bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment of chronic hepatitis C virus infection to increase access to cancer clinical trials in patients with hematologic malignancies: A prospective observational study.
Authors: Mustafayev Khalis , Naing Aung , Thomas Sheeba K. , Patel Krina K. , Pemmaraju Naveen , Daver Naval Guastad , Jiang Ying , Yepez Guevara Eduardo , Torres Harrys A. 
Published: June 2023

3142 Background: Most cancer patients with chronic hepatitis C virus (HCV) infection are excluded from cancer clinical trials (CCTs). The use of direct-acting antivirals (DAAs) to eradicate HCV and allow access to CCTs in HCV-infected cancer patients has not been studied. We aimed to evaluate the efficacy and safety of DAA treatment to increase access to CCTs in patients with chronic HCV infection and hematologic malignancies (HM). Methods: HCV-infected patients with HM seen at MD Anderson Cancer Center between 01/01/2016 and 01/31/2023 were enrolled in a prospective observational study. Those initially excluded from CCTs and then treated with DAAs to allow that cancer treatment were further analyzed (cases). HCV-infected cancer patients treated with DAAs but never enrolled in CCTs were used as controls. The 1:1 matching between cases and controls was based on the cancer type and stage, history of > 3 types of chemotherapy, and presence of cirrhosis. The primary outcomes were the efficacy and safety of DAAs. The secondary outcomes were overall survival (OS) and progression-free survival (PFS). Results: Twenty-four patients with HM initially excluded from CCTs because of HCV were enrolled. Twelve of them (50%) received DAAs to have access to CCTs and they were matched to 12 controls. Most of the cases were men (10; 83%), white (6; 50%), non-cirrhotic (10; 83%), and with HCV genotype 1 (9; 75%). Most patients in the control group were men (7; 58%), white (9; 75%), non-cirrhotic (8; 67%), and with HCV genotype 1 (9; 75%). Among the entire study group, adverse events occurred in 6 of the 24 patients (25%), and all were grade 1-2. No HCV-associated liver failure or death occurred. The overall sustained virologic response (microbiologic cure) after completion of antiviral therapy was 92%. Median OS was 74 months in the cases vs 52 months in the controls, median PFS was 30 months in the cases vs 33 months in the controls. When compared to controls in multivariate analysis, cases had significantly better OS (hazard ratio = 0.23, 95% CI = 0.06 to 0.85, p = 0.027). No significant differences were noted in PFS (p=0.13). Death due to progressive HM occurred in all 12 controls (100%) but only in 4 cases (33%) (p=0.001). Conclusions: DAA treatment increases access to CCTs and improves OS in patients with chronic HCV infection and HM. HCV infection should not be considered a contraindication to investigational cancer treatment. The use of DAAs to facilitate access CCTs could become one of the most common indications for DAAs in HCV-infected cancer patients.
Dupilumab for the treatment of dermatologic adverse events associated with MEK and EGFR inhibitors.
Authors: Gu Stephanie , Dusza Stephen W , Dunkel Ira J. , Drilon Alexander E. , Lacouture Mario E. , Markova Alina 
Published: June 2023

3143 Background: Mitogen activated protein kinase kinase inhibitors (MEKi) and epidermal growth factor receptor inhibitors (EGFRi) are targeted therapies used in the treatment of various cancers. Dermatologic adverse events (dAEs) are common with these medications. Dupilumab, a human monoclonal antibody that targets IL-4, is an FDA approved therapy for the treatment of atopic dermatitis. It has also shown utility in the treatment of many other skin disorders, including toxicities associated with anticancer therapies. In our study, we aim to evaluate the efficacy and safety of dupilumab for the treatment of MEKi/EGFRi associated dAEs. Methods: Patients who received dupilumab for the treatment of a dAE attributed to MEKi or EGFRi from 3/1/2017 to 10/1/2022 were identified at Memorial Sloan Kettering Cancer Center. Severity of dAEs was graded at baseline and follow up using Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Patient response to dupilumab was categorized into complete response (CR) (reduction to grade 0), partial response (PR) (reduction to grade 1), or no response (NR) (including change from grade 3/2 to grade ≥ 2). Results: A total of 17 patients (median age 62 years [5 – 87], 58.8% female) who received dupilumab for MEKi (70.6%) or EGFRi (29.4%) related dAEs were identified. Two patients on MEKi were also on concomitant BRAF inhibitors. Patients were white (88.2%), black (5.9%), and Asian (5.9%) and were all undergoing treatment for solid tumors. All dAEs had an eczematous phenotype; 16 were grade 2 (88.2%) and one (5.9%) was grade 3. The median time from dAE development to initiation of dupilumab was 121 days (5 – 1330). Following treatment, 15 patients (88.2%) experienced improvement, with 46.7% and 53.3% achieving CR and PR, respectively. Patients were on dupilumab for a median of 89 days (0-2556), with CR and PR patients exhibiting initial documented response after a median of 30 days (6 – 173). The median CTCAE grade decreased from 2 to 1, and the number of patients on topical and systemic steroids following addition of dupilumab decreased from 17 (100%) to 7 (41.2%) and 5 (29.4%) to 1 (5.9%), respectively. As a result of intolerable anti-cancer therapy-associated dAEs, 4 patients (all on MEKi) initially discontinued their antineoplastics. Three patients (75%) were successfully rechallenged with their original MEKi, while 1 (25%) was switched to another MEKi without subsequent dAE recurrence. No patients reported adverse events to dupilumab treatment. Conclusions: Patients may experience eczematous eruptions while undergoing treatment with MEKi or EGFRi. Dupilumab may be a safe and effective steroid sparing therapeutic option for the management of these dAEs.
The characteristics of metabolic related pathways under different anoikis activities revealed by pan-cancer analyses.
Authors: Xiao Shanshan , Liu Yang , Wang Li , Wang Qian , Wang Tao 
Published: June 2023

3150 Background: Anoikis is usually activated to eliminate extracellular matrix-detached cells. Cancers develop several mechanisms to escape from this cellular death signaling pathway which was associated with metabolic reprogramming in tumor development and progression. Comprehensively understanding the characteristics of anoikis activities in pan cancers facilitating better clinical treatment strategies. Methods: RNA-Seq data and related patient information were collected from 33 cancer types in TCGA database. We also obtained anoikis related genes (ARGs) from Harmonizome database. The related pathways of epithelial-mesenchymal transition (EMT) and reactive oxygen species (ROS) genes were collected from MSigDB. Autophagy genes were from HADb and metabolic intermediates were from published literatures. Firstly, pathway scores of anoikis and the related pathways were computed through single sample gene set enrichment analysis (ssGSEA). Then, survival analyses based on the anoikis scores were performed to achieve the threshold between the high anoikis (HA) or low anoikis (LA) sample groups. To study the drug efficacy, cell line transcriptome and IC50 data were obtained from GDSC database. Pearson correlations were computed between anoikis and other related pathways or immune cell infiltrations in each sample group. Results: Most ARGs were up-regulated in tumors, the same as the HA sample group. Differentially expressed genes between HA and LA were mostly involved in metabolic super-pathways, including metabolic intermediates (TCA cycle, carbohydrate, lipid, nucleotide, vitamin cofactor, and amino acid, etc.) and promoting anoikis-resistance pathways including EMT, inflammation and autophagy. Higher scores of anoikis related pathways were identified in HA across various cancers. Kaplan-Meier survival analysis revealed that HA in KIRC, KIRP, LAML, LGG, LUAD, PAAD, STAD, THYM, and UVM cancers had significantly worse clinical outcomes (p < 0.05). Functional enrichment analysis of ARGs through GSEA suggested that anoikis resistance was promoted, whereas anoikis was retarded in those cancers. However, patients in HA of several cancers had longer survives than LA, which may owe to the higher infiltrating levels of anti-tumor immune cells including CD8+ T, CD4+ memory activated T cells, particularly in BRCA, MESO, SARC, and UCEC cancers. Drug efficacy analysis revealed that BCL2 gene was significantly associated with sensitive drug response on Venetoclax, ABT737, and Tozasertib. And TLE1 and CAV1 were associated with Tozasertib resistance and AZD5991 resistance, respectively. Conclusions: The characteristics of anoikis activities and metabolic related pathways during tumor progression were comprehensively studied and the prognosis value of anoikis was further assessed by drug efficacy.
A powerful drug combination strategy targeting BRAF-mutant melanoma.
Authors: Rothermel Luke Daniel , Zarei Mehrdad , Loftus Alexander W , Hue Jonathan J. , Hajihassani Omid , Graor Hallie J , Winter Jordan Michael 
Published: June 2023

3152 Background: BRAF inhibitors, such as vemurafenib and dabrafenib, are effective in treating patients with melanoma harboring (V600E) BRAF mutations. These drugs block the activity of the mutated BRAF protein, which impacts the development and progression of melanoma. Despite initial efficacy, drug resistance reliably occurs leading to disease relapse. Here we show how BRAF inhibitors cause metabolic reprogramming in melanoma cells to achieve drug resistance and promote cell survival. Previously we demonstrated that wild-type isocitrate dehydrogenase 1 (wtIDH1) supports mitochondrial function and maintains redox homeostasis in melanoma, and that an FDA-approved mutant IDH1 inhibitor, ivosidenib (AG-120), is actually a potent wtIDH1 inhibitor. Thus, we hypothesized that wtIDH1 inhibition would synergize with BRAF inhibition. Methods: Metabolomic profiling using LC-MS determined the impact of BRAF inhibition on cellular metabolism. Cell viability was assessed by PicoGreen in drug combination assays. Synergism was calculated using the Bliss-Independence dose-response model for drug interaction. In vivo modeling of AG-120 in combination with BRAF inhibition used melanoma cell xenografts in athymic nude mice for tumor volume analyses, and survival studies were performed in both immunocompetent C57BL/6J mice (murine YUMM1.7 cells) and immunocompromised athymic nude mice (human A375 cells). Results: Metabolomics data suggest that BRAF-mutated melanoma cells treated with BRAF inhibitors increased oxidative metabolism and mitochondrial dependence (i.e., survival adaptations). These alterations suggest an opportunity for mitochondrial inhibitors to improve drug efficacy. Targeting wtIDH1 with AG-120 in combination with dabrafenib significantly reduced melanoma cell viability. A positive synergy score and Bliss score greater than 1 indicate that the combined treatment was more effective in reducing cell viability than either treatment alone. Further, the combination of AG-120 and dabrafenib was the most effective in vivo, reducing tumor growth in the BRAF-mutated melanoma xenograft model, and improving mouse survival compared to monotherapy controls. Mice tolerated combination therapy with no reduction in body weight observed. Conclusions: Our findings indicate that dual inhibition of mutated BRAF and wild-type IDH1 represents a novel treatment strategy for BRAF-mutated melanomas, with potential for application to other BRAF-mutated cancers (e.g., colon, hepatobiliary, thyroid, etc.).
Deep learning tumor heterogeneity metric from histopathology images vs next generation sequencing-derived scores for colon cancer prognostication.
Authors: Amiji Hatim , Sheridan Todd Brinsley , Chuang Jeffrey , Rubinstein Jill Carol 
Published: June 2023

3537 Background: Tumor heterogeneity is as an important determinant of clinical behavior in many cancer types, with increased heterogeneity thought to confer inferior clinical outcome. Sequencing based assessment of colon cancer has been used to quantify tumor heterogeneity and correlate it with survival, but is sensitive to the mutation calling algorithm utilized. Digitization of histopathology slides allows application of deep learning methods for image analysis. Automated slide annotation and feature extraction provides numeric representations of underlying phenotype from which tumor heterogeneity can be estimated. Here we compare the ability of a deep-learning tumor heterogeneity score (THS) to estimate overall survival in colon cancer patients to estimates produced by bulk sequencing derived mutant-allele tumor heterogeneity (MATH) and copy number variation (CNV) event scores. Methods: Digitized whole slide images (WSIs) from The Cancer Genome Atlas (TCGA) colon adenocarcinoma dataset are processed in a computational pipeline for tissue detection, numerical feature extraction, and cell type classification. WSIs are tiled and local THS calculated from imaging features. Corresponding MATH and CNV derived heterogeneity metrics are calculated from published sequencing data. Kaplan Meier curves are used to compare patient survival stratified by tumor heterogeneity as calculated by the three independent methods. Automated regional annotation identifies intra-tumoral and tumor-stromal boundary tiles and tumor THS is correlated to distance from the boundary. Results: Images from 379 patients (209 right-sided, 152 left-sided tumors) yielded 575,762 tiles. Automated annotation resulted in 272,791 intra-tumoral and 11,340 tumor-stromal boundary tiles. Stratification by imaging derived THS provided significant separation of overall survival curves (p < .01) in contrast to MATH and CNV methods (p > .05 for both). THS significantly separated the curves in right- but not left-sided cancers (p = .03 and .44, respectively). Evaluating THS as a function of distance from the tumor-stromal boundary, right-sided tumors showed significant decrease in THS with increasing distance from tumor edge. Conclusions: Our novel pipeline produced spatially resolved imaging data informed by underlying tumor phenotype without need for pathologist annotation. The resultant THS correlated with outcome and outperformed sequencing-based prognostication methods. The spatial information identified higher heterogeneity at the tumor edge than interior regions of right-sided, but not left-sided tumors, capturing known but poorly understood differences in colon tumors by location. Deep learning image analysis provided reproducible and cost-effective data with great potential both in clinical biomarker discovery and as a research tool.
Racial and genetic ancestry associations with gene expression patterns in a real-world cohort of colorectal cancer patients.
Authors: Hein David , Rhead Brooke , Pouliot Yannick , Guinney Justin , De La Vega Francisco M , Sanford Nina Niu 
Published: June 2023

3541 Background: There is a growing incidence of colorectal cancer (CRC) among young adults and persistent disparities in outcomes by race/ethnicity across all ages. Gene expression signatures, as well as consensus molecular subtypes (CMS) derived from these, have been proposed to predict prognosis and therapy response in CRC. However, it is unclear whether gene expression or CMS are associated with racial disparities observed in CRC. We assessed whether race or genetic ancestry are associated with CMS or gene expression patterns in a deidentified cohort of 1,768 CRC patients. Methods: Patients tumors’ underwent tumor profiling with the Tempus xT NGS 648-gene assay as well as full-transcriptome RNA sequencing. We used a set of 654 ancestry-informative markers to infer genetic ancestry likelihoods for Africa (AFR), America (AMR), East Asia (EAS), Europe (EUR), and South Asia (SAS). Race/ethnicity labels, often missing in real-world data, were imputed using ancestry proportions from the literature and adjusted based on observed metadata. Gene expression data was used to assign CMS to all patients (CMS1, 2, 3, 4 and indeterminate) using CMScaller, and multinomial logistic regression was used to assess associations with race/ethnicity imputed labels and ancestry proportions. We then assessed differential expression (DE) in the MSigDB hallmark and C2 BioCarta gene sets using four separate workflows. The first two workflows used limma-voom followed by ROAST to assess DE among the imputed labels and then among the ancestry proportions (isometric log ratio transformed). The second two workflows used GSVA followed by limma. Results: Among 1,768 patients, 240 were imputed non-Hispanic (NH) Black, 94 NH Asian, 261 Hispanic/Latino/Native American (HLN), and 1,173 NH White. NH Black patients had higher odds of CMS3 vs CMS1 (OR = 2.66, p < 0.001) and HLN patients had higher odds of indeterminate CMS vs CMS1 (OR = 1.90, p = 0.020), compared to NH White. AFR ancestry was significantly associated with CMS3 (OR = 1.05 per doubling in AFR proportion, p = 0.047) and indeterminate CMS (OR = 1.07, p = 0.023). In the gene set analysis, NH Black race/ethnicity was associated with over-expression of the BioCarta WNT pathway gene set. Both AFR ancestry and NH Black race/ethnicity were associated with under-expression of the MSigDB hallmark coagulation and BioCarta alternative complement gene sets and over-expression of the PITX2 pathway gene set (all significant with both ROAST and GSVA). Conclusions: We found that NH Black patients and AFR ancestry were associated with higher rates of CMS3, which is associated with KRAS mutation and was previously reported to be more common among Black patients. Indeterminate CMS associations with AFR ancestry and HLN highlights the need to use diverse patient cohorts when training unsupervised learning models to improve prognosis prediction in non-White patients.
Impact of number and size of colorectal metastases (CRM) on survival in patients with RAS wild-type metastatic colorectal cancer treated within the PanaMa trial (AIO KRK 0212).
Authors: Sommerhäuser Greta , Kurreck Annika , Beck Alexander , Fehrenbach Uli , Karthaus Meinolf , Fruehauf Stefan , Graeven Ullrich , Mueller Lothar , Koenig Alexander , Fischer Von Weikersthal Ludwig , Meyer-Knees Johanna Wanda , Ballhausen Alexej , Stahler Arndt , Heinemann Volker , Held Swantje , Alig Annabel Helga Sophie , Kasper Stefan , Stintzing Sebastian , Trarbach Tanja , Modest Dominik Paul ,   ASCO Authors' Group
Published: June 2023

3551 Background: In this exploratory analysis, we aim to evaluate surrogates of metastatic burden, namely number of CRMs and size of largest CRM, for their prognostic and predictive value on efficacy of maintenance therapy with 5-fluorouracil/leucovorin (FU/FA) plus panitumumab (pmab) or FU/FA alone in RAS wildtype mCRC patients treated within the PanaMa trial. Methods: Number of CRMs and size of largest CRM at baseline were determined taking into account target and non-target lesions measured by central radiological review. Median number of metastases was set as threshold (n≤/ > 10) to assess the prognostic and predictive value of CRM count on PFS and OS of maintenance therapy. A threshold of ≤/ > 50mm was set to evaluate the impact of the largest CRM on the above time-to-event endpoints. PFS and OS were expressed by Kaplan-Meier method and compared by log-rank testing. Hazard ratios (HR) with 95% CIs were estimated using Cox regression models. Results: Out of 248 patients receiving maintenance therapy, CT and MRI scans of 211 patients were centrally evaluable (FU/FA+ Pmab, n = 106; FU/FA alone, n = 105). At baseline, 50.1% of the patients were diagnosed with > 10 CRM. Median size of the largest CRM was 45 mm. Number of CRMs n≤10 was associated with favorable PFS, while both, number n≤10, and size of largest CRM ≤50mm correlated with favorable OS compared to n > 10 and size of largest CRM > 50mm, respectively. In patients with > 10 CRMs, and those with largest CRM sized > 50mm, PFS of maintenance therapy was significantly superior with FU/FA+ Pmab compared to FU/FA alone (Table). Conclusions: Metastatic burden was found to be prognostic for PFS and OS of maintenance therapy. Additionally, number and largest size of CRMs proofed predictive of PFS of maintenance therapy with Pmab, the primary endpoint of the trial. Patients with high metastatic burden at baseline appear to benefit particularly from Pmab-containing maintenance therapy. Clinical trial information: NCT01991873 . [Table: see text]
Efficacy and safety of fruquintinib plus investigator's choice of chemotherapy as second-line therapy in metastatic colorectal cancer: A multicenter, single-arm phase 2 trial.
Authors: Zhao Wensi , Li Liping , Huang Junping , Li Jun , Gong Wei , He Lilin , Chen Yuan , Wang Songlin , Yu Xiongjie , Han Qi , Ke Shaobo , Shi Wei , Chen Yongshun 
Published: June 2023

3582 Background: Emerging evidence suggested that chemotherapy in combination with anti-angiogenic targeted agents can achieve higher response in multiple solid tumors. Fruquintinib is a highly selective small-molecule VEGFR inhibitor that has been approved for the third-line treatment in metastatic colorectal cancer (mCRC) patients in China. Here, we assessed the efficacy and safety of fruquintinib plus investigator's choice of chemotherapy as second-line therapy in pretreated advanced mCRC patients. Methods: In this prospective, open-label, multicenter, single-arm phase 2 trial (ChiCTR2200059280), patients with mCRC progressed after first-line prior systemic treatment were administered fruquintinib (5~3mg, D1-21, Q4w) and investigator's choice of chemotherapy (fluorouracil ± irinotecan ± oxaliplatin, Q3w) for up to 8 cycles. Patients without disease progression (PD) were followed by fruquintinib maintenance until PD or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), overall survival (OS), and safety. Results: As the data cutoff on February 10, 2023, 37 patients have been enrolled and treated, with 31 evaluable for efficacy. Median age was 63 years (range, 44-76) and 22 (59.5%) were male. The left colon cancer involved in 28 patients (75.7%). All patients were microsatellite-stable phenotype and 11 (29.7%) had mutations in KRAS gene. 16 (43.2%) patients received prior anti-VEGF therapy. 20 (54.1%) and 11 (29.7%) patients had liver and lung metastases respectively. At a median follow-up of 8.4 months, 28 patients are still on treatment. The ORR is 48.4%, with 15 partial response. The DCR is 90.3%. At data cutoff, median PFS has not yet reached. 23 patients (74.2%) remained progression free at 6 months. In terms of safety, the regimen was well tolerated, mainly grade 1/2 adverse events (AEs). Grade 3/4 AEs were neutropenia (21.6%), leukopenia (10.8%), thrombocytopenia (5.4%), proteinuria, diarrhea, hand-foot syndrome and hypertension accounted for 2.7% respectively. 5 pts received reduced doses of fruquintinib. No treatment-related deaths occurred. Conclusions: Fruquintinib combined with chemotherapy followed by fruquintinib maintenance shows promising efficacy and manageable safety profile for mCRC patients in second-line setting. Updated follow up data will be presented in the future. Clinical trial information: ChiCTR2200059280 .