bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P1-16-07: A synthetic lethality treatment strategy for p53 mutant breast cancer
Authors: Bakin Andrei , Zonneville Justin , Wang Moyi , Alruwaili Mohammed , Eng Kevin , Iyer Renuka , Park Ben , Fountzilas Christos
Published: March 2022

Breast carcinomas commonly carry mutations in the tumor suppressor p53, while therapeutic efforts to target mutant p53 were largely unfruitful. Here we report preclinical data supporting a novel combination therapy strategy for treatment of p53-mutant cancers. Genomic data revealed a high expression activity of Base-Excision Repair (BER) pathways in p53-mutant breast cancers. We designed a new methodology for testing BER in live cells. The BER studies revealed a significant dysregulation in BER-mediated repair in p53-mutant cancer cells. Taken advantage in the BER defect, we developed a novel treatment strategy that specifically targets p53-mt cancers. We found that treatment with deoxyuridine analogues induced accumulation of DNA damage selectively in p53-mutant cells. Further, inhibitors of poly (ADP-ribose) polymerase (PARPi) greatly enhanced this response and increased cell death, although PARPi as a single agent was not effective. In contrast, normal cells responded to PARPi with activation of the p53-p21 axis and cell cycle arrest. Inactivation of p53 in p53 wild-type cell lines conferred the p53-mutant phenotype. Preclinical breast cancer studies revealed that the combination of deoxyuridine analogue with PARPi was more effective in inhibition of tumor growth and metastases than either drug alone. This work illustrates a novel combination therapy strategy that may improve survival rates and outcomes for thousands of breast cancer patients.

Citation Format: Andrei Bakin, Justin Zonneville, Moyi Wang, Mohammed Alruwaili, Kevin Eng, Renuka Iyer, Ben Park, Christos Fountzilas. A synthetic lethality treatment strategy for p53 mutant breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-16-07.
Abstract P1-24-05: Breast conserving surgery for non-metastatic inflammatory breast cancer: A National Cancer Database (NCDB) study
Authors: Angarita Fernando A. , Edge Stephen B. , Attwood Kristopher , Takabe Kazuaki , Young Jessica
Published: March 2022

Background: Single center studies have suggested breast conserving surgery (BCS) as treatment for inflammatory breast cancer (IBC). Given its infrequency, a multi-hospital database study is useful. This study reports the characteristics, outcomes, and prognostic factors of women with non-metastatic IBC who underwent BCS. Methods: The National Cancer Database (NCDB) was queried for women ≥18 years old with cT4dN0-3M0. Outcomes were compared between treatment groups. A Cox proportional hazards model assessed the relationship of variables and the overall survival (OS). Results: A total of 12,223 women were treated as follows: no surgery (12.8%), BCS (3.3%), and mastectomy (83.9%). BCS was significantly more common in academic/research institutions, South and North-East hospitals, no special type histology, triple negative breast cancer, single quadrant tumors, and node-negative tumors. Most patients who underwent BCS received chemotherapy (86.2%) and radiation therapy (61.9%), while hormonal therapy was infrequent (37.1%). Mortality was higher with BCS than mastectomy at 30 (1.3% versus 0.3%, p<0.001) and 90 (6.8% versus 1.5%, p<0.001) days post-surgery. Three- and five-year OS post-BCS was lower compared to mastectomy but higher than no surgery. Prognostic factors of OS for patients who underwent surgery included academic/research institutions, income ≥$63,000, hormone positive tumors, and receipt of chemotherapy and radiation therapy. Conclusion: BCS is offered to select women with non-metastatic IBC across NCDB participating hospitals. Caution is necessary while studying if surgery can be de-escalated in IBC. Standardized multidisciplinary care along with mastectomy remains the norm for patients with non-metastatic IBC.

Citation Format: Fernando A. Angarita, Stephen B. Edge, Kristopher Attwood, Kazuaki Takabe, Jessica Young. Breast conserving surgery for non-metastatic inflammatory breast cancer: A National Cancer Database (NCDB) study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-24-05.
Abstract P3-06-02: Exosomes produced by adipocytes induce EMT, immune exhaustion and tumor metastasis, in both in vivo and in vitro models of TNBC
Authors: Qiu Yuhan , Ross Conor , Jafari Naser , Kolla Manohar , Llevenes Pablo , Ennis Christina , Mazzeo Carla S , Mahdaviani Kiana , Ko Naomi Y , Denis Gerald V
Published: March 2022

Type 2 Diabetes (T2D) is a chronic inflammatory disease characterized by inflamed adipose tissue. Patients with triple negative breast cancer (TNBC) and comorbid T2D have higher risk of metastasis and shorter survival. However, mechanisms that couple T2D to TNBC outcomes are unknown. Here we hypothesize that exosomes, small vesicles secreted by tumor microenvironment breast adipocytes, drive epithelial-to-mesenchymal transition (EMT) in TNBC, immune exhaustion and metastasis via Ampk-Akt signaling.Methods: Exosomes were purified from conditioned media of 3T3-L1 mature adipocytes that were insulin-sensitive (IS) or insulin-resistant (IR), then characterized and quantified by NanoSight and surface markers, CD63. Murine 4T1 cells, a TNBC model, were treated with exosomes in vitro (3 days). To establish 3D organoids, 4T1 spheroids were treated with exosomes and embedded in Matrigel. For in vivo models, mammary fat pads of BALB/c mice were injected with 4T1 cells treated with IS vs IR exosomes. 4T1 tumors were harvested and mRNA extracted for qPCR, RNAseq, and Ingenuity Pathway Analysis. Metastatic sites in lung and liver were visualized by H&E staining and clonogenic assay. Immune exhaustion markers of tumor infiltrated lymphocytes (TILs) were measured by flow cytometry. Results: In 4T1 cells treated with IR exosomes, EMT was upregulated and PD-L1 expression increased. Tumor-bearing mice exhibited metastasis in exosome-treated groups, visualized by microscopy and clonogenic assay. Immune exhaustion markers showed modified expression in TILs from exosome-treated groups. RNA-seq analysis revealed differences among exosome-treated groups that suggest dysregulated Ampk-Akt pathways.Conclusion: Exosomes from IR adipocytes modify the tumor microenvironment, increase EMT and immune exhaustion markers on tumor cells and TILs, and promote metastasis to distant organs through Ampk-Akt. Metabolic diseases such as T2D reshape the TNBC tumor microenvironment, promoting metastasis and decreasing survival. Clearly, TNBC patients with T2D should be more closely monitored for metastasis than metabolically normal patients, with metabolic medications considered.

Citation Format: Yuhan Qiu, Conor Ross, Naser Jafari, Manohar Kolla, Pablo Llevenes, Christina Ennis, Carla S Mazzeo, Kiana Mahdaviani, Naomi Y Ko, Gerald V Denis. Exosomes produced by adipocytes induce EMT, immune exhaustion and tumor metastasis, in both in vivo and in vitro models of TNBC [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-06-02.
Abstract P3-06-07: Glutathione peroxidase 8 (GPX8) as a novel therapeutic target in triple negative breast cancer
Authors: Khatib Anees
Published: March 2022

Negative Breast Cancer (TNBC) accounts about 15% of the breast cancer incidence worldwide. While molecular subtypes which express estrogen and progesterone receptors (ER, PR) and the human epidermal growth factor receptor 2 (HER2, ERBB2) are favorable, TNBC is more associated with patient poor prognosis. GPX8 is a poorly characterized enzyme that resides in the endoplasmic reticulum, is an essential regulator of tumor aggressiveness. We found that GPX8 expression was induced by the epithelial-mesenchymal transition (EMT) program. Moreover, in breast cancer patients, GPX8 expression significantly correlated with known mesenchymal markers and poor prognosis. Strikingly, GPX8 knockout in TNBC mesenchymal-like cells (MDA-MB-231) resulted in an epithelial-like morphology, down-regulation of EMT characteristics, and loss of cancer stemness features. In addition, GPX8 knockout significantly delayed tumor initiation and decreased its growth rate in mice. We found that these GPX8 loss-dependent phenotypes were accompanied by the repression of crucial autocrine factors, in particular, interleukin-6 (IL-6). In these cells, IL-6 bound to the soluble receptor (sIL6R), stimulating the JAK/STAT3 signaling pathway by IL-6 trans-signaling mechanisms, so promoting cancer aggressiveness. We observed that in GPX8 knockout cells, this signaling mechanism was impaired as sIL6R failed to activate the JAK/STAT3 signaling pathway. Altogether, we present the GPX8/IL-6/STAT3 axis as a metabolic-inflammatory pathway that acts as a robust regulator of breast cancer cell aggressiveness. These findings motivated us to suggest GPX8 as a novel therapeutic target in TNBC.

Citation Format: Anees Khatib. Glutathione peroxidase 8 (GPX8) as a novel therapeutic target in triple negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-06-07.
Abstract P3-12-17: Breast cancer treatment related survival gains in the African breast cancer - Disparities in outcomes study
Authors: Foerster Milena , Kantelhardt Eva , Boucheron Pauline , dos-Santos-Silva Isabel , McCormack Valerie ,   the ABC-DO study team
Published: March 2022

Background: Breast cancer (BC) survival in Low and Middle Income Countries (LMICs), and particularly Sub Saharan Africa (SSA), is low and incidence rates are increasing. Accordingly, an almost 90% increase in annual BC mortality is projected to occur until 2040. The WHO Breast Cancer Global Initiative named comprehensive breast cancer treatment as one of three main pillars to reduce BC mortality. Here, we present the urgently needed up-to-date benchmark estimates of treatment effects on BC survival in SSA using data from the African Breast Cancer Disparities in Outcomes (ABC-DO) study.Methods: Since 2014 the hospital-recruited ABC-DO cohort follows-up women diagnosed with BC in five SSA countries. Socio-demographic, diagnostic, treatment and mortality data were obtained from medical records and via three-monthly follow-up calls with the patient. Cox proportional hazard models were fitted to estimate 5-year overall survival related to treatment initiation (surgery or systemic therapy) and treatment completion as time varying variates (surgery and systemic therapy completed) stratified by country and ethnicity and separate for localised and regional tumours. All models were adjusted for age, tumour grade, tumour size, node positivity, HIV status, and socioeconomic status. Results: Of 1699 ABC-DO women with invasive non-metastatic BC, 89% initiated BC treatment (from 72% in Nigeria to 100% in South African white women). Potentially curative treatment (surgery plus systemic therapy) was initiated by 63%, 22% initiated systemic treatment and 5 % only surgery. Initiated systemic therapy was completed by 49% of patients (from 16% in Nigeria to 70 % in South African black women). Median time to first treatment was 1.4 (IQR: 0.8–3) months and differed between countries (from 1.1 (0.6–1.7) in Namibian non-black to 3 (1.5–4.3) in Uganda). After 5 years, 49% (0.44 (CI: 0.31 – 0.62) ) of women initiating any treatment and 59% (0.39 (0.27 – 0.56) of women receiving surgery and initiating systemic treatment were still alive compared to 20% of women receiving no treatment. Conclusion: Timely and comprehensive BC treatment are needed to increase the very low survival rates in SSA.

Citation Format: Milena Foerster, Eva Kantelhardt, MD, Pauline Boucheron, Isabel dos-Santos-Silva, PhD, Valerie McCormack, the ABC-DO study team. Breast cancer treatment related survival gains in the African breast cancer - Disparities in outcomes study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-12-17.
Abstract P3-14-10: Breast cancer patterns, behavior and survival among American Indians in the west north central region and the other regions of the U.S.
Authors: Gaba Anu G , Cao Li , Renfrew Rebecca , Witte Deann , Wernisch Janet , Lutkemeier Denise , Egland Kristi , Crosby Ross
Published: March 2022

Purpose: American Indians (AIs) constitute the single largest racial minority in North Dakota and South Dakota. There are no studies looking at what sociodemographic or biological factors may play a role in affecting outcomes and mortality of breast cancer (BC) among AIs in the United States. Our study compared the BC patterns, behavior, and survival of AIs living in the West North Central Region (WNCR) of the U.S (which includes ND, SD, MN, NE, IO, KS, MO) to the AI BC patients in the remainder of the country. Methods: We used the records of all AI BC patients diagnosed between the years 2004-2016 from The National Cancer Database participant user files. All analyses were conducted using SPSS software (version 25). Results: Records were available for 6,466 AI BC patients, 798 were in the WNCR. There was no difference between WNCR and other regions in the stage distribution, mean age at diagnosis, morphology, hormonal/HER2 status, tumor size, lymph node status, or second cancers. The WNCR patients had less private insurance, lived in zip codes with lower median income, had more co-morbidities, and traveled longer distances for care (p<0.001 for each). They had higher grade cancers (p<0.001) at diagnosis. The WNCR patients were less likely to have received radiation therapy (p=0.015) but more likely to have received chemotherapy (p<0.001) and hormonal therapy (p=0.009) and had longer inpatient stay days after surgery (p<0.001). Time to first treatment and first treatment within 90 days (88.0% vs. 79.7%, p<0.001) was significantly better in the WNCR than in other regions of the country. Five year mortality rate was higher (16.3% vs. 11.1%, p<0.001) and cumulative survival was lower (p<0.001) in the WNCR as compared to AIs in other regions of the country. Univariate/multivariate analysis failed to identify variables that could explain the differences in 5 year mortality or cumulative survival between WNCR and other regions. Conclusion:AIs with BC in the WNCR had worse 5 year mortality and cumulative survival as compared to AIs in other regions in the US. Our analysis could not identify variables that explained the differences in mortality or cumulative survival between WNCR and other regions.

Citation Format: Anu G Gaba, Li Cao, Rebecca Renfrew, Deann Witte, Janet Wernisch, Denise Lutkemeier, Kristi Egland, Ross Crosby. Breast cancer patterns, behavior and survival among American Indians in the west north central region and the other regions of the U.S. [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-14-10.
Abstract P3-14-20: Racial and ethnic groups have different clustering of variants of uncertain significance
Authors: Beitsch Peter , Wernecke Chloe , Bontempo Kelly , Bentley Brenna , Graham Maureen , Whitworth Pat , Patel Rakesh
Published: March 2022

Background:Racial/ethnic disparities in minority access to genetic testing have perpetuated a higher likelihood of identifying an uncertain result in minority populations. Methods:Patient data was obtained from the Informed Genetics Annotated Patient Registry (iGAP), an IRB-approved multi-center longitudinal, observational study designed to capture genetic and genomic test results and their utilization and impact on treatment practices and outcomes. Patients self-declare race/ethnicity. Genetic panels contained between 1 and 148 genes and variant classification was determined by the performing genetic testing companies and reported as negative, variant of uncertain significance (VUS), likely-pathogenic, or pathogenic. Descriptive statistics were used to assess and compare data of these populations and germline genetic testing results indicating variant of uncertain significance. Results:Hispanic and African American patients had approximately twice as many uncertain results (VUS) compared to Caucasian patients for all cancer genes examined. Conclusions:Variant adjudication has disproportionately sorted out more uncertain results in Caucasians than Hispanics and African Americans. This leads to greater uncertainty in post-test counseling for these groups and should be a focus for lab testing companies going forward.

Citation Format: Peter Beitsch, Chloe Wernecke, Kelly Bontempo, Brenna Bentley, Maureen Graham, Pat Whitworth, Rakesh Patel. Racial and ethnic groups have different clustering of variants of uncertain significance [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-14-20.
Abstract P3-16-02: Enhancing impact and efficiency of financial support for cancer through use of AI: A nascent initiative of Indian cancer society
Authors: Vora Tushar , Khanna Nehal , Gokarn Anant , Rawat Ann , Ramarajan Naresh , Srivastava Gitika , Thorat Usha
Published: March 2022

Background: Since 2011, Indian Cancer Society-Cancer Cure Fund (ICS-CCF), established through donations of mutual fund dividends, has funded $27 million in treatment costs for 9800 underprivileged patients. For governance, a Due Diligence Team (DDT) of cancer experts from academic tertiary centers reviewed every planned treatment and authorized covering the treatment costs for evidence-based care. Since expert time is scarce, in 2019, ICS-CCF introduced NAVYA AI (AI) system to scale the prior authorization operation. AI is a clinically validated system that matches clinical data with evidence and expert recommended treatment options. The system can adapt to institutional guidelines such as ICS-CCF authorization criteria on published survival rates. In this prospective study, we explore application of AI in prior authorization, by assessing concordance with DDT expert decisions and potential time savings. Methods: Clinical data of beneficiaries were input in AI and if the output treatment options matched the planned treatment, the application was authorized, otherwise rejected. If AI did not output a decision, the application was deferred to DDT. Concordance between AI and DDT decisions, and DDT time spent on deferred applications, weremeasured. Results: From April 22nd, 2020 to June 9th, 2021, 1994 beneficiary applications were simultaneously reviewed by AI and DDT, of which 601 (30%) were breast cancer patients. AI “authorized” (1563/1994) or “rejected” (16/1994), 79.18% (1579/1267) of applications; and “deferred” 20.81% (415/1994) of applications. AI and DDT were 99.37% (1553/1563) concordant to authorize and 100% (16/16) concordant to reject a beneficiary application. DDT spent an average of 3.4 minutes/deferred application. Conclusions: A clinically validated AI system, 99% concordant with cancer experts in authorizing or rejecting 79% of beneficiary applications, promises a fivefold decrease in experts’ time, the scarcest resource for preauthorization. Subsequent to this study, ICS-CCF is awarding financial support directly based on AI authorize decisions. Similarly, health insurance organizations may consider a prospective study of the AI system in raising quality and efficiency of prior authorization thereby saving cost of time, money and expertise.

Citation Format: Tushar Vora, Nehal Khanna, Anant Gokarn, Ann Rawat, Naresh Ramarajan, Gitika Srivastava, Usha Thorat. Enhancing impact and efficiency of financial support for cancer through use of AI: A nascent initiative of Indian cancer society [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-16-02.
Abstract P3-18-02: Breast conservation plus radiotherapy provides superior survival benefit than mastectomy in triple negative breast cancer: A propensity matched national cancer database analysis
Authors: Cao Lifen , Towe Christopher W , Miller Megan E , Montero Alberto J , Shenk Robert
Published: March 2022

Background: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with a higher risk of locoregional and distance recurrence. Consequently, this population was considered poor candidate for breast conservation (BCT). Our study aim was to determine whether BCT plus radiotherapy (RT) was equivalent to mastectomy for TNBC after adjustment of selection bias of demographic and clinical characteristics. Methods: The National Cancer Database was queried for women diagnosed as primary unilateral invasive clinical T1-2N0-2 TNBC from 2004-2016. Patients who underwent mastectomy or breast conservation (partial mastectomy plus radiation) were included. A 1:1 propensity match with replacement was performed to compare breast conservation vs. mastectomy. Overall survival was analyzed using stratified multivariable Cox proportional hazard regression analysis.Results: Of 59,599 clinical T1-2N0-2 TNBC patients, 26,325 (44.2%) underwent mastectomy and 33,274 (55.8%) were treated with BCT. BCT patients were older (median age 59 vs. 54, p<0.001), had smaller tumors (cT1 61.7% vs. 42.9%, p<0.001) and node negative (cN0 85.8% vs. 73.7%, p<0.001). Propensity matching reduced the bias between mastectomy and breast conservation groups and generated 30,980 pairs for analysis. Median follow-up times were 41 months (range 6.97-95.8) and 39 months (range, 0.62 -94.06) for BCT and mastectomy groups, respectively. After matching, BCT+RT was associated with significantly higher OS compared to mastectomy ( 86.8% vs. 79.7%, p<0.001). The survival advantage was also present in multivariate cox regression after controlling age, race, insurance, facility type, clinical T and clinical N stage.Conclusions: Using both propensity matching and multivariate cox regression controlling for potential confounders, BCT+RT survival was superior to mastectomy in a retrospective analysis of a large cancer database.

Citation Format: Lifen Cao, Christopher W Towe, Megan E Miller, Alberto J Montero, Robert Shenk. Breast conservation plus radiotherapy provides superior survival benefit than mastectomy in triple negative breast cancer: A propensity matched national cancer database analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-18-02.
Abstract P3-19-05: Genomic machine learning model predicts radiation therapy benefit in early-stage breast cancer patients with high accuracy
Authors: Badal Kimberly , Foster Jerome , Haraksingh Rajini , John Melford
Published: March 2022

Background: Radiation therapy (RT) is frequently recommended for post-surgery treatment of early-stage breast cancer (BC) patients, though not all benefit. Clinical factors currently guide RT treatment decisions. This work presents a high-accuracy genomic machine learning (ML) model to predict RT-benefit in early-stage BC patients and a novel method for selecting genomic features for ML algorithms. Methods: Gene expression data from 477 early-stage BC patients treated with surgery and RT from the METABRIC cohort were obtained. Wilcoxon Rank Sum (Wilcox RS) test and Cox Proportional Hazards (Cox PH) were used to reduce the number of genes used to train 8 ML algorithms. Each ML algorithm was trained on a random subset of 80% of the data using 10-fold cross-validation and tested on the remaining 20% to assess its performance in predicting relapse status within 30 years. Results: The genomic data were reduced using Wilcox RS and Cox PH to a 1,596 gene set and a 977 gene set. These gene sets when used to train the 8 ML algorithms resulted in models that ranged in performance accuracies from 54.01% to 95.6%. The highest accuracies were obtained using Support Vector Machine (SVM977 - 93.41%, SVM1596 - 95.6%) and Neural Networks (NN977 - 92.31%, NN1596 - 93.41%). The accuracy of all models when tested on RT-untreated patients was 30-40% lower compared to RT-treated patients. SVM977 had the highest sensitivity of 91.09%. Members of the 977 gene set were enriched with genes involved in the cell cycle and differentiation as well as radiogenes. Conclusion: We developed an SVM model that used 977 differentially expressed genes as features that predicted RT-benefit in early-stage BC patients with 93.41% accuracy and 91.09% sensitivity. We also developed a novel genomic feature selection approach that used Wilcoxon RS followed by Cox PH that resulted in expression values of only 4% of all genes being used as features in the models.

Citation Format: Kimberly Badal, Jerome Foster, Rajini Haraksingh, Melford John. Genomic machine learning model predicts radiation therapy benefit in early-stage breast cancer patients with high accuracy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-19-05.
Abstract P3-20-08: Does contralateral prophylactic mastectomy improve survival in triple negative breast cancer?
Authors: Fasano Genevieve A , Bayard Solange , Chen Yalei , Marti Jennifer , Simmons Rache , Swistel Alexander , Bensenhaver Jessica , Nathanson S David , Petersen Lindsay , Proctor Erica , Davis Melissa , Newman Lisa
Published: March 2022

Background: Despite increased incidence of contralateral prophylactic mastectomy (CPM), there is insufficient evidence that it improves survival in women at average risk for breast cancer. In addition to BRCA1/2 mutation carriers, patients with estrogen-receptor negative tumors have been examined as a subgroup that may seek to benefit from CPM. In this study, we sought to investigate whether CPM improves survival in patients with triple negative breast cancer (TNBC).Study Design: Survival outcomes were evaluated for all TNBC patients from a multi-institutional database from 1999-2018 at New York Presbyterian - Weill Cornell Medical Center and Henry Ford Health System. Median follow-up time was 44.4 months.Results: 802 TNBC patients were evaluated. The median age was 57 years. 17% patients underwent CPM. Factors associated with CPM were White American race, younger age, presence of lymphovascular invasion (LVI), lack of mammography screen-detection, mastectomy surgery, postoperative adjuvant radiotherapy, and having had genetic testing. A borderline significant trend was observed in improved overall survival among patients undergoing CPM versus those not having CPM (5-year OS 95.1% vs. 85.0%; p = 0.05). Subset analysis of patients younger than 50 years of age at diagnosis demonstrated no improvement in overall survival for patients undergoing CPM versus those that declined CPM (94.3% v. 88.7%; p = 0.21). Conclusion: Our data demonstrate a trend in improved 5-year overall survival in TNBC patients undergoing CPM. However, in patients younger than 50 years at diagnosis, CPM did not confer a survival advantage.

Citation Format: Genevieve A Fasano, Solange Bayard, Yalei Chen, Jennifer Marti, Rache Simmons, Alexander Swistel, Jessica Bensenhaver, S David Nathanson, Lindsay Petersen, Erica Proctor, Melissa Davis, Lisa Newman. Does contralateral prophylactic mastectomy improve survival in triple negative breast cancer? [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-20-08.
Abstract P4-04-01: β2-adrenergic receptor signaling regulates metabolic pathways critical for the function of myeloid-derived suppressor cells
Authors: Mohammadpour Hemn
Published: March 2022

Summary Nerve-driven chronic adrenergic stress can suppress anti-tumor immunity. However, details are still missing or poorly understood. Catecholamines (epinephrine, norepinephrine) released by sympathetic nerves can activate adrenergic receptors present on nearly every cell type including myeloid derived suppressor cells (MDSCs). MDSCs are increasingly recognized as critical players in tumor immunology because, in addition to their fundamental roles in suppressing effector NK cells, CD8+ T cells and CD4+ T cells, they also play a direct role in tumor growth, differentiation and metastasis. Recently, we have shown that β2 adrenergic receptor signaling activated by chronic stress increases the immunosuppressive function of MDSCs, but the precise mechanisms remain unresolved. Building upon our earlier work, we now have discovered that the beta-2 adrenergic receptor (β2-AR) stress pathway drives the immune suppressive activity of MDSCs through altering their metabolism. First, we found that the expression of surface β2-AR on MDSCs increases with tumor growth in 4T1 breast cancer model and patients with breast cancer. We also found that β2-AR signaling decreases glycolysis, while increasing oxidative phosphorylation and fatty acid oxidation (FAO). β2-AR signaling also increased mitochondrial intensity and mitochondrial potential of MDSCs both in vitro and in vivo. β2-AR signaling in MDSCs also increased the expression of Carnitine Palmitoyltransferase 1A (CPT1A) necessary for the FAO-mediated immunosuppressive function of MDSCs. Blocking CPT1A using etomoxir decreased tumor growth and immunosuppressive function of MDSCs in Wild Type (WT) mice but not β2-AR-/- mice or severe combined immunodeficient mice (SCID) mice. Moreover, we found that β2-AR signaling increases autophagy and activates the arachidonic acid cycle, both required for increasing the release of the immunosuppressive mediator, PGE2 in both mouse MDSCs and. PBMCs derived MDSCs. Together, our data reveal that stress-driven β2-AR signaling is an important physiological determinant that regulates key metabolic pathways in MDSCs enabling their immunosuppressive function. These data reveal a major, physiologically relevant role for nervous activity and adrenergic stress in MDSC-tumor biology. Keywords: β2 adrenergic receptor, stress, MDSC, Metabolism, Breast Cancer,

Citation Format: Hemn Mohammadpour. β2-adrenergic receptor signaling regulates metabolic pathways critical for the function of myeloid-derived suppressor cells [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-04-01.
Abstract P4-07-12: An evaluation of lymphovascular invasion in relation to biology and prognosis according to subtypes in invasive breast cancer
Authors: Nishimura Reiki , Osako Tomofumi , Okumura Yasuhiro , Nakano Masahiro , Otsuka Hiroko , Fujisue Mamiko , Arima Nobuyuki
Published: March 2022

Background: Lymphovascular invasion (LVI) is associated with a poor outcome in breast cancer. The purpose of this study was to evaluate the clinical significance of LVI in primary breast cancer and to investigate disease-free survival (DFS) as a prognostic marker according to the breast cancer subtypes. The clinical significance of LVI was analyzed to investigate the biology and prognosis. Patients and Methods: This study examined 4,652 consecutive invasive breast cancer cases excluding the patients with non-invasive cancer, Stage IV and neo-adjuvant therapy from February 2002 to February 2021. Clinicopathological characteristics and prognosis of LVI positive and negative tumors were compared. LVI was evaluated in hematoxylin and eosin staining specimen from surgically resected samples. The ER, PgR, Ki-67, p53, HER2 status were evaluated using immunohistochemistry (IHC). Breast cancer subtypes were categorized based on the IHC data derived from ER/PgR, HER2 and Ki-67 (cutoff point: 20%) in invasive tumors. The median follow-up period was 95 months. Results: The LVI expression rates were 29.2%(low: 19.7% and high: 9.5%)in all primary cases. The LVI positive rate significantly correlated with ER/PgR negative, HER2 positive, p53 overexpression, higher Ki-67 index values, higher nuclear grade, positive nodes, and larger tumor. Moreover, the subtypes significantly correlated with LVI positivity; 20% in Luminal A, 34.6% in Luminal B, 40.9% in Lumina/HER2, 38.1% in HER2 enriched, and 29.8% in Triple Negative (TN). There were significant differences in DFS between LVI status in Luminal A, Luminal B, and TN subtypes, but there were no difference in the Luminal/HER2 and HER2 enriched subtypes. A multivariate analysis revealed that LVI was a significant factor in Luminal B and TN subtypes. Conclusion: LVI significantly correlated with the advanced and aggressive characteristics in breast cancer. Luminal A type had a lower LVI rate and HER2 type had a higher rate. Moreover, LVI was a significant prognostic factor in Luminal B and TN subtypes. These data suggest that the LVI status was useful in predicting the prognosis in HER2 negative breast cancer.

Citation Format: Reiki Nishimura, Tomofumi Osako, Yasuhiro Okumura, Masahiro Nakano, Hiroko Otsuka, Mamiko Fujisue, Nobuyuki Arima. An evaluation of lymphovascular invasion in relation to biology and prognosis according to subtypes in invasive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-07-12.
Abstract P4-09-07: Psychological impact of type of breast cancer surgery: A national cohort study
Authors: Ahn Soo Kyung , Oh Sohee , Kim Jongjin , Choi Jung-Seok , Hwang Ki-Tae
Published: March 2022

Background Type of breast surgery and breast reconstruction after mastectomy may affect the psychological well-being of breast cancer patients. The present study assessed the impact of different types of breast surgery on rates of psychological disorders in breast cancer patients. Patients & Methods This nationwide cohort study, based on Korean Health Insurance Review and Assessment Service (HIRA) claims data, included 26,259 patients who were diagnosed with invasive breast cancer and underwent surgery from June 1, 2017, to December 31, 2018. Associations between the incidence of psychological disorders and variables such as type of breast cancer surgery, patient age, and insurance type were evaluated by univariable and multivariable time dependent Cox regression analyses. Results Of the 26,259 patients, 9,394 (35.8%) underwent total mastectomy (TM) and 16,865 (64.2%) underwent partial mastectomy (PM); of the former, 4,056 (43.2%) underwent breast reconstruction surgery (RS). The median follow-up time for all patients was 194 days (interquartile range 74-334 days). A total of 4685 patients (17.84%) were newly diagnosed with psychological disorders after breast cancer surgery. Multivariable analysis showed that axillary lymph node dissection (ALND) was significantly associated with increased rates of overall psychological disorders (hazard ratio [HR] 1.337 p<0.0001), depression (HR 1.124 p=0.0462), anxiety (HR 1.459, p<0.0001) and insomnia (HR 1.238, p<0.0001). The rates of overall psychological disorders (HR 0.889, p=0.0002) and insomnia (HR 0.897, p=0.01) were significantly lower in patients who underwent TM than PM. The rates of overall psychological disorders (HR 0.837, p=0.0001) and insomnia (HR 0.831, p=0.0021) were also significantly lower in patients who underwent TM followed by RS than in patients who underwent PM. RS tended to reduce the rate of overall psychological disorders in patients who underwent TM. Subgroup analysis showed that, compared with PM, RS after TM significantly reduced the incidence of insomnia in younger patients (<50 years) and those who underwent sentinel lymph node biopsy (SLNBx). Conclusion In contrast to general belief, rates of overall psychological disorders and insomnia were higher in patients who underwent PM than TM. Compared with PM, RS after TM resulted in significantly lower rates of psychological disorders and insomnia in younger patients (age <50 years) and those who underwent SLNBx at a median < 1 year postoperatively. ALND was associated with increased rates of overall psychological disorders, depression, anxiety and insomnia.

Citation Format: Soo Kyung Ahn, Sohee Oh, Jongjin Kim, Jung-Seok Choi, Ki-Tae Hwang. Psychological impact of type of breast cancer surgery: A national cohort study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-09-07.
Abstract P5-05-08: CXCL16 as a potential therapeutic target of triple-negative breast cancer
Authors: Cho Sun Wook , Jang Mi Gyeong , Sun Hyun Jin , Lee Han Sai , Song Young Shin , Kim Seong Keun
Published: March 2022

CXCL16, as a chemotactic cytokine, promotes cancer proliferation, migration, and immune cell infiltration in tumor microenvironment. However, CXCL16 has been shown to play a conflicting role in breast cancer. The aim of this study was to investigate the therapeutic potential of CXCL16 in breast cancer. Breast cancer patients (n=1097) from the TCGA dataset were divided into two group according to the CXCL16 expressions, the CXCL16low (n=548) and the CXCLhigh (n=549) groups. Mean diagnostic ages were similar between groups (59 ± 13.5 vs 58 ± 12.9 years, P=0.233). The ratio of triple-negative breast cancer (TNBC) was significantly higher in the CXCLhigh than that of the CXCL16low groups (24.8 vs 6.8%, P<0.001), while the presence of distant metastasis or overall survivals were not different between groups. Interestingly, gene scoring analysis showed that oncogenic molecules including M2-macrophage- (r=0.36, P<0.001), efferocytosis- (r=0.42, P<0.001), and chemokine- (r=0.46, P<0.001) related gene sets showed significantly strong positive relations with the CXCL16 expressions in all patients including both TNBC (n=924) and non-TNBC (n=173). Additionally, the gene set score from PI3K/Akt pathway showed positive relation with the CXCL16 expressions in the non-TNBC (r=022, P<0.001) but not in the TNBC group. Next, a xenograft mouse model of TNBC was established with MDA-MB-231 cells, and anti-mouse CXCL16 antibody (designated as aCXCL16 group) or control IgG (designated as control group) were intravenously injected (25µg/100µl), twice per week. During 3 weeks, tumor growth was significantly delayed in the aCXCL16 than the control group by 37%. In conclusion, CXCL16 is highly expressed in TNBC and positively correlates with M2-macrophage related genes. Neutralizing CXCL16 by anti-CXCL16 shows therapeutic effects on the xenograft model of TNBC, suggesting that CXCL16 can be a potential therapeutic target for breast cancer.

Citation Format: Sun Wook Cho, Mi Gyeong Jang, Hyun Jin Sun, Han Sai Lee, Young Shin Song, Seong Keun Kim. CXCL16 as a potential therapeutic target of triple-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-05-08.
Abstract P5-14-15: Examining inequities related to inpatient hospital length of stay for breast cancer patients: A retrospective study during the COVID-19 pandemic
Authors: Kamaraju Sailaja , Canales Bethany , Wright Tamiah , Charlson John , Szabo Aniko , Wetzel Thomas , Power Steve , Campbell Grace
Published: March 2022

Purpose: In the state of Wisconsin, breast cancer patients from African American (AAs) communities have lower survival rates compared to their Caucasian counterparts. Multiple inequities related to sociodemographic factors, delays in diagnosis, advanced disease stage at presentation and presence of comorbidities including higher body mass index (BMI) contribute to these disparities, many of which have only widened during the COVID-19 pandemic. This study examined specific factors related to prolonged hospital length of stay (LOS) for breast cancer patients admitted to inpatient units during the pandemic. Methods: This analysis includes initial CY20 LOS medical record data for hospitalized patients 18 years and older with a diagnosis of breast cancer from 1/1/2020-12/31/2020. Supplemental data included disease registry and diagnostic data, and SES data determined by patient zip code. Poisson regression models with robust standard errors were used to compare the LOS index (LOSi) between groups of patients based on race, SES group, primary payer, and BMI. Results: A total of 272 patients with breast cancer that were admitted to inpatient oncology units were identified. Demographics included White (72.4%), Black (22.4%), and others (5.1%). Other characteristics included: low SES (8.8%), medium- low (9.5%), medium (15.4%), medium-high (11.0%), high SES (4.4%), and others (non-Milwaukee county) (50.7%),Medicaid (8.8%), Medicare (61.3%), Managed care (29.0%), and others (0.73%). Body mass varied among the patients; underweight (0.36%), overweight (30.8%), obese (41.5%). There were significant differences in LOSi: Black (LOSi=1.24, p=0.01), medium-low SES (LOSi=1.46, p=0.02), Medicaid (LOSi=1.40, p=0.00), underweight (LOSi=1.66, p=0.00), and overweight (LOSi=1.23, p = 0.01) patients had slightly longer LOSi, with LOSi ratio above 1. Conclusion: This study shows how patient-specific factors such as race, SES, primary payer, and BMI contribute to inpatient LOS for breast cancer patients. Healthcare systems may benefit by addressing indicators and patients’ factors to reduce hospital LOS, and ultimately healthcare costs.

Citation Format: Sailaja Kamaraju, Bethany Canales, Tamiah Wright, John Charlson, Aniko Szabo, Thomas Wetzel, Steve Power, Grace Campbell. Examining inequities related to inpatient hospital length of stay for breast cancer patients: A retrospective study during the COVID-19 pandemic [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-14-15.
Abstract P5-17-10: Anti-progranulin (GP88) antibody AG01 inhibitory effect on the growth of triple negative breast cancer cells
Authors: Serrero Ginette , Guha Rupa , Dong Jianping , Yue Binbin
Published: March 2022

Background: Triple negative breast cancer (TNBC) is characterized by invasiveness and short survival. Identifying novel TNBC targeted therapies to potentiate standard of care (SOC) therapy, is an unmet need. Progranulin (PGRN/GP88) is a biological driver of tumorigenesis, survival, and drug resistance in several cancers including breast cancer (BC). PGRN/GP88 tissue expression is an independent prognostic factor of recurrence while elevated serum PGRN/GP88 level is associated with poor outcomes such as progression of disease and shortened survival. Since PGRN/GP88 expression is elevated in 30% TNBC, we investigated the effect of inhibiting PGRN/GP88 effect on the proliferation and tumor growth of triple negative breast cancer cells. Methods: For this purpose, we have developed a neutralizing anti-human PGRN/GP88 monoclonal antibody AG01 and examined its effect on the proliferation, migration, signaling pathway activation and biomarker expression of two TNBC cell lines MDA-MB-231 and HS578-T expressing PGRN/GP88, both in vitro and in vivo. Results: The inhibition of PGRN/GP88 action by AG01 treatment reduced proliferation and migration in a dose-and time-dependent fashion in MDA-MB-231 and HS578-T cells. Western blot analysis showed decreased expression of phosphorylated protein kinases p-Src, p-AKT and p-ERK involved in proliferation and survival upon AG01 treatment for both cell lines. Transwell assay showed that AG01 treatment inhibited migration and invasion in a dose-dependent fashion. Microarray analysis of several oncoproteins in cells treated with AG01 or control antibody demonstrated the inhibition of the expression of several markers of migration and angiogenesis. In vivo xenograft studies with MDA-MB-231 cells injected in athymic nude mice showed that AG01 treatment inhibited tumor growth as well as Ki67 expression, mitotic index and microvessel counts when compared to antibody control treated mice. In vivo dose response of AG01 in MDA-MB-231 tumor bearing mice will be provided. Conclusion: TNBC is a disease with poor prognosis in need of novel targeted therapeutic solutions. PGRN/GP88 represents a therapeutic target for TNBC with two companion diagnostics (tissue test and ELISA to measure GP88 circulating levels). Blocking PGRN/GP88 with AG01 antibody treatment will provide novel targeted therapeutic option for TNBC which could address the issue of toxicity, and unresponsiveness associated with SOC. This work is supported by a grant CA 224718 from the National Cancer Institute to GS.

Citation Format: Ginette Serrero, Rupa Guha, Jianping Dong, Binbin Yue. Anti-progranulin (GP88) antibody AG01 inhibitory effect on the growth of triple negative breast cancer cells [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-17-10.
Abstract PD3-09: Cd73 may influence zoledronate-induced b- and t-cell accumulation into triple-negative breast tumors
Authors: Petruk Nataliia , Siddiqui Arafat , Määttä Jorma , Sandholm Jouko , Selander Katri
Published: March 2022

Background: CD73 is an ecto-5′-nucleotidase, which converts AMP to adenosine. In breast cancer, CD73 expression is associated with prognosis, treatment responses to anthracyclines and tumor immunity. Bisphosphonates (BP) inhibit osteoclast-mediated bone resorption. When given in the adjuvant setting, BPs increase survival among post-menopausal breast cancer patients. Since BPs also affect cells of the immune system, we hypothesized that CD73 expression may affect BP responses in triple negative breast cancer cells. Methods: Cell viability and IC50 BPs doses were determined by WST-8 kit. Apoptotic rate and cell cycle arrest were showed by FACS. The number of caspase3/7- positive cells was accessed by a red fluorescence emission via IncuCyteS3. The apoptosis-associated genes mRNA expression was determined by qPCR. To compare BP effect on TNBC tumoral responses in vivo, we used immune-competent mouse models of breast cancer. Tumors were stained by immunofluorescence and immunohistochemically.Results: Suppression of CD73 expression, but not of enzymatic activity significantly sensitized TNBC cells to nitrogen-containing BPs (n-BPs), especially to zoledronate in vitro. The stronger growth inhibitory effects of n-BPs in CD73-suppressed cells were associated with G1 cell cycle arrest and increased apoptosis, as compared with representative control cells in vitro. Zoledronate similarly inhibited both control and CD73-suppressed TNBC tumor growthin immune-competent mice. CD73 suppression in tumors led to the lower lung metastatic burden and metastases size. Zoledronate effect on increased apoptosis was similar in both groups, but significant in CD73-suppressed tumors. Impaired angiogenesis was shown by decreased CD34-positive cell number in CD73-suppressed tumors. Zoledronate significantly increased infiltration of CD45R/B220+ B cells and cytotoxic CD8+ T cells into CD73-suppressed tumors.Conclusions: Suppressed CD73 sensitizes TNBC cells to n-BP treatment, resulting inapoptosis activation and delayed proliferation in vitro. Zoledronate induces a more profound accumulation of CD45R/B220+ B cells and CD8+ T cells into TNBC tumors with the lack of CD73. Since tumor B-cell infiltration has been associated with favourable patient prognosis in breast cancer, the significance of this B-cell effect of zoledronate warrants further investigation.

Citation Format: Nataliia Petruk, Arafat Siddiqui, Jorma Määttä, Jouko Sandholm, Katri Selander. Cd73 may influence zoledronate-induced b- and t-cell accumulation into triple-negative breast tumors [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD3-09.