bluuebunny/crossref_metadata_2025 huggingface dataset:
Aggregated analysis of 1,000 patients with cancer to assess the benefits of integrated whole exome and whole transcriptome sequencing.
Authors: Chernyshov Konstantin , Love Anna , Senichkin Viacheslav , Sagaradze Georgy , Rumyantsev Konstantin , Kushnarev Vladimir , Postovalova Ekaterina , Kotlov Nikita , Ogloblina Anna , Bagaev Alexander , Fowler Nathan
Published: June 2023

3076

Background: As the field of precision medicine rapidly expands, clinical oncologists are turning to integrated whole transcriptome (WTS) and whole exome (WES) sequencing to identify the most effective treatment options. We performed a retrospective cohort analysis of WES and WTS data from 1,000 patients with 15 major cancer types to define meaningful relationships between transcriptomic-based tumor microenvironment (TME) subtypes and pan-cancer genomic biomarkers, such as tumor mutational burden (TMB) and microsatellite instability (MSI) status, that are prognostic for outcome and predictive for checkpoint inhibitor response. Methods: We retrospectively analyzed WES/WTS data from cancer patients for biomarkers using our internal bioinformatics workflow. Using transcriptome-based methods described by Bagaev et al., samples were classified into one of four TME subtypes prognostic of patient outcome ( Cancer Cell, 2021). Statistical analysis consisted of Spearman’s rank correlation. Results: Comprehensive WES and WTS analysis provided by the BostonGene Tumor Portrait Test identified biomarkers based on accepted guidelines specific to the patient's cancer type in 22.5% of cases. In addition, we revealed a correlation between WTS and IHC for cancer-relevant genes, including CDX2 (R = 0.68), KRT7 (R = 0.85), KRT20 (R = 0.86), NECTIN4 (R = 0.81), and TACSTD2 (R = 0.81), indicating WTS may also be beneficial for estimating protein expression levels for cancer-specific biomarkers. Analysis of the TME showed that Fibrotic (F) and Immune Desert (D) were the most common subtypes. The F and D subtypes were linked to poor prognosis and were especially prevalent in liver and pancreatic cancers, respectively. TMB-high and MSI status were more prevalent in the immune-enriched subtypes, Immune-Enriched, Fibrotic (IE/F) and Immune-Enriched, Non-fibrotic (IE), over the less favorable F and D subtypes. The frequency of TMB-high and MSI status also differed in both IE subtypes associated with favorable prognosis, suggesting that TME subtyping provides additional prognostic power independent of TMB-high and MSI status. Conclusions: A deep interrogation of our integrated approach to genomic and transcriptomic profiling confirmed the advantages of a unified molecular analysis of tumor traits. We identified clinically significant biomarkers based on molecular features, demonstrated additional capabilities of TME analysis, and illustrated significant correlations between WTS and IHC data. These findings indicate that comprehensive WTS and WES analysis can assist clinicians in optimizing treatment plans as the landscape of personalized therapy continues to grow. [Table: see text]
Alternative allele frequency recallibration after NGS data analysis.
Authors: Ivanov Maxim , Yakushina Valentina , Fedyanin Mikhail
Published: June 2023

3077

Background: With the spread of NGS in routine clinical practice data analysis methods actively evolve to increase and refine information yield. Not much attention is given to variant allele fraction (VAF) estimation though it impacts clinical insignificance of subclonal somatic variants and identification of variant origin. Methods: Real-world sequencing data of 2379 samples (including 781 tumor-only and 1598 blood-only sequencing datasets) obtained via amplicon-based sequencing was used for the retrospective analysis of variant allele frequency estimation of identified genetic variants employing different methods including ITVC, SiNVICT, Mutect2 and SGA. Original method (AODvAF) utilizing alignment-free algorithm based on wild-type and alternative genome subsequence abundance estimation was developed and compared with the original output from NGS data analysis software. Anticipated VAF estimation was based on analyte type and database annotation. Results: Across 3447 identified potentially germline variations (PGV) VAF estimations provided by ITVC, SiNVICT and SGA were highly correlated (Pearson correlation coefficient [PCC] 1.00), while Mutect2 and AODvAF demonstrated discordant results (Mutect2/AODvAF vs ITVC PCC 0.87/0.82). VAF miscalculation defined by absolute difference between estimated and anticipated VAF of 10% and more was noted for 25%, 26%, 22%, 15% and 7% for ITVC, SiNVICT, SGA, Mutect2 and AODvAF respectively. Across 308 pathogenic BRCA1, BRCA2, PALB2 mutations identified in blood-only sequencing 25, 15, 16, 10 and 5 were characterized by VAF of 30% and lower based on ITVC, SiNVICT, SGA, Mutect2 and AODvAF estimations respectively (54, 49, 33, 51 and 9 for VAF 40% and lower), which may lead to misinterpretation of these variants as post-zygotic. Automatic in-silico annotation of variant origin (germline vs somatic) based on ISOWN was correct for 89%, 91%, 94%, 93% and 98% of these variants. Variant origin for 55 pathogenic variants of genes associated with hereditary cancer syndromes identified in tumor-only sequencing was verified by Sanger sequencing. Cohen's kappa coefficient for variant origin discrimination (Sanger vs in-silico prediction) was 0.91, 0.90, 0.91, 0.94 and 0.97 based on VAF provided by ITVC, SiNVICT, SGA, Mutect2 and AODvAF respectively. Conclusions: Accurate VAF calculation allows precise variant origin identification and impacts interpretation of variants. Developed method allows correction of VAF after NGS data core analysis.
In silico approaches to patient selection: Credentialing elraglusib as a novel treatment in metastatic melanoma resistant to checkpoint inhibitors.
Authors: McDermott Joseph , Weiskittel Taylor , Borden Brittany , Cavalcante Ludimila , Giles Francis J. , Carneiro Benedito A. , Li Hu , Mazar Andrew Paul
Published: June 2023

3079

Background: Elraglusib (9-ING-41), a novel inhibitor of GSK-3β, has been evaluated in >230 patients (pts) with advanced malignancies including metastatic melanoma in the 1801 phase 1/2 trial (NCT03678883). Pts with melanoma treated with single agent elraglusib demonstrated clinical benefit including a durable complete response despite multiple prior lines of therapy including checkpoint inhibitors (CPI). Methods: We collected data from numerous -omic modalities in the 1801 trial to characterize markers of elraglusib response with bioinformatics and machine learning (ML). Genomic panels were collected on 105 pts. The most frequent tumor types included colorectal cancer (n=35), pancreas (n=31), lung (n=15) and metastatic melanoma (n=12). Pts were treated with elraglusib as a single agent or in combination with chemotherapy. Pathway based features were generated by quantifying the percent of each Reactome pathway that was mutated. These pathway features were iteratively evaluated for their performance in shallow neural networks predicting patient RECIST with each model using 5-15 randomly selected features at a time. Publicly available genomic data from an anti-PD-1 trial in patients with metastatic melanoma (Hugo et al., 2017) was transformed into pathway-based features and input into the final model to predict elraglusib response in this population. Results: Our final pathway based genomic model for elraglusib response performed with a training accuracy of 93% and a test accuracy of 88% on the 1801 patients. We then tested the model on metastatic melanoma patients who were treated with anti-PD-1 therapy. We found that patients from Hugo et al. were predicted to respond to elraglusib (22/26). In addition, most patients with tumors resistant to anti-PD-1 therapy were also predicted to respond to elraglusib (10/12). Finally, we tested the model on metastatic melanoma patients treated with elraglusib in the 1801 study that had failed CPI and for whom -omic data was available. The model correctly identified 5/5 patients that demonstrated clinical benefit (1 CR, ongoing>1400 days; 4 prolonged OS of 107, 256, 357, and 556 days). Conclusions: We applied robust in-silico modeling developed using 1801 trial data to develop a rationale for the development of elraglusib in the treatment of metastatic melanoma including patients that failed or were refractory to anti-PD-1 treatment. This model correctly identified metastatic melanoma patients in 1801 with good clinical outcomes that had failed prior CPI treatment. Further, we present this in silico approach as a robust way to repurpose prior clinical study genomics and ML modeling for population enrichment during the clinical development of novel drugs. Clinical trial information: NCT03678883 .
Intrapatient comparative efficacy of selective RET inhibitors using growth modulation index in patients with RET aberrant cancers.
Authors: Gouda Mohamed Alaa , Ahmed Jibran , Nelson Blessie Elizabeth , Nardo Mirella , Roszik Jason , Cabanillas Maria E. , Hu Mimi I-Nan , Busaidy Naifa Lamki , Sherman Steven I. , Dadu Ramona , Naing Aung , Karp Daniel D. , Rodon Ahnert Jordi , Hong David S. , Elamin Yasir Y , Blumenschein George R. , Heymach John , Meric-Bernstam Funda , Subbiah Vivek
Published: June 2023

3086

Background: Selective RET inhibitors (RETi) have changed the paradigm for treatment of RET altered cancers. Current evidence on their efficacy comes from single-arm basket trials. In this study, we performed intrapatient efficacy comparison between approved selective RETi (selpercatinib and pralsetinib) and prior and/or subsequent therapies. We used growth modulation index (GMI) as a tool to compare efficacy, where a value of >1.33 is presumed a cutoff to establish superior efficacy. Methods: We included patients with RET-positive tumors who were treated at our institution as part of RETi clinical trials. We excluded patients with no other systemic therapy received before or after the RETi of interest. We also excluded patients who received both drugs to avoid overlapping efficacy bias, and patients who were treated for ≤ 30 days or had non-evaluable disease. Since some patients have been treated beyond progression or discontinued RETi due to intolerance, we used ratios for both time to treatment takeoff (TTT) and time to progression (TTP) to compare efficacy of RETi (at the RETi treatment line (n)) to prior therapy (n-1) and to subsequent therapy (n+1). GMI was defined as the ratio between TTT/TTT (n±1) or TTP to TTP (n±1). Results: We included 66 patients who received RETi and met our inclusion criteria [39 received selpercatinib and 27 received pralsetinib]. Most patients had GMI>1.33 using either TTT or TTP (61% (n=40) and 58% (n=38), respectively). The median GMI based on pre-RETi therapy was 2.1 and 1.6 (using TTT and TTP, respectively); while the median GMI based on post-RETi therapy was 4.9 and 4.4 (using TTT and TTP, respectively). Patients with GMI>1.33 were more likely to have PR as best response compared to patients with GMI<1.33 (85% vs 53%, p=0.005 using TTT; and 87% vs 54%, p=0.003 using TTP). GMI using TTT (n/n-1) was higher in patients with RET fusions compared to patients with RET mutations (3.7 vs 1.4, p=0.048). GMI using TTT and GMI using TTP(n/n+1) were lower in patients with WBCs <8 at baseline (2.6 vs 13.8, p=0.014; 2.6 vs 11.1, p=0.014; for TTT and TTP) and GI cancer diagnosis (0.4 vs 9.3, p=0.042; 0.4 vs 10.4, p=0.042; for TTT and TTP). Conclusions: Intrapatient efficacy comparisons are feasible using GMI calculations and provide a proof of concept on the favorability of selective RETi compared to other systemic therapies. [Table: see text]
Proposition of a drug score to predict the clinical usefulness of therapeutic dose monitoring of oral molecularly targeted therapies.
Authors: Geraud Arthur , Combarel David , Funck-Brentano Christian , Beaulien Quentin , Zahr Noel , Broutin Sophie , Massard Christophe , Besse Benjamin , Gougis Paul
Published: June 2023

3091

Background: Therapeutic drug monitoring (TDM) consists in measuring and interpreting drug concentrations in biological fluids to personalize drug dosage. This method is widely used for drugs with a narrow therapeutic index ( e.g., immunosuppressants or neuroleptics agents). In onco-hematology, current recommendations of TDM for oral molecularly targeted therapies (oMTT) differ among molecules, making it difficult to identify good TDM candidates. This study aims to propose a quantitative approach with a score to predict the clinical usefulness of TDM of oMTT. Methods: We selected the four key parameters needed for an oMTT to be a good candidate for TDM (e.g. interpatient pharmacokinetic variability, feasible dose-adaptation strategy, exposure-efficacy relationship, exposure-safety relationship). We collected each drug’s pharmacokinetic (PK) and pharmacodynamics variables from drug labels, Center for Drug Evaluation and Research reports and early trials data. The score was defined from oMTT’s exposition variability (variability score: coefficient of variation of drug exposition, the impact of food and proton pump inhibitors), technical complexity (PK linearity, active metabolite, half-life), efficacy (Exposure-response relationship (ERR)) and safety (maximum tolerated dose, Exposure-safety relationship (ESR)). The global score ranged from 0 to 100. To assess the relevance of the score, we evaluated molecules from other therapeutic classes with known strong recommendations of TDM (clozapine, everolimus, voriconazole). Results: In September 2021, we collected data from sixty-seven oMTTs. Scores were normally distributed (mean 48.3, standard deviation 15.6) and varies from 15 for acalabrutinib to 80 for sunitinib. Scores of drugs with strong recommendation of TDM were 68, 68 and 64 for clozapine, everolimus as an immunosuppressant, and voriconazole, respectively. We hypothesized that a score above 60 might be associated with relevant indications of TDM. Fifteen molecules had a score above 60 (sunitinib (80), cabozantinib (76.5), nilotinib (76), abemaciclib (76), axitinib (75), sorafenib (69.5) gefitinib (69.5), trametinib (67.5), talazoparib (67), crizotinib (66), pazopanib (65), sonidegib (63.5), neratinib (62.5), panobinostat (62) and imatinib (60.5)). Conclusions: We defined a score to identify good candidates for TDM in onco-hematology. Usefulness of TDM in oncology should be confirmed prospectively prioritizing these molecules.
Characterizing the landscape of RING-type E3 ubiquitin transferase-altered (RNF43 alt) colorectal cancer (CRC) and defining unique subsets with potential therapeutic vulnerabilities in microsatellite instability-high (MSI-H) CRC.
Authors: Naqash Abdul Rafeh , Nassar Amin , Macera Lisa , Mauer Elizabeth , Guinney Justin , Chao Calvin Y. , Adib Elio , Petricoin Emanuel , Mittra Arjun , Takebe Naoko , Cannon Timothy Lewis
Published: June 2023

3134

Background: RNF43 is a tumor suppressor gene that represses the WNT/β-catenin pathway. Emerging data show that RNF43 alt are commonly present in MSI-H CRC with improved outcomes to immune checkpoint inhibitors (ICI). We evaluated whether genomic and transcriptomic analysis of MSI-H RNF43 alt CRC defines distinct subsets with potential therapeutic vulnerabilities. Methods: We analyzed CRC tumors (any stage/ subtype) sequenced with Tempus xT assay (DNA-seq of 648 genes at 500x coverage, full transcriptome RNA-seq). RNF43 alt were defined as pathogenic/likely pathogenic per OncoKB, or copy number aberrations (CNA); deep deletions, or amplifications (>8x). RNF43 alt vs. wildtype (wt) were compared using Chi-squared/Fisher’s Exact tests or Wilcoxon rank-sum tests to evaluate differences in biomarkers. Gene Set Variation Analysis (GSVA) was applied to gene expression data to derive single-sample pathway enrichment scores. ICI-treated MSI-H CRC from the MSKCC cohort (n = 74), publicly available in AACR GENIE v13, was used to assess the overall survival (OS) using the Kaplan-Meier method. Results: RNF43 alt was identified in 5.2% (635 of 12,243) CRC tumors. CNA accounted for 6% of RNF43 alt CRC. RNF43 alt vs. RNF43 wt CRC was associated with older age (median 69 vs. 59 years, p < 0.001), more prevalent in females (56% vs 43%; p < 0.001). A detailed comparison of RNF43 alt vs. RNF43 wt CRC with p < 0.001 are shown (Table). Of MSI-H CRC (n = 714), 51% were RNF43 alt, with 80% being RNF43 p.GLY659fs. Among MSI-H RNF43 alt CRC, BRAF alt was co-mutated in 59%, with BRAFV600E constituting 99%. Median TMB was higher for MSI-H RNF43 alt vs. MSI-H RNF43 wt (40 vs. 31 mut/MB, p < 0.001). Among MSI-H CRC, GSVA identified significant downregulation of Cetuximab_benefit pathway and upregulation of IGF1R and PI3K/AKT pathways in RNF43 alt vs RNF43 wt. Among ICI-treated MSI-H CRC (n = 74) from the MSKCC cohort, no significant OS difference (HR 0.81 [95%CI: 0.34 – 1.97]; p = 0.65) was noted for RNF43 alt (n = 42) vs. wt (n = 32). Conclusions: RNF43 alt are common in MSI-H CRC and associated with potentially actionable genomic and transcriptomic signatures. Functional characterization of interplay between the WNT signaling and therapeutically relevant pathways (PI3K/AKT, BRAF, IGF1R, Cetuximab benefit) to better define optimal ICI combination approaches in MSI-H RNF43 alt CRC is ongoing. [Table: see text]
Exploring expression levels of HER2, HER3, MET, Claudin18.2, and MUC16 across 16 cancer types using an artificial intelligence-powered immunohistochemistry analyzer.
Authors: Shin Seunghwan , Cho Soo Ick , Choi Sangjoon , Lee Taebum , Kim Seulki , Jung Wonkyung , Mostafavi Mohammad , Brattoli Biagio , Ryu Jeongun , Park Seonwook , Pereira Sergio , Nesmith Ken , Park Jiyoung , Seo Melody SeungHui , Kim Huijeong , Kim Seokhwi , Ock Chan-Young
Published: June 2023

3135

Background: Quantifying tumor-associated antigen (TAA) expression levels on tumor cells (TC) from immunohistochemistry (IHC) stained slides has been widely used to predict response to novel anti-tumor agents. However, obtaining the precise quantification of TAA expression levels from various cancer types is still challenging. To quantify five targets of interest, we applied an artificial intelligence (AI)-powered analyzer to 16 cancer types. Methods: AI-powered whole slide image (WSI) analyzers were developed using IHC positive or negative tumor cells (TC) from PD-L1 22C3 pharmDx and HER2 4B5 datasets, annotated by pathologists. The universal model was trained by IHC-positive or negative TCs from all datasets, while the second model was trained by the intensity of positive (from 1+ to 3+) or negative TCs from the HER2 dataset. Both AI models were applied to the pan-cancer tissue microarray dataset (n = 1,370) with MUC16, CLDN18.2, MET, HER3, and HER2 IHC staining, respectively. The expression levels of those TAAs were calculated with tumor proportion score (TPS) or ASCO/CAP scoring criteria for HER2 in 16 cancer types including biliary tract, breast, colorectum, esophagus, head and neck, kidney, liver, lung, ovary, bladder, pancreas, prostate, stomach, thyroid, cervical, and endometrial cancer. Results: Based on the TPS of 1% or more, the positivity of MUC16 and CLDN18.2 were most frequently observed in ovary (51.6%) and kidney (24.2%), respectively, and MET and HER3 in colorectum (63.8%; 40.5%). The five most highly expressed tumors and their frequency of TPS≥1% are shown. HER2 3+ tumor cells were most highly expressed in the breast, followed by the bladder. Conclusions: This study describes the TAA expression levels in various tumors using an AI-powered IHC analyzer. This method could be useful for exploring target cancer types and predicting response to novel TAA targeted agents. [Table: see text]
Evolution of HER2 scores after neoadjuvant systemic therapy in breast cancer.
Authors: Chong Esther G , Jeon Won Jin , Pham Bryan , Castillo Dan Ran , Mehta Akhil , Pairawan Seyed , Denham Laura , Nagaraj Gayathri
Published: June 2023

3139

Background: Breast cancer (BC) is a malignancy with a wide array of histopathological characteristics and tumor heterogeneity leading to major clinical implications for management. With the recent approval of antibody-drug conjugates (ADCs) for human epidermal growth factor receptor 2 (HER2)-low advanced BC, there is increased significance for characterizing the spectrum of HER2 expression in the curative setting. Methods: We conducted a single institution retrospective review of patients with BC who received neoadjuvant systemic therapy (NAST) followed by definitive surgical resection from 2008 to 2022. The initial tumor biopsies were tested for estrogen receptor (ER), progesterone receptor (PR), and HER2 status per ASCO/CAP guidelines and repeated on the residual tumor tissue after NAST. HER2 status was categorized into HER2-negative (IHC 0), HER2-low (IHC 1 or IHC 2/ Fluorescence in situ hybridization [FISH] negative), and HER2-positive (IHC 2/ FISH positive or IHC 3). Concordance and discordance with HER2 status in the pre and post NAST tumor samples were analyzed using descriptive statistics. Results: Of 340 patients with BC who received NAST, 55 patients with residual disease had pre and post treatment biomarker data available for analysis. Prevalence of HER2-low was 70.9 % (39/55) in the pretreatment tumors while it was 58.2% (32/55) in the post treatment tumors. 40% of tumors (22/55) had HER2 discordance while 60% (33/55) demonstrated concordance with HER2 expression after NAST. Among the changes in HER2 status, a shift from HER2-low to HER2-negative status occurred most frequently in 18.2% of tumors (10/55). In tumors with HER2 discordance, 36.4% (8/22) were also noted to have changes in ER or PR status while this was seen in 48.5% (16/33) of tumors with HER2 concordance. For rates of recurrence, 22.7% (5/22) of patients in the HER2 discordant group had relapsed compared to 18.2% (6/33) patients in the HER2 concordant group. Conclusions: Dynamics of HER2 expression is increasingly important in the rapidly changing therapeutic landscape of BC. Our study shows high prevalence of HER2-low expression in tumors with residual disease after NAST and frequent conversion of HER2-low to HER2-negative status with NAST. Further studies are warranted to determine the clinical and therapeutic relevance of biomarker evolution and tumor heterogeneity in the curative setting. [Table: see text]
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 .
Efficacy and safety of irinotecan-eluting HepaSphere transarterial chemoembolization combined with hepatic arterial infusion chemotherapy for unresectable colorectal liver metastases.
Authors: Feng Aiwei , Gao Song , Guo Jianhai , Kou Fuxin , Liu Shaoxing , Zhang Xin , Liu Baojiang , Wang Xiaodong , Chen Hui , Xu Haifeng , Liu Peng , Cao Guang , Gao Qinzong , Zhu Xu
Published: June 2023

3585

Background: Both drug-eluting bead transarterial chemoembolization (DEB-TACE) and hepatic arterial infusion chemotherapy (HAIC) are recommended for unresectable colorectal liver metastases (CRLM) treatment. However, the combined application of DEB-TACE and HAIC is not widely accepted. The aim of this single-center retrospective study was to evaluate the efficacy and safety of Irinotecan-eluting HepaSphere chemoembolization combined with HAIC for unresectable CRLM. Methods: Patients with age older than 18 years, histologically confirmed CRLM and treated with Irinotecan-eluting HepaSphere chemoembolization plus HAIC from Oct 2020 to Jan 2022 were enrolled. Patients who had synchronously received other local treatments were excluded. Hepatic progression-free survival (hPFS) and PFS were calculated using Kaplan-Meier method. Adverse events (AE) were evaluated with CTCAE 5.0. Results: The eligible population was 101, composed of 66 males and 35 females. Among them, 54% patients had one of KRAS or NRAS or BRAF gene mutation and ECOG of 62% patients was 1. In addition, 59% patients were refractory to second standard line or above systemic therapy and mean interventional treatment cycles were 3.3. As the follow-up cutoff date was Dec 31, 2022, median duration of follow-up was 17.9 months (95% CI,16.185-19.615). Median hPFS was 8.7 months (95% CI, 6.744-10.658) while median PFS was 6.2 months (95% CI, 5.048-7.352). For the patients who were refractory to second line or above systemic therapy, hPFS and PFS was 6.2 months (95% CI, 4.899-7.501) and 5.2 months (95% CI, 3.682-6.718) respectively. Overall survival has not been reached yet. There were 7 patients achieved clinical complete response. Overall response rate was 41.6% and disease control rate was 82.2%. There was no treatment-related death. 28 patients (27.7%) experienced grade 3 or higher toxicities. The most common treatment related AE were aspartate transaminase/alanine transaminase elevation (41.6%) and bilirubin elevation (40.6%). The hematologic AE included anemia (27.7%), leukopenia (27.7%), neutropenia (14.9%) and thrombocytopenia (28.7%). Conclusions: The combination of Irinotecan-eluting HepaSphere chemoembolization and HAIC is effective and safe for unresectable CRCLM, even for patients who are refractory to second or above systemic therapy, indicating it is a promising regional treatment with improved outcome.