bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 365: Detection of homologous recombination deficiency across cancer types by a real-time activity-based functional biomarker
Authors: Lee Chih-Ying , Lei Kai-Hang , Huang Shih-Han , Ko Min-Yu , Chang Ko-Yu , Lin Po-Han , Chen Yu-Li , Cheng Wen-Fang , Chi Peter 
Published: July 2021

Abstract
Homologous recombination (HR) is an error-free repair pathway to eliminate DNA double-strand breaks and crucial for maintaining genome stability. Pathogenic mutations in genes involved in HR, such as BRCA1 and BRCA2, lead to homologous recombination deficiency (HRD) and sensitive cells to poly(ADP-ribose) polymerase inhibitors (PARPi). As such, the selection of HRD cancer patients becomes an important clinical need. In addition to sequencing HR-related genes, recent studies have developed several approaches to detect HRD including genomic scar score, mutational signatures analysis, and RAD51 foci formation assay. However, these assays are not on a real-time basis and provide an indirect estimation of HR status. To overcome these limitations, we have successfully developed a virus-based functional assay to directly quantify HR activity in cells. Our method detects HR status in a real-time and tumor-only manner. By using this activity-based functional assay, we reveal a universal activity threshold for identifying HRD across cancer types. Here, we present a promising method to accurately detect primary ovarian cancer cells with HRD. Clinical samples that be quantified as HRD show a significant response to PARPi. Therefore, our method can serve as a functional biomarker and companion diagnostic for PARPi.
Citation Format: Chih-Ying Lee, Kai-Hang Lei, Shih-Han Huang, Min-Yu Ko, Ko-Yu Chang, Po-Han Lin, Yu-Li Chen, Wen-Fang Cheng, Peter Chi. Detection of homologous recombination deficiency across cancer types by a real-time activity-based functional biomarker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 365.
Abstract 397: ECM2 mutation can serve as a potential efficacious predictor of immunotherapy in melanoma patients
Authors: Yu Qitao , Zeng Aiping , Zhao Yun , Huang Xiaochun , Xie Wenzhuan , Huang Mengli , Bei Ting 
Published: July 2021

Abstract
Background: Epithelial-mesenchymal transition (EMT) has been reported to play a pivotal role in tumor immunosuppression and immune evasion. In multiple solid tumors, PD-L1 expression was much higher in “mesenchymal” compared with that in “epithelial”, indicating patients with mesenchymal phenotypes are more likely to benefit from PD-1/PD-L1 immunotherapy. ECM2 encodes a putative extracellular matrix protein, which involves in cell-cell and/or cell ECM recognition processes, thereby may affecting EMT. However, the predictive value of ECM2 in cancer immunotherapy has not been revealed.
Method: Seven independent public cohorts of NSCLC, melanoma, and pan-cancer, including Rizvi, Van Allen, MSKCC, OAK/POPLAR, Miao, and Samstein cohorts were used to investigate the correlation between ECM2 mutation and clinical events, such as objective response rate (ORR), overall survival (OS), and progression free survival (PFS).
Result: Across all the analyzed cancer types, ECM2 mutation has a strong connection with better outcomes to immune checkpoint inhibitors only in melanoma cancer. ECM2-mutated group was significantly associated with higher ORR (75.0% vs 13.9%, P = 0.013), longer OS (35.9 months vs 8.5 months, 95% CI, 0.02-1.09, P = 0.032) than ECM2-wide-type group. PFS between these two groups was comparable (8.15 months vs 2.8 months, 95% CI, P = 0.25). Furthermore, melanoma patients harboring ECM2 mutation exhibited significantly higher TMB compared with ECM2-wide-type patients in Van Allen cohort (1279.5 mut/Mb vs 125.5 mut/Mb, P = 0.0056).
Conclusion: This study demonstrated that ECM2 mutation can serve as a potential predictor for a favorable response to ICIs in melanoma patients.
Citation Format: Qitao Yu, Aiping Zeng, Yun Zhao, Xiaochun Huang, Wenzhuan Xie, Mengli Huang, Ting Bei. ECM2 mutation can serve as a potential efficacious predictor of immunotherapy in melanoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 397.
Abstract 398: Tumor mutational burden estimated by whole-exome sequencing across multiple cancer types
Authors: Xu Fei , Wei Jinwang , Zhang Xiaochen , Liu Jun , Dai Chun , Wang Guan , Xu Qiang 
Published: July 2021

Abstract
Purpose: Tumor mutational burden (TMB) is emerging as a promising biomarker in immune checkpoint inhibitor therapy. Although whole-exome sequencing (WES) is the gold standard to quantify TMB, most TMB measurements in routine diagnostic applications were done by gene panels due to their lower cost and technical accessibility. Therefore, data is lacking for WES derived TMB in several major tumors. However, panel derived TMB can be misleading because research found its correlation with WES derived TMB was compromised when a subset of samples with high TMB values were excluded from the dataset. In this study, we aim to establish the landscape of WES derived TMB in six tumor types in Chinese patients, test the association between WES-TMB and patient survival in immunotherapy, and compare the performance between WES-TMB and panel-TMB.
Methods: We recruited 357 patients who had received immune checkpoint inhibition (ICI) therapy, representing six types of cancers (see Results for the list). We analyzed the tumors and patient-matched blood samples using WES and called somatic mutations of the patients. We defined our WES-TMB as the total number of somatic nonsynonymous mutations in the tumor exome. In each of the tumor types tested, we assigned the patients with the upper tertile TMB values as the high-TMB group and the remaining two thirds of patients as the low-TMB group.
Results: The distribution of WES-TMB medians are highly variable among different tumors, ranging from 2.71 (cholangiocarcinoma), 2.97 (nervous system tumor), 3.69 (gastric cancer), 4.31 (hepatocellular carcinoma), 4.64 (colorectal cancer), to 5.67 (lung cancer) mutations/Mb. This trend is almost the same as other TMB studies done with panel sequencing, despite the values derived from WES tend to be lower. Additionally, TMB was significantly associated with overall survival in colorectal patients receiving ICI. The high-TMB group also showed better overall survival in hepatocellular carcinoma and gastric cancer.
Conclusion: TMBs derived from panel are overestimated compared to that derived from WES although that doesn't affect the rank of TMBs in different cancer types. It is rational to define TMB subgroups by percentile within different cancer types. These results support TMB as a biomarker to predict clinical benefit to ICI therapy in colorectal cancer.
Citation Format: Fei Xu, Jinwang Wei, Xiaochen Zhang, Jun Liu, Chun Dai, Guan Wang, Qiang Xu. Tumor mutational burden estimated by whole-exome sequencing across multiple cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 398.
Abstract 403: The landscape of PD-L1 expression in lung cancer harboring EGFR mutations
Authors: Zhang Linlin , Gong Fuyu , Meng Fanlu , Wang Xin , Zhong DianSheng 
Published: July 2021

Abstract
Background: Results from previous studies indicated that lung cancer patients harboring EGFR sensitizing mutations may receive unfavorable outcomes from immunotherapy. The present study aims to investigate the landscape of PD-L1 expression in lung cancer harboring EGFR mutations.
Methods: Tissue samples were subjected to NGS in a College of American Pathologists-certified and Clinical Laboratory Improvement Amendments-accredited lab for driver oncogene mutations and PD-L1 expression.
Results: A total of 22143 lung cancer patients were selected, including 12278 (55.4%) male and 9865 (44.6%) female with a median age of 63. There are 9560 patients has the EGFR mutation, and the frequency of EGFR mutation is 43.2%. Among the EGFR mutation patients, 1602 patients have been collected tumor tissue, and the PD-L1 expression have been tested by FDA-approved SP263 and 22C3 antibodies. Among all the EGFR mutation cases assessed PD-L1 expression (n=1602), low PD-L1 expression levels (&lt;1%) were more than half proportion with 56.5% (n=905), PD-L1 expression level of 1%-49% accounted for 31.2% (n=905), PD-L1 expression level of 50%-79% accounted for 9.1% (n=146), PD-L1 expression level of 80%-89% accounted for 1.8% (n=29), and PD-L1 expression level higher than 90% accounted for 1.4% (n=22).
Conclusion: Our study supported that NSCLC patients harboring sensitizing oncogenic mutations may potentially benefit from anti-PD-1/L1 especially for those with positive indicators of immunotherapy with strong positive PD-L1 expression.
Citation Format: Linlin Zhang, Fuyu Gong, Fanlu Meng, Xin Wang, DianSheng Zhong. The landscape of PD-L1 expression in lung cancer harboring EGFR mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 403.
Abstract 417: Role of programmed cell death protein-1 (PD-1)-targeted immunotherapy in hepatocellular carcinoma
Authors: Li Shaohua , Mei Jie , Wang Qiaoxuan , Wei Wei , Lu Lianghe , Zou Jingwen , Zhao Rongce , Guo Zhixing , Ling Yihong , Wen Yuhua , Lin Wenping , Zheng Lie , Chen Minshan , Guo Rongping 
Published: July 2021

Abstract
Background: Anti-programmed cell death protein-1 (PD-1) immunotherapy has shown promising outcomes in patients with advanced hepatocellular carcinoma(HCC). In practice anti-PD-1 drugs were mostly a part of combination therapy, especially in the Asia-Pacific region. We aimed to evaluate the effectiveness and safety of PD-1 inhibitors in combination therapies for HCC patients through real-world data.
Methods: Between January 2018 and December 2019, patients with HCC who received anti-PD-1 immunotherapy were screened for eligibility. The primary efficacy endpoints included tumor response rate, overall survival(OS), and progression-free survival(PFS). Safety was assessed by immune-related adverse events (iAEs). Univariate and multivariate analyses were conducted to identified the risk factors of prognosis.
Result: A total of 322 patients were included in our study. Anti-PD-1 immunotherapy was combined with locoregional interventional approaches (62.1%) and tyrosine kinase inhibitors TKIs (66.5%). The 3-, 6-, 12- and 18-month OS rate were 97.1%, 90.5%, 72.9%, and 57.3%, respectively. The 3-, 6-, 12- and 18-month PFS rate were 82.3%, 66.5%, 42.1%, and 30.3%, respectively. Overally, objective response rate (ORR) was 38.5%, and disease control rate (DCR) was 83.9%. The total rate of grade 3-4 treatment-related AEs was 5.9%, and laboratory-related AEs was 8.7%.
Conclusion: PD-1-targeted immunotherapy as a part of a combination therapy, was a safe and effective treatment for intermediate and advanced HCC.
Citation Format: Shaohua Li, Jie Mei, Qiaoxuan Wang, Wei Wei, Lianghe Lu, Jingwen Zou, Rongce Zhao, Zhixing Guo, Yihong Ling, Yuhua Wen, Wenping Lin, Lie Zheng, Minshan Chen, Rongping Guo. Role of programmed cell death protein-1 (PD-1)-targeted immunotherapy in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 417.
Abstract 460: Novel breast cancer biomarker in liquid biopsies and its immune regulatory role
Authors: Ibrahim Safaa A. , Riehl Valerie , Beaman Kenneth D. 
Published: July 2021

Abstract
The discovery of a feasible and specific biomarkers is required for early detection of breast cancer. Breast cancer secretes microvesicles (MV) in large quantities to blood circulation to communicate with distant cells such as immune cells to support tumor growth and prepare the metastatic niche. Our recent studies detected a specific peptide from the a2 isoform vacuolar ATPase (a2NTD) as a component of the MV of breast cancer cells and not from MV of normal mammary epithelial cells. a2NTD expression positively correlates with the invasiveness of breast cancer cells, modulates immune cells, and promotes tumor growth, and metastasis. Detection of a2NTD in liquid biopsies and determination of its regulatory role will offer a feasible and specific biomarker for breast cancer. We revealed that a2NTD were highly expressed in exosomes isolated from plasma of breast cancer patients (BC-Ex) in comparison to isolated exosomes from normal donors (N-Ex). BC-Ex induces the gene expression and the secretion of cancer promoting factors from PBMCs such as IL-8, MCP-1, TNF-α and MMP-9 relative to vehicle control or N-Ex. Angiogenesis assay showed that secreted factors from BC-Ex treated PBMCs promote tube formation in HUVEC cell line. In addition, treatment of whole blood from healthy volunteers with MDA MB-231 MV or recombinant a2NTD drives the neutrophil transition from high density neutrophils (HDN) to Low density neutrophils (LDN). Flow cytometrical analysis showed that LDN possess the PMN-MDSCs markers CD11b+ CD15+ CD14- CD33- HLA-DR-. In addition, a2NTD treatment was associated with decreased internal staining of Arg-1 in neutrophils and the release of Arg-1 suggesting that a2NTD reprograms neutrophils to have immunosuppressive phenotype. Together, this data shows that a2NTD can be a potential predictor of the growth and metastasis of breast cancer.
Citation Format: Safaa A. Ibrahim, Valerie Riehl, Kenneth D. Beaman. Novel breast cancer biomarker in liquid biopsies and its immune regulatory role [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 460.
Abstract 462: The development of a highly efficient diagnostic marker combined with PSA of prostate cancer (PCa)
Authors: Lee SeungBaek , Kim JungJin 
Published: July 2021

Abstract
Prostate-Specific Antigen (PSA) is a well-known diagnosis maker for detecting prostate cancer (PCa) using a serum test. However, PSA testing remains controversial because it shows a high false-positive rate and lacks the sensitivity of PCa patients with low PSA levels, although patients have metastasis. Recently, we found an E3 ubiquitin ligase, WSB1, highly expressed in PCa patients with low PSA levels. Overexpressed WSB1 is found in various human cancers, such as pancreatic cancer, lung cancer, breast cancer, and PCa. Especially with PCa, WSB1 is highly expressed in metastatic PCa. Using RNA seq. database from PCa patients (65 primaries and 25 metastasis), we found that WSB1 is highly expressed in 90% (9/10) of patients among ten primary patients with normal PSA levels and 100% (6/6) of patients among six metastasis patients with normal PSA levels. WSB1 expression shows a significant correlation with aggressive PCa progression. Furthermore, WSB1 can secrete into cell culture media like PSA. Therefore, we suggest that WSB1 could be a highly efficient marker combined with PSA for PCa diagnosis as well as being developed as a screening test for the early detection of PCa in the high-risk group.
Citation Format: SeungBaek Lee, JungJin Kim. The development of a highly efficient diagnostic marker combined with PSA of prostate cancer (PCa) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 462.
Abstract 493: A novel humanized B-hPD-1/hPD-L1/hTIGIT mouse model reveals enhanced efficacy of combined TIGIT and PD-L1 blockade against cancer
Authors: Liu Chonghui , Zhou Xiaofei , Guo Yanan , Lin Eugene , Yu Luke (Zhaoxue) , Shen Yuelei 
Published: July 2021

Abstract
Immune checkpoint blockade targeting PD-1/PD-L1 has enjoyed tremendous success in the clinic against various advanced stage cancers, unleashing potent and durable immune-mediated control of tumors while vastly improving patient survival. However, only a portion of patients truly benefit, while other cancers, such as breast, prostate, pancreatic, and colon cancers, are largely resistant to PD-1/PD-L1 therapy alone. Targeting additional immunosuppressive proteins could boost the efficacy of anti-PD-1/PD-L1 therapy and bring the benefits of immunotherapy to more patients. TIGIT is a recently identified immune checkpoint protein mainly expressed by T and NK cells. CD155 (PVR) is a high-affinity receptor of TIGIT, while CD112 and CD113 bind it with weaker affinity. CD155 and CD112 can engage CD226, an NK activating receptor also expressed on some CD8+ T cells, and trigger killing of tumors. Competitive binding of TIGIT to CD155 and CD112 would prevent signaling through CD226. Therefore, anti-TIGIT blocking antibodies may enhance the function of NK cells and T cells. Preclinical studies have shown that inhibition of TIGIT promotes proliferation and function of T cells. Combined blockade of both TIGIT and PD1/PD-L1 has also shown superior efficacy over monotherapy against tumors in early phase clinical trials. Given the intensive interest in combined TIGIT and PD-1/PD-L1 therapies for cancer, Biocytogen has established a novel human PD-1/PD-L1/TIGIT triple knock-in (TKI) mouse as a vital tool to pre-clinically evaluate the in vivo efficacy of combined human TIGIT and PD1/PD-L1 blocking agents against tumors compared to either alone. Exon 2 of the mouse PD-1 gene, exon 3 of mouse PD-L1, and exon 2 of mouse TIGIT were replaced by their human homologs in B-hPD-1/hPD-L1/hTIGIT mice. Human PD-1, PD-L1, and TIGIT proteins were expressed in homozygous B-hPD-1/hPD-L1/hTIGIT but not wildtype mice. Immune profiles of B-hPD-1/hPD-L1/hTIGIT mice were similar to those in wild-type C57BL/6 mice, and abnormalities were not observed. Importantly, we showed that combining anti-human PD-L1 and anti-human TIGIT antibodies significantly inhibited the growth of MC38-hPD-L1 tumor cells implanted into B-hPD-1/hPD-L1/hTIGIT mice. Thus, our novel hPD-1/hPD-L1/hTIGIT TKI mice will be very useful for investigating the in vivo efficacy of TIGIT antibodies currently in company pipelines both alone and combined with PD1/PD-L1 antibody drugs.
Citation Format: Chonghui Liu, Xiaofei Zhou, Yanan Guo, Eugene Lin, Luke (Zhaoxue) Yu, Yuelei Shen. A novel humanized B-hPD-1/hPD-L1/hTIGIT mouse model reveals enhanced efficacy of combined TIGIT and PD-L1 blockade against cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 493.
Abstract 535: Molecular profiling of brainstem gliomas by liquid biopsy
Authors: Pan Changcun , Li Tian , Jiang Liping , Yan Hai , Zhang Liwei 
Published: July 2021

Abstract
Background: Brainstem gliomas are heterogeneous diseases, many of which are difficult to safely resect and have limited treatment options due to their location. These constraints pose challenges to biopsy, which limits the use of routine molecular profiling and identification of personalized therapies. Here, we explored the potential of sequencing of circulating tumor DNA (ctDNA) isolated from the cerebrospinal fluid (CSF) of brainstem glioma patients as a less invasive approach for tumor molecular profiling.
Cohorts and Methods:A retrospective analysis of brainstem glioma patients with CSF and tumor tissue available was completed. CSF was obtained from patients either intraoperatively (91.2%, 52/57), from ventricular-peritoneal shunt (3.5%, 2/57), or by lumbar puncture (5.3%, 3/57), all prior to surgical manipulation of the tumor. Deep panel sequencing of glioma-associated genes was performed on CSF-derived ctDNA and, where available, matched blood and tumor DNA from 57 patients, including nine medullary and 23 diffuse intrinsic pontine gliomas (DIPG). In addition, we have now completed a prospective study, in which 12 preoperative CSF samples were obtained from lumbar puncture and used to isolate and characterize ctDNA.
Results: In the retrospective analysis, at least one tumor-specific mutation was detected in over 82.5% of CSF ctDNA samples (47/57). In cases with primary tumors harboring at least one mutation, alterations were identified in the CSF ctDNA of 97.3% of cases (36/37). In over 83% (31/37) of cases, all primary tumor alterations were detected in the CSF, and in 91.9% (34/37) of cases, at least half of the alterations were identified. Among ten patients found to have primary tumors negative for mutations, 30% (3/10) had detectable somatic alterations in the CSF. Finally, mutation detection using plasma ctDNA was less sensitive than sequencing the CSF ctDNA (38% vs. 100%, respectively). In the prospective study, at least one tumor-specific mutation was detected in over 83.3% of CSF ctDNA samples (10/12), which is consistent with the data from the retrospective cohort.
Conclusion: Our study indicates that deep sequencing of CSF ctDNA is a reliable technique for detecting tumor-specific alterations in brainstem tumors. This approach may offer an alternative approach to stereotactic biopsy for molecular profiling of brainstem tumors.
Citation Format: Changcun Pan, Tian Li, Liping Jiang, Hai Yan, Liwei Zhang. Molecular profiling of brainstem gliomas by liquid biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 535.