bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-08-32: Genetic variation and the role of multi-gene testing for hereditary breast cancer: A single institution experience
Authors: Lu Kit Yu , Smith Meagan , Verbiar Julia , Minor Haleigh , Lapse Jennifer , Blair Latesha , Torp Lisa 
Published: March 2020

Abstract
Introduction: The introduction of multi-gene testing for hereditary forms of breast cancer has changed the clinical approach to genetic testing for breast cancer patients. Recent consensus guideline now recommends genetic testing for all patients with a personal history of breast cancer and updated testing to those who have had negative germline BRCA 1 and 2 testing. This is a single institutional experience regarding the use and outcomes of multi-gene testing and updated testing.
Methods: This is a retrospective analysis of germline multi-gene testing for breast cancer patients at our institution. Information on tumor histology, personal and family history of cancer, age at diagnosis, and genetic testing information was obtained through records review.
Results: Between January 1, 2015 and December 31, 2018, 1568 breast cancer patients were diagnosed or treated at our institution. Of those, 26% of the patients had genetic results (age range 23-87; median age 52; &lt;1% Male; 88% non-Hispanic whites, 8% blacks, 2% Asians, 2% Hispanics). Eight percent of the patients were found to carry a pathogenic variant that the NCCN guidelines designated as sufficient evidence to have an increased risk for breast cancer. Of those, only 3.4% were BRCA 1 and 2 mutations. The prevalent pathogenic variants found in multi-gene testing were BRCA 1/ 2 (3.4%), CHEK2 (2.2%), PALB2 (1%), TP53 (1%), PMS2 (1%), MYTYH (0.74%), FANCC (0.25%), ATM (0.25%), MSH2 (0.25%), MSH6 (0.25%), NBN (0.25%), and RAD51C (0.25%). Fifteen patients had initial testing looking only for the presence of germline BRCA 1 and 2 mutations. Of those, updated expanded testing identified an additional two patients who carried a pathogenic variant that was previously unidentified.
Conclusion: Multi-gene testing and expanded panel testing of all breast cancer patients could increase the detection of pathogenic variants and may have a potential clinical impact for patients and their family. Further understanding of genetic patterns and variation in multi-gene testing is needed. Increasing public awareness and decreasing the cost of genetic testing are also important to improve the rates of multi-gene testing.
Citation Format: Kit Yu Lu, Meagan Smith, Julia Verbiar, Haleigh Minor, Jennifer Lapse, Latesha Blair, Lisa Torp. Genetic variation and the role of multi-gene testing for hereditary breast cancer: A single institution experience [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-32.
Abstract P6-08-36: Uptake of preventive surgeries in a prospective cohort of BRCA1/2 healthy women
Authors: Nejo Priscila , Bexiga Catarina , Fragoso S. , Mayer A , Santos S , Louro P , Luis A , Moura C , Clara Ana , Vaz Fatima 
Published: March 2020

Abstract
PURPOSE
Previous studies referred to uptake of preventive surgeries (PS) in BRCA1/2 healthy carriers in ages older than recommended (35yrs). Since our population has a higher prevalence of BRCA2 mutations (usually associated with an older age at Breast Cancer diagnosis) we proposed to study ages and type of preventive surgeries uptaken by BRCA1/2 women included in prospective follow up.
PATIENTS AND METHODS
Review of all healthy (without a previous cancer diagnosis) BRCA1/2 carriers included in our program from January 2000 to June 2019. Follow-up started after genetic testing. Men were excluded from this analysis.
RESULTS
A total of 5504 cases (4021 index, 1483 relatives) consented for BRCA1/2 testing. We identified 238 healthy BRCA1/2 carriers (BRCA2:158 (66.4%) vs BRCA1 80 (33.6%). Median age at genetic diagnosis was 38.9 yrs (16-78). With a median follow up of 4yrs, bilateral adnexectomy (BA) was the most frequent PS observed (45 BRCA2 and 28 BRCA1 cases) with 15/45 % and 6/28% undergoing BA and bilateral mastectomy (BM) simultaneously. Bilateral mastectomy was uptaken by 14% BRCA2 women and 10% BRCA1 women. Median ages for PS were: BRCA2-AB: 47,4 (28-71), BRCA1-AB: 46.7 (37-59); BRCA2-BM: 36.6 (31-52) and BRCA1-BM:42.5 (30-55). Isolated BM was observed in 7 BRCA2 cases and 2 BRCA1 cases. Most of women submitted to BA, also underwent total hysterectomy (HT): 65% for BRCA2 and 61% BRCA1. Most cases (88% non-adherent) adhere to radiological surveillance, 111/238 with annual breast S MRI and mammography. All pts submitted to BM are prescribed at least one breast MRI to check for remaining breast tissue.
CONCLUSION
Our data reveal that even if, in general, BRCA1/2 women uptake preventive surgeries at a later age that recommended, we observed a strong adherence to radiological (most with breast MRI) surveillance. BA is the PS most frequently observed but, surprisingly for healthy women, most cases also underwent TH. BRCA2 healthy women uptaken bilateral mastectomy at an earlier age than BRCA1 women. It´s possible that BRCA1 women, when deciding for BM also decided for BA.
Citation Format: Priscila Nejo, Catarina Bexiga, S. Fragoso, A Mayer, S Santos, P Louro, A Luis, C Moura, Ana Clara, Fatima Vaz. Uptake of preventive surgeries in a prospective cohort of BRCA1/2 healthy women [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-36.
Abstract P6-10-29: Circular RNAs in exosomes derived from breast cancer: Promising biomarkers for diagnosis and prognosis of triple negative breast cancer (TNBC)
Authors: Yang Sujin , Tang Jinhai 
Published: March 2020

Abstract
Background: With the recent development of transcriptome sequencing technology, circular RNAs (circRNAs) have attracted extensive attention from researchers. Exosomes are usually recognized as a type of membrane vesicles containing RNA (mRNA, miRNA, circRNAs and other non-coding RNAs), proteins and lipids, and may be used as promising biomarkers for disease diagnosis. Unfortunately, circRNAs still remains many action mechanisms of circRNAs cannot be understood completely in the process of tumor development. The study aims to explore novel circRNAs and their potential functions in the treatment and progonsis of TNBC.Materials & methods: A combinative strategy of RNA-sequencing (RNA-seq) technique, RT-qPCR and bioinformatic analysis was employed to unearth the potential mechanism of differential circRNAs in serum-exosomes (n=20) and tissues (n=20) from TNBC patients.Results: Combination of the two datasets from differential circRNAs in serum-exosomes and tissues, the result showed that three circRNAs (has-circRNA-LPXN, has-circRNA-NUFIP2 and has-circRNA-HSDL2) were significantly differentially-expressed in both datasets. RT-qPCR used to verify these three circRNAs in cells and serum-exosomes also found has-circRNA-LPXN was down-regulated and has-circRNA-HSDL2 was up-regulated, which was valuable for breast cancer diagnosis by analyzing these circRNAs in serum-exosomes from BCa patients compared with healthy people.
Conclusion: The expression levels of has-circRNA-LPXN and has-circRNA-HSDL2 were found significantly different both in serum-exosomes and tissues of TNBC and these circRNAs might function as competing endogenous RNAs and play vital roles in the development of TNBC. More importantly, we constructed two circRNAs-miRNAs networks and provided new insight into prognosis and therapy of TNBC from circRNAs in the serum-exosomes.
Citation Format: Sujin Yang, Jinhai Tang. Circular RNAs in exosomes derived from breast cancer: Promising biomarkers for diagnosis and prognosis of triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-29.
Abstract PD2-03: CDK4/6 inhibitor-resistant ER+ breast cancer cell lines are hypersensitive to TTK inhibition
Authors: Bretones Isabel Soria , Thu Kelsie L , Silvester Jennifer , Kiarash Reza , Fletcher Graham C , Cruickshank Jennifer , Bray Mark R , Mak Tak W , Cescon David W 
Published: March 2020

Abstract
Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i), in combination with hormonal therapies, have become standard of care for the treatment of estrogen receptor-positive (ER+)/HER2-negative metastatic breast cancer. Despite demonstrating significant improvements in progression-free survival, acquired resistance to these inhibitors invariably develops. Recent analyses of clinical samples have identified emergent genomic alterations conferring acquired resistance to CDK4/6i, and begin to define the biology of this new clinical entity. Discovery of vulnerabilities of CDK4/6i-resistant tumours is imperative to improve the survival of this group of patients. We modeled CDK4/6i resistance in ER+ breast cancer cell lines using two complementary approaches: (1) spontaneous development of resistance upon continuous exposure to the palbociclib for 6-9 months, and (2) genetic engineering of RB1 loss of function. In both cases, palbociclib resistance was confirmed by colony formation and cell proliferation assays. To identify potential therapeutic strategies for CDK4/6i-resistant cells, we tested the in vitro activity of novel cell cycle inhibitors using sulforhodamine B (SRB) cytotoxicity assays. CFI-402257, a selective TTK inhibitor now in Phase I testing, induced significantly increased cytotoxicity in different CDK4/6i-resistant models compared to parental cell lines, including but not exclusively those with RB1 loss. CFI-402257 treatment caused defects in cell cycle progression and increased DNA damage and genomic instability in CDK4/6i-resistant cells, while these effects were mild in parental, CDK4/6i-sensitive cell lines. In some cases, these phenotypes were accompanied by an increase in apoptotic signaling. Analysis of the molecular determinants of these effects are being evaluated (additional results will be presented). In xenografts derived from MCF7 cells, CFI-402257 treatment completely abrogated the growth of RB1-KO tumours and had a much less pronounced effect on wild-type tumours. In summary, our results nominate the TTK inhibitor CFI-402257 as a promising therapeutic strategy for breast cancer patients who progress after CDK4/6 inhibition. A clinical trial testing this strategy is being launched.
Citation Format: Isabel Soria Bretones, Kelsie L Thu, Jennifer Silvester, Reza Kiarash, Graham C Fletcher, Jennifer Cruickshank, Mark R Bray, Tak W Mak, David W Cescon. CDK4/6 inhibitor-resistant ER+ breast cancer cell lines are hypersensitive to TTK inhibition [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD2-03.
Abstract PD6-5: The association between radiotherapy and contralateral breast cancer risk in young BRCA1/2-associated breast cancer patients
Authors: van Barele Mark , Akdeniz Delal , Heemskerk-Gerritsen Bernadette AM , Baaijens Margreet HA , Sattler Margriet GA , Schmidt Marjanka K , Jager Agnes , Hooning Maartje J ,   HEBON collaborators
Published: March 2020

Abstract
Background: Long-term side-effects of cancer treatment are becoming more important as survival improves. Secondary cancer is a concern after radiotherapy, especially for patients treated at a young age. Since the BRCA1/2 genes play an essential role in DNA-repair, carriers of BRCA1/2 mutations are possibly more susceptible to the harmful side-effects of radiotherapy.
Aim: To investigate whether breast cancer (BC) patients with a BRCA1/2 mutation are at increased risk of developing contralateral breast cancer (CBC) after treatment with adjuvant radiotherapy at a young age.
Methods: BRCA1/2 mutation carriers previously diagnosed with BC were selected from the Dutch national HEBON study. We used a left-truncated Cox proportional hazards model to estimate the association between radiotherapy (yes/no) and CBC risk, stratifying for age (&lt;40 vs ≥40) and censoring for contralateral prophylactic mastectomy.
Results: Median follow-up was 10.1 years for the radiotherapy group (n=901), and 9.3 years for the non-radiotherapy group (n=609) (p=0.072). Median age at BC diagnosis and the distribution of BRCA1 and BRCA2 carriers was similar for both groups. Radiotherapy overall was not significantly associated with a higher risk of CBC (adjusted hazard ratio (HR) 1.31; 95%CI 0.91-1.89, n=1510). Six-hundred and forty patients were less than 40 years of age at BC diagnosis. Those treated with radiotherapy (n=366) had a higher stage and less often underwent mastectomy and prophylactic contralateral mastectomy.
Stratifying by age at diagnosis yielded a HR of 1.66 (95%CI 0.93-2.95) for age&lt;40 and a HR of 1.01 (95%CI 0.64-1.61) for age≥ 40.
Conclusion: BRCA1/2 mutation carriers irradiated for primary BC under the age of 40 may have an increased risk of developing CBC.
Citation Format: Mark van Barele, Delal Akdeniz, Bernadette AM Heemskerk-Gerritsen, Margreet HA Baaijens, Margriet GA Sattler, Marjanka K Schmidt, Agnes Jager, Maartje J Hooning, HEBON collaborators. The association between radiotherapy and contralateral breast cancer risk in young BRCA1/2-associated breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD6-5.
Abstract PD8-08: Characterization of spatial and temporal heterogeneity of ER positive metastatic breast cancer using serial biopsies
Authors: Allen Read K. , Pinto Christopher J. , Fitzgerald Donna M. , Huynh Tiffany G. , Chen Christopher T. , Juric Dejan 
Published: March 2020

Abstract
Background: Metastatic breast cancer is characterized by a remarkable level of temporal and spatial heterogeneity. Management decisions based on a single tissue biopsy are therefore inherently limited by sampling bias and by dynamic changes in the receptor status and the mutational profile of the tumor. Methods: We characterized 41 serially enrolled patients on the tissue collection protocol DFHCC 13-416, who had ER+/HER2- breast cancer at the time of diagnosis of early stage disease. Results: 36 out of 41 patients (87.8%) had at least one biopsy in the metastatic setting. The number of biopsies in the metastatic setting ranged from one to seven. Two most frequently biopsied sites were liver (24.4%) and recurrent breast lesions (22.0%). Six out of 41 patients (14.6%) developed ER loss over the course of treatment. Estrogen receptor status conversions were noted in both the liver and in the recurrent breast lesions. PR loss was far more common, noted in 24 out of 41 patients (58.5%). Nine of these patients (21.9%) were PR negative at the time of diagnosis and an additional 15 patients (36.6%) lost PR expression during the course of their therapy. Median time to the loss of ER expression was 6.83 years from the initial diagnosis, while the median time to the loss of PR expression was 4.97 years, consistent with sequential decrease in ER dependence, resulting in loss of PR expression and increased dependence on other survival pathways. Genomic and transcriptomic profiling of all serially collected tissues with reconstruction of phylogenetic trees is ongoing and will be presented at the meeting. Conclusions: Compared to previously published reports, high proportion of patients in this cohort had their metastatic disease confirmed and subsequently followed by serial biopsies. In majority of patients, receptor status changes follow a predictable pattern starting with loss of PR expression, followed by complete loss of ER expression. Concomitant changes in the mutation status of both ER and other co-mutated genes, as well as any associated transcriptomic changes may shed light into new interdependencies and vulnerabilities associated with these dynamic receptor status changes.
Citation Format: Read K. Allen, Christopher J. Pinto, Donna M. Fitzgerald, Tiffany G. Huynh, Christopher T. Chen, Dejan Juric. Characterization of spatial and temporal heterogeneity of ER positive metastatic breast cancer using serial biopsies [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD8-08.
Abstract PD8-10: Regulation of breast tumor metastasis by the dynamic interaction between the TMEM doorway macrophage, tumor and endothelial cells
Authors: Surve Chinmay , Harney Allison S. , Chen Mary , Wang Yarong , Ye Xianjun , Lin Yu , Sharma Ved , Stanley Richard , Oktay Maja H. , Condeelis John S. 
Published: March 2020

Abstract
Tumor cell intravasation is an essential step in the metastatic cascade, but its exact mechanism is not completely understood. We have previously shown that the direct physical association of a tumor cell over-expressing Mena, a Tie2hi/Vegfhi macrophage and an endothelial cell, creates a micro-anatomic doorway called “tumor microenvironment of metastasis” (TMEM). TMEM are responsible for cancer cell intravasation and dissemination to distant sites. The density of TMEM doorways is a clinically validated prognostic marker of distant metastasis in breast cancer patients. Although we know that TMEM doorways create increased localized vascular permeability which cancer cells utilize to intravasate, the precise molecular mechanisms relating TMEM-doorway function and intravasation has not been elucidated. Active TMEM doorways are found in pre-invasive and invasive ductal breast carcinoma as well as in metastatic foci in lymph nodes and lungs, indicating that TMEM-mediated cancer cell dissemination occurs not only at the primary tumor site but also at metastatic sites, which may perpetuate metastatic dissemination even after removal of the primary tumor. Thus it is essential to understand the exact molecular mechanism of TMEM-doorway function so that specific targeted therapies can be developed to intercept systemic cancer cell dissemination. We outline here the exact molecular mechanism of TMEM-doorway functions. TMEM doorway endothelial cell-secreted Ang2 (a Tie2 ligand) stimulates VEGF expression and production by the Tie2hi TMEM macrophage. Subsequently, the TMEM doorway tumor cell- secreted CSF1 stimulates local secretion of VEGF from the Tie2hi TMEM macrophages, leading to dissociation of endothelial adherens and tight junctions near TMEM and cancer cell intravasation. In addition, we show that acute blockage of CSF1R and Tie2-Ang2 signaling by inhibitors and blocking antibodies both in vitro and in mammary tumors leads to decreased macrophage VEGF production and secretion, decreased tumor cell trans-endothelial migration, and decreased TMEM-dependent vascular permeability, tumor cell dissemination and circulating tumor cells. This is the first description of the molecular mechanisms regulating TMEM doorway function and thus represents a major step in defining new biomarkers and targets for the treatment of metastatic tumors.
Citation Format: Chinmay Surve, Allison S. Harney, Mary Chen, Yarong Wang, Xianjun Ye, Yu Lin, Ved Sharma, Richard Stanley, Maja H. Oktay, John S. Condeelis. Regulation of breast tumor metastasis by the dynamic interaction between the TMEM doorway macrophage, tumor and endothelial cells [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD8-10.
Abstract B103: Molecular heterogeneity of gastric cancer explained by methylation-driven key regulators
Authors: Yoo Seungyeul , Chen Quan , Wang Li , Wang Wenhui , Chakravarthy Ankur , Busuttil Rita , Boussioutas Alex , Fenton Tim R. , Zhang Jiangwen , Fan Xiaodan , Leung Seut-Yi , Zhu Jun 
Published: March 2020

Abstract
Gastric cancer (GC) is a heterogeneous disease in which diverse genetic, genomic, and epigenetic alterations can accumulate in different molecular and histologic subtypes. Tumor microenvironment (TME) also contributes to the heterogeneity of GC. To investigate what molecular features of tumor cells drive GC heterogeneity, we developed an integrative causal model, called Integrative Sequential Causality Test (ISCT), to identify key regulators of GC by integrating DNA methylation, copy number variation, and transcriptomic data. Applying ISCT to three GC cohorts that contain methylation, CNV, and gene expression data, 11 common methylation-driven key regulators were identified: ADHFE1, CDO1, CRYAB, FSTL1, GTP, PKP3, PTPRCAP, RAB25, RHOH, SFN, and SORD. Based on these 11 genes, gastric tumors resolved into three groups that were associated with known molecular subtypes, Lauren classification, tumor stage, and patient survival, suggesting significance of the methylation-driven key regulators in molecular and histologic heterogeneity of GC. We also investigated the relationship between TME and the methylation-driven key regulators and showed that both immune/stromal proportions in TME and tumor cell genomics variations contributed to expression variations of the methylation-driven key regulators. Especially, FSTL1, significantly associated with patient survival and tumor progression as well as stromal proportion in TME, was expressed at high level in both stromal and cancer cells, indicating its potential role in mediating tumor-stroma interactions. In summary, this study suggests that genetic, genomic, and epigenetic alterations as well as their interactions with TME contribute to heterogeneity of GC.
Citation Format: Seungyeul Yoo, Quan Chen, Li Wang, Wenhui Wang, Ankur Chakravarthy, Rita Busuttil, Alex Boussioutas, Tim R. Fenton, Jiangwen Zhang, Xiaodan Fan, Seut-Yi Leung, Jun Zhu. Molecular heterogeneity of gastric cancer explained by methylation-driven key regulators [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B103.