bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3201: Single-cell trajectory analysis reveals a melanoma-driven distinct hematopoietic response in murine spleen
Authors: Kara Nihan , Samusik Nikolay , Shi Xiaoshan , Lomas Chip , Widmann Stephanie , Tyznik Aaron J. 
Published: July 2021

Abstract
Growing evidence suggests that tumor progression can interfere with normal hematopoiesis and skew the host system to undergo myeloid biased changes. Hematopoietic stem and progenitor cells (HSPCs) are a rare population of precursor cells giving rise to progeny that replenish blood cells throughout life. HSPCs are mainly localized in the bone marrow niche in healthy adults, however pathophysiological conditions such as cancer can cause extramedullary hematopoiesis in organs like the spleen. In this study, we investigated tumor-driven phenotypic and molecular alterations in the HSPC compartment at a single-cell level during extramedullary hematopoiesis using single-cell multiomics. We used a B16-F10 melanoma mouse model to uncover the tumor-mediated changes. Mice with tumor-burden showed splenomegaly and alterations in the composition of the HSPC compartment in the spleen consistent with extramedullary hematopoiesis. We then isolated four HSPC populations, including Lin- Sca1+ cKit+ (LSK), common myeloid progenitor (CMP), granulocyte-macrophage progenitor (GMP) and megakaryocyte-erythrocyte progenitor (MEP) cells from the spleen and bone marrow of melanoma-burdened mice using the BD FACSMelody™ Cell Sorter. Next, we used an integrated workflow on the BD Rhapsody™ Single-Cell Analysis System for the downstream single-cell multiomics analysis. We utilized oligo-conjugated antibodies for NGS-based sample multiplexing and protein detection (BD® Single-Cell Multiplexing Kit, BD® AbSeq Assay), along with whole transcriptome analysis for a comprehensive analysis of mRNA expression. Data analysis using the X-shift algorithm paired with single-cell force-directed layout visualization enabled delineation of the developmental trajectories of HSPC populations and exploration of phenotypic and transcriptomic changes across different hematopoietic subpopulations and across distinct anatomic sites. The analysis also identified unique hematopoietic cell clusters present during melanoma-driven extramedullary hematopoiesis in the spleen. Overall, our findings highlight melanoma-driven perturbations in hematopoiesis by utilizing advanced single-cell multiomics technology.
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Citation Format: Nihan Kara, Nikolay Samusik, Xiaoshan Shi, Chip Lomas, Stephanie Widmann, Aaron J. Tyznik. Single-cell trajectory analysis reveals a melanoma-driven distinct hematopoietic response in murine spleen [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 3201.
Abstract 322: Protein expression shift and potential diagnostic markers through proteomics profiling of A549 lung cancer cells
Authors: Olajuyin Ayobami Matthew , Olajuyin Adefunke Kafayat , Wang Ziqi , Xu Zhiwei , Raji Hayatu M. , Okeke Malachy I. , Zhang Xiaoju 
Published: July 2021

Abstract
Highlights:-Adenocarcinoma lung cancer is common but difficult to diagnose. - Little is known for its proteome when methanol extract of Calotropis procera was used for the treatment groups. -In the treatment versus control groups, about 413 proteins were upregulated while about 626 proteins were downregulated. -Some of the proteins are potential diagnostic markers.
Objectives: Adenocarcinoma lung cancer is a common type of lung cancer but the therapeutic and diagnosis are problematic. We focused on the protein expression of Adenocarcinoma lung cancer using A549 cancer cells and unveiled novel diagnostic makers and mechanisms in which methanol extracts of Calotropis procera ameliorate the disease.
Methods: A549 lung cancer cell lines were obtained and we have 3 control groups and 3 treatment groups. The treatment groups were treated with 80 ug/ml of methanol extracts of Calotropis procera leaf and proteins were extracted for tandem mass tag mass spectrometry. Differential protein expression was performed between treatment groups and controls and the identified proteins were analyzed for pathway enrichment. Selected proteins were further validated in another set of samples using a more quantitative method.
Results: In the treatment versus control, about 413 proteins were upregulated while about 626 proteins were downregulated. Conclusion: This balanced proteomics method not only offers important understandings of protein expression and pathways but also discover potential diagnostic markers for adenocarcinoma lung cancer. It also reveals the molecular mechanisms in which the methanol extracts of Calotropis procera leaf prevent carcinogenesis.
Citation Format: Ayobami Matthew Olajuyin, Adefunke Kafayat Olajuyin, Ziqi Wang, Zhiwei Xu, Hayatu M. Raji, Malachy I. Okeke, Xiaoju Zhang. Protein expression shift and potential diagnostic markers through proteomics profiling of A549 lung cancer cells [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 322.
Abstract 347: TET1 mutation as potential biomarker for immune checkpoint blockade in colorectal cancer
Authors: Yu Shaojun , Zhang Ding , Chen Shiqing 
Published: July 2021

Abstract
Background: TET1, a DNA demethylase, is encoded by TET1 gene. At present, TET1 mutation has been reported to be associated with enhanced tumor immunogenicity and activated anti-tumor immunity across multiple cancers. However, the clinical effect of TET1 mutation on immunotherapy in colorectal cancer is little known.
Methods: 876 patients with colorectal cancer were enrolled in this study. Genomic profiling of DNA was performed on formalin-fixed paraffin-embedded tumor samples by NGS with 733 cancer-related genes panel. The somatic and germline mutation data were both obtained. Benign and likely benign mutations were excluded from our analysis. Programmed death ligand-1(PD-L1) expression status was determined by immunohistochemistry, evaluated with the combined positive score (CPS) and tumor proportion score (TPS). The efficiency of immunotherapy was analyzed in a cohort of 85 patients with colorectal cancer from Morris et al.
Results: 40 of 876 patients (4.75%) harbored TET1 mutations, including nonsynonymous, frameshift and stopgain mutations. Totally, 66 TET1 single nucleotide mutation were identified. Median tumor mutation burden (TMB) value with TET1 mutations was 109.2 mutations/MB, significantly higher than 6.1 mutations/MB in TET1 wild-type group (p&lt;0.001). Microsatellite instability-high (MSI-H) appeared more frequently in TET1 mutations group than TET1 wild-type group (50.0% vs 5.0%, p&lt;0.001). For PD-L1 TPS, compare to TET1 wild type groups, the positive rate of PD-L1 expression in TET1 mutations was higher significantly (6.7% vs 2.7%, p&lt;0.001). The same thing happened with PD-L1 CPS (50.0% vs 23.3%, p&lt;0.001). Possibly, TET1 mutation was a potential marker for immunotherapy. The results were validated in a clinical cohort of immunotherapy, including 85 patients with colorectal cancer. The median overall survival was non-reached in 7 patients with TET1 mutations compare to 13 months in TET1 wild-type group (HR: 0.28, 95% CI 0.11-0.69, P=0.006).
Conclusions: TET1 mutation was strongly associated with higher TMB, MSI-H and PD-L1 expression and improved OS in patients receiving immune checkpoint blockade treatment, suggesting that TET1 mutation is a novel predictive biomarker for immunotherapy in colorectal cancer.
Citation Format: Shaojun Yu, Ding Zhang, Shiqing Chen. TET1 mutation as potential biomarker for immune checkpoint blockade in colorectal 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 347.
Abstract 350: Co-expression and predictive value of HER family members for the response to therapy with cetuximab in patients with metastatic colorectal cancer
Authors: Khelwatty Said A. , Puvanenthiran Soozana , Essapen Sharadah , Bagwan Izhar , Seddon Alan M. , Modjtahedi Helmout 
Published: July 2021

Abstract
Background: Overexpression of the EGFR is common in patients with a wide range of cancers and the EGFR is an important target for therapy with monoclonal antibodies (mAbs) based drugs. Of these, cetuximab and panitumumab have been approved for the treatment of patients with metastatic colorectal cancer (mCRC). However, therapeutic benefits are seen in a subset of such patients and the duration of response can also be short. Indeed, there is currently no reliable predictive biomarkers for the selection of patients who benefit from therapy with the anti-EGFR antibodies. While KRAS mutation is currently used as an important negative predictive biomarker for the response to therapy with anti-EGFR mAbs, not all patients with wild type KRAS gain benefit from therapy with anti-EGFR mAbs and objective responses have been reported in mCRC patients with KRAS mutations.
Aim: The aim of this study was to investigate the predictive value of EGFR and its dimerization partner (i.e. all other members of the HER family) for the response to treatment with cetuximab in patients with wild-type KRAS status mCRC.
Methods: Using immunohistochemistry (IHC) we investigated the co-expression and predictive value of all four members of the HER family, for the response to cetuximab in 144 mCRC patients and in 21 paired primary tumours and their metastatic sites.
Results: Co-expression of all four members of the HER family were found in 10% of the cases examined. The expression of wtEGFR was an indicator of poorer overall survival and the membranous expression of HER2 and HER3 3+ intensity was associated with a shorter progression free survival (PFS). In contrast, the cytoplasmic expression of HER2 was associated with better PFS. In 48% and 71% of the cases examined, there were discordance in the expression of EGFR or one or more HER family members in paired primary and related metastatic tumours, respectively.
Conclusion: Our results implicate the importance of large prospective investigation of the expression level and predictive value of not only the therapeutic target (i.e. EGFR protein) but also its dimerization partners for the response to therapy with anti-EGFR mAbs and other forms of HER inhibitors in both the primary tumours and metastatic sites in colorectal cancer.
Citation Format: Said A. Khelwatty, Soozana Puvanenthiran, Sharadah Essapen, Izhar Bagwan, Alan M. Seddon, Helmout Modjtahedi. Co-expression and predictive value of HER family members for the response to therapy with cetuximab in patients with metastatic colorectal 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 350.
Abstract 36: ARAF mutations confer resistance to RAF dimer inhibitors in NRAS and BRAF mutant melanoma
Authors: Malek Shiva 
Published: July 2021

Abstract
Belvarafenib, a potent and selective RAF dimer inhibitor, exhibits clinical activity in BRAFV600E and NRAS mutant melanoma patients. Here, through generation of belvarafenib resistant NRAS mutant melanoma cells and through analysis of circulating tumor DNA from patients treated with belvarafenib, we identified novel recurrent mutations in ARAF, within the kinase domain. ARAF mutants conferred resistance to belvarafenib in both a dimer and kinase activity dependent manner. Belvarafenib induced ARAF mutant dimers, and dimers containing mutant ARAF were active in the presence of inhibitor. ARAF mutations may serve as a general resistance mechanism for RAF dimer inhibitors as the mutants exhibit reduced sensitivity to a panel of RAF dimer inhibitors. The combination of RAF plus MEK inhibition may be used to delay ARAF driven resistance and suggests a rational combination for clinical use. Taken together, our findings reveal specific and compensatory functions for the ARAF isoform and implicate ARAF mutations as a driver of resistance to RAF dimer inhibitors.
Citation Format: Shiva Malek. ARAF mutations confer resistance to RAF dimer inhibitors in NRAS and BRAF mutant melanoma [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 36.
Abstract 366: Identification of a clinically significant pan-cancer biomarker for homologous recombination deficiency
Authors: Takamatsu Shiro , Brown JB , Yamanoi Koji , Yamaguchi Ken , Hamanishi Junzo , Kobayashi Takashi , Mandai Masaki , Matsumura Noriomi 
Published: July 2021

Abstract
[Background] Genomic alterations in BRCA1/2 and the ‘genomic scar' signatures are associated with homologous recombination DNA repair deficiency (HRD) and serve as therapeutic biomarkers for sensitivity to platinum and PARP inhibitors in breast and ovarian cancers. However, the clinical significance of these biomarkers in other homologous recombination repair (HRR) pathway genes or in other cancer types is not fully understood.
[Method] From the TCGA and the AACR GENIE project databases, we obtained clinical and genomic data of patients with multiple solid cancers, evaluated both locus-specific LOH in HRR pathway gene mutations and two genomic scar signature scores (HRD score and mutational signature 3), identified potential HRD cases, and examined the efficacy of DNA-damaging drugs in these HRD cases.
[Results] Germline and somatic gene mutations in the HRR pathway genes with locus-specific LOH were significantly enriched in cases having high genomic scar scores, whereas those without the LOH were not enriched. Somatic mutations without the LOH were remarkably enriched in hypermutated cases and considered to be passenger mutations. The mutation rate and frequency with LOH in the HRR pathway genes varied widely by cancer type. When stratifying patients by gender and presence of TP53 mutation, the correlation between the two genomic scar scores and the resulting optimal cutoff values for biallelic HRR pathway gene alterations differed greatly. The potential HRD cases that were selected by the two genomic scar cutoffs and biallelic HRR pathway gene alterations showed significantly high gene expression-based HRD scores. In Cox proportional hazard multivariate analyses with covariates of age, stage, gender, HRD, and TP53 mutation, HRD was a good prognostic factor in the group with DNA-damaging agents, but a poor one in the group without the agents.
[Conclusion] Increased attention on locus-specific LOH in HRR pathway gene alterations and the differences in genomic scar signatures stratified by gender and TP53 mutation is newly warranted in order to properly assess HRD in a pan-cancer manner. The results in the present study proved the clinical significance of HRD across cancer types and may contribute to the development of personalized medicine based on HRD.
Citation Format: Shiro Takamatsu, JB Brown, Koji Yamanoi, Ken Yamaguchi, Junzo Hamanishi, Takashi Kobayashi, Masaki Mandai, Noriomi Matsumura. Identification of a clinically significant pan-cancer biomarker for homologous recombination deficiency [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 366.
Abstract 375: High tumor mutation burden predicts unfavorable clinical outcome in EGFR-mutated lung adenocarcinoma treated with targeted therapy
Authors: Lee Seung Hyeun , Sung Ji-Youn 
Published: July 2021

Abstract
Purpose: Although high tumor mutation burden (TMB) has shown association with benefit from immune checkpoint blockade therapies, its implications in lung cancer patients with driving mutations are still unclear. The objective of this study is to determine the association between TMB and treatment outcome in epidermal growth factor receptor (EGFR)-mutated lung cancer treated with tyrosine kinase inhibitors (TKIs).
Methods: We evaluated TMB in EGFR-mutant, lung adenocarcinoma patients who received first-line EGFR-TKIs. TMB was estimated by next-generation sequencing with a cancer gene panel (Oncomine™ Tumor Mutation Load Assay). We compared the response rate (RR), progression-free survival (PFS), overall survival (OS), and frequency of secondary T790M mutation according to the different TMB groups.
Results: Among the 131 patients who were treated with EGFR-TKIs, a total of 63 patients were eligible for the analysis. TMB was stratified by tertiles; low (≤2.13 mutations/Mb), intermediate (2.14-4.25 mutations/Mb), and high (&gt;4.25 mutations/Mb). The TMB levels were not associated with any clinical parameters. The RR was significantly lower in the high TMB group than in the other groups (43.5% vs. 72.1% vs. 78.5%, all p = 0.01). In multivariate analysis, high TMB was independently associated with a shorter PFS in the overall population (hazard ratio [HR] = 2.64, p = 0.004), and associated with shorter OS in patients with exon 19 deletion (HR = 2.55, p = 0.041) compared with low TMB. The frequencies of secondary T790M mutation after TKI failure were not different among the different TMB groups.
Conclusion: High TMB was associated with unfavorable clinical outcome in patients with lung adenocarcinoma treated with EGFR-TKIs. Although further large-scaled studies are required, our data suggest that high TMB may be a predictive biomarker for adverse treatment outcomes and may constitute a distinct subgroup warranting tailored therapeutic approach in this clinical setting.
Citation Format: Seung Hyeun Lee, Ji-Youn Sung. High tumor mutation burden predicts unfavorable clinical outcome in EGFR-mutated lung adenocarcinoma treated with targeted therapy [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 375.
Abstract 376: Prognostic significance of Glasgow prognostic score in NSCLC patients treated with immunotherapy after platinum-based cytotoxic chemotherapy
Authors: Kang Hye Seon , Kim In Kyoung , Kim Jin Woo 
Published: July 2021

Abstract
Introduction: The Glasgow prognostic score (GPS) reflects the host systemic inflammatory response and is validated prognostic factor in lung cancer. However, little is known about the prognostic role in non-small cell lung cancer (NSCLC) patients treated with immunotherapy after platinum-based cytotoxic chemotherapy.
Patient and Methods: This study used a lung cancer cohort of the Catholic Medical Center of Korea between January 2018 and June 2020. We included the patients who were diagnosed with unresectable advanced stage NSCLC or recurrent disease after pulmonary resection and had received at least one regimen of platinum-based chemotherapy before being administered immunotherapy. The patients with NSCLC treated with anti-PD1 or anti-PD-L1 (pembrolizumab, nivolumab, or atezolizumab) and assessed the prognostic value of the GPS. The GPS was calculated using C-reactive protein and albumin concentrations within 1 week before starting anti-PD1 or anti-PD-L1 treatment.
Results: A total of 78 patients with NSCLC treated with immunotherapy as 2nd or 3rd line therapy after platinum-based chemotherapy. Kaplan-Meier analyses revealed that higher GPS was significant predictors of shorter progression free survival (PFS) (Log rank &lt; 0.001) and overall survival (OS) (Log rank &lt; 0.001). In cox-regression multivariate analysis, the hazard ratios for disease progression were 2.146 (95% CI: 0.814-5.656; P = 0.123) for a GPS of 1 and 9.73 (95% CI: 2.931-32.298, P &lt; 0.001) for a GPS of 2 relative to a GPS of 0. Older age (P = 0.033), lower PD-L1 expression (P = 0.036) and higher GPS (P = 0.007) were independently associated with shorter OS.
Conclusion: Higher GPS were identified as one of poor prognostic factor for OS and PFS in NSCLC patients received immunotherapy as 2nd or 3rd line therapy after platinum-based chemotherapy.
Citation Format: Hye Seon Kang, In Kyoung Kim, Jin Woo Kim. Prognostic significance of Glasgow prognostic score in NSCLC patients treated with immunotherapy after platinum-based cytotoxic chemotherapy [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 376.
Abstract 379: Effects on immunotherapy of EGFR mutation subtypes in non-squamous NSCLC
Authors: Tang Haibo , Li Xiaoning , Xie Wenzhuan , Huang Mengli 
Published: July 2021

Abstract
Background: Genetic alternations of Epidermal growth factor receptor (EGFR) in lung cancer had shown associated with response or resistance to anti-PD-1 therapy. However, there is a lack of understanding of the clinical significance of EGFR mutation subtypes in non-squamous non-small cell lung cancer (NSCLC).
Methods: We retrospectively analyzed 510 patients with non-squamous NSCLC treated with anti-PD-(L)1 monotherapy from four independent cohorts. The tumor tissues from the patients were subjected to MSK-IMPACT panel target sequencing or whole exome sequencing. The association between clinical features and specific EGFR alterations was analyzed.
Results: EGFR positivity was 13.33% (68/510), which is close to the proportion in CheckMate-057 (14.09%), while is higher than in KEYNOTE-010 (8.33%). Compared with 68 EGFR alteration lung cancers, DCR, ORR and durable clinical benefit (DCB) were better in patients with EGFR wide-type (Chi-square test, p = 0.0021, 0.0436 and 0.0014, respectively), while the PFS and OS in EGFR wide-type group was not significantly longer than the EGFR positive group (Log-rank test, p =0.1310 for PFS and 0.7730 for OS). Among EGFR positivity, the incidence of L858R only, T790M only, L858R/T790M mixed and others were 23.53%, 19.12%, 11.76% and 45.59%, respectively. A significant difference in survival among the four subtypes of EGFR positive group was observed, mutation of T790M only showed a worse PFS and OS probability compared to the other subtypes (p&lt;0.001 and p = 0.002), whereas mutation of L858R only showed a poorer PFS (p=0.05).
Conclusion: Mutation of T790M in non-squamous NSCLC prospects worse survival than other EGFR mutations, while mutation of non-L858R and non-T790M subtypes was not a worse factor than EGFR wide-type group. The heterogeneity of EGFR alternations may be beneficial for establishing the uses of PD-(L)1 therapies for lung cancers.
Citation Format: Haibo Tang, Xiaoning Li, Wenzhuan Xie, Mengli Huang. Effects on immunotherapy of EGFR mutation subtypes in non-squamous NSCLC [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 379.