bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 5039: Visualization and analysis of cancer genomics data using UCSC Xena
Authors: Goldman Mary , Craft Brian , Zhu Jingchun , Haussler David
Published: June 2022

UCSC Xena (http://xena.ucsc.edu/) is a web-based visual integration and exploration tool for multi-omic data and associated clinical and phenotypic annotations. Researchers can easily view and explore public data, their own private data, or both using the Xena Browser. Private data are kept on the researcher's computer and are never uploaded to our public servers. The toll supports Mac, Windows, and Linux.

Questions Xena can help you answer:

1) Is overexpression of this gene associated with lower/higher survival?

2) What genes are differentially expressed between these two groups of samples?

3) What is the relationship between mutation, copy number, expression, etc for this gene?

Xena showcases seminal cancer genomics datasets from TCGA, the Pan-Cancer Atlas, GDC, PCAWG, ICGC, and more; a total of more than 1500 datasets across 50 cancer types. We support virtually any type of functional genomics data: SNPs, INDELs, copy number variation, gene expression, ATAC-seq, DNA methylation, exon-, transcript-, miRNA-, lncRNA-expression, and structural variants. We also support clinical data such as phenotype information, subtype classifications and biomarkers. All of our data is available for download via python or R APIs, or using our URL links.

Our signature Visual Spreadsheet view shows multiple data types side-by-side enabling discovery of correlations across and within genes and genomic regions. We also have dynamic Kaplan-Meier survival analysis, powerful filtering and subgrouping, differential gene expression analysis, charts, statistical analyses, genomic signatures, and the ability to generate URLs to live views. We link out to the UCSC Genome Browser as well as MuPIT/CRAVAT and TumorMap.

New features include:

- Genome-wide differential gene expression analysis

- New interface for filtering samples and creating subgroups

- New interface to create charts and graphs

- Violin plots on any numerical data

- Loading of Microsoft Excel files

- A new Publication Page showcasing publications and authors that use UCSC Xena

Our beta prototype for visualizing single-cell data delivers million-cell-scale multi-omics data for interactive visualization in a web browser.

Citation Format: Mary Goldman, Brian Craft, Jingchun Zhu, David Haussler. Visualization and analysis of cancer genomics data using UCSC Xena [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5039.
Abstract 5054: Breast cancer survival analysis with the size of the infiltrative cancer area
Authors: Choi JunYoung , Kwak Tae-Yeong , Kim Sun Woo , Chang Hyeyoon
Published: June 2022

Background: Analyzing breast cancer prognosis factors is important for survival analysis. In general, the approximate size of the tumor is considered in pathologic staging, but it is not known whether the exact size of the infiltrative cancer area is related to the patients' survival. To analyze the effectiveness of the size of the infiltrative cancer area for survival analysis of patients, we developed a machine learning algorithm that predicts death risk by analyzing clinical data and the actual size of the infiltrative cancer area from hematoxylin and eosin stained whole slide images (WSIs) of breast cancer.

Design: To obtain an area of infiltrative cancer, an experienced pathologist conducted annotations using WSIs of breast cancer resection tissue. The data analyzed in this study was from The Cancer Genome Atlas’s breast cancer data set (TCGA-BRCA). There were 871 WSIs labeled with survival events and periods, and several clinical features according to patients including the age at diagnosis, ER, PR, HER2 status, and pathologic TNM stages. We extract the size of the infiltrative cancer area from annotations and incorporate them with clinical features. There existed 53 uncensored data, and we splitted the whole dataset into 8:2 for training/validation. We performed 5-fold cross validation with random sampling. We trained a Cox Regression model with features and compared C-index according to features.

Result: The C-index with the infiltrative cancer area for the test set was 0.806. This figure is an improvement of 0.2 from 0.781 without the infiltrative cancer area. The hazard ratio of the infiltrative cancer area was 1.84. The p-value of the infiltrative cancer area was 0.019 for the log-rank test.

Conclusion: This result shows that the infiltrative cancer area is a useful feature even in the presence of the TNM stage.

Citation Format: JunYoung Choi, Tae-Yeong Kwak, Sun Woo Kim, Hyeyoon Chang. Breast cancer survival analysis with the size of the infiltrative cancer area [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5054.
Abstract 5082: Proteomic analysis of extracellular vesicles from oncology donor samples purified using an alternating current electrokinetic microelectrode chip
Authors: Hinestrosa Juan P. , Lewis Jean M. , Searson David J. , Balcer Heath I. , Gonzalez David J. , Krishnan Rajaram
Published: June 2022

In this study, we evaluated the ability to detect novel proteins on extracellular vesicles (EVs) following isolation using an alternating current electrokinetic (ACE) microarray. EVs circulating in blood contain a wealth of biomarkers that are thought to reflect the tumor’s proteome; however, detecting the full diversity of EV proteins may depend on choice of method to purify EVs for analysis. We compared an ACE microarray isolation method with a conventional chemical precipitation method to isolate EVs from blood plasma cancer and control samples. EVs were isolated from 1 mL each of control or pancreatic cancer patient plasma using the ExoVerita platform (Biological Dynamics) or ExoQuick Ultra kit (System Biosciences). Purified EVs were processed using tandem mass tag (TMT)-based multiplexing mass spectrometry proteomics (ThermoFisher Scientific) and the resulting peptide spectra were analyzed and quantified to determine the proteins present. Additional analyses, such as bioanalyzer measurements of contaminating plasma proteins and nanoparticle tracking analysis were performed in parallel to further characterize the isolated EVs. Cancer EVs isolated by ACE were enriched in proteins related to cancer functions when compared to non-cancer control EVs. They also showed enrichment in ontology clusters such as NABA core matrisome proteins, with depressed expression of wound healing family proteins. In contrast, EVs isolated using chemical purification demonstrated enrichment chiefly in proteins functionally grouped into immune system or blood regulation functions. After analyzing EVs isolated by ACE, a total of fifty-one (51) proteins were observed to be upregulated in the cancer donor samples. EV isolation method choice significantly impacted the proteomic profile observed. EV isolation using ACE-based technology can provide more insights into understanding the proteome by possibly reducing or removing non-specific proteins from the EVs. With better separation of EVs from blood proteins, the EV proteins identified may have greater biological significance.

Citation Format: Juan P. Hinestrosa, Jean M. Lewis, David J. Searson, Heath I. Balcer, David J. Gonzalez, Rajaram Krishnan. Proteomic analysis of extracellular vesicles from oncology donor samples purified using an alternating current electrokinetic microelectrode chip [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5082.
Abstract 5084: KMT2D and PIK3CA mutation as potential factors to predict adjuvant chemotherapy efficacy in surgical triple negative breast cancer
Authors: Wang Xue , Du Feng , Yue Jian , Si Yiran , Cui Lina , Zhang Bei , Zhao Xiaochen , Xu Binghe , Yuan Peng
Published: June 2022

Background: Chemotherapy is the most common treatment strategy for triple negative breast cancer (TNBC) patients. Nevertheless, due to adverse drug reactionsthe molecular high heterogeneity of TNBC and no appropriate meaningful efficacy markers, it is still difficult to establish preferred therapeutic strategies and predict the outcomes for TNBC. This study was to investigate the potential predictors and therapeutic targets based on genetic features.

Methods: A total of 386 TNBC patients were randomized 1:1 to receive either six cycles of paclitaxel + cisplatin (TP) or four cycles of epirubicin + cyclophosphamide followed by four cycles of docetaxel (EC-T) adjuvant chemotherapy after surgery (NCT01150513), which were described previously. Finally, 149 TNBC patients with clinical and tumor sequencing data availability were retrospectively analysed by NGS for 733 cancer-related genes. All tumor samples were collected during the surgical operation and subjected to NGS for evaluating genomic mutations and the potential predictors. Cox regression model and Kaplan-Meier method were applied to evaluate disease-free survival (DFS).

Results: In the surgical cohort receiving adjuvant chemotherapy, 74 patients received platinum and 75 received platinum-free chemotherapy as adjuvant chemotherapy. The most frequently mutated genes in this surgical TNBC cohort were TP53 (84%), BRCA1 (18%), BRCA2 (15%), POL1 (13%), PTEN (12%), REV3L (11%), FANCC (10%), and PARP4 (10%). We analyzed the associations between 733 cancer-related gene mutations and DFS after adjuvant chemotherapy. For the TP group, PIK3CA mutation (19%, 14/74) was discovered to correlate with poor DFS for patients treated with platinum-containing adjuvant therapy (HR=3.2, P=0.037), and KMT2D mutation (15%, 11/75) display worse DFS for patients treated with EC-T platinum-free group (HR=3.0, p=0.039). However, BRCA1/2 mutation (24%, 35/149) was found to be associated with poor prognosis (HR=2.1 (95% CI: 1-4.6), p=0.047), irrespective of therapeutic regimen.

Conclusions: In this population of surgical TNBC patients, NGS analysis identified potential predictive markers. PIK3CA mutation in TP platinum-containing group and KMT2D mutation in EC-T platinum-free group were significantly associated to poor prognosis for adjuvant chemotherapy in triple negative breast cancer.

Citation Format: Xue Wang, Feng Du, Jian Yue, Yiran Si, Lina Cui, Bei Zhang, Xiaochen Zhao, Binghe Xu, Peng Yuan. KMT2D and PIK3CA mutation as potential factors to predict adjuvant chemotherapy efficacy in surgical triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5084.
Abstract 509: Tumor inflammation signature (TIS) in residual disease is associated with survival in breast cancer patients with high risk of recurrence
Authors: Galvez-Nino Marco , Castillo Miluska , Bernabe Luis , Suarez Nancy , Sanchez Joselyn , Roque Katia , Neciosup Silvia , Gomez Henry , Castaneda Carlos
Published: June 2022

Background: The assessment of tumor inflammation signature (TIS) quantifies the adaptive immune response in the tumor microenvironment and is emerging as a predictor of clinical benefit in breast cancer. In this study we evaluated the ability of TIS to be a prognostic biomarker of survival benefit in patients with moderated and high residual disease after neoadjuvant chemotherapy (NAC) in breast cancer patients and its correlation with residual TILS after NAC.

Methods: We analyzed 46 samples of residual disease of breast cancer patients who received NAC and were under surgery between 2013 - 2018, with high risk of recurrence defined as Residual Cancer Burden (RCB) group II and III. TIS signature was evaluated using the Research Use Only version of 18-gen signature algorithm. Median of TIS score was 5.88, TIS score were categorized in four groups by quartiles and defined as low TIS score (lower quartile, score ≤ 4.82) and high TIS score (score > 4.82). In addition, we quantified the percentage of stromal TILS in residual disease, categorizing level of TILS in high and low level using median (20%) as a cut-off. Survival analysis was performed with Kaplan-Meier method and the associations with Cox regression model. Correlation between TIS and TILS was performed whit Pearson coefficient. Clinical data was collected of medical records.

Results: The median age at diagnosis was 50 years (26y - 78y), 65.2% of patients were Luminal B subtype, 63% were clinical stage IIIB, 26.2% were RCB II and 73.9% RCB III. No correlation between TIS score and percentage of stromal TILS was founded (p = 0.264). After median follow-up of 60 months, estimated median PFS for high TIS score was 71.7 vs 18.2 months for low score (HR = 0.28, 95% CI [0.13-0.64], p = 0.002), and estimated median OS for high TIS score was non-reached vs 40.9 months for low score (HR = 0.28, 95% CI [0.11-0.68], p = 0.005). Did not found differences in PFS (p = 0.408) and OS (p = 0.773) by level of TILS.

Conclusions: High TIS score in moderated/high residual disease after neoadjuvant chemotherapy is associated with survival benefit expressed in prolonged PFS and OS. Level of TILS in residual disease did not show differences in survival and its percentage did not have correlation with TIS score.

Funding: FONDECYT-198-2015/280-INNOVATEPERU-EC-2017.

Citation Format: Marco Galvez-Nino, Miluska Castillo, Luis Bernabe, Nancy Suarez, Joselyn Sanchez, Katia Roque, Silvia Neciosup, Henry Gomez, Carlos Castaneda. Tumor inflammation signature (TIS) in residual disease is associated with survival in breast cancer patients with high risk of recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 509.
Abstract 5191: BCL-2 inhibitor APG-2575 promotes anti-tumor immunity through converting tumor-associated macrophages into M1 phenotype in non-small cell lung cancer
Authors: Luo Fan , Lu Fei-teng , Qiu Miao-zhen , Pan Wen-tao , Zhang Lin , Zhao Hong-yun , Zhang Li , Yang Da-jun
Published: June 2022

The main challenges for immune checkpoint inhibitors (ICIs) are ascribable to tumor immunosuppressive microenvironment and a lack of sufficient activated CD8+ T cell infiltration. Modifying tumor-associated macrophages (TAMs) strategies have attracted attention for ameliorating tumor immunosuppression and improving anti-tumor immunity. Here, by applying human hematopoietic stem cell (HSC) reconstruction NSG mice and murine C57BL/6 syngeneic tumor xenografts, we demonstrated that APG-2575 combined with PD-1 blockade exerted synergistic antitumor activity, which was associated with the increased recruitment of CD8+ cytotoxic T lymphocytes. Additionally, we found that APG-2575-mediated antitumor T cell immunity is macrophage dependent, and it could function as an anticancer immune regulator that repolarizes TAMs from M2 to pro-inflammatory M1 phenotype. Mechanistically, APG-2575 enhanced M1 polarization through increasing the activated NF-κB binding to the NLRP3 promoter. In parallel, the enhanced expression of NLRP3 mediated the activation of pro-inflammatory caspases and the subsequently elevation of CCL5 and CXCL10 chemokines production by M1 macrophages. As a result, APG-2575-mediated macrophages transition could improve tumor immunosuppression, thus skewing the cytokines profiles into immunostimulatory one in the TME and further enhancing antitumor T cell immunity. These results provided a novel promising strategy for NSCLC treatment and warranted future clinical evaluation of combination therapy of APG-2575 and ICIs.Key words: BCL-2, APG-2575, ICIs, macrophages, non-small cell lung cancer.

Citation Format: Fan Luo, Fei-teng Lu, Miao-zhen Qiu, Wen-tao Pan, Lin Zhang, Hong-yun Zhao, Li Zhang, Da-jun Yang. BCL-2 inhibitor APG-2575 promotes anti-tumor immunity through converting tumor-associated macrophages into M1 phenotype in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5191.
Abstract 5195: Humanized CD3E,D,G mice: An ideal model for efficacy study of CD3-bispecific antibodies
Authors: Yang xiaoliu , Ju cunxiang , zhang mingkun , zhao jing
Published: June 2022

CD3-targeting bispecific antibodies (CD3 bsAb) are designed to simultaneously bind to T cells and tumor cell antigens, leading to T-cell activation, proliferation, and tumor cell death. To create a better animal model for studies of CD3-TCBs, we developed the BALBc-hCD3EDG model by gene editing technology, Briefly, a large human genomic fragment containing CD3E,CD3D,CD3G as well as regulatory elements was introduced into the BALBc mouse genome and animals carrying human CD3E,D,G integration were selected to establish the new strain. The BALBc-hCD3EDG mice have a normal immune system and successfully express human CD3E,CD3D,CD3G on the T cell surface. As expected, cytotoxicity of activity T cells by redirecting with CD3-CD20 bsAb was observed in in vitro T cell-mediated killing assays using an A20 cell expressing human CD20. Furthermore, the growth of subcutaneously engrafted CT26 and hCD20-A20 tumors in BALBc-hCD3EDG mice, was strongly inhibited by CD3-TCB antibody treatment. In conclusion, the CD3EDG humanized mice are ideal models for preclinical studies of bispecific antibodies and other immunotherapies.

Citation Format: xiaoliu Yang, cunxiang Ju, mingkun zhang, jing zhao. Humanized CD3E,D,G mice: An ideal model for efficacy study of CD3-bispecific antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5195.
Abstract 5200: The incidence and risk factors of hyperprogressive disease(HPD) in non-small cell lung cancer(NSCLC) treated with immune checkpoint inhibitors(ICI)
Authors: Kim Hyeonseon , Lee Yeun Ho , Song Chiwoo , Kim Leeseul , Kim Min Jeong , Choi Horyun , Kim Jinah , Chae Young Kwang
Published: June 2022

Background: HPD is an unexpected rapid acceleration of tumor growth reported for patients treated with ICI. The definition of HPD is not fully established and risk factors are uncertain. Our aim in this study was to find the incidence of HPD as well as its significant clinical and genetic risk factors.

Method: A total of 203 patients with NSCLC who received ICI at Northwestern Memorial Hospital during 2008-2020 were included. Tumor growth kinetics (TGK) on immunotherapy and TGK pre-immunotherapy were collected and TGK ratio (TGKR) was calculated. HPD was defined as TGKR≥2.

Result: HPD was observed in 16% (n=33) of patients. HPD was significantly associated with high ECOG (3-4 vs 1-2) [OR = 4.52, 95% CI = 1.31 to 16.29, P = 0.01], presence of bone metastasis [OR = 2.51, 95% CI = 1.10 to 5.28, P = 0.01], neutrophils/lymphocyte ratio(NLR) ≥5 [OR = 2.68, 95% CI = 1.24 to 5.81 P = 0.01], thrombocytosis (platelet count >450k) [OR = 5.31, 95% CI = 2.07 to 14.70, P=0.0003], and treatment with PD-L1 inhibitor vs PD-1 inhibitor [OR = 2.14, 95% CI= 0.97 to 4.68, P= 0.068]. HPD was inversely associated with positive PD-L1 expression [OR = 0.34, 95% CI = 0.13 to 0.86, P = 0.01], ICI combined with chemotherapy vs ICI monotherapy [OR = 0.24, 95% CI = 0.055 to 0.97, P=0.04], and positive TTF-1 expression [OR = 0.46, 95% CI = 0.21 to 1.02, P=0.057]. HPD was not associated with histology of NSCLC (adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and large cell neuroendocrine carcinoma), age(<70, ≥70), sex, smoking history, number of metastatic lesions (<3, ≥3), brain metastasis, liver metastasis, brain metastasis before treatment initiation, EGFR mutation, TP53 mutation, BRAF mutation, and TNM staging.

Conclusion: The incidence of HPD in NSCLC treated with ICI was consistent with current literature. High NLR and platelet count are suggestive of an immunosuppressive environment that could contribute to the rapid growth of tumors. To our knowledge, this is the first study to report an inverse correlation of PD-L1 expression and TTF-1 expression with HPD. The strength of our study lies in a large number of patients. Further studies on validating risk factors of HPD and exploring their associated mechanisms are warranted.

Citation Format: Hyeonseon Kim, Yeun Ho Lee, Chiwoo Song, Leeseul Kim, Min Jeong Kim, Horyun Choi, Jinah Kim, Young Kwang Chae. The incidence and risk factors of hyperprogressive disease(HPD) in non-small cell lung cancer(NSCLC) treated with immune checkpoint inhibitors(ICI) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5200.
Abstract 5207: Mitoxantrone in combination with TGFβ and PD-1 blockade remodels the tumor immune landscape enhancing neuroblastoma antitumor immunity
Authors: Lucarini Valeria , Melaiu Ombretta , D'Amico Silvia , Pastorino Fabio , Tempora Patrizia , De Ninno Adele , Businaro Luca , Ponzoni Mirco , Locatelli Franco , Fruci Doriana
Published: June 2022

Poor infiltration of functioning T cells renders tumors unresponsive to checkpoint-blocking immunotherapies. Here, we employed a combinatorial in situ immunomodulation strategy based on the administration of selected immunogenic drugs and immunotherapy to sensitise two mouse models of neuroblastoma (NB) sparsely infiltrated by T cells to the host antitumor immune response. Using multiple in vitro, ex vivo, and in vivo approaches, we found that mitoxantrone treatment curbed NB growth and promoted tumor regression when combined with TGFβ and PD-1 blockade in aggressive NB models. This combined immunotherapy strategy resulted in the enrichment of a variety of both innate and adaptive immune cells into the TME, and the concomitant production of inflammatory chemokines involved in remodelling the tumor’s immune landscape. Mitoxantrone in combination with TGFβ and PD-1 blockade could be used to reshape the functional repertoire of intratumoral immune cells, restoring the entire immune cell cycle and overcoming the immunosuppressive microenvironment of aggressive NB.

Citation Format: Valeria Lucarini, Ombretta Melaiu, Silvia D'Amico, Fabio Pastorino, Patrizia Tempora, Adele De Ninno, Luca Businaro, Mirco Ponzoni, Franco Locatelli, Doriana Fruci. Mitoxantrone in combination with TGFβ and PD-1 blockade remodels the tumor immune landscape enhancing neuroblastoma antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5207.
Abstract 521: The role of the E3 ubiquitin ligase Parkin in clear cell renal cell carcinoma
Authors: Esser Laura Kristin , Branchi Vittorio , Shaker Farhad , Simon Adrian Georg , Stephan Carsten , Kristiansen Glen , Buness Andreas , Schorle Hubert , Toma Marieta I.
Published: June 2022

Introduction: The E3 ubiquitin ligase Parkin has been described in several cancer entities, including clear cell renal cell carcinoma (ccRCC). Decreased Parkin expression is associated with poor prognosis. We aimed to clarify the biological role of Parkin in ccRCC and to evaluate its expression in a clinically characterized renal cancer cohort.

Methods: We analyzed cell lines and clinically annotated patient material with qPCR (n=63), immunohistochemistry (n=262), LC-mass spectrometry and performed functional analyses in cell line models.

Results: We found that overexpression of Parkin results in a less aggressive phenotype in the clear cell renal cell carcinoma cell line 786-O indicated by lower migration and invasion. Mass spectrometry revealed decreased levels of several proteins in Parkin expressing cells. One of these proteins was cyclin kinase subunit 2 (CKS2). The introduction of a C431S mutation in the catalytic domain of the Parkin gene abolished the effect of decreased migration. In addition, knockdown of CKS2 in cells lacking Parkin caused decreased migration suggesting that the effect of Parkin is CKS2 mediated. Furthermore, the correlation of CKS2 and tumor grading is highly significant and high levels of CKS2 are associated with shorter survival times.

Conclusions: Parkin plays a major role in ccRCC biology, regulation cell migration and invasion, possibly exerted by CKS2 signaling. In consequence CKS2 appears to be an interesting prognostic biomarker in clear cell renal cell carcinoma and might also serve as a new therapy target.

Citation Format: Laura Kristin Esser, Vittorio Branchi, Farhad Shaker, Adrian Georg Simon, Carsten Stephan, Glen Kristiansen, Andreas Buness, Hubert Schorle, Marieta I. Toma. The role of the E3 ubiquitin ligase Parkin in clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 521.
Abstract 5231: Case report: dramatic response to Crizotinib in a patient with synchronous multiple primary lung cancer positive for a novel ARL1-MET fusion
Authors: Ma Qing , Kong Lingping , Zhong Diansheng
Published: June 2022

Background: With the use of high-resolution chest imaging system, an increasing number of lung cancer patients are being diagnosed with multiple primary lung cancer (MPLC). Although surgery is considered as the first choice of treatment for early MPLC, targeted therapy is essential in the management of unresectable MPLC. To date, the driver oncogenes reported in the patients with MPLC are limited, and MET fusion has not yet been reported in MPLC.

Case presentation: In this case, we reported a female patient with simultaneous MPLC (sMPLC). A novel ARL1-MET fusion was detected in her right lung tumor tissues using next-generation sequencing (NGS). The patient achieved about 5-month progressive-free survival (PFS) after receiving Crizotinib for the unresectable right lung malignancies.

Conclusion: To the best of our knowledge, this case provided the first clinical evidence that the novel ARL1-MET fusion might be an actionable mutation in sMPLC.

Citation Format: Qing Ma, Lingping Kong, Diansheng Zhong. Case report: dramatic response to Crizotinib in a patient with synchronous multiple primary lung cancer positive for a novel ARL1-MET fusion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5231.
Abstract 5250: Association between UGT1A1 gene polymorphism and safety and efficacy of irinotecan monotherapy as the second-line treatment for advanced gastric cancer
Authors: Lv Huifang , He Yunduan , Nie Caiyun , Chen Beibei , Wang Jianzheng , Xu Weifeng , Zhao Jing , Chen Xiaobing , Zhang Junling
Published: June 2022

Objective: Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) is a key enzyme in irinotecan metabolism. However, the relationship between UGT1A1 genotype and the safety and efficacy of irinotecan monotherapy in the treatment of Chinese advanced gastric cancer remains unclear.

Methods: A total of 110 patients were enrolled. Intravenous irinotecan was administered every 3 weeks. Irinotecan dose was selected according to the polymorphism of UGT1A1 gene, which was divided into 3 groups: UGT1A1*6 wild-type (GG type): 125mg/m2, d1, d8; UGT1A1*6 mutant heterozygosity (GA type) 100mg/m2, d1, d8; UGT1A1*6 homozygosity mutation (AA type) 75mg/m2, d1, d8 or paclitaxel 125mg/m2, d1, d8. UGT1A1 genotypes were determined by direct sequencing or next-generation sequencing of genomic DNA extracted from peripheral blood.

Results: Among 110 patients of the subjects, the genotypes of UGT1A1*28 were wild-type in 78 patients (70.91%), mutant heterozygosity in 28 (25.45%) and mutant homozygosity in 4 (3.64%). UGT1A1*6 were GG in 67 cases (60.91%), GA in 35 cases (31.82%), and AA in 8 cases (7.27%). There were two heterozygous mutations in 3 patients, and no homozygous mutation was detected. A total of 10 cycles of irinotecan were administered, with a median of five cycles per patient. There was no significant difference in the risk of delayed diarrhea and granulocytopenia in patients with different UGT1A1*28 genotypes (P>0.05), while there was significant difference in the risk of delayed diarrhea and granulocytopenia in patients with different UGT1A1*6 genotypes (P<0.05). The dose intensity of irinotecan was different in patients with different subtypes of UGT1A1*6 gene, and the dose intensity of heterozygous mutant patients was lower than that of wild-type patients. However, there were no significant differences in PFS and OS among patients with different subtypes after dose adjustment and program adjustment (P>0.05).

Conclusion: UGT1A1*6 gene polymorphism was significantly associated with diarrhea and neutropenia induced by irinotecan. The safety and effectiveness of antitumor therapy might be significantly improved by individualized drug administration according to the results of UGT1A1*6 gene polymorphism.

Citation Format: Huifang Lv, Yunduan He, Caiyun Nie, Beibei Chen, Jianzheng Wang, Weifeng Xu, Jing Zhao, Xiaobing Chen, Junling Zhang. Association between UGT1A1 gene polymorphism and safety and efficacy of irinotecan monotherapy as the second-line treatment for advanced gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5250.
Abstract 5258: Mortality patterns among cancer survivors receiving care in dedicated survivorship clinics
Authors: Ramsey Katherine R. , Chapman Patricia H. , Palos Guadalupe R. , Rodriguez Maria A.
Published: June 2022

Introduction: The number of deaths occurring among cancer survivors continues to be an outcome of concern. Our survivorship clinics provide risk stratification care for patients who have completed their curative treatment and are seen annually in a site-specific clinic. Here we describe mortality rates among adult patients receiving care in eleven site-specific survivorship clinics.

Procedures: We conducted an analysis of 29,418 adult patients seen in our survivorship program from 2008-2021. Medical records were reviewed and categorized by each survivorship clinic. Eligibility criteria were: patients ≥18, treated for curative intent, completed their primary course of treatment, past the highest risk of recurrence, and transitioned based on site-specific survivorship algorithms. Descriptive statistics summarize the results.

Results: There were 26475 survivors alive and 2943 deaths (Table 1). Of those alive, the greatest number were diagnosed with breast, genitourinary, and gastrointestinal malignancies. Death rates ranged from 2% to 38%, with the highest percent in stem cell transplant, head and neck, and gynecology malignancy survivors. 29% of deceased patients had died within one year of their transition from oncology care to survivorship clinics.

Conclusions: Our results indicate differences in mortality risk among different cancer survivors; those who received transplants or were diagnosed with gynecologic or head/neck cancers had higher death rates. Survivors in these groups have short and long-term health risks which may require more proactive care. Current analyses are underway on the cause of death among patients who passed away within the first year of the transition to survivorship.

Table 1. Total Number of Patients Seen by Clinic, Alive or Deceased Status, and Average Years Between First Appointment and Death (N=29418) Clinic Total No. No. Alive Percent Alive No. Deaths PercentDeaths Avg Years from First Appt to Death Breast 11972 11219 94% 753 6% 4 GI 837 787 94% 50 6% 3 GU 4264 3952 93% 312 7% 4 Gyn 1284 1175 91% 109 8% 4 Head & Neck 2763 2482 90% 281 10% 3 Lymphoma 759 707 93% 52 7% 4 Melanoma 1234 1174 95% 60 5% 3 Sarcoma 87 85 98% 2 2% 1 Stem Cell Transplant 3141 1917 61% 1224 39% 1 Thoracic 489 461 94% 28 6% 2 Thyroid 2588 2516 97% 72 3% 4

Citation Format: Katherine R. Ramsey, Patricia H. Chapman, Guadalupe R. Palos, Maria A. Rodriguez. Mortality patterns among cancer survivors receiving care in dedicated survivorship clinics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5258.
Abstract 527: A streamlined workflow for liquid biopsy extraction and highplex digital PCR analysis using the Maxwell® RSC system and 6-color Crystal Digital PCR™
Authors: Jovelet Cécile , Remy Myrtille , Menanteau Mylene , White Doug , Horejsh Douglas , Mallory Allison
Published: June 2022

Circulating cell free DNA (cfDNA) extracted from liquid biopsy samples have become established sample types for characterizing oncology targets. Currently, there are several extraction protocols and genomic platforms for researchers to select when interrogating genetic information.

The focus of this work was to identify a flexible method for sample extraction that seamlessly integrates into a straightforward and sensitive genetic analysis workflow from plasma samples. Here, we present a workflow combining the Maxwell RSC system for automated cfDNA extraction and Crystal Digital PCR on the naica system for ultrasensitive high-plex detection from liquid biopsy samples of EGFR mutations in non-small cell lung cancer (NSCLC) and PIK3CA mutations and HER2 amplification in breast cancer.

By bridging sample extraction with the Maxwell RSC system and high-plex digital PCR with the 6-color naica® system, we detected with high sensitivity and precision 32 common and rare somatic EGFR mutations in exons 18, 19, 20, and 21, representing more than 90% of EGFR mutations described in NSCLC. Furthermore, following the same extraction and sample testing workflow, we simultaneously detected a set of PIK3CA mutations and HER2 amplification from cfDNA samples. This proof-of-concept workflow creates the foundation for further development of streamlined sample-to-answer protocols that will better assist cancer researchers across the biomarker testing landscape.

Citation Format: Cécile Jovelet, Myrtille Remy, Mylene Menanteau, Doug White, Douglas Horejsh, Allison Mallory. A streamlined workflow for liquid biopsy extraction and highplex digital PCR analysis using the Maxwell® RSC system and 6-color Crystal Digital PCR™ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 527.
Abstract 5294: MDX-124, a novel annexin-A1 antibody, induces significant anti-cancer activity in multiple preclinical models
Authors: Dempsey Fiona C. , Al-Ali Hussein , Crichton Scott J. , Fabian Charlene , Pepper Chris , Qian Bin-Zhi , Li Xue-Feng , Parris Christopher N.
Published: June 2022

Annexin-A1 (ANXA1) is secreted from both cancer and immune cells in response to several physiological stimuli and modulates cellular functions through interactions with formyl peptide receptors (FPR1/2). Overexpression of ANXA1 has been observed in multiple cancers, including triple-negative breast (TNBC), colorectal, lung, pancreatic, gastric and prostate, and correlates with poor prognosis and decreased overall survival. ANXA1 has also been shown to promote cancer cell proliferation, angiogenesis, migration and drug resistance, and to modulate the tumor microenvironment. MDX-124 is a novel humanized antibody targeting ANXA1. Previously we presented data demonstrating its significant anti-proliferative activity. Here we provide further data on the mechanism of action of MDX-124, notably its impact on tumor growth, cell cycle arrest and migration in several preclinical cancer models. Incubation of pancreatic (BxPC-3), lung (A549) and TNBC (MDA-MB-231) cancer cell lines with MDX-124 for 24 h decreased the proportion of cells in S-phase by up to 18.3% with a concomitant increase in G1 phase of up to 33.5% versus untreated cells. This effect occurred in a dose-dependent manner and is consistent with an MDX-124 mediated increase in cell cycle arrest. After 72 h incubation with MDX-124, the migratory ability of gastric (AGS), prostate (PC-3), TNBC (MDA-MB-231), lung (A549), pancreatic (MIA PaCa-2) and colorectal (LoVo) cancer cells was significantly reduced in a dose-dependent manner when compared to untreated controls. Proteomic analysis following incubation of MDX-124 with a panel of cancer cell lines for 72 h demonstrated substantial alterations in the level of expression and phosphorylation of multiple key oncogenic proteins. In the MycCaP-Bo syngeneic model of bone metastatic prostate cancer, mice treated with the murine analog of MDX-124 (10 mg/kg, BIW) had a 52% reduction in mean tumor growth after 14 days compared to isotype control treated mice. In conclusion, our data indicate that targeting ANXA1 with MDX-124 inhibits key tumorigenic processes in several clinically challenging cancer indications. MDX-124 therefore provides an innovative approach to cancer therapy. Medannex initiated a First-In-Human study in Q4 2021 to evaluate MDX-124 in solid malignancies known to overexpress ANXA1.

Citation Format: Fiona C. Dempsey, Hussein Al-Ali, Scott J. Crichton, Charlene Fabian, Chris Pepper, Bin-Zhi Qian, Xue-Feng Li, Christopher N. Parris. MDX-124, a novel annexin-A1 antibody, induces significant anti-cancer activity in multiple preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5294.
Abstract 5296: Poly(ADP-ribose) polymerase-1 expression is a good survival marker in pancreatic cancers, unlike other solid cancers
Authors: Yim Kwangil , Thakur Nishant , Alam Mohammad Rizwan , Abdul-Ghafar Jamshid , Chong Yosep , Seo Kyung Jin , Shin Ok Ran
Published: June 2022

Purpose: Poly(ADP-ribose) Polymerases-1 (PARP-1) is well known as poor survival factor in various solid cancers and its inhibitors have shown promising results in clinical trials. However, in pancreatic ductal adenocarcinoma (PDAC), there is only one study with good prognostic result. We assessed the prognostic significance of PARP-1 in PDAC

Methods: From 1998 to 2020, 194 patients with radical surgery for PDAC were enrolled in Yeouido St. Mary’s hospital (n = 84) and Uijeongbu St. Mary’s hospital (n=110). After making tumor microarray, PARP-1 immunohistochemistry was conducted and we analyzed H score with image analyzer (QuantCenter, 3DHistech, Budapest, Hungary).

Results: High expression of PARP1 (OS: p = 0.004, CSS: p = 0.007, DFS: p < 0.001) was good survival factor in univariate analysis. Old age (OS: p = 0.018, CSS: p = 0.041, DFS: p = 0.050 ), high stage (OS: p = 0.004, CSS: p = 0.009, DFS: p = 0.817), lymphatic invasion (OS: p < 0.001, CSS: p < 0.001, DFS: p = 0.001), venous invasion (OS: p < 0.001, CSS: p < 0.001, DFS: p = 0.109), perineural invasion (OS: p < 0.001, CSS: p < 0.001, DFS: p < 0.001) and high grade tumor differentiation (OS: p = 0.005, CSS: p = 0.003, DFS: p = 0.001 ) was poor survival factor in log rank test. In multivariate analysis, PAPR1 was independent good survival factor (OS: p = 0.002, CSS: p = 0.005, DFS: p < 0.001).

Conclusion: Our study revealed that PARP1 expression was good survival factor in PDAC unlike other solid cancers. In our observation, studies with larger datasets or on the mechanism of PARP1 in PDAC are necessary in order to use PARP inhibitor in PDAC.

Citation Format: Kwangil Yim, Nishant Thakur, Mohammad Rizwan Alam, Jamshid Abdul-Ghafar, Yosep Chong, Kyung Jin Seo, Ok Ran Shin. Poly(ADP-ribose) polymerase-1 expression is a good survival marker in pancreatic cancers, unlike other solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5296.
Abstract 5300: Therapeutical antibody against TIGIT disrupts inhibitory signaling and restores antitumor immunity
Authors: Zhao Hui , Zhang Meng , Guo Zhengcheng , Zhang Cong , Li Shuliang , Wu Guojin
Published: June 2022

T cell immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed mainly on T cell and NK cells. And because of its central role in limiting antitumor immune response and few immune-related adverse events with defect TIGIT, it has been an attractive target in cancer immunotherapy recently. Here we describe a humanized antibody against TIGIT by blocking its function and mediating ADCC to deplete TIGIT positive Treg cells. The antibody was derived from hybridoma of mice immunized with TIGIT-mFc. Comparing to TIGIT antibody in clinical (Tiragolumab), this antibody had higher affinity to 293T cells overexpressing human TIGIT (EC50=0.45nM vs 1.3nM) or cyno TIGIT (EC50=2.6nM vs 13nM), and also had higher binding affinity to activated CD8 T cell from PBMC (EC50=0.65nM vs 1.47nM), with lower Kd (0.9nM vs 1.8nM). This antibody also more efficiently blocked TIGIT binding to its ligand CD155 overexpressed on 293T cells with FACS assay than Tiragolumab (IC50=1nM vs. 1.4nM). In the cell-based reporter assay, the antibody had a lower IC50 than Tiragolumab (5nM vs. 21nM). When the primary CD8 T cell was co-cultured with 293T cells overexpressing CD155 and anti-CD3 scFv (OKT3) on the surface, the antibody increased the secretion of INF-γ along with an increase of antibody concentration. At last, this antibody-mediated depletion of TIGIT positive Treg from PBMC cultured in vitro with higher efficiency than Tiragolumab. In sum, the antibody described here was a better candidate drug targeting TIGIT for cancer immunotherapy

Citation Format: Hui Zhao, Meng Zhang, Zhengcheng Guo, Cong Zhang, Shuliang Li, Guojin Wu. Therapeutical antibody against TIGIT disrupts inhibitory signaling and restores antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5300.
Abstract 5301: GDF-15 neutralizing antibody restores cancer-induced cachexia
Authors: Wu Guojin , Liang Jinming , He Feng , Zhang Meng , Guo Zhengcheng , Ning Jinying
Published: June 2022

Growth and differentiation factor 15 (GDF-15) is a member of the transforming growth factor β superfamily. Elevated GDF-15 level was often the result of pathological conditions, including autoimmune disease and cancer. Increased GDF-15 caused metabiotic disorders such as anorexia and cachexia, and GDF-15 became an attractive target for metabolic intervention. Here, we developed a humanized GDF-15 neutralizing antibody (H53E5-8V2) from hybridoma of mice immunized with GDF-15-mFc. H53E5-8V2 had high affinity to GDF-15 (Kd=0.05nM), and demonstrated a stronger binding to coated GDF-15-HIS than Ponsegnomab (Pfizer Inc.) with ELISA assay (EC50=0.33nM vs 0.73nM). H53E5-8V2 also had strong binding to cynoGDF15 (EC50=0.3nM). In ELISA blocking assay, H53E5-8V2 disrupted the interaction of GDF-15 and GFRAL with a lower concentration than Ponsegnomab (EC50=0.25nM vs. 0.5nM). In addition, H53E5-8V2 neutralized GDF-15 in the culture medium and blocked GDF-15 induced GFRAL signaling more efficiently than Ponsegnomab in reporter cell assay (EC50=0.13nM vs. 0.27nM). H53E5-8V2 was stable and had a serum half-life of 9 days in mice with a single antibody injection. And it prevented body weight decrease of the mouse with HT1080 xenograft tumor, MC38 overexpressing GDF-15, or subcutaneous injection of protein GDF-15 fused with mouse Fc at C terminal. These results suggested that H53E5-8V2 was a good candidate drug for the treatment of cachexia.

Citation Format: Guojin Wu, Jinming Liang, Feng He, Meng Zhang, Zhengcheng Guo, Jinying Ning. GDF-15 neutralizing antibody restores cancer-induced cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5301.
Abstract 5323: Analytic and clinical validation of a new pan-cancer NGS liquid biopsy test for the detection of copy number variations, fusions/exon skipping, somatic variants and indels
Authors: Audetat Audrey , Tschida Cherie , Kreston Sarah , Jackson Leisa , Mellert Hestia , Stephen Adam , Pestano Gary A.
Published: June 2022

Liquid biopsy tests are an integral part of the molecular diagnostic workup of patients with multiple cancer types. We have extended validation studies of a new liquid biopsy test panel that uses an amplicon-based targeted next-generation sequencing (NGS) panel with a semiconductor-based system, the Ion GeneStudio S5 Prime. The workflow requires very low input (20 ng) of cell-free nucleic acids extracted from human plasma and has been demonstrated to yield results in less than 72 hours from sample receipt at the laboratory. This report details the analytic performance of the test panel for detecting copy number variations (CNVs), fusions and exon skipping variants in plasma. These data add to previously reported validation data for the detection of somatic nucleotide variants (SNV) and indels [97.7% - 100% concordant with orthogonal droplet digital PCR (ddPCR) tests]. The updated study sample sets included consented clinical and normal healthy, donor specimens, and reference cell lines to detect fusions and exon skipping [HCC78 (ROS1), CRL-5935 (EML4-ALK), KM12 (NTRK1) and HTB-178 (MET exon 14 skipping)], and CNVs [CRL-5928 (HER2 gain), SK-BR-3 (HER2, CDK6, EGFR and MYC gains), HCC-827 (EGFR gain) and CRL-5909 (MET gain)]. The limit of detection (LOD) for fusion/skipping was initially established at a molecular coverage of 42 copies and was then verified by detection of three additional fusion/skipping variants. The LOD for CNVs was initially established at 1.40 fold-change and was then verified with the detection of three additional CNVs. Verification was conducted with specimens near the initially established LOD. In the precision studies, all expected fusion/skipping variants were detected in all runs and all days of testing (n=18/18) generating a hit rate of 100%. An average CV of 20.5% (range 8.7% to 34.8%) for repeatability and 20.8% (range 15.7% to 30.5%) for reproducibility was established. Twenty eight of 29 CNVs were detected, generating a hit rate of 96.6%. An average CV of 1.85% (range 0% to 5.49%) for repeatability and 6.59% (range 1.65% to 9.22%) for reproducibility was established for detected CNVs. We conclude that the validated test panel meets the criteria for being rapid, highly sensitive and specific, and has utility for the reporting of clinically relevant variants of interest in multiple cancer types.

Citation Format: Audrey Audetat, Cherie Tschida, Sarah Kreston, Leisa Jackson, Hestia Mellert, Adam Stephen, Gary A. Pestano. Analytic and clinical validation of a new pan-cancer NGS liquid biopsy test for the detection of copy number variations, fusions/exon skipping, somatic variants and indels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5323.