bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P5-11-04: Differentially expressed genes and their pathways in breast cancer patients with mesenchymal CTC
Authors: Mego Michal , Hadzega Dominik , Minarik Gabriel , Soltysova Andrea , Nemcova Petra , Kalavska Katarina , Karaba Marian , Benca Juraj , Sedlackova Tatiana , Pindak Daniel , Klucar Lubos 
Published: March 2023

Abstract
Background: Circulating tumor cells (CTC) with phenotype of epithelial-mesenchymal transition (CTC_EMT) represent novel subpopulation of CTC associated with inferior outcome in primary breast cancer (PBC). However, molecular characterization of primary tumors associated with this CTC subpopulation is lacking. The aim of this study was to identify signaling pathways associated with presence of CTC_EMT in PBC patients using a comprehensive genomics approach. Methods: This translational study included 17 patients with PBC and 5 donors of normal breast tissue. CTC_EMT were detected before surgery by quantitative RT-PCR assay for expression of epithelial-mesenchymal transition (EMT) genes (TWIST1, SNAIL1, SLUG, ZEB1). Total RNA was extracted, in parallel, from fresh frozen primary tumor and whole-trancriptome profiles were obtained using RNA sequencing and additionally mRNAs profiles by microarray. Genes expressions were further validated by qRT-PCR. Results: Analyzing RNA sequencing and microarray data, we found set of genes differentially expressed in absence or presence of CTC_EMT in PBC. We identified 157 genes differentially expressed in CTC_EMT phenotype compared to patients with non-detectable CTC. Namely, keratin family is represented by genes KRT5, KRT14, KRT17. Gene ontologies related to membrane structure or communication and immunology appears to be involved in CTC-related processes, pathways related to cell junction and various signaling pathways including PI3K and Ras-signaling appear to be significant in processes leading to CTC EMT presence. Conclusions: We suspect multiple genes of having a role in primary tumour processes leading to CTC EMT production in breast cancer patients. Data suggest, that PI3K & Ras-signalling and pathways related to cell junction are the key pathways for changes inside of primary tumour tissue between CTC EMT and CTC- phenotype of breast cancer patients. We propose, additional study with single-cell resolution is needed for better understanding of the processes.
Citation Format: Michal Mego, Dominik Hadzega, Gabriel Minarik, Andrea Soltysova, Petra Nemcova, Katarina Kalavska, Marian Karaba, Juraj Benca, Tatiana Sedlackova, Daniel Pindak, Lubos Klucar. Differentially expressed genes and their pathways in breast cancer patients with mesenchymal CTC [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 P5-11-04.
Abstract P5-12-06: Comprehensive analysis of DNA damage repair gene germline mutations in Chinese breast cancer patients
Authors: Liao Ning , Cao Li , Zhang Guochun , Wang Junyun , Yang Airong , Wang Yulei , Li Kai , Wen Lingzhu , Ren Chongyang , Jia Minghan , Li Cheukfai , Mok Hsiaopei , Chen Bo , Lai Jianguo , Xiao Weikai 
Published: March 2023

Abstract
Background: Germline DNA damage repair (DDR) mutations has been associated with increased cancer risk, PARP inhibitor therapeutic opportunity for breast cancer (BC) patients. However, the profile of germline mutations in BC covering comprehensive DDR genes remains unclear.
Methods: A total of 341 women with breast cancer who tested 102 germline related genes (including 50 DDR genes) between April 2021 to May 2022 in Guangdong Provincial People’s Hospital were identified. Variants were classified into pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign and benign groups according to the ACMG/AMP Standards and Guidelines. We defined pathogenic and likely pathogenic variants as deleterious mutations.
Results: The median age of 341 breast cancer patients was 48 (range, 20-89) at the first diagnosis of BC. A total of 47 patients (13.78%) carried 53 deleterious germline variants in 21 cancer predisposition genes, 16 of which were DDR genes. DDR deleterious mutations were detected in genes including BRCA2 (n=18), BRCA1(n=7), FANCA (n=4), PMS2 (n=4), PALB2(n=2), RECQL4(n=2), PALB2 (n=2), etc. The younger age at diagnosis (less than 40-year-old) were significantly associated with deleterious mutations in DDR pathway(P=0.02). At least one VUS was identified in 238 (69.79%) patients. The top 5 DDR VUS genes were FANCM (n=21), ATM (n=20), RAD54L (n=17), FANCD2 (n=15) and ATR (n=14). Breast or ovarian cancer family history were significantly correlated with VUS germline mutations in DDR pathway(P=0.039). Interesting, we found that patients with pCR efficacy of neoadjuvant therapy were more likely to have VUS mutations in DDR pathway (table 1).
Conclusion: We provided a comprehensive view of germline DDR gene mutations in BC patients and also analyzed the association between clinical characteristics and germline DDR mutation status. DDR mutations are prevalent in Chinese BC patients. Patients with younger and breast or ovarian cancer family history were more likely to carry DDR alterations. Moreover, patients with higher frequency of DDR VUS mutations may benefit from neoadjuvant therapy.
Table 1. Clinicopathological characteristics between germline mutation carriers and non-carriers
Citation Format: Ning Liao, Li Cao, Guochun Zhang, Junyun Wang, Airong Yang, Yulei Wang, Kai Li, Lingzhu Wen, Chongyang Ren, Minghan Jia, Cheukfai Li, Hsiaopei Mok, Bo Chen, Jianguo Lai, Weikai Xiao. Comprehensive analysis of DNA damage repair gene germline mutations in Chinese breast cancer patients [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 P5-12-06.
Abstract P6-01-28: Tangling the clinicopathological significance of MRE11-RAD50-NBS1 complex in sporadic breast cancers
Authors: Alblihy Adel , Shoqafi Ahmed 
Published: March 2023

Abstract
The MRE11–RAD50–NBS1 (MRN) complex is critical for genomic stability. Although germline mutations in MRN may increase breast cancer susceptibility, such mutations are extremely rare. Here, we have conducted a comprehensive clinicopathological study of MRN in sporadic breast cancers. We have protein expression profiled for MRN and a panel of DNA repair factors involved in double-strand break repair (BRCA1, BRCA2, ATM, CHK2, ATR, Chk1, pChk1, RAD51, γH2AX, RPA1, RPA2, DNA-PKcs), RECQ DNA helicases (BLM, WRN, RECQ1, RECQL4, RECQ5), nucleotide excision repair (ERCC1) and base excision repair (SMUG1, APE1, FEN1, PARP1, XRCC1, Pol β) in 1650 clinical breast cancers. The prognostic significance of MRE11, RAD50 and NBS1 transcripts and their microRNA regulators (hsa-miR-494 and hsa-miR-99b) were evaluated in large clinical datasets. Expression of MRN components was analysed in The Cancer Genome Atlas breast cancer cohort. We show that low nuclear MRN is linked to aggressive histopathological phenotypes such as high tumour grade, high mitotic index, oestrogen receptor- and high-risk Nottingham Prognostic Index. In univariate analysis, low nuclear MRE11 and low nuclear RAD50 were associated with poor survival. In multivariate analysis, low nuclear RAD50 remained independently linked with adverse clinical outcomes. Low RAD50 transcripts were also linked with reduced survival. In contrast, overexpression of hsa-miR-494 and hsa-miR-99b microRNAs was associated with poor survival. We observed large-scale genome-wide alterations in MRN-deficient tumours contributing to aggressive behaviour. We conclude that MRN status may be a useful tool to stratify tumours for precision medicine strategies.
Citation Format: Ahmed Shoqafi. Tangling the clinicopathological significance of MRE11-RAD50-NBS1 complex in sporadic breast cancers [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 P6-01-28.
Abstract P6-01-44: Alteration of DNA methylation landscape in breast patients treated with adjuvant chemotherapy
Authors: Ho Peh Joo , Khng Alexis Jiaying , Tan Benita Kiat Tee , Tan Ern Yu , Lim Geok hoon , Tan Su-Ming , Tan Veronique Kiak Mien , Lim Elaine Hsuen , Hartman Mikael , Li Jingmei 
Published: March 2023

Abstract
Background Exposure to cytotoxic chemotherapy treatment may alter DNA methylation (DNAm) in treated patients. Methods We performed DNAm analysis in 1,244 and 897 breast cancer patients treated and not treated by adjuvant chemotherapy using the Illumina MethylationEPIC array (1,804 blood, 337 saliva). DNAm changes of 620,095 individual CpGs and 41,581 promoters were evaluated using linear regression models, adjusting for age at diagnosis, ethnicity, years between sample collection and diagnosis and cell-type heterogeneity. Results from datasets normalized separately were combined by meta-analysis (random effects model). Gene set enrichment analyses were conducted to identify key processes or pathways associated with chemotherapy treatment. Results A total of 425 differentially methylated CpGs and 20 promoters were significantly associated with chemotherapy treatment (p&lt; 5e-8). Enriched gene sets among 3,495 chemotherapy-associated promoters (unadjusted p&lt; 0.05, preranked by Z scores) included three suppressed Gene Ontology (GO) terms that survived Bonferroni correction (GO:0002376, immune system process; GO:0009605, response to external stimulus; and GO:1903034: regulation of response to wounding). Using meta-analysis regression coefficients for all promoters as a ranking metric, olfactory transduction (KEGG, hsa04740) was found to be significantly suppressed (unadjusted p=6.38e-06, adjusted p=0.002). Taste transduction (hsa04742, unadjusted p=1.73e-03, adjusted p=0.565) was the next most significantly suppressed pathway. Conclusion The enrichment of imprinted genes within biological processes and pathways suggests a biological mechanism by which chemotherapy treatment could affect immune response, wound healing and changes in the perceptions of smell and taste.
Citation Format: Peh Joo Ho, Alexis Jiaying Khng, Benita Kiat Tee Tan, Ern Yu Tan, Geok hoon Lim, Su-Ming Tan, Veronique Kiak Mien Tan, Elaine Hsuen Lim, Mikael Hartman, Jingmei Li. Alteration of DNA methylation landscape in breast patients treated with adjuvant chemotherapy [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 P6-01-44.
Abstract P6-01-45: Correlation of an immune-related 8-gene panel with the efficacy of neoadjuvant chemotherapy for breast cancer
Authors: Liu Chun-Yu , Huang Chi-Cheng , Tsai Yi-Fang , Chao Ta-Chung , Lin Yen-Shu , Feng Chin-Jung , Lai Jiun-I , Chen Ji-Lin , Chen Yen-Jen , Chiu Jen-Hwey , Hsu Chih-Yi , Tseng Ling-Ming 
Published: March 2023

Abstract
Introduction: Neoadjuvant chemotherapy, one of systemic treatment of breast cancer, is employed for downstaging of inoperable tumor. Pathological complete response (pCR) after neoadjuvant chemotherapy is associated with good prognosis for breast cancer. The critical role of anti-tumor immune responses in conventional chemotherapy and targeted therapy has been reported. However, the pCR-associated immune genes are still ambiguous. Materials and Methods: Thirty-seven primary breast cancer patients receiving neoadjuvant chemotherapy as the first-line treatment for breast cancer were recruited in this VGH-TAYLOR study (NCT04626440). Total RNA of fresh tumor tissues was isolated and then reverse transcribed into cDNA. The Oncomine Immune Response Research Assay was employed for examination of immune-related gene expressions. In silico analyses were performed using the public databases, including Gene Expression Omnibus, Kaplan-Meier plotter, ROC Plotter, Cancer Therapeutics Response Portal, and The Cancer Genome Atlas. Results: Patients achieved a pCR were associated with lower tumor stage and HER2 expression. The next-generation sequencing-based analysis showed that the expression of eight genes were higher in tissues of patients with pCR than non-pCR, including KLRK1, IGJ, CD69, CD40LG, MS4A1, CD1C, KLRB1, and CA4. The 8-gene score was associated with better recurrence-free survival in patients receiving chemotherapy. Data from an ROC Plotter database showed that higher expressions of IGJ, CD69, and MS4A1 in patients respond to neoadjuvant chemotherapy compared to non-responders. In silico analysis revealed that the negative correlation between pCR-associated gene expressions and IC50 values suggesting the gene high expression was sensitive to the drugs. Moreover, the levels of pCR-associated gene were downregulated in breast tumor tissues and positively correlated with immune cell infiltrations. Conclusion: We identified eight immune genes which were associated with better prognosis and drug responses. The 8-gene score may serve as a prognostic marker for breast cancer patients who receiving neoadjuvant chemotherapy.
Citation Format: Chun-Yu Liu, Chi-Cheng Huang, Yi-Fang Tsai, Ta-Chung Chao, Yen-Shu Lin, Chin-Jung Feng, Jiun-I Lai, Ji-Lin Chen, Yen-Jen Chen, Jen-Hwey Chiu, Chih-Yi Hsu, Ling-Ming Tseng. Correlation of an immune-related 8-gene panel with the efficacy of neoadjuvant chemotherapy for 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 P6-01-45.
Abstract P6-04-04: Clinical Relevance of PD-L1 and CD8 Expression in Triple Negative Breast Cancer
Authors: Bago-Horvath Zsuzsanna , Marhold Maximilian , Heber Ulrike , Bartsch Rupert , Fitzal Florian , Singer Christian F. , Filipits Martin 
Published: March 2023

Abstract
Background: Immune checkpoint inhibitors such as PD-L1 are promising therapy targets in triple negative breast cancer (TNBC). In the present study, we examined the clinical relevance of PD-L1 and CD8 expression in TNBC patients treated with adjuvant chemotherapy. Methods: FFPE tumor material from 118 patients with early TNBC treated between 1999 and 2012 was included in our analysis. Immunohistochemical (IHC) expression of PD-L1 was determined by immune score using the diagnostic antibody SP142 (Ventana). CD8 IHC was performed using the SP57 antibody (Ventana). Follow-up data were available for all 118 patients with a median follow up time of 19.4 years. Biomarkers were examined as continuous or categorical variable (predefined cutoffs). Invasive disease-free survival (IDFS) and overall survival (OS) were analyzed using Cox regression models. Results: The median PD-L1 immune score was 1% and PD-L1 expression was classified as positive in 79/116 (68.1%, cutoff ≥1%) cases. Median CD8 expression was 10% and was scored as positive in 51/115 (44.3%, cutoff &gt;10%) samples. Significant associations were observed between PD-L1 expression and tumor grade, Ki67, and CD8 expression. PD-L1-positive tumors were more frequently in the G3 group (p=0.006) and had higher Ki67 (p&lt; 0.001) and higher CD8 expression (p&lt; 0.001). PD-L1 but not CD8 expression was associated with IDFS or OS. Univariate Cox regression analyses showed that PD-L1-negative patients had a shorter IDFS (HR 0.52, 95%CI 0.30-0.89, p=0.02) and showed a trend towards shorter OS (HR 0.56, 95%CI 0.30-1.03, p=0.06). CD8 expression was neither associated with IDFS (HR 0.74, 95%CI 0.43-1.27, p=0.27) nor with OS (HR 0.87, 95%CI 0.48-1.60, p=0.66). In multivariate analyses, PD-L1 expression was an independent prognostic factor for IDFS (HR 0.51, 95%CI 0.29-0.88, p=0.016) but not for OS (HR 0.53, 95%CI 0.28-1.01, p=0.052). Conclusions: Our results suggest that PD-L1 but not CD8 expression assessed by IHC predicted outcome in TNBC. Further analysis of larger, suitable patient cohorts is warranted to further assess the prognostic and predictive value of PD-L1 expression.
Citation Format: Zsuzsanna Bago-Horvath, Maximilian Marhold, Ulrike Heber, Rupert Bartsch, Florian Fitzal, Christian F. Singer, Martin Filipits. Clinical Relevance of PD-L1 and CD8 Expression in 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 P6-04-04.
Abstract P6-09-05: Using Mixed Methods to Examine Clinician and Patient Use of Terminology to Describe Trastuzumab Biosimilars
Authors: Papautsky Elizabeth , Salunke Devika , Montague Hannah , Carlson Martha , Johnson Sheila , Attai Deanna , Lustberg Maryam 
Published: March 2023

Abstract
Although the uptake of trastuzumab biosimilars to treat HER2-positive breast cancer is growing, knowledge gaps remain for both, patients and clinicians. In a mixed-methods study, inconsistencies in terminology used to describe trastuzumab biosimilars. We analyzed open-ended questions from surveys (n = 143 breast cancer patients, n = 33 medical oncologists) and interviews (n = 8 patients, n = 4 oncologist, nurse, pharmacists) indentifying terminology as an a priori (top-down) category for qualitative thematic analysis. We specifically looked for examples of inconsistent or incorrect use of terminology in the interviews. Findings suggest that 1) terminology used to refer to trastuzumab biosimilars is variable across patients and some is not representative of the formal definition (e.g. generic, generic-like, interchangeable, Herceptin, generic Herceptin (as per how their oncologist refers to biosimilars) and 2) clinicians discussed the challenges of talking about biosimilars in a manner that is both understandable to patients and accurate. Specifically, one pharmacist highlighted concerns around this complexity and suggested that it should be part of clinician education to use the correct terminology, rather than using the term generic. A medical oncologist said that “Explaining biosimilars to a patient can be challenging” as part of their survey response. Lack of consistent terminology for trastuzumab biosimilars is a potential barrier to effective patient-clinician communication on this topic and may perpetuate lack of comprehension on the part of patients. Further, the intentional use (to make information more digestible to patients) of incorrect terminology by clinicians has the potential to negatively impact the patient-clinician relationship in cases where patients identify conflicting information on their own. The adoption of terminology that is consistent across clinicians and patient-facing resources on the introduction and description of trastuzumab biosimilars, may serve to facilitate common grounding among all roles.
Citation Format: Elizabeth Papautsky, Devika Salunke, Hannah Montague, Martha Carlson, Sheila Johnson, Deanna Attai, Maryam Lustberg. Using Mixed Methods to Examine Clinician and Patient Use of Terminology to Describe Trastuzumab Biosimilars [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 P6-09-05.
Abstract P6-11-13: Ferroptosis Heterogeneity in Triple-Negative Breast Cancer Reveals an Innovative Immunotherapy Combination Strategy
Authors: Yang Fan , Xiao Yi , Ding Jia-Han , Jiang Yi-Zhou , Shao Zhi-Ming 
Published: March 2023

Abstract
Treatment of triple-negative breast cancer (TNBC) remains challenging. Deciphering the orchestration of metabolic pathways in regulating ferroptosis will provide new insights into TNBC therapeutic strategies. Here, we integrated the multiomics data of our large TNBC cohort (n=465) to develop the ferroptosis atlas. We discovered that TNBCs had heterogeneous phenotypes in ferroptosis-related metabolites and metabolic pathways. The luminal androgen receptor (LAR) subtype of TNBC was characterized by the upregulation of oxidized phosphatidylethanolamines and glutathione metabolism (especially GPX4), which allowed the utilization of GPX4 inhibitors to induce ferroptosis. Furthermore, we verified that GPX4 inhibition not only induced tumor ferroptosis but also enhanced antitumor immunity. The combination of GPX4 inhibitors and anti-PD1 possessed greater therapeutic efficacy than monotherapy. Clinically, higher GPX4 expression correlated with lower cytolytic scores and worse prognosis in immunotherapy cohorts. Collectively, this study demonstrated the ferroptosis landscape of TNBC and revealed an innovative immunotherapy combination strategy for refractory LAR tumors.
Citation Format: Fan Yang, Yi Xiao, Jia-Han Ding, Yi-Zhou Jiang, Zhi-Ming Shao. Ferroptosis Heterogeneity in Triple-Negative Breast Cancer Reveals an Innovative Immunotherapy Combination Strategy [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 P6-11-13.
Abstract P6-12-02: Connecting Fluctuations in Estrogen Production, Release, and Action with Hormone-Dependent Gene Expression in Breast Cancers
Authors: Kim Hyung Bum , Kraus William L. 
Published: March 2023

Abstract
Estrogens are steroid hormones that play a key role in a wide range of physiological and pathological processes. Estrogen receptor-alpha, ERɑ, functions primarily as a nuclear transcription factor (TF) through ligand-dependent activation by 17β-estradiol (E2), the predominant naturally-occurring estrogen. This results in dimerization, DNA binding to cis-regulatory elements called enhancers, and gene regulatory function of ERɑ. In vivo, E2 production and action fluctuates during reproductive cycles and possibly even in a circadian manner. In tissues and cells, E2-regulated gene expression is dynamic, with rapid induction of enhancer formation and target gene expression (or repression), followed by enhancer “decommissioning” and cessation of the gene regulatory effects. The effects of sustained E2 production and signaling, fluctuations in E2 levels, and removal of E2 on estrogen-regulated gene expression are unknown. Classical experiments exploring the gene regulatory effects of E2 involve stimulation of cultured cells throughout the duration of the experiment with a continuous and typically high dose of hormone, with the cells harvested at the end of the stimulation period. While this has allowed us to understand the molecular underpinnings of signal-dependent transcription, it has not allowed analysis of physiological fluctuations in estrogen signaling involving periods of stimulation (i.e., the presence of hormone) and non-stimulation (i.e., the absence of hormone). In our studies, we are applying a combination of next generation sequencing techniques and fluorescence microscopy to investigate signal-dependent responses to fluctuating and short duration E2 exposures using ERɑ-positive MCF-7 human breast cancer cells after E2 treatment and removal. Our initial results suggest that different E2 target genes respond differently to low dose E2 treatment and E2 withdrawal. Moreover, for some E2 target genes, sustained E2 treatment may not be required for a complete E2 transcriptional response. With these studies, we hope to connect physiological aspects of E2 production, release, and action with the molecular mechanisms of E2-dependent gene expression - an aspect of our understanding of estrogen signaling that has been lacking.
Citation Format: Hyung Bum Kim, William L. Kraus. Connecting Fluctuations in Estrogen Production, Release, and Action with Hormone-Dependent Gene Expression in Breast Cancers [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 P6-12-02.