bluuebunny/crossref_metadata_2025 huggingface dataset:
Antibacterial Activity of Venom from the Puff Adder (Bitis arietans), Egyptian Cobra (Naja haje), and Red Spitting Cobra (Naja pallida)
Authors: Okumu Mitchel Otieno , Eyaan Kennedy Lojau , Bett Luke Kipkorir , Gitahi Nduhiu
Published: March 2023

Bitis arietans (Puff adder), Naja haje (Egyptian cobra), and Naja pallida (Red spitting cobra) venoms were tested for antimicrobial activity. This evaluation employed disc diffusion and microbroth dilution techniques. Gram-positive bacteria (Bacillus cereus and Staphylococcus aureus) and Gram-negative bacteria (Escherichia coli, Klebsiella pneumonia, and Salmonella typhi) were used. Aztreonam (30 µg), cefpodoxime (10 µg), cefoxitine (30 µg), streptomycin (25 µg), ceftriaxone (30 µg), nalidixic acid (30 µg), tetracycline (30 µg), and sulfamethoxazole (25 µg) were used as controls. All tests were conducted in triplicate (n = 3). Results. The activity of B. arietans venom against Gram-negative bacteria was significantly lower (

p
<
0.001

) than that of controls. The efficacy of B. arietans venom and sulfamethoxazole against both Gram-positive and Gram-negative bacteria was not significantly different (

p
>
0.9999

). The efficacy of B. arietans venom against Gram-positive bacteria was significantly lower (

p
<
0.001

) than cefoxitin, streptomycin, and tetracycline. The efficacy of N. haje venom against Gram-negative bacteria was significantly lower (

p
<
0.001

) than that of controls. There was no significant difference in the antimicrobial efficacy of N. haje venom and controls against Gram-positive bacteria (

p
=
0.3927

to

p
=
0.9998

). There was no significant difference in the efficacy of N. pallida venom and controls against Gram-negative bacteria (

p
=
0.3061

to

p
=
0.9981

). There was no significant difference in the efficacy of N. pallida venom and controls against Gram-positive bacteria (

p
=
0.2368

to

p
>
0.9999

). Conclusions. Of all the tested venoms, only Naja pallida venom showed good efficacy against both Gram-positive and Gram-negative bacteria.
Rare Presentation of Small Bowel Obstruction Secondary to Intestinal Leiomyoma in a Patient with Crohn’s Disease
Authors: Behers Benjamin J. , Behers Brett M. , Perez Ryan C. , Grewal Kabir , Cyriac Joe , Makar Joanne , Novak Russell W.
Published: March 2023

Small bowel obstructions (SBOs) are surgical emergencies that can occur with mechanical blockage of the intestinal lumen. These blockages are most commonly caused by adhesions or hernias, but can also result from intestinal neoplasms. This case report documents the rare occurrence of SBO due to a submucosal leiomyoma. This case was complicated by the patient’s longstanding history of Crohn’s disease, which has a considerable overlap in symptomatology with SBOs. This may have resulted in a delay in the patient’s diagnosis. Leiomyomas should always be considered as a potential, albeit rare, cause of SBO.
Product Line Optimization for Car-Sharing Platforms in the Sustainable Transportation
Authors: Zhang Zichen , Wang Yuan
Published: March 2023

As the sharing economy develops in sustainable transportation, car-sharing platforms improve the allocation efficiency of idle cars to customers. However, as the travel demand increases, and the vehicle type becomes various, the sharing market faces a new challenge to satisfy the customers’ diverse needs for quality-differentiated cars. Each customer would like to choose the right car type, while the manufacturing firm and the e-commerce platform should set the right car price for profit maximization. How to match the platform’s product line with the customer’s choice behavior becomes a problem for all the stakeholders in the sharing economy. From the perspective of customer heterogeneity, we establish a game-theoretic framework to study product line optimization in business-to-consumer (B2C) and consumer-to-consumer (C2C) sharing. We solve the optimal quality decision and the optimal pricing strategy for the manufacturing firm and the e-commerce platform in the sharing economy. In numerical experiments, we investigate how the sensitivity of the quality and the cost can jointly influence the profits of sustainable transportation. Our findings show that within the product line, the firm’s selling profit in the C2C sharing is negatively influenced by the sharer’s valuation, while the platform’s sharing profit in the B2C sharing is independent of either buyer’s valuation. We give some policy implications for scholars, practitioners, and policymakers in the sharing economy and point out some limitations and recommendations for the product line design.
Effects of Thermal Radiation and Chemical Reaction on Hydromagnetic Fluid Flow in a Cylindrical Collapsible Tube with an Obstacle
Authors: Mwamba Nictor , Okelo Abonyo Jeconia , Awuor Kennedy Otieno
Published: March 2023

The aim of this research is to study the effects of thermal radiation and chemical reaction on hydromagnetic fluid flow in a cylindrical collapsible tube with an obstacle. The fluid flow is governed by continuity, momentum, energy, and concentration equations. Similarity transformation has been used to convert the obtained PDEs into ODEs. The collocation method has been used to numerically solve the ODEs. The method has been implemented in MATLAB using the bvp4c inbuilt function. The effects of the nondimensional parameters on velocity, temperature, and concentration have been presented graphically. Additionally, the skin‐friction coefficient, the Nusselt number, and the Sherwood number have been discussed and are presented in a tabular form. The findings demonstrated that increasing the Reynolds number causes a rise in the fluid temperature and velocity. The fluid velocity decreases as the Hartmann number and the weight of the obstacle increase but increases with increasing Grashof numbers. The temperature of the fluid increases as the radiation parameter, or Eckert number, increases, but decreases as the Prandtl number increases. As the Soret number rises, so do the fluid’s temperature and concentration distribution. With an increase in the unsteadiness parameter, the fluid velocity and the concentration distribution decrease, whereas the opposite is seen in temperature. As the Schmidt number, the concentration Grashof number, and the chemical reaction parameter increase, the fluid’s concentration decreases. There is an increase in skin‐friction coefficient with increasing Prandtl number, Eckert number, Soret number, thermal Grashof number, concentration Grashof number, thermal radiation parameter, Hartmann number, and unsteadiness parameter, while a decrease is observed with increasing Reynolds number. The Nusselt number increases with an increase in the Prandtl number, Eckert number, thermal radiation parameter, Hartmann number, and unsteadiness parameter. A slight decrease in the Nusselt number has been observed with increasing thermal Grashof number. The Sherwood number decreases with increasing Prandtl number, chemical reaction parameter, and thermal radiation parameter but increases with increasing Schmidt number, Eckert number, and Soret number. The research has the potential for a wide range of applications including but not limited to the medical field and other physical sciences.
CCNE1andPLK1Mediate Resistance to Palbociclib in HR+/HER2− Metastatic Breast Cancer
Authors: Guerrero-Zotano Ángel , Belli Stefania , Zielinski Christoph , Gil-Gil Miguel , Fernandez-Serra Antonio , Ruiz-Borrego Manuel , Ciruelos Gil Eva Maria , Pascual Javier , Muñoz-Mateu Montserrat , Bermejo Begoña , Margeli Vila Mireia , Antón Antonio , Murillo Laura , Nissenbaum Bella , Liu Yuan , Herranz Jesús , Fernández-García Daniel , Caballero Rosalía , López-Guerrero José Antonio , Bianco Roberto , Formisano Luigi , Turner Nicholas , Martín Miguel
Published: March 2023

Purpose:

In hormone receptor–positive (HR+)/HER2− metastatic breast cancer (MBC), it is imperative to identify patients who respond poorly to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and to discover therapeutic targets to reverse this resistance. Non-luminal breast cancer subtype and high levels of CCNE1 are candidate biomarkers in this setting, but further validation is needed.

Experimental Design:

We performed mRNA gene expression profiling and correlation with progression-free survival (PFS) on 455 tumor samples included in the phase III PEARL study, which assigned patients with HR+/HER2− MBC to receive palbociclib+endocrine therapy (ET) versus capecitabine. Estrogen receptor–positive (ER+)/HER2− breast cancer cell lines were used to generate and characterize resistance to palbociclib+ET.

Results:

Non-luminal subtype was more prevalent in metastatic (14%) than in primary tumor samples (4%). Patients with non-luminal tumors had median PFS of 2.4 months with palbociclib+ET and 9.3 months with capecitabine; HR 4.16, adjusted P value < 0.0001. Tumors with high CCNE1 expression (above median) also had worse median PFS with palbociclib+ET (6.2 months) than with capecitabine (9.3 months); HR 1.55, adjusted P value = 0.0036. In patients refractory to palbociclib+ET (PFS in the lower quartile), we found higher levels of Polo-like kinase 1 (PLK1). In an independent data set (PALOMA3), tumors with high PLK1 show worse median PFS than those with low PLK1 expression under palbociclib+ET treatment. In ER+/HER2− cell line models, we show that PLK1 inhibition reverses resistance to palbociclib+ET.

Conclusions:

We confirm the association of non-luminal subtype and CCNE1 with resistance to CDK4/6i+ET in HR+ MBC. High levels of PLK1 mRNA identify patients with poor response to palbociclib, suggesting PLK1 could also play a role in the setting of resistance to CDK4/6i.
Abstract ED11-1: Hormone receptor positive breast cancer
Authors: Ma Cynthia
Published: March 2023

Estrogen receptor (ER) positive breast cancer is a heterogeneous group of diseases. While the major goal of neoadjuvant treatment in patients with locally advanced disease is to downstage the cancer to facilitate resectability and breast-conserving surgery, there is increasing evidence that response in the neoadjuvant setting has prognostic implications in predicting long term relapse outcomes. However, questions remain as to strategies that optimize neoadjuvant treatment selection of endocrine therapy versus chemotherapy, and whether adjuvant therapy could be tailored based on treatment response in the neoadjuvant setting. In this lecture, we will discuss evolving data regarding pathologic and molecular characteristics of ER positive breast cancer that assist with treatment selection in the neoadjuvant setting and the potential role of pathologic and biomarker response to neoadjuvant endocrine therapy in tailoring adjuvant chemotherapy decisions.

Citation Format: Cynthia Ma. Hormone receptor positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED11-1.
Abstract ED6-2: RT: How short can it be
Authors: Krug David
Published: March 2023

Adjuvant whole-breast radiotherapy for breast cancer has traditionally been delivered over the course of 5 weeks. In the past decades, there has been a paradigm shift towards moderate hypofractionation with 15-16 fractions over 3 weeks based on randomized controlled trials demonstrating comparable oncological safety, decreased acute toxicity and similar long-term toxicity compared to conventional fractionation. More recently, ultra-hypofractionated whole-breast radiotherapy delivered with 5 fractions over 1 week or 5 weeks has been introduced into the clinic. Furthermore, the increasing use of partial-breast irradiation with a de-escalation of the target volume to the region of the lumpectomy cavity has further allowed acceleration of radiotherapy delivery for patients with breast cancer. This lecture will summarize recent advances and data on hypofractionation for breast cancer.

Citation Format: David Krug. RT: How short can it be [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED6-2.
Abstract F2-2: Neutrophil elastase and anti-tumor effects
Authors: Becker Lev
Published: March 2023

Cancer cell genetic variability and similarity to host cells have stymied development of broad anti-cancer therapeutics. Our innate immune system evolved to clear genetically diverse pathogens and limit host toxicity; however, whether/how innate immunity can produce similar effects in cancer is unknown. Here, we show that human, but not murine, neutrophils release catalytically active neutrophil elastase (ELANE) to kill many cancer cell types while sparing non-cancer cells. On a molecular level, ELANE proteolytically liberates the CD95 death domain, which interacts with histone H1 isoforms to selectively eradicate cancer cells. In pre-clinical models, ELANE attenuates primary tumor growth and produces a CD8+ T cell-mediated abscopal effect to attack distant metastases, therapeutic effects that are improved on by porcine pancreatic elastase, an ELANE homolog that better resists protease inhibitors in the tumor microenvironment. Altogether, our studies suggest that ELANE kills genetically diverse cancer cells with minimal toxicity to non-cancer cells, raising the possibility of developing it as a broad anti-cancer therapy.

Citation Format: Lev Becker. Neutrophil elastase and anti-tumor effects [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr F2-2.
Abstract P1-05-17: Radiomic models based on dynamic contrast-enhanced magnetic resonance imaging predict the immunophenotype reflecting spatial distribution of CD8+ tumor-infiltrating lymphocytes in breast cancer
Authors: Jeon Seung Hyuck , Kim So-Woon , Seo Mirinae , Lim Yu Jin
Published: March 2023

Purpose: This study aimed to develop noninvasive magnetic resonance imaging (MRI)-based radiomic models to predict immunophenotypes of breast cancer. Methods: A total of 182 breast cancer patients who underwent upfront surgery were analyzed, divided into training (n = 137) and validation (n = 45) cohorts. Dynamic contrast-enhanced (DCE)-MRI was acquired, and immunophenotype was determined on the surgical tumor sections: immune-inflamed (high degree of CD8+ T cells infiltrated), -excluded (CD8+ T cells accumulated at invasive margin but not efficiently infiltrated in tumor bed), and -desert (CD8+ T cells absent within tumor and at margins). Based on 833 radiomic features extracted after manual delineation, the least absolute shrinkage and selection operator method was used to build radiomic models. Results: Our radiomic models from the whole tumor sections showed moderate performance in predicting the immune-inflamed versus non-inflamed tumors, showing the highest AUC values, of 0.659 and 0.671 for training and validation cohorts, respectively. Combining the models, much improved predictability was observed, with AUC values of 0.973 and 0.985 for training and validation cohorts, respectively. Other radiomic features from tumor periphery data discriminated immune-excluded versus immune-desert status, with AUC values of 0.993 and 0.984 for training and validation cohorts, respectively. The combined models were also applicable to predicting immunophenotype for different molecular subtypes, with AUC values ≥ 0.867. Conclusions: By integrating the immunohistochemistry profiles, we established MRI-derived radiomic models to predict the detailed immunophenotype of breast cancer. This study suggests the feasibility of noninvasive assessment of tumor immune status in real-world clinics.

Citation Format: Seung Hyuck Jeon, So-Woon Kim, Mirinae Seo, Yu Jin Lim. Radiomic models based on dynamic contrast-enhanced magnetic resonance imaging predict the immunophenotype reflecting spatial distribution of CD8+ tumor-infiltrating lymphocytes in breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-17.
Abstract P2-06-03: Dietary exposure to acrylamide and breast cancer risk: results from the NutriNet-Santé cohort
Authors: Bellicha Alice , Wendeu-Foyet Gaëlle , Coumoul Xavier , Koual Meriem , Pierre Fabrice , Guéraud Françoise , Zelek Laurent , Debras Charlotte , Srour Bernard , Sellem Laury , Kesse-Guyot Emmanuelle , Julia Chantal , Galan Pilar , Hercberg Serge , Deschasaux-Tanguy Mélanie , Touvier Mathilde
Published: March 2023

Background: Acrylamide is classified as a probable human carcinogen by the IARC but epidemiological evidence on the carcinogenicity of acrylamide from dietary sources is limited. This study aimed to investigate the associations between dietary acrylamide and breast cancer risk in the NutriNet-Santé cohort. Methods: This prospective cohort study included 80,597 French women (mean [SD] age at baseline: 40.8 [14] years) during a mean (SD) follow-up of 8.8 (2.3) years. Acrylamide intake was evaluated using repeated 24h dietary records (n= 5.5 [SD 3.0]), linked to a comprehensive food composition database. Associations between acrylamide intake and breast cancer risk (overall, premenopausal and post-menopausal) were assessed by Cox hazard models adjusted for known risk factors. Results: The mean (SD) dietary acrylamide intake was 30.1 (21.9) µg/d (main contributors: coffee, potato fries and chips, pastries and cakes, and bread). During follow-up, 1016 first incident breast cancer cases were diagnosed (431 premenopausal, 585 postmenopausal). A borderline significant positive association was observed between acrylamide intake and breast cancer risk overall (HRQ4 vs Q1= 1.21 [95% CI: 1.00-1.47]) and a positive association was observed with premenopausal cancer (HRQ4 vs Q1= 1.40 [95% CI: 1.04-1.88]). Restricted cubic spline analyses suggested evidence for non-linearity of these associations, with higher HR for intermediate (Q2) and high (Q4) exposures. Receptor-specific analyses revealed a positive association with estrogen receptor-positive breast cancer, which represented 86% of total cancer cases. Acrylamide intake was not associated with post-menopausal breast cancer. Conclusions: Results from this large prospective cohort study suggest the potential deleterious role of dietary acrylamide in breast cancer etiology, especially in premenopausal women, and provide new insights that should encourage further mitigation strategies to reduce the content of acrylamide in food.

Citation Format: Alice Bellicha, Gaëlle Wendeu-Foyet, Xavier Coumoul, Meriem Koual, Fabrice Pierre, Françoise Guéraud, Laurent Zelek, Charlotte Debras, Bernard Srour, Laury Sellem, Emmanuelle Kesse-Guyot, Chantal Julia, Pilar Galan, Serge Hercberg, Mélanie Deschasaux-Tanguy, Mathilde Touvier. Dietary exposure to acrylamide and breast cancer risk: results from the NutriNet-Santé cohort [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-06-03.
Abstract P2-21-06: The relationship between the gene expression difference of fibroblasts in the tumor microenvironment and metastasis of triple-negative breast cancer
Authors: Heo Woo Hang , Lee Woochan , LI SONGBIN , Kim Jong-Il , Moon Hyeong-Gon
Published: March 2023

Background Triple negative breast cancer (TNBC) is a breast cancer subtype with increased risk of distant metastasis, especially to lung and liver. In addition to the intrinsic characteristics of tumor cells, the molecular features of the tumor microenvironment cells can also regulate the metastasis process of TNBC. In this study, we tried to characterize the transcriptomic features of microenvironment fibroblasts associated with the distant metastasis of TNBC. Method We established PDX models by obtaining tumor tissues from 26 triple-negative breast cancer patients and transplanting them into the mammary fat pads of immunodeficient mice. When the PDX tumors grew sufficiently in the fat pads, we excised them and saved the mice to assess whether each PDX tumor was capable of developing spontaneous distant metastasis. We used bulk RNA sequencing and single cell RNA sequencing to determine the transcriptomic features associated with the distant metastasis. Results We classified the 26 TNBC PDX models based on their in vivo metastasis capacity and the clinical outcomes of the corresponding patients. Non-metastatic PDX models were defined as the lack of developing distant metastasis in either mouse experiment or clinical follow-up data (n=5). PDX models were defined as metastatic models when they developed distant metastasis in both mouse and human (n=4). We performed single cell RNA sequencing using the nine PDX tumors and observed a substantial gene expression differences of fibroblasts in the tumor microenvironment between the metastatic and non-metastatic PDX models. The fibroblasts of the metastatic PDX models showed up-regulation of genes involved in the response to hypoxia, inflammatory response, neutrophil chemotaxis, cellular response to IL-1, positive regulation of cell proliferation, and negative regulation of apoptotic process. Moreover, this difference of gene expression between metastatic and non-metastatic TNBC PDX models were not identified by the bulk RNA sequencing data. Conclusion By using the single cell RNA sequencing using the TNBC PDX models, we identified key features of fibroblasts in the tumor microenvironment that contributes to the metastasis capacity of TNBC. Further studies are on-going to elucidate the underlying mechanisms.

Citation Format: Woo Hang Heo, Woochan Lee, SONGBIN LI, Jong-Il Kim, Hyeong-Gon Moon. The relationship between the gene expression difference of fibroblasts in the tumor microenvironment and metastasis of triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-21-06.
Abstract P2-26-03: TRAF3 as a regulator of breast cancer aggressiveness
Authors: Papanastasiou Anastasios , Sirinian Chaido , Theakou Maria , Peroukidis Stavros , Chaniotis Dimitrios , Kalofonos Haralabos , Koutras Angelos
Published: March 2023

TRAF3 (TNF Receptor Associated Factor 3) is a regulator of NF-κB signaling, acting mainly as an inhibitor of the alternative NF-κB pathway through the interaction with other TRAF molecules and the downregulation of NIK (MAP3K14) kinase. While NF-κB has a well-established role in breast cancer development and progression, TRAF3 which acts as a ubiquitin-ligase in the NF-κB cascade has never been studied in mammary carcinomas. Here by employing breast cancer cell lines in invasion and colony formation assays, we show that TRAF3 forced expression inhibits aggressive traits of breast cancer cells. In addition, immunohistochemistry (IHC) for TRAF3 protein in breast cancer FFPE samples and analysis of TRAF3 gene expression from publicly available data sets, indicates that TRAF3 mRNA and protein expression in breast cancer tissue correlates with Recurrence Free Survival (RFS), Overall Survival (OS) and other clinicopathological parameters such as Histological Grade and proliferation index (ki-67). To our knowledge this is the first report on TRAF3 protein in breast cancer providing preliminary evidence for an inhibitory role of this protein in breast cancer development and progression.

Citation Format: Anastasios Papanastasiou, Chaido Sirinian, Maria Theakou, Stavros Peroukidis, Dimitrios Chaniotis, Haralabos Kalofonos, Angelos Koutras. TRAF3 as a regulator of breast cancer aggressiveness [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-26-03.
Abstract P2-26-04: Human papillomavirus protein E6 regulates Toll like receptor-9 expression in breast cancer cells
Authors: Parviainen Essi , Nurmenniemi Sini , Bravaccini Sara , Pirini Francesca , Ravaioli Sara , Jukkola Arja , Selander Katri S.
Published: March 2023

Toll like receptor-9 (TLR9) is an innate immunity DNA-receptor, which is widely expressed in various cancers, including breast cancer. Low TLR9 expression in cancer cells was initially associated with poor prognosis among patients with triple negative breast cancer. We have now discovered a similar association also among among other breast cancer subtypes. The mechanism for TLR9-associated poor prognosis is not currently known, but our ongoing studies suggest that it may be due to poor chemotherapy responses. Regulation of TLR9 expression in breast cancer is poorly understood. It has been demonstrated that in cervical cancers, TLR9 expression is suppressed by human papillomavirus (HPV) infections. Although breast cancer is not typically considered HPV-associated, there are reports of HPV in breast cancer. The aim here was to test the hypothesis, that HPV-infections suppress TLR9 expression also in breast cancer. To study this, human breast cancer cells were infected with HPV16 E6-oncoprotein, followed by measurement of TLR9 mRNA and protein in vitro. We also aimed to compare the presence of HPV DNA with TLR9 protein expression in clinical breast cancer specimens. We further studied E6-infection effects on breast cancer proliferation, migration, and invasion. E6-infection decreased TLR9 protein expression in TNBC but not in estrogen receptor expressing (ER+) cells. E6-overexpression significantly altered breast cancer proliferation, but the impact was opposite in TNBC and ER+ cells. No effect on migration and invasion was observed. E6-transfected breast cancer cells were significantly less sensitive in vitro to chemotherapies typically used for the treatment of breast cancer in the adjuvant setting. In vivo studies are pending. HPV DNA was not detected in a pilot cohort of clinical breast cancer specimens (n=37) among Northern Finnish breast cancer specimens. These results indicate that HPV may affect breast cancer TLR9 expression and thereby breast cancer prognosis, through treatment responses. Although HPV was not detected in the small pilot set of our clinical samples, this issue needs to be further studied in larger data sets.

Citation Format: Essi Parviainen, Sini Nurmenniemi, Sara Bravaccini, Francesca Pirini, Sara Ravaioli, Arja Jukkola, Katri S. Selander. Human papillomavirus protein E6 regulates Toll like receptor-9 expression in breast cancer cells [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-26-04.
Abstract P2-26-14: CDK4/6 inhibitors modulate the ubiquitin–proteasome pathway in ER+ breast cancer by downregulation of UBE2C/S/T
Authors: Lin Chih-Yi , Yu Chung-Jen , Liu Chun-Yu , Chao Ta-Chung , Huang Chi-Cheng , Tseng Ling-Ming , Lai Jiun-I
Published: March 2023

Despite significant improvement in therapeutic development in the past decades, breast cancer remains a formidable cause of death for women worldwide. The hormone positive subtype (HR(+)) (also known as luminal type) is the most prevalant category of breast cancer, comprising ~70% of patients. The clinical success of the three CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib has revolutionized the treatment of choice for metastatic HR(+) breast cancer. Accumulating evidence demonstrate that the properties of CDK4/6 inhibitors extend beyond inhibition of the cell cycle, including modulation of immune function, sensitizing PI3K inhibitors, metabolism reprogramming, kinome rewiring, modulation of the proteosome, and many others. The ubiquitin–proteasome pathway (UPP) is a crucial cellular proteolytic system that maintains the homeostasis and turnover of proteins. By transcriptional profiling of the HR(+) breast cancer cell lines MCF7 and T47D treated with Palbociclib, we have uncovered a novel mechanism that demonstrate the CDK4/6 inhibitors suppress the expression of three ubiquitin conjugating enzymes UBE2C, UBE2S, UBE2T. Further validation in the HR(+) cell lines show that Palbociclib and ribociclib decrease UBE2C at both the mRNA and protein level, but this phenomenon was not shared with abemaciclib. These three E2 enzymes modulate several E3 ubiquitin ligases, including the APC/C complex which plays a role in G1/S progression. We further demonstrate the UBE2C/UBE2T expression levels are associated with breast cancer survival, and HR(+) breast cancer cells demonstrate dependence on the UBE2C. Our study suggests a novel link between CDK4/6 inhibitor and UPP pathway, adding to the potential mechanisms of their clinical efficacy in cancer.

Citation Format: Chih-Yi Lin, Chung-Jen Yu, Chun-Yu Liu, Ta-Chung Chao, Chi-Cheng Huang, Ling-Ming Tseng, Jiun-I Lai. CDK4/6 inhibitors modulate the ubiquitin–proteasome pathway in ER+ breast cancer by downregulation of UBE2C/S/T [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-26-14.
Abstract P3-05-49: Number of involved organs at baseline is prognostic for overall survival in patients with metastatic breast cancer: Results from the AGMT_MBC-Registry
Authors: Rinnerthaler Gabriel , Gampenrieder Simon P. , Tinchon Christoph , Petzer Andreas , Balic Marija , Heibl Sonja , Sandholzer Margit , Zabernigg August F. , Egle Daniel , Hager Christopher , Pichler Petra , Roitner Florian , Andel Johannes , Strasser-Weippl Kathrin , Knauer Michael , Hubalek Michael , Singer Christian F. , Greil Richard
Published: March 2023

Background: Hormone-receptor (HR) status, HER2 Status, de novo metastatic disease, distant recurrence-free interval (DRFI), and visceral disease are known prognostic factors in metastatic breast cancer (MBC). Therefore, in the majority of clinical trials, randomization is stratified for these parameters. Whether the number of involved organs at baseline has an additional prognostic value was examined in this analysis.

Patients and methods: The AGMT-MBC-Registry is a multicenter nationwide ongoing retrospective and prospective registry for MBC patients in Austria. In this analysis, patients with known HR status, HER2 status, and available survival data were included. Multivariable hazard ratios were estimated by COX proportional hazard models. For variable selection a backward stepwise model selection using the Akaike information criterion was performed.

Results: As of 04/05/2022, 2,235 patients have been included in the registry, of which 1,840 patients fulfilled the inclusion criteria. In two different multivariable COX proportional hazard models for overall survival, the number of involved organs was a highly statistically significant independent prognostic factor: (1) a model including the number of involved organs at baseline together with known prognostic factors (see Table 1); (2) a stepwise selection model additionally including menopausal status and involved metastatic organ sites (bone, liver, lung, brain, and lymph nodes) separately. This effect was maintained in sensitivity analysis taking different breast cancer subtypes as well as visceral and non-visceral disease into account.

Conclusion: The number of involved organs at baseline is an independent prognostic factor in MBC and should be considered as a stratification factor in randomized trials.

Table 1. Multivariable Model for overall survival.

Citation Format: Gabriel Rinnerthaler, Simon P. Gampenrieder, Christoph Tinchon, Andreas Petzer, Marija Balic, Sonja Heibl, Margit Sandholzer, August F. Zabernigg, Daniel Egle, Christopher Hager, Petra Pichler, Florian Roitner, Johannes Andel, Kathrin Strasser-Weippl, Michael Knauer, Michael Hubalek, Christian F. Singer, Richard Greil. Number of involved organs at baseline is prognostic for overall survival in patients with metastatic breast cancer: Results from the AGMT_MBC-Registry [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-49.
Abstract P4-03-44: A Case Series of Male Breast Cancer Patients at Methodist Dallas Medical Center
Authors: Nong Huy , Moparty Vasu , Manhas Atisha
Published: March 2023

Male breast cancer is a rare disease accounting for less than 1% of all breast cancer diagnosis. Male breast cancers occur later in life and are more estrogen receptor-positive compared to female breast cancers. Breast cancer in men is often diagnosed later and survival rates are lower than in female cases. The aim of this retrospective study is to analyze the epidemiological, clinical and therapeutic data of all male breast cancer cases over the span of 11 years to at Methodist Dallas Medical Center between 2010 – 2021. During this time period, there was a total of 1,784 cases of breast cancer diagnosed. There were 8 cases male breast cancers, accounting for 0.45% of all breast cancer cases. The average age of diagnosis was 69.5 years old. The most common type of male breast cancer was invasive ductal carcinoma with 7 cases (87.7%). The remaining 1 case (12.5%) were ductal carcinoma in situ (DCIS). 100% of our male breast cancer cases were estrogen receptor and progesterone receptor positive. No male breast cancer case had Her2/Neu receptor over-expression. Of all male breast cancer cases, 75% had a family history of cancer suggesting that genetic factors play a significant role in the development of breast cancer in men. At time of diagnosis, 4 cases (50 %) were staged at cT4 and the remainder of cases were between cT0 - cT2. 37.5% of all cases had sentinel lymph node involvement at time of diagnosis. From the time period of 2010 – 2014 there were no incidences of male breast cancer; however, from 2015 – 2021 there were 8 total cases. There were 2 cases (25%) of death.

Number of Male Breast Cancer Cases by Year Number of Male Breast Cancer Cases by Year

Number of male breast cancer cases diagnosed by year at Methodist Dallas Medical Center

Epidemiological and Clinical Data of Male Breast Cancer Cases

Citation Format: Huy Nong, Vasu Moparty, Atisha Manhas. A Case Series of Male Breast Cancer Patients at Methodist Dallas Medical Center [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-44.
Abstract P4-07-26: Development of CDCP1-targeting antibody-drug conjugate for Triple negative and metastatic breast cancer
Authors: Gough Madeline , Khan Tashbib , Kwah Kayden , He Yaowu , Ratnayake Gishan , Pyke Christopher , Snell Cameron , Hooper John , Kryza Thomas
Published: March 2023

Introduction: CUB-domain containing- protein 1 (CDCP1) is a transmembrane receptor involved in the progression of several cancers. Recent studies demonstrate that CDCP1 is a rational target for the development of innovative targeted therapies for cancer including theranostics agents and antibody-drug conjugates. Objective/Methods: To determine the therapeutic potential of CDCP1 in breast cancer, we investigated its expression in multiple cohorts of breast cancer tissues by immunohistochemistry, as well as in various preclinical models including cell lines, primary cells and patient-derived xenografts using flow cytometry, western blot and immunofluorescence staining. Then, we evaluated the capacity of the CDCP1-targeting chimeric antibody ch10D7 to specifically accumulate in breast cancer lesions in in vivo preclinical models including patient-derived xenografts and breast cancer metastasis models. Finally, we determined the efficacy of the ch10D7-MMAE antibody-drug conjugate to kill breast cancer cells in vitro and breast tumours ex-vivo and in vivo. Results: The CDCP1 receptor is expressed at targetable level in a significant proportion of breast cancer cases with high/intermediate expression detected in ~30% of localized ER-positive cases, ~50% of metastatic ER-positive cases and >70% of Triple negative or HER2-positive cases. Similar proportion of expression was detected in cellular models. We demonstrated that ch10D7 antibody labelled with the radionucleotide Zircodium-89 specifically accumulates in breast cancer lesions in vivo allowing the detection of mammary-fat pad implanted patient-derived xenografts and of breast cancer metastasis by PET/CT imaging. Finally, we confirmed that the ch10D7-MMAE antibody-drug conjugate is very efficient at inducing cell death in vitro as well as controlling primary tumour and metastatic tumour burden in pre-clinical models, conferring a significant survival advantage compared to classical therapy. Conclusion: Our work demonstrates that CDCP1 is a potential target to detect and limit the progression of breast tumours and that biomolecules specifically recognising this receptor are promising agents which could improve survival of patients.

Citation Format: Madeline Gough, Tashbib Khan, Kayden Kwah, Yaowu He, Gishan Ratnayake, Christopher Pyke, Cameron Snell, John Hooper, Thomas Kryza. Development of CDCP1-targeting antibody-drug conjugate for Triple negative and metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-26.
Abstract P5-03-04: PIK3CA mutation prevalence in hormone receptor positive breast cancer patients in United Arab Emirates
Authors: Azribi Fathi , Hourani Mohammad , Magdub Sulaman , Alawadhi Aydah , Yousif Ali , Dawoud Emad , Qawasmeh Khaled Al , Ameri Mouza Al , Trad Diaeddine , Bennini Nouri , Ahmed Mohamed , Ansari Jawaher
Published: March 2023

Background: The Phosphatidylinositol-4,5-bisphosphonate 3-kinase catalytic subunit alpha (PIK3CA) gene is mutated in about 30-40% of hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) breast cancer (BC) patients. For HR+/HER2- advanced breast cancer patients with disease progression following endocrine-based therapy, the NCCN guideline recommends testing for PIK3CA mutations with tumour or liquid biopsy to identify suitable patients for targeted therapy with alpelisib, an oral α-specific PI3K inhibitor in combination with fulvestrant. The primary objective of this study was to evaluate the proportion and distribution of PIK3CA mutational landscape of HR+ve BC patients at the largest cancer centre in the United Arab Emirates (UAE). Material and methods: Retrospective review of consecutive HR+ve BC patients at Tawam Hospital for whom PIK3CA testing was requested. DNA was extracted from the samples and a targeted resequencing assay was used for mutation detection in exons 7, 9 and 20 of the PIK3CA gene. Sequencing was carried out using the Next Generation Sequencing platform Ion GeneStudio S5 Prime System with a detection limit of 2-5% of the mutant allelic content. Results: 124 patients with HR+ve BC were enrolled in the present study. The pathology samples were considered unsuitable/unsatisfactory in 18 cases. The median age was 51.5 years (range 31-90). All patients were female, 54% were post-menopausal and 49% presented with de-novo metastatic disease. Of the 106 eligible patients, PIK3CA mutations were detected in 33 (31%) patients, the most common being H1047R (45%) and E545K (30%) mutations in exons 20 and 9, respectively. Other less common mutations included C420R mutations (6%) in exon 7, E542 (6%) in exon 9 and H1047Y (3%) in exon 20. 9% of patients had more than one hotspot mutations, primarily in exons 9 and 20. Of the 12 HER2 +ve patients tested, 3 had PIK3CA mutations, most commonly the H1047R mutation in exon 20. Conclusion: The prevalence of PIK3CA mutations and the presence of most common hotspot mutations in exons 20 and 9 was consistent with prior published studies. The clinical relevance of PIK3CA mutations in HER2 +ve BC patients needs further assessment.

Citation Format: Fathi Azribi, Mohammad Hourani, Sulaman Magdub, Aydah Alawadhi, Ali Yousif, Emad Dawoud, Khaled Al Qawasmeh, Mouza Al Ameri, Diaeddine Trad, Nouri Bennini, Mohamed Ahmed, Jawaher Ansari. PIK3CA mutation prevalence in hormone receptor positive breast cancer patients in United Arab Emirates [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-03-04.
Abstract P6-05-18: Reasons for Delay in Indian Women Presenting with Primary Stage III or IV Breast Cancer: An Observational Study
Authors: KHARE SIDDHANT , Doda Vidushi , IRRINKI R N NAGA SANTOSH
Published: March 2023

Background: Developing countries like India share higher burden of deaths due to breast cancer, despite having lower incidence than the west. Greater proportion of patients presenting with advanced stages of cancer is one of the reasons for this disparity. Since the factors leading to such delay have not been well studied in Indian patients, we decided to perform this study. Methodology: This was an observational study conducted from Jan 2021 to July 2022. Purposive Non-Random sampling was used and patients who had stage 3 or 4 breast cancer and were between 18-80 years of age were recruited. Interview was done on a one-to-one basis in a secluded area. Descriptive statistics were used, and chi-square was used to study the association of socio-demographic and clinical variables with the delay status of the breast cancer. Results: A total of 75 participants were enrolled in the study with mean age of 52.5 years and SD of 12.5 years. Out of these, 74 had lump as their first symptom. Only 14 of these 74 presented early i.e., within 3 months of onset of symptoms. Rest 60 participants presented late (more than 3 months after onset of symptoms). Between these two groups, difference in incidences of pregnancy associated lumps (0% in < 3 months vs 13.1% in ≥ 3 months, p=0.002), patients being afraid of treatment related complications (0% in < 3months vs 6.6% in ≥ 3 months, p=0.039) and their inability to decide because of lack of knowledge (0% in < 3months vs 6.6% in ≥ 3 months, p=0.039) were statistically significant. To our surprise, the thought that the lump was harmless and painless, embarrassment, limited access to healthcare and distance from the nearest healthcare facility, financial limitations, educational status, socio-economic status, family history of breast cancer, fear of mutilating surgeries and use of traditional medicine or spiritual care didn’t have significant effect on whether the patients presented within or after 3 months of onset of symptoms. On the question of COVID pandemic related delay, only 16% of all patients cited this as an additional reason for delay and this was again, not different between the patients who presented within or after 3 months of onset of symptoms. Conclusions: Health promotion in terms of proper evaluation of pregnancy related lumps and awareness about the management options of breast cancer may help patients to present earlier to healthcare facilities and may help in improving breast cancer related outcomes in developing countries like India.

Citation Format: SIDDHANT KHARE, Vidushi Doda, R N NAGA SANTOSH IRRINKI. Reasons for Delay in Indian Women Presenting with Primary Stage III or IV Breast Cancer: An Observational Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-18.
Abstract P6-05-60: People with metastatic breast cancer face barriers to finding information and support
Authors: Pugh-Yi Robin H. , Welcsh Piri , Owens Kelly , Rose Diane , Kuhn Erica , Dearfield Craig T. , Friedman Susan
Published: March 2023

People with metastatic breast cancer face barriers to finding information and support Background FORCE, a national nonprofit organization developed a health communication tool to help patients assess research relevance, key findings, and the quality of media reporting on cancer to support informed and shared health decision-making. People with metastatic breast cancer (mBC) are a priority population. Methods The organization conducted a survey about awareness of and access to breast cancer information and supportive services for people living with metastatic breast cancer. The organization promoted the survey through e-mail and social media, and a network of partner organizations that serve the metastatic breast cancer community. The survey invited respondents to volunteer to participate in focus groups and a follow-up survey in order to support efforts to serve this priority population. Results and Conclusions While interest in clinical trials was high, many users reported that thy do not know how to find an appropriate clinical trial. A majority of the 335 respondents were interested in information about clinical trials, treatment side effects, research findings, long-term health issues, diet/exercise, fatigue, and emotional health. Three quarters of the respondents indicated that they had never participated in a clinical trial, 67% indicated they would be interested in participating in the future, and about 40% indicated they did not know how to find a clinical trial recruiting people with metastatic breast cancer. Approximately one-third of participants were unable to obtain referrals to services they sought. Other barriers to services included lack of insurance coverage, lack of availability, and the COVID-19 public health emergency. Focus group responses indicate that women with mBC find the health communication tool to be useful, and appropriate in language, images, and tone. Results indicate that women with mBC are interested in finding information about clinical trials and other topics related to treatment side effects and quality of life. FORCE and partners are incorporating these results into tailored online resources to meet the needs of the mBC community.

Citation Format: Robin H. Pugh-Yi, Piri Welcsh, Kelly Owens, Diane Rose, Erica Kuhn, Craig T. Dearfield, Susan Friedman. People with metastatic breast cancer face barriers to finding information and support [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-60.