tbuckley/cabot-search huggingface dataset:
Abstract PS18-10: Tumor-Infiltrating Lymphocytes and Breast Cancer Mortality in Racially and Ethnically Diverse Participants of the Northern California Breast Cancer Family Registry
Authors: Julia Ransohoff, Iain Miller, Jocelym Koo, Vishal Joshi, Allison Kurian, Kimberly Allison, Esther John, Melinda Telli
Journal: Cancer Research (2024)

Abstract Purpose: Greater stromal tumor-infiltrating lymphocyte (sTIL) percentage in pre-treatment breast tumor specimens is associated with superior response to neoadjuvant chemotherapy and survival. We hypothesized that sTIL-survival associations vary by race and ethnicity and mediate survival disparities. Patients and Methods: We evaluated pre-treatment percentages of sTILs in deciles for 284 women enrolled in the Northern California Breast Cancer Family Registry and diagnosed with a first primary invasive breast cancer from 1995-2005. We assessed associations of continuous sTIL scores and lymphocyte-predominant breast cancer (LPBC, defined as ≥50% lymphocytic infiltration of tumor stroma or cell nests) with clinical and epidemiologic characteristics using regression analysis and with breast cancer-specific mortality (BCM) and overall mortality (OM) using Cox proportional hazards regression. Results: The cohort was diverse (64% from racially and ethnically minoritized populations) with near-complete (98%) germline BRCA1/2 testing and long-term follow-up (average 16.2 years, range: 1.3-26.7). In multivariable analyses, higher sTIL score was associated with reduced BCM [LPBC versus non-LPBC: HR=0.44 (95% confidence interval 0.20-0.98); and per decile increase in sTIL score: HR=0.80 (0.69-0.93)], with the strongest association in the subset of patients with hormone receptor-negative disease [HR=0.71 (0.57-0.88) and HR=0.37 (0.14-0.94), respectively]. While there was no significant difference in sTIL score between racial and ethnic groups, the continuous sTIL-survival association was statistically significant among non-Hispanic White [HR=0.73 (0.57-0.94)] and Asian American [HR=0.56 (0.35-0.89)] women but was not seen among African American and Hispanic women. Conclusion: We identified novel sTIL-BCM differences by race and ethnicity, with better survival associated with sTIL enrichment among non-Hispanic White and Asian American but not among African American or Hispanic women. Additional studies are needed to determine whether survival and particularly the response to immunotherapy are differentially mediated by immune factors between racial and ethnic groups. Multivariable Cox Proportional Hazards Regression Models of Breast Cancer-Specific and Overall Mortality. Citation Format: Julia Ransohoff, Iain Miller, Jocelym Koo, Vishal Joshi, Allison Kurian, Kimberly Allison, Esther John, Melinda Telli. Tumor-Infiltrating Lymphocytes and Breast Cancer Mortality in Racially and Ethnically Diverse Participants of the Northern California Breast Cancer Family Registry [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 PS18-10.
Abstract PO5-04-06: Enhancing Antitumor Activity of Her2 CAR T cells through TR2BB Co-Expression and Cytokine Signal 3 Incorporation
Authors: Diego Chamorro, Lauren Somes, Emily Madaras, Saisha Nalawade, Paul Shafer, Andres Mosquera, Mary Kathryn McKenna, Valentina Hoyos
Journal: Cancer Research (2024)

Abstract Chimeric antigen receptor T cells (CARTs) targeting Her2 represent a promising approach for the treatment of patients with Her2 expressing breast cancers (BC). Her2 CARTs confront major challenges within the immune-suppressive tumor microenvironment (TME) of breast cancer, which inhibits sustained T cell proliferation and persistent antitumor activity. To bolster Her2 CARTs' expansion and persistence, we engineered a TNF-related apoptosis-inducing ligand receptor 2 (TR2) specific scFv connected to the endodomain of 4-1BB (TR2BB). TR2BB co-expressing Her2 CARTs exhibited enhanced antitumor potential against BC tumors by triggering myelod derived suppressor cell (MDSC) apoptosis, thereby remodeling the TME and promoting T cell proliferation. Despite better tumor control in mice receiving CAR.TR2BB T cells, recent trials have demonstrated the importance of incorporating a cytokine signal for optimal tumor control in patients with solid tumors. Thus, we hypothesized that we could further augment anti-tumor activity of Her2 CAR.TR2BB T cells against BC by incorporating a cytokine signal 3 through IL-15 or C7R. We engineered the CARTs to (1) ectopically produce IL-15, a crucial T-cell homeostasis and survival cytokine, and (2) express a constitutively active IL-7 receptor (C7R) that triggers IL-7 receptor signaling independently of ligand or the common receptor gamma chain (γc). Our repeat weekly tumor challenge assay revealed that CAR.TR2BB.IL15 T cells outperformed CAR.TR2BB.C7R and CAR.TR2BB in T cell proliferation. Both CAR.TR2BB.IL15 and CAR.TR2BB.C7R exhibited improved cytotoxic potential after three weeks of antigen stimulation compared to CAR.TR2BB alone in comparison with CAR.TR2BB alone. Furthermore, in our in vivo xenograft NSG mouse models implanted with Her2 expressing breast cancer cell line and MDSCs, CAR.TR2BB.IL15 T cells showed superior tumor control and improved survival rates. In summary, the addition of IL15 transgene to our TME targeting Her2 CARTs provides an advantage in terms of T cell persistence, proliferation, and tumor control in in vitro and in vivo models. These promising preclinical results propel us to apply this optimized Her2 targeting CART therapy in a phase I clinical trial for patients with metastatic Her2-expressing breast cancers. Citation Format: Diego Chamorro, Lauren Somes, Emily Madaras, Saisha Nalawade, Paul Shafer, Andres Mosquera, Mary Kathryn McKenna, Valentina Hoyos. Enhancing Antitumor Activity of Her2 CAR T cells through TR2BB Co-Expression and Cytokine Signal 3 Incorporation [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 PO5-04-06.
Abstract PS03-01: Single cell analysis of paired lymph nodes and primary tumors in breast cancer patients
Authors: Marit Fjørtoft, Inga Rye, Kanutte Huse, June Myklebust, Hege Russnes, Margit Riis, Ole Christian Lingjærde, Øystein Garred, Karin Teien Lande, Inger Riise Bergheim, Ellen Schlichting
Journal: Cancer Research (2024)

Abstract A sentinel lymph node (SN) is the primary node draining the tumor and is assumed to be affected early in the metastatic process. The sentinel node holds a key position in the immune response against tumor in breast, and represents a unique connection between the tumor and the host immune response. We hypothesize that the immune profile in the primary tumor and the paired lymph node (LN) is different during tumor progression. 3.7 million single cells from paired primary tumor and lymph nodes from 33 breast cancer patients (Oslo2 cohort) was analyzed by single cell mass cytometry (CyTOF) with a 47 antibody immune panel and characterized by a semi-automatic gating approach (FlowSOM). Tumor cells were found in 11 LN. When analyzing the leucocytes from LN we identified a significant difference in immune cell type skewing towards higher abundance of memory CD4 and CD8 T cells expressing an exhausted phenotype in LN with metastasis. In addition, a higher abundance of activated Tregs and significantly lower abundance of resting Tregs was found in the metastatic LNs compared to the sentinel lymph nodes. The change in immune composition and exhaustion was correlated to the metastatic tumor burden. The skewing towards an exhausted immune profile was also found in larger primary tumors compared to smaller primary tumors. We further analyzed tumor cells from 8 patients with paired primary tumor and LN. No differences were identified in the primary tumor when stratified by LN status, but LNs with smaller metastasis expressed lower levels of epithelial markers essential in the Epithelial-to-Mesenchymal Transition such as E-cadherin, Pan Cytokeratin and EpCAM – this in contrast to the LN with manifested metastasis in the axilla which expressed higher levels of epithelial markers and lower levels of mesenchymal markers such as Vimentin and CD44. We identified a skewing in the immune profile from a naive phenotype towards a memory and exhausted phenotype in CD8 and CD4 T cell population in LN with manifested metastasis, as well as in larger primary tumors. We also identified that tumor cells in smaller metastatic tumors resembled a “mesenchymal like” phenotype compared to in the larger manifested tumors. These results suggest that the immune suppression is correlated with the tumor burden. Citation Format: Marit Fjørtoft, Inga Rye, Kanutte Huse, June Myklebust, Hege Russnes, Margit Riis, Ole Christian Lingjærde, Øystein Garred, Karin Teien Lande, Inger Riise Bergheim, Ellen Schlichting. Single cell analysis of paired lymph nodes and primary tumors in breast cancer patients [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 PS03-01.
Abstract PO4-10-07: Understanding Psychological distress in patients prior to breast cancer diagnosis:Mixed Methods Study
Authors: Yan Gao, Jinnan Gao
Journal: Cancer Research (2024)

Abstract Purpose:While the association between diagnosis of breast cancer and post-diagnosis psychological distress has been well documented, data regarding pre-diagnosis psychological distress in the breast cancer population are limited. The purpose of the current study is to measure the distress levels of patients prior to breast cancer diagnosis, to identify the categories of distress they have, and describe the experience of distress of patients before diagnosis. Methods: This study uses a mixed research method of cross-sectional survey and qualitative interviews. In the quantitative part, a cross-sectional survey of 118 patients with completed breast biopsies awaiting pathological diagnosis was conducted using the National Comprehensive Cancer Network’s (NCCN’s) Distress Thermometer(DT) and Problem List (PL), In the qualitative part, 15 patients were invited using convenient and purposive sampling. Data was collected using a semi-structured face-to-face interview and recorded. The transcribed text was analyzed using Colaizzi's phenomenological method. Results: The results reveal that 63.6% of patients reported a higher level of psychological distress (n=75, scoring≥4).Most patients had emotional (98%) or physical (64%) problems. Among these, worry or anxiety (47.5%), fear (33.1%), finances (21.2%), sadness and depression(18.6%), and grief or loss(15.3%) were the most frequently reported problems. Multivariate logistic regression analysis showed that the factors associated with psychological distress before the diagnosis of breast cancer patients were age, education level. The experience of patients before diagnosis emerged five themes: Very high psychological distress index; Strong uncertainty; The demand of information; Guilt for the family; Hoped for psychological support from the health care team. Conclusions: Psychological distress is prevalent prior to breast cancer diagnosis and may merit early intervention. Understanding patients’ distress may help guide future psychosocial needs assessments and interventions to promote patient quality of life. Table 1 Sample characteristics (n=118). Table 2 Univariate analysis of predictors associated with psychological distress Table 3 The binary logistic regression model of psychological distress Citation Format: Yan Gao, Jinnan Gao. Understanding Psychological distress in patients prior to breast cancer diagnosis:Mixed Methods Study [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 PO4-10-07.
Abstract PO5-02-13: Distinct differences in the prognostic implication of tumor size for invasive lobular carcinoma of breast when compared to invasive ductal carcinoma
Authors: Ik Beom Shin, Eunhye Kang, Ji-Jung Jung, Hawjeong Lee, Jin Young Byeon, Yunhee Choi, Changjin Lim, Jong-Ho Cheun, Hong-Kyu Kim, Han-Byoel Lee, Wonshik Han, Hyeong-Gon Moon
Journal: Cancer Research (2024)

Abstract Purpose Invasive lobular carcinoma (ILC) is the second common types of breast cancer and its clinicopathological feature and outcomes differ from invasive ductal carcinoma (IDC). However, in terms of survival outcomes, there are conflicting data on the prognostic implication of the ILC when compared to that of IDC. This study aims to evaluate the survival outcomes of patients diagnosed with ILC at single center and compared them with those of IDC. Methods We reviewed the data of the 13,034 IDC patients and 935 ILC patients who were treated between January 2005 and December 2022 at Seoul National University Hospital. We investigated the overall treatment outcomes of two histologic types with a special focus on the tumor size and lymph nodes. Result ILC exhibited distinct characteristics compared to IDC, including a larger tumor size (2.6 ± 1.8 vs. 1.9 ± 1.1 cm, p &amp;lt; 0.001) and a higher hormone receptor positivity (97.4% vs. 79.3%, p &amp;lt; 0.001). Additionally, the presence of lymphovascular emboli was lower in ILC (8.0% vs. 24.6%, p &amp;lt; 0.001). While IDC patients showed slightly better overall survival (OS) than ILC (10-year OS, ILC 89.9% vs. IDC 91.1%, the difference was not statistically significant (p = 0.85). However, distant metastasis-free survival (DMFS) was significantly higher in ILC (10-year DMFS, ILC 93.2% vs. IDC 89.9%, p = 0.001). Age at diagnosis, tumor size, presence of lymphovascular emboli, high expression of Ki-67, and higher pathologic N stage were poor prognostic markers for ILC. Multivariate analysis for DMFS showed that age, high expression of Ki-67 and higher pathologic N stage were poor prognostic markers for ILC. Tumor size was not an independent prognostic factor for DMFS (HR: 0.92, 95% CI: 0.72-1.17, p = 0.491) and for OS (HR: 1.18, 95% CI: 0.99-1.41, p = 0.060) in ILC. Conclusion Our data suggest that the tumor size, which is a well-known prognostic factor in IDC, carries distinctly different prognostic implication in ILC. These observation indicate that adjuvant treatment decisions based on tumor size can be tailored to different histologic subtypes of breast cancer. Citation Format: Ik Beom Shin, Eunhye Kang, Ji-Jung Jung, Hawjeong Lee, Jin Young Byeon, Yunhee Choi, Changjin Lim, Jong-Ho Cheun, Hong-Kyu Kim, Han-Byoel Lee, Wonshik Han, Hyeong-Gon Moon. Distinct differences in the prognostic implication of tumor size for invasive lobular carcinoma of breast when compared to invasive ductal carcinoma [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-02-13.
Abstract PS03-09: Age-related normal breast tissue features differ in women with germline BRCA1/2 mutations
Authors: Anita Grigoriadis, Mario Parreno-Centeno, Siyuan Chen, Gregory Verghese, Esther Lips, Cheryl Gillett, Louise Jones, Sarah Pinder
Journal: Cancer Research (2024)

Abstract Ageing, a breast cancer risk factor, can be reflected in histologically normal breast tissue (NBT). However, the relationship between age-related histological features and cancer risk is not fully understood. We propose that biological and microscopic features can be identified in seemingly histologically NBT in gBRCA1/2m carriers that are indicative of the earliest tissue changes of breast cancer, potentially as a result of accelerated tissue ageing. To study NBT, we have put in place a unique and scalable repository, named OASIS, storing currently &amp;gt;2,000 digitised whole slide images (WSI) of H&amp;E-stained NBT from individuals with long clinical follow-up. These tissues are from individuals with a spectrum of risk for developing breast cancer and derived from reduction surgery from non-gBRCA1/2m carriers, risk reducing masectomies, and from contralateral and peri-tumoural NBT from gBRCA1/2m carriers and women with breast cancer. Across 6 NBT resources, 70 selected WSIs were manually annotated for epithelial cells, fibrous stroma and adipocytes, resembling the "ground truth". Extensive comparisons of different tile sizes, tile overlapping ratios, stain normalisation techniques and deep learning (DL) feature extractors were conducted to implement a Tissue-Classifier, which achieved 95% accuracy in 3-fold cross-validation. Based on the MobileNet architecture, a DL-framework achieved a sensitivity of 81.2% and specificity of 81.8% (84.7% AUC) in predicting Tissue-Age based on discernible histological patterns in healthy women. In gBRCA1/2m carriers, we discovered features of accelerated tissue ageing (e.g. degree of lobule involution), indicating that the biological NBT age differs from their chronological age. Our DL-based framework robustly captured histological patterns to predict tissue components and age. The global organisation of these patterns showed variations in WSIs of women with different risks of developing breast cancers, which may provide new insights into premalignant alterations in NBT. Citation Format: Anita Grigoriadis, Mario Parreno-Centeno, Siyuan Chen, Gregory Verghese, Esther Lips, Cheryl Gillett, Louise Jones, Sarah Pinder. Age-related normal breast tissue features differ in women with germline BRCA1/2 mutations [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 PS03-09.
Abstract PO4-28-11: Murine Breast Cancer Cell Culture Supernatant Induces CAF-like and TAM-like Traits in Normal Cells
Authors: Biplov Sapkota, Naveen Chintalaramulu, Abhishek Pandit, Shilpa Thota, Rizwana Begum, Joseph Francis
Journal: Cancer Research (2024)

Abstract Several studies in the past have demonstrated the role of cell-to-cell interaction (crosstalk) between tumor cells and normal (nontumorigenic) cells in cancer progression and metastasis. Within the tumor microenvironment (TME), these interactions have a potential to transform the phenotypes and the behaviors of normal cells. Application of the 2D in-vitro cultures has been limited due to its inability to replicate the complex in-vivo TME. Conditioned Medium (CM) obtained from cultured cancer cells contains secreted growth factors that potentially regulate the phenotype and the functionality of normal cells. In this study, a culture of normal murine fibroblast NIH3T3 and macrophage RAW 264.7 cells with conditioned medium (CM) obtained from malignant mammary epithelial 4T1 cells (4T1CM) resulted in an altered phenotype with increased cell viability. 4T1CM treated NIH3T3 and RAW 264.7, in comparison with the respective control cells, resulted in an upregulation of the genes including- α-smooth muscle actin (αSMA), IL-10, CD206, and vascular endothelial growth factor (VEGF). In addition, 4T1.CM treated NIH3T3 showed an EMT phenotype as indicated by the regulation of EMT markers such as, E-cadherin, β-catenin, N-cadherin, and Vimentin. Interestingly, an upregulation of cyclooxygenase-2 (COX-2) and programmed death-ligand 1 (PDL-1) was observed in 4T1CM treated RAW 264.7, a tendency towards exhibiting an inhibitory immune response. Intriguingly, NIH3T3 cells conditioned with 4T1CM demonstrated an upregulation of stemness markers including- sex determining region Y-box 2, and Aldehyde dehydrogenase. Collectively, our study suggested a role for 4T1CM in transforming the normal NIH3T3 and RAW 264.7 into cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs). RNAseq experiments are underway to map differentially expressed genes (DEGs) that potentially regulate the 4T1CM induced transformation of NIH3T3 and RAW 264.7 cells. Furthermore, invitro drug testing in 3D model of these transformed cells to target the pathway intermediates may provide novel therapeutic intervention strategies. Citation Format: Biplov Sapkota, Naveen Chintalaramulu, Abhishek Pandit, Shilpa Thota, Rizwana Begum, Joseph Francis. Murine Breast Cancer Cell Culture Supernatant Induces CAF-like and TAM-like Traits in Normal Cells [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 PO4-28-11.
Abstract PO4-28-05: Prolactin drives labile iron transfer from macrophages to breast cancer cells through CD44
Authors: Reagan Farrell, Nicholas Pascuzzi, Yi-Ling Chen, Miguel Torres, Mary Kim, Lauren Gollahon, Kuan-Hui Chen
Journal: Cancer Research (2024)

Abstract Cancer cells are “ferrophilic” and exhibit great dependence on iron. While iron metabolism is closely related to tumor development, the source of iron and the mechanisms cancer cells adopt to actively acquire iron is not well understood. In the present study, we discovered a novel function of the lactating hormone, prolactin, in the regulation of iron transport. In breast cancer cells using mouse triple negative breast cancer cell lines EO771 and Py230 for demonstration, prolactin stimulation increased intracellular labile iron pool. Analyses of gene expression involved in iron transport revealed dramatic induction of CD44, a surface receptor for iron bound hyaluronan. Other genes involved in iron uptake including transferrin receptor (TFRC), CD163 and divalent metal transporter 1 (DMT1) were not changed. The utilization of neutralizing antibodies against CD44 significantly blocked prolactin mediated labile iron pool accumulation in breast cancer cells. In contrast to what was found in breast cancer cells, prolactin had the opposite impact on immune macrophages. Prolactin treatment increased ferroportin (FPN I, iron exporter) but had no influence on all iron uptake transporters leading to net iron release by macrophages. To further determine if the iron released by macrophages can be a direct source of iron utilized by breast cancer cells, we conducted co-culture work of macrophages with pre-stained labile iron pool and breast cancer cells without any iron staining and found a gradual increase of fluorescent iron pool developed in breast cancer cells over time. In conclusion, our work presents a multidisciplinary regulation of iron transport among prolactin, macrophages, and cancer cells. The novel regulatory role of prolactin to drive iron flow can provide new information on fine-tuning immune responses in tumor microenvironment and potentially benefit the development of novel therapeutics. Citation Format: Reagan Farrell, Nicholas Pascuzzi, Yi-Ling Chen, Miguel Torres, Mary Kim, Lauren Gollahon, Kuan-Hui Chen. Prolactin drives labile iron transfer from macrophages to breast cancer cells through CD44 [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 PO4-28-05.