tbuckley/cabot-search huggingface dataset:
Abstract PO4-09-08: Perceptions and Experiences of Black Women on Family History Sharing and Genetic Testing for Hereditary Breast and Ovarian Cancer
Authors: Kirsten Riggan, Jane Yap, Ewan Cobran, Michele Halyard, Sarah James, Marion Kelly, Daphne Phillips, Megan Allyse
Journal: Cancer Research (2024)

Abstract Black women experience significant disparities in morbidity and mortality related to hereditary breast and ovarian cancer (HBOC). Early identification of women with HBOC is essential for proactive screening and timely diagnosis. However, evidence suggests that Black women receive genetic testing for HBOC at lower rates than their White counterparts. We conducted in-depth qualitative interviews with 107 Black women with a personal or family history of breast or ovarian cancer, to understand their perceptions of their familial risk of HBOC and interest in genetic testing. In phase 1 of this study, participants were recruited from the networks of patient support organizations and historically Black sororities representing mostly highly educated and well insured patients. In phase 2, participants were recruited from a family medicine safety net clinic in Jacksonville, FL for socioeconomic diversity. Participants in both cohorts frequently expressed a lack of awareness about their family cancer history and identified many barriers to family disclosure of a cancer diagnosis. These include a culture of silence around medical issues and a belief that personal difficulties should be kept to oneself. Practical and cultural barriers to family history sharing were magnified among those with lower socioeconomic status. Many participants in both cohorts indicated a strong desire to understand their own risk of HBOC. They also expressed interested in genetic testing to proactively mitigate risk to themselves and future generations. Understanding of the potential relevance of HBOC testing to one’s personal health and post-test actionability was variable across both groups, although perceptions of genetic testing were generally favorable. These findings suggest that culturally tailored educational materials and alternative clinical modalities to collect family health history may be beneficial to improve timely identification of Black women who meet NCCN Guidelines for HBOC testing. Specifically, greater attention should be given to addressing barriers that led to underestimation of HBOC risk among patients experiencing disparities driven by adverse social determinants of health. Citation Format: Kirsten Riggan, Jane Yap, Ewan Cobran, Michele Halyard, Sarah James, Marion Kelly, Daphne Phillips, Megan Allyse. Perceptions and Experiences of Black Women on Family History Sharing and Genetic Testing for Hereditary Breast and Ovarian 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 PO4-09-08.
Abstract PO5-27-05: Computational design and validation of a novel peptide-drug conjugate for treatment of triple negative breast cancer
Authors: Francine Liu, Andrew Zhai, Ozge Yoluk, Aron Broom, Tracy Stone, Glenn Butterfoss, Serban Popa, Tianyu Li, Lucas Siow, Christopher Ing, David White
Journal: Cancer Research (2024)

Abstract Sortilin (SORT1) is a member of the vacuolar protein sorting 10 protein (Vps10p) family that functions as a receptor regulating peptide and protein trafficking between the plasma membrane, lysosomes, and trans-golgi network. As a cell surface receptor, SORT1 is able to mediate efficient endocytosis of extracellular ligands to the lysosomal compartment. Numerous reports have identified enriched SORT1 expression in a variety of tumor types, including triple-negative breast cancer (TNBC), a subtype of breast cancer associated with aggressive clinical behavior and poor disease outcomes. We sought to exploit SORT1-dependent internalization of peptides as a platform for rapid and specific chemotherapy delivery into TNBC cells. Using ProteinStudio (our proprietary computation-enabled design capabilities), we generated high-affinity SORT1 targeting peptides that exhibit efficient receptor dependent internalization and lysosomal localization. Alternative computational approaches such as AlphaFold2 failed to recapitulate the peptide design. Peptide drug conjugates (PDCs) were generated via a linkage strategy that combines our designed peptides to the antimitotic agent monomethyl auristatin E (MMAE). Our PDC molecules exhibit potent tumor regression in a MDA-MB-231 TNBC cell derived xenograft model, thereby highlighting the potential of SORT1-engaging PDCs as an efficacious targeted chemotherapeutic delivery strategy. Citation Format: Francine Liu, Andrew Zhai, Ozge Yoluk, Aron Broom, Tracy Stone, Glenn Butterfoss, Serban Popa, Tianyu Li, Lucas Siow, Christopher Ing, David White. Computational design and validation of a novel peptide-drug conjugate for treatment of triple negative 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 PO5-27-05.
Abstract PO4-24-12: Premenopausal breast cancers show higher proportion of immunologically cold tumors and are associated with distinct immune cell infiltrate
Authors: Vidya P Nimbalkar, Snijesh VP, Savitha Rajarajan, Annie Alexander, Rakesh Ramesh, B S Srinath, Jyothi S Prabhu
Journal: Cancer Research (2024)

Abstract Background Breast cancers (BC) in the young women tend to have poor outcomes and higher proportion of aggressive subtypes. Immunotherapy has shown promising results lately, especially for aggressive categories like triple negative breast cancers (TNBC). Success of the immunotherapy is shown to be dependent on the tumor immune microenvironment (TIME) which plays important role in disease progression and response to therapy. Though numerous studies have demonstrated immune hot tumors are associated with better prognosis, mechanism of immunologically hot TIME is not yet deciphered. Material and methods Gene expression data derived from RNA sequencing (n=40) of primary BC was used to divide them into immune hot and cold tumors by using 15 gene signature (Wang et al., Sci. Adv. 2021). Average expression of the hot and cold (hot=12 and cold=3) genes was derived for each tumor and median value of their ratio was used to categorize them into immunologically hot and cold tumors. Association of the hot and cold tumors with clinical characteristics was examined. CIBERSORT algorithm was used to identify immune cell subtypes and Kaplan Meier survival analysis was performed to assess the prognostic significance. Similar analysis was replicated in TCGA (n=1083) dataset. Results Equal proportion of immune hot and cold tumor was observed in the cohort. Higher proportion of cold tumors were observed in younger and premenopausal (p=0.002) patients. Subtype analysis showed higher proportion of cold tumors in TNBC compared to hormone receptor positive tumors (p&amp;lt; 0.0001). No significant difference was observed in other clinicopathological characteristics between the groups. Further analysis of cold tumors for immune cell subtypes, categorized by the menopausal status showed higher proportion of plasma cells and CD4 memory resting cells and lower proportion of M2 macrophages and B memory cell in premenopausal (n=129, TCGA) compared postmenopausal (n=322, TCGA) tumors. In addition, premenopausal cold tumors were associated with better overall survival compared to postmenopausal group (p=0.001). Conclusion Younger premenopausal women with BC are likely to have more immunologically cold tumors. Though circulating levels of sex steroid hormones is the predominant difference between the pre and postmenopausal women, its influence on TIME and therapeutic significance must be explored. Citation Format: Vidya P Nimbalkar, Snijesh VP, Savitha Rajarajan, Annie Alexander, Rakesh Ramesh, B S Srinath, Jyothi S Prabhu. Premenopausal breast cancers show higher proportion of immunologically cold tumors and are associated with distinct immune cell infiltrate [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 PO4-24-12.
Abstract PO5-25-02: Microenvironment based co-culture dependence of breast cancer and immune cell interactions on functional outcomes
Authors: Karen Norek, Jacob Kennard, Kenneth Fuh, Robert Shepherd, Kristina Rinker, Olesya Kharenko
Journal: Cancer Research (2024)

Abstract The tumour microenvironment (TME) includes physical forces from interstitial fluid flow and cell-cell interactions that modulate cancer development and progression through activation of multiple oncogenic pathways leading to tumor growth and metastatic spreading. We previously reported on the role of physical forces on epithelial to mesenchymal transition (EMT) and S100 gene family expression and cell to cell adhesion properties with implications to normal breast development and cancer. Signals from the tumor exit the local tumor environment through interstitial fluid transport and cell migration where they can be found in the blood stream. We developed a whole blood RNA gene expression biomarker panel coupled with proprietary software capable of identifying the presence of an active breast cancer signature at early stages of disease with clinical study results previously reported. Here we report on results from transcriptomic and function studies with cell interaction models. Cancer cells can influence immune cells through direct contact or via secreted molecules causing the immune cells to undergo functional changes. To investigate mechanisms involved in the induction of these alterations in a model system, we performed co-culture studies with human monocytic cells and breast cancer cells. Interaction of human monocytic cells with the breast cancer cells caused significant changes in both behavior and transcriptomes. Moreover, using RNAseq and pathway analysis we demonstrated that the changes induced through the exposure to the more aggressive triple negative (TNBC) phenotype were distinct from the alterations triggered upon contact with an ER+ breast cancer cell line. We also show that cancer-immune crosstalk triggers EMT as well as activation of multiple oncogenic pathways associated with cell migration and invasion, cell chemotaxis and cell-to-cell interactions. As the interplay between cancer and immune cells plays an important role in cancer progression, these findings provide important insight into key mechanisms controlling these outcomes. Citation Format: Karen Norek, Jacob Kennard, Kenneth Fuh, Robert Shepherd, Kristina Rinker, Olesya Kharenko. Microenvironment based co-culture dependence of breast cancer and immune cell interactions on functional outcomes [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 PO5-25-02.
Abstract PO5-22-11: Radiotherapy-associated Complications in Breast Cancer patients treated with Nipple-Sparing Mastectomy: Results of the Reconstruction-after-Mastectomy AGO R02 Registry
Authors: Florentia Peintinger, Elisa Sieghartsleitner, Bernhard Pfeifer, Gunda Pristauz-Telsnigg, Georg Tsangarakis, Rüdiger Hochstätter, Rupert Koller, Ursula Denison, Christopher Hager, Roland Reitsamer
Journal: Cancer Research (2024)

Abstract Nipple-Sparing mastectomy (NSM) followed by implant-based breast reconstruction is an oncologically safe procedure increasingly used in patients with breast cancer. A proportion of patients treated with NSM will be receiving adjuvant radiotherapy according to contributing factors indicating radiotherapy use. Methods Data from six breast centers in Austria were entered in the AGO R02 Registry from women who underwent breast reconstruction after mastectomy between 2012 and 2022 to evaluate complications associated with surgical techniques and selection of patients. Univariate analysis was used to identify factors that may impact surgical outcome. Results The registry included a total of 744 female patients. Of 913 NSMs, 730 NSMs were followed by implant-based reconstruction. Adjuvant radiotherapy was administered in 132/730 patients (18%). In this group minor complications (infection, hematoma) were observed in 6 patients (4.5%) and major complications requiring additional surgery (wound breakdown, skin and/or nipple necrosis) were observed in 16 patients (12.1%) in a short term follow up of 4 months (mean). In the group of patients without adjuvant radiotherapy minor complications (infection, hematoma) were observed in 33 patients (4.5%) and major complications (wound breakdown, skin and/or nipple necrosis) were observed in 75 patients (10.3%). In both groups no statistically significant association was observed between complications and age, body mass index, diabetes, preoperative chemotherapy, implant position (pre/subpectoral), use of mesh. Smoking and chemotherapy were the only factors associated with higher proportion of minor complications in patients not receiving radiotherapy. Conclusions Women treated with adjuvant radiotherapy after NSM followed by implant-based reconstruction have a higher incidence of major complications requiring additional surgery in comparison with women treated without radiotherapy in a short term follow up. Considering new radiotherapy techniques/volumes and early multidisciplinary planning may optimize multimodal treatment in these patients. Supported by AGO Österreich Citation Format: Florentia Peintinger, Elisa Sieghartsleitner, Bernhard Pfeifer, Gunda Pristauz-Telsnigg, Georg Tsangarakis, Rüdiger Hochstätter, Rupert Koller, Ursula Denison, Christopher Hager, Roland Reitsamer. Radiotherapy-associated Complications in Breast Cancer patients treated with Nipple-Sparing Mastectomy: Results of the Reconstruction-after-Mastectomy AGO R02 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 PO5-22-11.
Abstract PO5-24-10: Clinical significance and immune landscape analyses of the immune related genes based prognostic signature for HER2 positive breast cancer
Authors: Xiaofen Li, Wenfen Fu, Yushuai Yu, Jie Zhang, Chuangui Song
Journal: Cancer Research (2024)

Abstract Objective: To date, significant breakthrough has yet to be achieved in immunotherapy for HER2-positive breast cancer (HPBC). In this study, we aimed to construct a risk model for predicting prognosis and therapy response and evaluating the tumor immune landscape in HPBC patients. Methods: Differentially expressed immune-related genes (IRGs) were used as input to weighted correlation network analysis (WGCNA) to identify modules of highly correlated gene. An optimal prognostic TPBC-IRGs signature were constructed by least absolute shrinkage and selection operator (LASSO) cox regression. Survival analysis and ROC curves were analyzed to identify the predictive value in a training cohort and external validation cohorts. With three GEO datasets and samples from our center, the anti-HER2 therapeutic efficacy in HPBC patients was predicted through this prognostic model. Additionally, the immunotherapy outcome was forecasted using IMvigor210 dataset. We also investigated the connection between high and low-risk populations and immune checkpoints and analyzed immune infiltration levels of these populations with several algorithms. Ultimately, we develop a combined model and nomogram by integrating the risk score with clinical factors. Results: 11 key genes associated with overall survival (OS) in the blue module were selected for further analysis. A 3-gene signature (CX3CL1, RARB, TANK) based prognostic risk model was developed. The Kaplan-Meier survival curve revealed that patients with high-risk score had shorter OS compared with the low-risk group. The AUC of the training cohort at 1-, 3- and 5-year were 0.718, 0.784 and 0.767. The performance of the risk model was validated with GSE25066 and GSE55348. It’s showed that the risk scores of HPBC who were resistant to trastuzumab were significantly higher than those of patients who were sensitive to trastuzumab. The results indicated that the levels of immune checkpoints expression (such as PD-1, CTLA4 and TIGIT) and immune infiltration were higher in low-risk group than in high-risk group. The combined model showed better prognostic prediction accuracy compared to the clinical model or gene signature alone (1-year AUC=0.910;3-year AUC=0.832;5-year AUC=0.882). Conclusion: The immune gene-based risk profile and combined prognostic model in this study may hold promise for clinical use in predicting the prognosis and treatment efficacy of HPBC patients. figure3. Construction of HPBC-IRGs signature based prognostic model. Citation Format: Xiaofen Li, Wenfen Fu, Yushuai Yu, Jie Zhang, Chuangui Song. Clinical significance and immune landscape analyses of the immune related genes based prognostic signature for HER2 positive breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-24-10.
Abstract PO5-25-05: Crosstalk between adipocyte and tumor cells with ESR1 mutations via adipsin enhances tumor growth
Authors: Artem Belyakov, Kideok Jin
Journal: Cancer Research (2024)

Abstract While endocrine therapies have shown clinical benefits for breast cancer with ESR1 mutations, resistance development is a significant challenge. Evidence suggests that the complement system is critical to tumor development, and recent studies highlight the role of adipsin in breast cancer growth. In a previous study, we characterized the role of complement pathway-mediated adipsin in ESR1 mutant cell lines (Y537S and D538G), identifying the upregulation of adipsin, C3, and C3aR in ESR1 mutant cells. The interaction between C3a and C3aR enhanced ESR1 mutant cell growth, and inhibiting C3aR abolished cell growth and increased apoptosis. Combining C3aR inhibitors with fulvestrant or CDK4/6 inhibitors had a synergistic inhibitory effect on ESR1 mutant cells. Our findings suggest that the complement pathway plays a role in ESR1 mutant cell proliferation and that C3aR is a potential target to mitigate ESR1 mutant breast cancer growth and metastasis. Additionally, we demonstrated the critical role of the feedback loop of adipsin in ESR1 mutant cell growth in adipocyte crosstalk. Using differentiated mouse 3T3-L1 adipocytes induced with tumor-conditioned media from ESR1 mutant cells, we observed the upregulation of adipsin, C3, and C3a in the adipocyte secretome, which enhanced C3a levels. Blocking the interaction between C3a and C3aR in ESR1 mutant cells using a C3aR inhibitor significantly inhibited ESR1 mutant cell growth compared to wild-type cells and enhanced apoptosis. Our findings suggest that upregulation of adipsin from ESR1 mutant cells and adipocytes in crosstalk increases tumor cell growth. Future studies will investigate the critical role of adipsin's auto- and paracrine effects in breast cancer with ESR1 mutations. Citation Format: Artem Belyakov, Kideok Jin. Crosstalk between adipocyte and tumor cells with ESR1 mutations via adipsin enhances tumor growth [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 PO5-25-05.
Abstract PO5-27-10: Next generation antibody drug conjugates: Multi-payload conjugates targeting multiple mechanisms of cell killing
Authors: Marco Lobba, Devin Trinter, Maxwell Nguyen, Daniel Gutierrez, Samantha Brady, Chanez Symister, Andrew Lau, Richard Kendall, Saurabh Johri, Matthew Francis
Journal: Cancer Research (2024)

Abstract Background: ADCs have had tremendous impact on patient outcomes in breast cancer and are rapidly moving towards second line use. However, many patients fail to respond or relapse after treatment with ADC therapies due to tumor heterogeneity and resistance to ADC payloads. Method: CatenaBio has developed a novel Multi-Payload-Conjugate (MPC) system capable of attaching distinct payloads at different sites to the same antibody, enabling the production of single-molecule targeted combination therapies with defined DAR. Results: We screened combinations of different payloads targeting several different mechanisms attached to trastuzumab at different drug-antibody ratios to optimize tumor cell killing. These targeted combination ADCs demonstrated robust killing in both HER2 high and low tumor cell lines. Conclusion: Antibody Drug Conjugates have revolutionized the treatment of high HER2 positive breast cancer. More recently advances have been made in the design of ADCs to expand indications to include HER2 low as well as HER2 negative patients. These constructs offer the next step in ADC design and allow for the combination of multiple mechanisms of action in a single MPC that are highly effective across multiple breast cancer cell lines. These molecules offer the potential to circumvent tumor resistance pathways and deliver deeper and more durable responses. Disclosures: Marco Lobba, Devin Trinter, Maxwell Nguyen, Daniel Gutierrez, Samantha Brady, Chanez Symister, Andrew Lau, Richard Kendall, and Saurabh Johri are employed by Catena Biosciences. Matthew Francis is a co-founder and advisor to Catena Biosciences. Citation Format: Marco Lobba, Devin Trinter, Maxwell Nguyen, Daniel Gutierrez, Samantha Brady, Chanez Symister, Andrew Lau, Richard Kendall, Saurabh Johri, Matthew Francis. Next generation antibody drug conjugates: Multi-payload conjugates targeting multiple mechanisms of cell killing [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 PO5-27-10.
Abstract PO5-28-01: Dynamics of Adipocyte Progenitors in the Mammary Gland during Obesity
Authors: Sharon Kwende, Prashant Nuthalapati, Dun Ning, Jacqulene Sunder Singh, Purna Joshi
Journal: Cancer Research (2024)

Abstract Being overweight or obese is associated with a higher risk of breast cancer (BC) and worse disease-free and overall survival compared to normal-weight BC patients. The underlying biological basis for this association is attributed to alterations in the endocrine and inflammatory milieu of adipose tissue. However, existing chemotherapy and endocrine therapy are not effective in obese BC patients. There is a critical need to pin down adipose tissue cell types that may govern increased BC risk and adverse outcome in obesity. Adipocyte progenitors are immature mesenchymal cells in adipose tissue that have adipocyte differentiation potential and reported to be dysfunctional in obesity. In previous research, we first reported mammary adipocyte progenitors (MAPs) expressing Platelet-Derived Growth Factor Receptor alpha (PDGFRα) in the stromal microenvironment that transition into epithelial lineages during expansion of the murine mammary epithelium. The contribution of MAPs to shaping a pro-tumorigenic mammary tissue milieu in obesity is not known. Here, using diet-induced obesity MAP reporter and lineage tracing mouse models combined with single-cell RNA sequencing, we reveal elevated PDGFRα+ MAPs in the local mammary stroma in obesity. MAPs in the obese mammary gland manifest alterations in proliferation, cell state and molecular mechanisms, generating an inflammatory, cancer-prone tissue microenvironment. Our findings uncover the MAP lineage as a key contributor to forging an aberrant mammary gland in obesity, providing insight into the potential utility of targeting this cell population for eradicating BC risk related to augmented adiposity. Citation Format: Sharon Kwende, Prashant Nuthalapati, Dun Ning, Jacqulene Sunder Singh, Purna Joshi. Dynamics of Adipocyte Progenitors in the Mammary Gland during Obesity [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 PO5-28-01.