bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3452: Pre-clinical development of next generation selective estrogen receptor degrader - SAR439859
Authors: Sun Fangxian , Cheng Jane , Sullivan Amy , Malkova Natalia , Shomali Maysoun , McManus Jesseca , Levit Mikhail , Bangari Dinesh , El-Ahmad Youssef , Sidhu Sukhvinder , Debussche Laurent , Bouaboula Monsif 
Published: September 2020

Abstract
Abstract: Nearly 70% or more of newly diagnosed cases of breast cancer (BC) are estrogen receptor positive (ER+) where endocrine therapy is a primary treatment. However, substantial evidence describes a continued role of ER signaling in tumor progression, where approximately 40% of patients on endocrine therapy develop resistance that include mutations in ER that drive a constitutively active receptor. SAR439859 is a novel next generation SERD (selective estrogen receptor degrader) with potent antagonist and degradation activity against ER both wild type and mutant and currently evaluated as a single agent and in combination with palbociclib in a Phase I/II clinical trial (NCT03284957). Here we describe the preclinical development of this molecule in multiple xenografts and demonstrated significant anti-tumor efficacy/regression in ER+ BC models including MCF7-ESR1 mutant-Y537S and endocrine therapy resistant patient-derived xenograft tumor models. The molecule also demonstrated strong synergistic activity with CDK4 inhibitor palbociclib. SAR439859 has a favorable safe profile and no uterotrophic activities. Collectively, these results show that SAR439859 is an oral, selective estrogen receptor antagonist and degrader that could provide therapeutic benefit to ER+ breast cancer patients. In conclusion, SAR439859 demonstrates broad anti-tumor activity in ER+ breast cancer cell line/PDX models. Anti-tumor efficacy correlates with PK exposure/PD modulation in target tissue. SAR439859 also has synergistic activity with CDK4 inhibitor Palbociclib.
Citation Format: Fangxian Sun, Jane Cheng, Amy Sullivan, Natalia Malkova, Maysoun Shomali, Jesseca McManus, Mikhail Levit, Dinesh Bangari, Youssef El-Ahmad, Sukhvinder Sidhu, Laurent Debussche, Monsif Bouaboula. Pre-clinical development of next generation selective estrogen receptor degrader - SAR439859 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3452.
Abstract 3493: Interactions between adiponectin pathway polymorphisms and obesity on breast cancer risk among African American postmenopausal women
Authors: Nam Gina E. , Zhang Zuo-Feng , Rao Jianyu , Zhou Hua , Jung Su Yon 
Published: September 2020

Abstract
Purpose: A decreased circulating adiponectin concentration is associated with obesity and an increased breast cancer risk among postmenopausal women. Yet, the interplay between adiponectin-associated genetic variants, obesity, and breast cancer risk is unclear in African American (AA) postmenopausal women. We examined adiponectin pathway polymorphisms for their association with breast cancer risk among AA postmenopausal women. We also explored a gene-environment interaction between adiponectin pathway polymorphisms and obesity for the risk of breast cancer.
Method: Using the Women's Health Initiative SNP Health Association Resource Study, we identified 37 single-nucleotide polymorphisms (SNPs) in relation to the adiponectin pathway. Body-fat distributions were determined using three independent indices including body mass index (BMI), waist-to-hip ratio (WHR), and waist circumference (WC). We used multiple Cox proportional hazards regression models to estimate hazard ratios and 95% confidence intervals (CIs) for the association with breast cancer. Obesity-stratified analysis and tests for the joint effects with the SNPs were conducted.
Results: Of 7,991 AA postmenopausal women, 402 reported of having an invasive breast cancer with a mean follow-up of 14.5 years. The majority were obese, had low WHR (&lt; 0.85), and had high WC (&lt; 88 cm). Of 37 adiponectin pathway-related SNPs, 3 SNPs were significantly associated with breast cancer risk (KCNK9 rs2468677, OR8S1-LALBA rs11168618, and EIF4A2 rs266719). Among women who have under or normal bodyweight, the minor allele GG genotype of NMU rs13434995 had an elevated risk of postmenopausal breast cancer compared to those with the major allele AA genotype. Women who carry the heterozygous TC genotype of OR8S1-LALBA rs11168618 and are obese jointly increased the risk of breast cancer (relative excess risk due to interaction = 0.58, 95% CI = 0.35, 0.80).
Conclusion: Our findings revealed the association between the previously confirmed adiponectin pathway-related SNPs and breast cancer risk among AA postmenopausal women. We also demonstrated that obesity plays an important role as an effect modifier in the relationship between the SNPs and breast cancer, suggesting 1) the potential use of metabolic and genetic biomarkers for identifying a greater risk for breast cancer and 2) support for the research to promote interventions to those with risk genotypes, thus reducing breast cancer risk.
Citation Format: Gina E. Nam, Zuo-Feng Zhang, Jianyu Rao, Hua Zhou, Su Yon Jung. Interactions between adiponectin pathway polymorphisms and obesity on breast cancer risk among African American postmenopausal women [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3493.
Abstract 3502: Do obese patients present with worse breast cancer
Authors: Wang Melinda , Huang Julian , Chagpar Anees 
Published: September 2020

Abstract
Background: Obesity is a known risk factor for breast cancer development; however, it is unclear whether obesity results in worse disease in terms of stage at presentation, receptor profile, and tumor grade. We sought to determine the relationship between obesity and disease status at presentation in patients undergoing mastectomy for breast cancer.
Methods: Medical records of breast cancer patients undergoing mastectomy at our institution between January 2010 and April 2018 were retrospectively reviewed. Patients were separated into obese (BMI ≥ 30) and non-obese (BMI &lt; 30) categories, and compared using non-parametric statistical analyses.
Results: Of the 927 patients in this cohort, 292 (31.3%) were obese. Sociodemographic and clinicopathologic factors of the obese and non-obese patients are shown in the table below. In general, obese patients were more likely to present with node positive disease (27.1% vs. 19.2%, p = 0.008) and positive triple negative status (10.0% vs. 15.4%, p = 0.026). Controlling for the potential confounders of race and insurance status, obesity remained associated with triple negative status (95%CI: 1.04 - 2.46; p = 0.033) and node positive disease (95%CI:1.17 - 2.31; p = 0.004).
Factors associated with obese vs. non-obese mastectomy patientsFactorNot Obese (n = 635)Obese (n = 292)p-valueAge (yrs); median52520.494Race: White: no. (%)506 (79.7%)220 (75.3%)&lt;0.001Race: Black: no. (%)49 (7.7%)52 (17.8%)Race: Asian: no. (%)35 (5.5%)5 (1.7%)Race: Other: no. (%)45 (7.1%)15 (5.1%)Insurance: Uninsured: no. (%)4 (0.6%)1 (0.3%)0.003Insurance: Medicaid: no. (%)63 (9.9%)54 (18.5%)Insurance: Medicare: no. (%)92 (14.5%)40 (13.7%)Insurance: Military: no. (%)11 (1.7%)9 (3.1%)Insurance: Private: no. (%)465 (73.2%)188 (64.4%)Node positive: no. (%)122 (19.2%)79 (27.1%)0.008Multifocality/Multi centricity: no. (%)142 (22.7%)68 (23.4%)0.800Presence of DCIS: no. (%)490 (77.2%)213 (72.9%)0.186Median invasive tumor size (cm)0.500.700.094AJCC Stage: 0: no. (%)217 (34.3%)90 (30.9%)0.073AJCC Stage: I: no. (%)207 (32.8%)78 (26.8%)AJCC Stage: II: no. (%)139 (22.0%)82 (28.2%)AJCC Stage: III: no. (%)65 (10.3%)40 (13.7%)AJCC Stage: IV: no. (%)4 (0.6%)1 (0.3%)ER+: no. (%)505 (79.5%)222 (76.0%)0.425PR+: no. (%)424 (66.8%)194 (66.4%)0.943Her2+: no. (%)95 (15.3%)30 (10.5%)0.111Triple negative: no. (%)62 (10.0%)44 (15.4%)0.026
Conclusion: Obese patients tend to present with more aggressive breast cancer, independent of sociodemographic factors.
Citation Format: Melinda Wang, Julian Huang, Anees Chagpar. Do obese patients present with worse breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3502.
Abstract 3525: Epidemiology and clinicopathology prognostic factors of TFEB translocation renal cell carcinoma (TBRCC): Analysis of updated pooled database
Authors: Haddad Philip A. , Hammoud Dalia , Gallagher Kevin 
Published: September 2020

Abstract
Renal cell carcinomas harboring the t(6;11) (p21;q12) translocation with a specific Alpha(MALAT1)-TFEB gene fusion is a recognized rare subtype of the Microphthalmia Transcription factor (MiT) family of translocation RCC. TBRCC is an indolent disease that occurs at a younger age. Though it may take on a wide spectrum of morphology, TBRCC has been classically characterized by distinctive biphasic morphology with larger epithelioid cells and smaller cells clustered around eosinophilic spheres formed by basement membrane material. This analysis was conducted to update and expand our existing knowledge of this rare disease. In order to study the demographic characteristics, cytogenetic and molecular signatures, survival, and prognostic factors, we compiled a pooled database of 140 cases. Kaplan-Meier survival curves were constructed. Cox proportional-hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on survival. The median age was 32 (3-78) years with a peak incidence between ages 17 and 30 years. Males and females were afflicted equally. The median overall survival (OS) of the whole group was not reached with more than 78% alive at 10 years. The group's median disease-free survival (DFS) was 96 months. Six percent of this cohort recurred. Among patients who recurred, the median time to recurrence was 24(6-75) months. Sex did not impact OS or DFS. Similarly, the molecular partner of the TFEB gene fusion, Alpha (MALAT1) versus others, did not seem to impact OS or DFS. The presence of necrosis seemed to adversely impact OS (HR:14.3, p&lt;0.0001) and DFS (HR:14.4, p&lt;0.0001). Nuclear grade negatively impacted DFS, the higher the grade the worse the DFS. The presence of eosinophilia, psammoma bodies, and pigmentation did not affect OS or DFS. Similarly, the histologic morphology, biphasic vs others, did not affect OS or DFS. Multivariate analysis revealed older age (HR:1.08, p=0.01) and larger tumor size (HR:10.12, p=0.002) adversely impacted OS. This study presents an updated epidemiologic and clinicopathologic data from a pooled cohort of patients with TBRCC. Age, size, and necrosis were found to adversely impact the OS. However, higher nuclear grade only adversely impacted the cohort's DFS.
Citation Format: Philip A. Haddad, Dalia Hammoud, Kevin Gallagher. Epidemiology and clinicopathology prognostic factors of TFEB translocation renal cell carcinoma (TBRCC): Analysis of updated pooled database [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3525.
Abstract 3534: The study of Lynch syndrome in a special population reveals a strong founder effect and an unusual mutational mechanism in familial adenomatous polyposis
Authors: Siraj Abdul K. , Parvathareddy Sandeep K. , Bu Rong , Masoodi Tariq , Alobaisi Khadija , Alrasheed Maha , Ahmed Saeeda O. , Qadri Zeeshan , Annaiyappanaidu Padmanaban , Benito Allianah , Rala Dionne R. , Al-Kuraya Fowzan , Al-Kuraya Khawla S. 
Published: September 2020

Abstract
Lynch syndrome (LS) is the leading cause of hereditary colorectal cancer (CRC). Germline mutations in DNA mismatch-repair (MMR) genes (MLH1, PMS2, MSH2, and MSH6) are known to cause LS in the heterozygous state. Biallelic mutations in these genes cause mismatch repair cancer syndrome (MMRCS), a very rare childhood cancer syndrome that predisposes to CRC among other cancer types. In this study, we aimed to characterize the mutational landscape of LS in a large CRC cohort (n=1,207) from a population with high rates of consanguinity. The overall contribution of germline mutations in LS gene was comparable to that observed in outbred populations (26/1207). Remarkably, however, we also observed the unusual homozygous occurrence of a founder PMS2 mutation. The homozygous individual presented with massive adenomatous polyposis of the colon at age 8 years, and mutation analysis of multiple polyps revealed the occurrence of multiple independent somatic APC mutations. Our study highlights a previously unrecognized role of LS genes in triggering APC-driven tumors, a phenomenon facilitated by consanguinity.
Citation Format: Abdul K. Siraj, Sandeep K. Parvathareddy, Rong Bu, Tariq Masoodi, Khadija Alobaisi, Maha Alrasheed, Saeeda O. Ahmed, Zeeshan Qadri, Padmanaban Annaiyappanaidu, Allianah Benito, Dionne R. Rala, Fowzan Al-Kuraya, Khawla S. Al-Kuraya. The study of Lynch syndrome in a special population reveals a strong founder effect and an unusual mutational mechanism in familial adenomatous polyposis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3534.
Abstract 3568: Ferroptosis induced by xCT abrogation is dependent on GPX4 protein expression regulated by L-cystine/cysteine metabolism
Authors: Zhang Yanyu , Huang Peng 
Published: September 2020

Abstract
Nutrients in the tumor microenvironment play an essential role in tumor development and proudly impact cancer metabolism. The xCT antiporter, which mediates cellular uptake of L-cystine coupled with glutamate export, has been considered as a promising therapeutic target due in part to its high expression in cancer cells to promote L-cystine uptake as a precursor for glutathione (GSH) synthesis to maintain redox homeostasis. Although inhibition of xCT has been shown to have anticancer effect in multiple models, emerging evidence also reveals that blocking xCT function could confer survival advantages to cancer cells. These opposite observations suggest that xCT inhibition could be a double-edged sword, and its impact on the overall outcome (cancer-inhibitory or tumor-promoting) is likely context-dependent via yet unknown mechanisms. Here, we show that the expression of glutathione peroxidase 4 (GPX4) is a key molecular determinant that decides the cell fate when xCT is suppressed. In cells with low or no expression of GPX4, inhibition of xCT causes severe ROS stress leading to massive cell death via ferroptosis. In contrast, high expression of GPX4 confers cancer cells the ability to escape ROS-induced ferroptosis. Mechanistic study suggests that the intracellular L-cysteine plays a major role in regulating GPX4 protein level, likely via direct binding to GPX4 and stabilize the protein. Pharmacological and genetic disruption of xCT in cancer cells induces dramatic ferroptosis in culture conditions lacking L-cysteine, whereas the presence of L-cysteine in culture or in vivo renders cancer cells resistance to xCT abrogation. Importantly, genetic knockout of xCT by CRISPR/cas9 reduces cancer cell proliferation in culture but promotes tumor growth in vivo, suggesting that the metabolic changes induced by xCT disruption favor cell growth in vivo. Biochemical and molecular analyses show that the in vivo microenvironment containing L-cysteine enables the xCT-disrupted cells to maintain a high GPX4 level, and thus prevents ferroptosis. Furthermore, metabolic flux using U-13C5 glutamine reveals that xCT abrogation leads to intracellular accumulation of more glutamate, which promotes cancer cell survival and proliferation in the low glucose tissue microenvironment in vivo. Our study has identified GPX4 as a key molecule that determines cell fate under metabolic stress induced by xCT suppression, and suggests that modulation of L-cystine/cysteine metabolism might be an effective strategy to overcome ferroptosis-resistant cancer cells.
Citation Format: Yanyu Zhang, Peng Huang. Ferroptosis induced by xCT abrogation is dependent on GPX4 protein expression regulated by L-cystine/cysteine metabolism [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3568.
Abstract 3579: Pimozide combined with paclitaxel demonstrates a significant antitumor effect in head and neck squamous cell carcinoma
Authors: Nakamura Shintaro , Ozawa Hiroyuki , Yamasaki Juntaro , Okazaki Shogo , Yoshikawa Momoko , Soma Tomoya , Asoda Seiji , Nagano Osamu , Sekimizu Mariko , Saito Shin , Yoshihama Keisuke , Mikoshiba Takuya , Ogawa Kaoru , Saya Hideyuki 
Published: September 2020

Abstract
Background: Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common cancer in the world. Despite the development of various treatments, the five-year survival rate for HNSCC is about 50-60% and has not been improved in recent years. Immune checkpoint inhibitors are promising, but the effect of those is limited. The development of new reagents having different mechanisms against tumor progression is still needed. From the result of drug screening, Pimozide (PMZ), an antipsychotic drug used for the treatment of schizophrenia and chronic psychosis, demonstrated a strong antitumor ability to HNSCC cells expressing high level of CD44v. In this study, we examined the combined effects of PMZ and paclitaxel (PTX) for HNSCC cells.
Methods: Using HNSCC cell lines (FaDu, Detroit562, HSC-2, OSC-19), the antitumor effects of PTX, PMZ, and the combination of PTX and PMZ were evaluated by MTS assay. Moreover, the reactive oxygen species (ROS) expression level under each drug administration was measured by flow cytometry. Moreover, PTX, PMZ (0.45mg/kg), PMZ (1mg/kg), PTX+PMZ were administered to the xenograft model by OSC-19. The tumor was resected after those treatments. The expression of CD44v, ALDH3A1, and NRF2 was evaluated by immunohistochemistry (IHC) of FFPE tissues from those extracted tumors.
Results: PMZ single-agent inhibited tumor growth in various tumor cell lines, and the
antitumor effect was enhanced by concomitant use of PTX. PMZ, which significantly increased ROS of tumor cells, was more effective than PTX in OSC-19, which was a chemoresistant cell line expressing high CD44v. Xenograft model exhibited that tumor growth was suppressed in PTX+PMZ group than in PTX and PMZ single-agent group. IHC staining revealed that PMZ administration restrained CD44v expression, and ALDH3A1 expression markedly decreased in PMZ treated tumors, but not in PTX treated tumors.
Conclusions: PMZ dramatically induced ROS production in tumor cells. These data suggest that aldehyde produced by ROS might suppress HNSCC tumor growth. The results from this study indicated that PMZ could be a novel therapeutic reagent for HNSCC in combination with existing anticancer drugs.
Citation Format: Shintaro Nakamura, Hiroyuki Ozawa, Juntaro Yamasaki, Shogo Okazaki, Momoko Yoshikawa, Tomoya Soma, Seiji Asoda, Osamu Nagano, Mariko Sekimizu, Shin Saito, Keisuke Yoshihama, Takuya Mikoshiba, Kaoru Ogawa, Hideyuki Saya. Pimozide combined with paclitaxel demonstrates a significant antitumor effect in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3579.
Abstract 3621: Characterization of BRAF mutation in Chinese colorectal cancer patients using next generation sequencing
Authors: Wang Hui , Wu Hao , Zhou Yifan , Zhang Bei , Sun Danpeng , Jiang LIihua , Chen Hui , Bai Yuezong , Zhang Zhe 
Published: September 2020

Abstract
Objective: BRAF alterations were characterized into three classes according to their dependency with upstream gene alterations in activating the MARK signaling pathway, giving clinical doctors clues of inhibitors selection for therapy. However, the characterization of BRAF mutation in Chinese colorectal cancer patients was unknown.
Methods: Colorectum tissue samples were collected from 2155 patients and performed the next generation sequencing (NGS) using a validated commercial panel containing essential genes in RAS-RAF-MARK and PI3K-AKT-mTOR pathways. BRAF mutations were characterized into Class I (kinase-activated, codon 600), II (kinase-activated, non-codon 600) and III (kinase-impaired).
Results: There were 9031 pathogenic and likely pathogenic somatic mutations were detected in 2137 out of 2155 samples, among which 149 (7.0%), 1048 (48.6%), 82 (3.8%), 2 (0.1%), 8 (0.4%), 362 (16.8%), 90 (4.2%) were found caring BRAF, KRAS, NRAS, HRAS, EGFR, PIK3CA and PTEN mutations, respectively. A total of 19 unique BRAF mutations were detected. The Class I (BRAFV600E), Class II and Class III accounted for 76.0%, 6.7% and 13.3% of all BRAF mutations. Higher incidence of co-occurrence of Class III mutations and RAS mutations were observed in our study, which might be due to their RAS-dependent way in activating downstream signaling pathway. Class III patients might be more sensitive to EGFR inhibitor and receive more benefits from survival than other classes.
Conclusions: In our study, the mutation type, frequency, classification of BRAF mutations and co-occurrence with BRAF and other driver gene mutations were explored in a large cohort of Chinese colorectal cancer patients, which might help to suggest proper therapy methods.
Citation Format: Hui Wang, Hao Wu, Yifan Zhou, Bei Zhang, Danpeng Sun, LIihua Jiang, Hui Chen, Yuezong Bai, Zhe Zhang. Characterization of BRAF mutation in Chinese colorectal cancer patients using next generation sequencing [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3621.