With the rise of immunotherapies as a treatment option for various cancers, there is a critical need to understand the mechanisms through which cancers evade the immune system. Targeting such mechanisms holds the key to improve patient response to immunotherapy, especially in breast cancer where efficacy rates remain low. In a subset of poor outcome Triple Negative Breast Cancers, cytotoxic T cells are excluded from the tumor nest and restricted to the surrounding stroma, a phenomenon known as stromal restriction. Our data from genetically engineered mouse models and human tumors identified that the secreted cytokine Chitinase-3 like 1 (Chi3l1) promotes stromal restriction of T cells in several tumor types including breast, lung and colon. Chi3l1 ablation in pre-clinical models of breast cancer results in increased T cell infiltration into the tumor nest which delayed mammary tumorigenesis and improved response to immunotherapy. We further demonstrate that Chi3l1 promotes T cell exclusion through the direct induction and deposition of neutrophil extracellular traps (NETs) which form a barrier that restricts T cell entry. Neutrophil depletion or pharmacological disruption of NET formation abrogates Chi3l1-induced T cell exclusion and histologically phenocopies Chi3l1 ablation. Thus, our results indicate that Chi3l1 is a major immunosuppressive cytokine that promotes breast cancer progression by inducing NET formation and inhibiting T cell infiltration. Given the importance of T cell infiltration in immune elimination of nascent tumors, the future targeting of Chi3l1 should improve immunotherapy efficacy and outcomes in patients with tumors characterized by a T cell excluded microenvironment. Citation Format: Tarek Taifour, Sherif Samer Attalla, Dongmei Zuo, Yu Gu, Virginie Sanguin-Gendreau, Hailey Dall-Proud, Emilie Solymoss, Tung Bui, Hellen Kuasne, Vasilios Papavasiliou, Chun Geun Lee, Suchitra Kamle, Peter Siegel, Jack Elias, Morag Park, William Muller. Tumor Derived Chitinase-3 like 1 Induces Neutrophil Extracellular Traps that Promote T cell Exclusion and Resistance to Immunotherapies 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 PO2-25-01.
Abstract SoA1-03: Current overview of immunotherapy in breast cancer
Authors: S. Loi
Journal: Cancer Research (2024)

Abstract T cell checkpoint inhibitors are now standard of care for patients with triple negative breast cancer. Currently these agents are combined with combination cytotoxic chemotherapy. In this talk we will cover the composition of the immune infiltrate, rationale for T cell therapies, more or less chemotherapy and biomarkers of response and resistance. Citation Format: S. Loi. Current overview of immunotherapy 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 SoA1-03.
Abstract PO2-24-09: Prolonged Effects of Hypoxia in Luminal Breast Cancer Cells Promotes an Aggressive Phenotype
Authors: Aidan Moriarty, Oihana Iriondo, Desirae Mecenas, Yilin Li, Yonatan Amzaleg, Remi Klotz, Min Yu
Journal: Cancer Research (2024)

Abstract Aidan Moriarty Mentor: Dr. Min Yu Hypoxic Memory in Breast Cancer Cells Metastasis is the main cause of tumor-related mortality in breast cancer patients. Improving our understanding of the metastatic cascade is imperative to improve patient outcomes. Prior research indicates cancer cells with increased metastatic potential have acquired adaptive properties induced by factors in the tumor microenvironment (TME), including hypoxia. However, previous hypoxia research has been primarily focused on signaling changes that occur when cancer cells are in the hypoxic TME and does not account for long-term changes that may occur once cancer cells re-enter normoxia, such as when they metastasize. Our research in patient-derived circulating tumor cell (CTCs) lines and breast cancer cell lines has indicated that certain transcriptional changes are maintained after cells leave hypoxia, and that these post-hypoxic CTCs maintain a higher metastatic potential compared to cells not exposed to hypoxia. Taking an un-biased approach to define changes in hypoxia-exposed breast cancer cells upon reoxygenation, we performed bulk RNA-Seq on luminal breast cancer cell lines in various oxygen conditions over time. We found that a subset of genes that were differentially expressed in hypoxic conditions were maintained as up- or down-regulated after cells were reoxygenated, indicating a “hypoxic memory”. Additionally, a subset of genes were differentially expressed in the post-hypoxic cells compared to normoxia controls, demonstrating novel and prolonged gene expression changes induced by hypoxia exposure. We performed functional assays and observed that this post-hypoxic state is associated with a more aggressive phenotype in vitro. Current research in our lab is on-going to understand the epigenetic changes that may be responsible for this hypoxic memory to further understand the consequences of hypoxic memory in CTC biology and metastasis. Finally, we have designed a dual-reporter hypoxia-tracing system to validate our findings in vivo. This research will improve our understanding of the prolonged influence of hypoxia on metastatic potential in breast cancer cells and has the potential to inform future therapeutic strategies. Citation Format: Aidan Moriarty, Oihana Iriondo, Desirae Mecenas, Yilin Li, Yonatan Amzaleg, Remi Klotz, Min Yu. Prolonged Effects of Hypoxia in Luminal Breast Cancer Cells Promotes an Aggressive Phenotype [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 PO2-24-09.
Abstract PO5-10-02: Neighborhood deprivation index and time to initiation in patients with metastatic breast cancer
Authors: Sneha Rajendran, Dianxu Ren, Marina Petruzzi, Margaret Rosenzweig
Journal: Cancer Research (2024)

Abstract Background Cyclin-dependent kinase 4 and 6 inhibitors (CDKi) are first-line therapy for patients with estrogen-positive (ER+) metastatic breast cancer (MBC). The accessibility, usability, and outcomes according to demographic factors have not been well studied in real world practice. Methods Retrospective review of patients with ER+ MBC prescribed first line CDKi therapy at a large NCI-designated cancer center from January 2015 through December 2022. Patient records were abstracted for outcomes including 1) time from CDKi prescription to drug initiation (TTI), 3) time from CDKi initiation to progression, and 3) time from CDKi initiation to death/or 6/30/2022. Patient variables collected were: patient age (continuous), race (patient self-report – Black, White, Other), partner status (Married, Not married), Insurance type (Medicare, Medicaid, Private); Mean BMI; Number of comorbidities (5 categories). Neighborhood deprivation index (NDI) was determined from the patient’s address with higher scores indicating more deprivation. Descriptive, comparative, and correlational statistics were used. Results A total of 173 patients were included in the analysis. Mean age – 63.1, (SD 12.7, range 24-94); race – White n=157, Black n=16; marital status – Married n=102, Not married n=71; mean NDI – 61.0 (SD 23.7, range 6-100); mean BMI – 28.9 (SD 6.9, range 16-48); number of comorbidities – 0 n=35, 1-2 n= 35, 3-4 n = 55, 5-6 n = 20, 7+ n = 28; insurance type – Medicare n = 115, Medicaid n = 21, Private n = 37. TTI: the median TTI was 14 days. There were no statistically significant differences in TTI based on age, race, NDI, or other demographic variables. Time to progression: in the multivariate model, younger age at diagnosis and Medicaid insurance were associated with shorter time to progression. Overall survival: not married, younger age at diagnosis, and Medicaid insurance were associated with shorter overall survival. Discussion Demographic factors are associated with diverse outcomes of MBC therapy, not attributed to delay in CDKi treatment initiation. Personalization of support during MBC illness according to risk factors for worse outcomes may help to equalize incomes. Citation Format: Sneha Rajendran, Dianxu Ren, Marina Petruzzi, Margaret Rosenzweig. Neighborhood deprivation index and time to initiation 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 PO5-10-02.
Abstract PO5-09-10: Inflammatory Breast Cancer Patient Profile in a Population of Puerto Rican Women
Authors: Luz Arroyo-Cruz, Michelle Martinez-Montemayor
Journal: Cancer Research (2024)

Abstract Background: Breast cancer (BC) is the most frequently diagnosed cancer type, as well as the leading cause of cancer death among women in Puerto Rico (PR). Moreover, inflammatory breast cancer (IBC) is a highly aggressive BC subtype. The current study aimed to describe the patient profile and the clinicopathological characteristics of IBC tumors in Hispanic women living in Puerto Rico. Methods: This is a retrospective, population-based study using the Puerto Rico Central Cancer Registry (PRCCR) database and the Health Insurance Linkage Database (PRCCR-HILD) to identify and describe the patient profile of Puerto Rican women diagnosed with IBC from 2008 to 2018. Variables such as age at diagnosis, staging variables, tumor receptor subtypes, treatment received, and overall survival (OS) were studied. Statistical analysis methods were employed to describe the population, estimate survival curves and examine the risk of dying. Results: We identified a total of 51 patients. The mean age at diagnosis of IBC in the current study was 59 years old, which is older than the mean age at diagnosis of IBC for women in the mainland US, but younger than the mean age of women that are diagnosed with BC in PR (63 years old). A total of 62.8% of patients had no metastases at diagnosis and 64.7% were diagnosed with stage III disease. Most tumors presented with ER+/PR+/Her2- (21.6%), or a triple-negative (ER-/PR-/Her2-, 15.7%) tumor concordance. The OS during the 12 months post-diagnosis was 66%, whereas at 36 months, OS decreased to 39%. The triple-negative subtype had the worst survival at 36 months (36%). Women with stage IV disease and those with ER-/PR- tumor subtype had a higher risk of dying. Conclusions: This is the first research to describe the patient profile and characteristics of women diagnosed with IBC in Puerto Rico. Our results suggest that the Puerto Rican IBC patient population presents unique characteristics. This research increases awareness about this lethal disease in PR. Citation Format: Luz Arroyo-Cruz, Michelle Martinez-Montemayor. Inflammatory Breast Cancer Patient Profile in a Population of Puerto Rican 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 PO5-09-10.
Abstract PO5-09-04: Oncotype DX Breast Recurrence Score® analysis in early-stage breast cancer associated with CHEK2, ATM and PALB2 germline pathogenic variants
Authors: Fatma Akkoc Mustafayev, Angelica Gutierrez Barrera, Diane Liu, Banu Arun
Journal: Cancer Research (2024)

Abstract Background: The 21-gene assay (Oncotype DX Recurrence Score, RS) is the only clinically validated assay to determine the prognosis in hormone-positive, HER2-negative breast cancer (BC) patients treated with endocrine therapy alone by predicting locoregional and distant recurrence. Outcomes of Oncotype RS in BRCA-associated BC has been studied previously, but the results of RS analysis in BC patients with the other BC susceptibility genes have not been documented. This study evaluates the clinical and pathological characteristics of BC patients with ATM, CHEK2 and PALB2 germline pathogenic variants (PV). Methods: Patients with invasive hormone-positive, HER2-negative BC who have had Oncotype DX Breast Recurrence Score® testing and who underwent genetic testing in the Breast Medical Oncology and the Breast Clinical Cancer Genetics Clinic at the University of Texas MD Anderson Cancer Center (MDACC) were identified from the prospectively maintained research database. Clinical and tumor characteristics were analyzed using descriptive statistics. Results: Between 1996 and June 2023, 5652 patients with Oncotype RS were included in this analysis. Amongst those 828 BC patients had genetic testing and 81 patients were found to have a pathogenic variant: 17 patients with a CHEK2 mutation, 10 patients with an ATM mutation, and 18 patients with a PALB2 mutation. Among patients with CHEK2 PV, median Oncotype RS was 17 (5–32) overall, 21 (13–32) for patients age &amp;lt; 50, and 14.5 (5–28) for patients age ≥50 (p= 0.2). Among patients with ATM PV, median RS was 16.5 (3–54) overall, 25 (10–54) for patients age &amp;lt; 50, and 14.5 (3–29) for patients age ≥50 (p= 0.19). Among patients with PALB2 PV, median RS was 26.5 (15–40) overall, 20 (15–40) for patients age &amp;lt; 50, and 31 (26–37) for patients age ≥50 (p= 0.012). Further patient and tumor characteristics are shown in Table 1. Conclusion: This is a single-institutional cohort of hormone-positive, HER2-negative BC patients who had Oncotype RS and who underwent genetic testing. Further analysis on clinical and tumor pathological characteristics and long-term outcome is ongoing. Table1. Patient and tumor characteristics Citation Format: Fatma Akkoc Mustafayev, Angelica Gutierrez Barrera, Diane Liu, Banu Arun. Oncotype DX Breast Recurrence Score® analysis in early-stage breast cancer associated with CHEK2, ATM and PALB2 germline pathogenic variants [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 PO5-09-04.
Abstract PO3-18-07: Therapeutic Potential of Combining Eltanexor with Tamoxifen to Treat Primary and Metastatic Estrogen Receptor Positive (ER+) Breast Cancers
Authors: Vedant Jain, Myra Kamdar, Hannah McGee, Qianying Zuo, Jin Young Yoo, Yosef Landesman, Christopher Walker, Zeynep Madak-Erdogan
Journal: Cancer Research (2024)

Abstract Estrogen receptors are key pathway initiators in the aggressive development of more than two-thirds of all breast cancers. Tamoxifen (TAM) is a selective estrogen receptor modulator that disables the ER pathway and inhibits the progression of ER+ breast cancer. Unfortunately, 10-40% of patients with ER+ breast cancer who were treated with TAM experience recurrence and metastasis within 10 years. We have previously identified exportin 1 (XPO1) to be more highly expressed in breast cancers with acquired TAM resistance compared to TAM-sensitive counterparts and showed that a combination treatment of TAM with an XPO1 inhibitor, selinexor, is an effective method of tumor suppression in preclinical models. In this study we investigated the activity of eltanexor, an investigational second generation XPO1 inhibitor with minimal penetration of the blood-brain barrier, to inhibit cancer growth without leading to weight loss. Our results show that mice harboring MCF7-ESR1Y537Sxenograft tumors had significantly less (P &amp;lt; .05) flank tumor growth when administered a treatment regimen of TAM and eltanexor compared to control mice. In metastatic tumor models, we observed decreased metastatic burden in mice harboring MCF7-ESR1 D538G and MCF7-ESR1Y537S tumors when co-administered TAM and eltanexor. We did not observe weight changes in either model. Our findings suggest that eltanexor may be a relevant treatment for further exploration in the context of a TAM combination therapy for treatment of ER+ breast cancer. Citation Format: Vedant Jain, Myra Kamdar, Hannah McGee, Qianying Zuo, Jin Young Yoo, Yosef Landesman, Christopher Walker, Zeynep Madak-Erdogan. Therapeutic Potential of Combining Eltanexor with Tamoxifen to Treat Primary and Metastatic Estrogen Receptor Positive (ER+) Breast Cancers [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 PO3-18-07.
Abstract PO2-23-11: SMAD4 depletion contributes to endocrine therapy resistance by ERBB signaling in HR+HER2- breast cancer
Authors: Kang Li, Dan Shu, Han Li
Journal: Cancer Research (2024)

Abstract Objectives: Endocrine therapy resistance is a significant clinical challenge for patients with estrogen receptor (ER)-positive breast cancer. Dysregulation of the ER and ERBB signaling pathways plays a key role in endocrine therapy resistance. However, it is unclear how these pathways are integrated during resistance development. SMAD4 is involved in multiple stages of tumorigenesis, but its role in endocrine resistance development remains elusive. Here, we aimed to investigate the role of SMAD4 in the development of acquired endocrine therapy resistance in ER-positive breast cancer. Methods: CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) screening was conducted to identify genes involved in regulating the sensitivity of T47D cells to 4-hydroxytamoxifen (OHT). Bioinformatics analysis was performed to explore the clinical significance of SMAD4. The differential expression of SMAD4 in cells before and after endocrine treatment was assessed by RT-qPCR and immunoblotting. Loss-/gain-of-function assays were conducted to validate the phenotype. RNA-seq and phenotype rescue experiments were used to explore the underlying mechanisms. Drug combination experiments were performed to assess the therapeutic effect on SMAD4-depleted cells. Results: CRISPR screening identified SMAD4 as a key determinant of endocrine therapy resistance. Bioinformatic analysis showed that SMAD4 expression was downregulated in breast cancer tissues and that low expression was associated with poor patient prognosis. Differential expression analysis after endocrine therapy treatment showed that endocrine therapy downregulated the expression of SMAD4. In vitro and in vivo models further demonstrated that SMAD4 downregulation leads to endocrine therapy resistance. Transcriptome sequencing analysis identified that the ER, ERBB and PI3K/Akt/mTOR signaling pathways were aberrantly activated upon SMAD4 depletion. Further analysis revealed that the PI3K/Akt/mTOR pathway may contribute to the regulation of ERBB on ER signaling to some extent. The aberrant activation of autophagy in phenotype rescue experiments was found to reduce the rescue effect of the combination of 4-hydroxytamoxifen (OHT) and lapatinib (LAPA). Finally, drug combination experiments verified that the combined use of OHT, LAPA and hydroxychloroquine (CQ) produced a synergistic effect in SMAD4-depleted cells. Conclusions: Taken together, our findings demonstrate that SMAD4 plays a crucial role in endocrine therapy resistance and suggest a reasonable treatment strategy for ER-positive breast cancer patients who are resistant to endocrine therapy. Citation Format: Kang Li, Dan Shu, Han Li. SMAD4 depletion contributes to endocrine therapy resistance by ERBB signaling in 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 PO2-23-11.
Abstract PO3-18-03: Preoperative single-dose camrelizumab and/or microwave ablation in women with early-stage breast cancer: A randomized window-of-opportunity trial
Authors: Wenbin Zhou, Hui Xie, Qiang Ding, Shui Wang
Journal: Cancer Research (2024)

Abstract Immune checkpoint blockade (ICB) has shown low response rates for advanced breast cancer, and combinatorial strategies are needed to improve the effect of ICB. As an effective local therapy, microwave ablation (MWA) may be a trigger of antitumor immunity. This window-of-opportunity trial was conducted to determine the safety and feasibility of camrelizumab (anti-PD-1 antibody) combined with MWA in the treatment of early-stage breast cancer preoperatively. The peripheral immune response was also investigated. 60 participants were randomized to receive single-dose camrelizumab alone (n=20), microwave ablation (n=20), or both camrelizumab and microwave ablation (n=20), preoperatively. Camrelizumab and MWA were well tolerated alone and in combination. Different from that in single-dose camrelizumab or MWA group, participants showed stable quantity of blood cells after the combination therapy. After the combination therapy, peripheral CD8+T cells showed enhanced cytotoxic and effect-memory functions. Clonal expansional CD8+T cells showed different functions from emergent clones after the combination therapy, suggesting that the expansional clones may play a vital role in the enhanced biological functions of CD8+T cells. Enhanced interactions between clonal expansional CD8+T cells and monocytes was observed, suggesting monocytes contributed to enhanced functions of clonal expansional CD8+T cells. MHC I related pathways and interferon signaling pathways were activated in monocytes by the combination therapy. In conclusion, camrelizumab combined with MWA was feasible for the treatment of early-stage breast cancer. The peripheral CD8+T cells were activated after the combination therapy, dependent on monocytes with activated MHC I pathways. Citation Format: Wenbin Zhou, Hui Xie, Qiang Ding, Shui Wang. Preoperative single-dose camrelizumab and/or microwave ablation in women with early-stage breast cancer: A randomized window-of-opportunity trial [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 PO3-18-03.
Abstract SoA1-02: Engineered T cell therapies- what is the outlook for breast cancer?
Authors: V. Hoyos Velez
Journal: Cancer Research (2024)

Abstract With the promising outcomes seen in hematological malignancies, engineered T-cell therapies, notably chimeric antigen receptor (CAR) therapies, have emerged as breakthroughs in the field of oncology. Yet, their prospect in treating breast cancer and other solid tumors remains a topic of intense investigation. This presentation aims to delve into the diverse engineered T-cell treatments, contextualizing their role in breast cancer. We explore the intrinsic therapeutic challenges these modalities face and the concerted efforts in the scientific community to overcome them. We will look at the current clinical trial landscape for CAR-T cell therapies in breast cancer, underscoring their potential in shaping breast cancer treatment in the years to come. Citation Format: V. Hoyos Velez. Engineered T cell therapies- what is the outlook for 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 SoA1-02.