Genetic Alterations Research Articles

Decoding immune dysregulation in AML: Insights from integrated genomic and transcriptomic analysis.

6519 Background: Acute Myeloid Leukemia (AML) is an aggressive hematologic malignancy marked by abnormal proliferation of myeloid progenitor cells, often leading to poor outcomes and high relapse rates. While the genetic underpinnings of AML are well-documented, the role of immune dysregulation in its progression remains underexplored. This study integrates whole exome sequencing (WES) and transcriptome analysis to identify genetic mutations, transcriptional alterations, and immune regulatory disruptions, with a focus on their contributions to hematopoiesis and immune dysfunction. Methods: WES and RNA sequencing were performed on 10 AML patient samples to investigate somatic mutations, differential gene expression, and immune-related pathways. WES data were analyzed to detect mutations in AML-associated genes, while transcriptomic analysis compared gene expression profiles between AML cells and normal hematopoietic stem cells (HSCs). Bioinformatic tools, including differential expression analysis, Gene Set Enrichment Analysis (GSEA), and pathway mapping, were employed to identify key regulatory networks. Single-cell RNA sequencing (scRNA-seq) was conducted to assess cellular heterogeneity and differentiation dynamics, with a focus on immune cell subsets and pathways involved in immune evasion. Results: Analysis revealed recurrent mutations and dysregulation in genes critical to hematopoiesis, apoptosis, and immune regulation, including RUNX1, FLT3, CEBPA, TP53, WT1, GATA2, and TET2 . Transcriptomic profiling highlighted distinct gene expression patterns in AML cells, with significant disruption in cell cycle control, differentiation, and apoptosis. Dysregulated immune pathways, such as IL-7R and PD-1, were identified as key contributors to immune cell activation impairment and immune tolerance. scRNA-seq data provided insights into the cellular heterogeneity of AML, uncovering altered lineage differentiation and immune subset composition, which may facilitate immune evasion and disease progression. Conclusions: This integrative analysis illuminates the interplay between genetic mutations, transcriptional dysregulation, and immune dysfunction in AML. The findings underscore the pivotal role of immune pathways, such as IL-7R and PD-1, in AML pathogenesis, presenting them as potential therapeutic targets. By linking genetic and immune alterations, this study advances our understanding of AML biology and highlights the need for therapies addressing both genetic and immune dysfunctions to improve clinical outcomes.

Effect of co-occurring TP53 and intracellular proliferation pathway mutations on disease recurrence and survival benefits in head and neck cancers.

e18046 Background: Head and neck cancer (HNC) is often driven by genetic alterations, particularly co-occurring mutations in TP53 gene and key proliferation pathways. Offering continuous low-dose treatment (Oral metronomic chemotherapy) has shown potential in improving survival outcomes by minimizing toxicity while also targeting cellular molecular drivers. However, treatment of HNC remains challenging due to factors such as tumor heterogeneity, late-stage diagnosis, and treatment resistance. Recurrence in HNC is often due to the presence of residual or drug-resistant tumor cells that poses significant challenges to long-term survival. This study focuses on the genomic profiles of patients with disease recurrence and their association with survival benefits of adjuvant therapy. Methods: We investigated the molecular profiles of 22 HNC patients in adjunct with clinical follow-up data. A total of twenty-one patients had previously undergone surgery and 14 patients had disease recurrence. 6 patients had oral metronomic chemotherapy (OMCT) of which 4 had a combination of nivolumab. 3 patients were also undergoing maintenance immunotherapy. Next Generation Sequencing (NGS) test was performed using OncoIndx Assay (Aarthi et al., 2024). Results: Molecular analysis of 63.6% (n=14) of patients who were reported with clinical recurrence were continued with further treatment. 21.4% (n=3/14) of patients with recurrence were detected with compound TP53 mutations while 64.3% (n=9/14) showed co-occurrence of TP53 mutations with cell progression and intracellular proliferation pathway alterations. 92.9% (n=13/14) of patients with recurrence also showed positive PD-L1 expression. Interestingly, genomic profiling of patients under OMCT showed co-occurrence of TP53 with cell progression (CDKN2A) and intracellular proliferation pathway alterations (MYC, NRAS, KRAS) in 83.3% (n=5/6) patients indicating survival benefits. Conclusions: Although cell proliferative mutations were found predominant in patients with recurrence, it only included downstream intracellular proliferative genes and not cell surface receptors like EGFR. Thus, co-occurrence of TP53 mutations with key proliferative pathways were not only indicative of recurrence but also suggestive of treatment benefits from OMCT in the study cohort since all patients showed overall survival between 8 months to more than 4 years.

Decoding SPP1 regulation: Genetic and nongenetic insights into its role in disease progression.

Decoding SPP1 regulation: Genetic and nongenetic insights into its role in disease progression.

Establishing a comprehensive panel of patient-derived xenograft models for high-grade endometrial carcinoma: molecular subtypes, genetic alterations, and therapeutic target profiling.

Establishing a comprehensive panel of patient-derived xenograft models for high-grade endometrial carcinoma: molecular subtypes, genetic alterations, and therapeutic target profiling.

Genomic and immunophenotypic landscape of early-stage pulmonary carcinoid tumors.

8030 Background: Pulmonary carcinoids (PCs), which encompass atypical carcinoids (ACs) and typical carcinoids (TCs), represent a rare category of lung cancer characterized by low to moderate malignancy. However, there is a limited understanding of the genomic and immune characteristics associated with PCs on a global scale. Methods: This study included a cohort of 126 surgically resectable Chinese PC patients, comprising 44 ACs and 82 TCs. Next-generation sequencing utilizing a 578-gene panel was conducted on 90 of PC patients, followed by the calculation of tumor mutation burden (TMB). Additionally, immunohistochemical staining for PD-L1 (n=108) and CD8 (n=94) was carried out to investigate the characteristics of the tumor microenvironment in PCs. Results: The most frequently altered genes in early-stage PCs were identified as EGFR (n=16, 18%), KMT2C (n=11, 12%), LRP1B (n=10, 11%), MEN1 (n=10, 11%), and NOTCH2 (n=9, 10%). Dysregulation of the RTK/RAS, NOTCH, and PI3K pathways was commonly observed in these PCs. Notably, genetic alterations in TP53, ARID1A, and CUL3 were more prevalent in ACs compared to TCs. However, TMB, PD-L1 expression, and CD8+ T cell infiltration were found to be low in early-stage PCs, with no significant differences observed between ACs and TCs. We identified age, gender, TNM stage, tumor type, smoking status, TMB, and LRP1B mutation, as indicators of poor prognosis, and further established a molecular classification that categorizes early-stage PCs into three distinct subtypes, each associated with varying clinical outcomes. Conclusions: We depicted the genetic and immune landscape of early-stage PCs and subsequently proposed a molecular classification based on the status of LRP1B mutation and smoking history. Our research offers novel insights into the biological mechanisms of PCs which contributes to the individualized treatment for Chinese PC patients.

Molecular evolution of driver mutations in cancer with microsatellite instability and their impact on tumor progression: Implications for precision medicine in patients with UCEC.

Molecular evolution of driver mutations in cancer with microsatellite instability and their impact on tumor progression: Implications for precision medicine in patients with UCEC.

Analysing the impact of size of NGS panel in defining first line therapeutic strategies in NSCLC.

3070 Background: NCCN recommends the analysis of 8 genes (EGFR, ALK, ROS1, BRAF, KRAS, MET, RET, ERBB2, and NTRK1/2/3) for NSCLC patients to identify efficacious target therapies. Concerned with the rising incidence of sub-optimal response to first-line therapy and rather early progression of disease we performed retrospective analysis in a subset of patients treated at our hospital in order to streamline molecular evaluation strategies. Methods: In this study, we retrospectively evaluated the impact of NGS panel sizes in therapy-naïve NSCLC patients. 242 therapy naïve patients evaluated for molecular genetic profiling were stratified into three groups based on gene panel size: a) Small panel (<20 genes): Focused on NCCN-recommended genes, b) Medium panel (50–100 genes): Included organ agnostic genes, c) Comprehensive panel (>100 genes): Included genomic signatures like TMB, MSI & HRD scores. Results: Of 242 therapy-naïve NSCLC patients, 60% (145/242) were evaluated using a small panel of which 13% (19/145) had no detectable genetic alterations while 37% (54/145) had 1 st line targetable mutations, 31% (45/145) exhibited both targetable and resistance causing mutations, and 19% (28/145) showed only resistance causing mutations. In the 50–100 genes Panel, comprising 29% (70/242) of patients, 10% (7/70) had no genetic alterations, while 26% (18/70) had 1 st line targetable mutations, 30% (21/70) demonstrated both targetable and resistance mutations, and 34% (24/70) harboured only resistance causing mutations. Finally, in the comprehensive NGS group (>100 genes), which accounted for 11% (25/242) of cases, only 4% (1/25) lacked detectable genetic alterations; while, 12% (3/25) had 1 st line targetable mutations, 32% (8/25) exhibited both targetable and resistance causing mutations, and 52% (13/25) showed only resistance causing mutations. Conclusions: a. Increase in gene panel size results in reduction of true negatives. Hence smaller panels may not necessarily capture resistance causing mutations. b. As the gene panel size increases, the detection of actionable driver mutations (e.g., EGFR, ALK) remains consistent; however, there is a notable shift in the mutation profile, with a decrease in cases harbouring only targetable mutations and an increase in those exhibiting both actionable and resistance causing mutations. Hence opting for comprehensive NGS profiling at baseline may increase diagnostic costs marginally, but will have significant impact in designing more effective 1 st line therapeutic strategies.

Comprehensive molecular analysis of phase IB/II trial of durvalumab plus doxorubicin combination in patients with advanced soft-tissue sarcoma.

11555 Background: We conducted an open-label, phase IB/II study to determine the activity and safety of the standard-of-care, doxorubicin in combined with the anti-PD-L1 immune checkpoint inhibitor, durvalumab, in patients with anthracycline-naïve soft tissue sarcoma (STS) and identified patients who would likely benefit from combination treatment. Methods: In this phase IB/II trial (NCT03798106), we enrolled patients with metastatic and/or recurrent STS had not received anthracycline chemotherapy and PD-L1/PD-1 inhibitor. Tumor biopsies were obtained from all patients prior to treatment for targeted sequencing, RNA sequencing, and Opal multiplexed immunofluorescence staining. Results: No DLTs were observed during the phase II and recommended phase II dose was defined at doses of 75/m 2 doxorubicin and proceed the phase II part. Of 41 evaluable patients, an objective response rate of 31.7% and the median progression free survival was 8.2 months (95% CI, 7.3-9.0) and median overall survival was 24.1 months (95% CI, 7.6-40.3). In the prespecified genomic analysis, using a multivariate Cox proportional regression model with clinical factors in combined with PD-1 cell density and signaling pathways, genetic alterations in RTK/RAS (HR 6.446, [95 % CI, 1.934-21.486]; P=0.002) and PD-1 density (HR 0.214, [95 % CI, 0.071=0.649]; P=0.006) were identified as the independent predictors of PFS . High PD-1 tumors without RTK/RAS pathway alteration had longer PFS (16.9 months) than the others (7.4 months for RTK/RAS alteration or PD-1 high, 1.0 months for RTK/RAS pathway alteration and PD-1 low group, P<0.001). In the gene set analysis, antigen processing and presentation, interferon alpha response, and interferon gamma response showed significantly higher scores in PD1 high without RTK/RAS pathway alteration. Conclusions: Durvalumab combined with doxorubicin demonstrated promising efficacy in an unselected STS cohort, with a manageable toxicity profile. In exploratory correlative analysis, we identified potential role of RTK/RAS signaling and PD-1 expression as independent predictors for the efficacy, although further investigations are needed. Clinical trial information: NCT03798106 .

Screening of TROP2, Nectin-4, and HER2 in osteosarcomas: In pursuit of a target.

e23511 Background: Osteosarcoma (OS), the most common malignant bone tumor, primarily affects adolescents and young adults and is associated with poor outcomes. This highlights the need for prognostic and predictive biomarkers and novel therapeutic targets. Trophoblast cell surface antigen 2 (TROP2) is a glycoprotein that facilitates the transmission of intracellular calcium signals, while Nectin-4 is a transmembrane protein that plays a vital role in cell-to-cell adhesion. Research has shown that the upregulation of those genes contributes to tumor cell proliferation and metastasis. Human epidermal growth factor receptor 2 (HER2) is a transmembrane protein and oncogene amplified in various malignancies. Nectin-4 overexpression in OS has been demonstrated to enhance tumor cell proliferation and migration by activating the PI3K/AKT signaling pathway. Although TROP2 and Nectin-4 are recognized as targets for antibody-drug conjugates (ADCs) which have received approval in urothelial and breast cancers, there is still a lack of understanding regarding their significance in OS. Similarly, although HER2 expression has been studied in several malignancies and agents targeting HER2 are approved for breast and gastric carcinoma, its importance in OS has not been investigated. Methods: Our study aimed to assess the expression of TROP2, Nectin-4 and HER2 in OS and their clinicopathological correlations. We first examined publicly available data from The Cancer Genome Atlas (TCGA) to investigate genetic alterations of these genes in OS. Next we retrospectively analyzed samples from OS patients diagnosed between 2015 and 2021 and treated at our center using immunohistochemistry (IHC) for TROP2, Nectin-4 and HER2. Results: Nectin-4 alterations, including amplifications and elevated mRNA expression, were present in 15% of TCGA OS samples, while TROP2 displayed genetic alterations in 16% and HER2 presented mRNA expression alterations in 18%. Although there were no correlations between TROP2 or Nectin-4 levels and overall survival, tumors with expression of either marker exhibited a significantly higher tumor mutational burden (TMB) (q < 0.001) and mutation count (q < 0.001). In our study, IHC for TROP2 and HER2 returned negative results in all samples, while two out of ten patients (20%) showed positive Nectin-4 membrane staining. Both patients had extraskeletal OS with lung metastases; one presented with de novo metastatic disease, while the other experienced progression of lung metastases following adjuvant chemotherapy. Conclusions: With the limitations of the small sample size, our findings suggest that Nectin-4 and TROP2 are expressed in a subset of OS patients and may be more prevalent in tumors with a higher TMB. While further studies are necessary to evaluate the expression rates of these markers in OS, their potential value as therapeutic targets for ADCs and combinations with immune checkpoint inhibitors is noteworthy.

Macroscale genomic alterations in histomolecular invasive lobular carcinoma compared to other breast cancer subtypes.

1049 Background: Although invasive lobular carcinoma (ILC) is often classified as a separate breast cancer (BC) subtype with distinct molecular features, options for diagnosis and treatment remain similar to other BCs. Using an integrated histomolecular approach to classify 617 BC samples into either histomolecular ILC (hmILC) or histomolecular no special type (hmNST) subsets, we compared their macroscale genomic alterations to describe biological traits of the ILC BC subtype, which may lead to improved approaches in BC therapies. Methods: A total of 617 BC FFPE samples were subject to whole-exome and bulk RNA sequencing analysis. hmILC subset was defined based on CDH1 truncation/deletion or low CDH1 expression (z-score < -2.5×MAD), while all other samples were classified as hmNST. Copy number variations (CNVs) were assessed using Sequenza to detect recurrent amplifications/gains and deletions; homologous recombination deficiency (HRD) scores were calculated based on large-scale state transitions and loss-of-heterozygosity events; tumor mutational burden (TMB) scores were evaluated as percent of mutations per megabase; and mutational signatures were deconvoluted using maftools R package. Results: Genome-wide CNV analysis revealed distinct patterns in hmILC compared to hmNST. hmILC showed hallmark deletions at regions harboring CDH1 (16q), while gains were observed significantly more frequently at regions harboring FCGR3A (1q) compared to hmNST. Elevated APOBEC activation signature expression was found in 32% hmILC vs. 19% hmNST samples (p = 0.002, chi-squared test). HRD-positive cases were less frequent in the hmILC subset (25%) compared to hmNST (42%) (p = 0.001). In contrast, hmILC tumors more frequently demonstrated high TMB scores compared to hmNST (10% vs. 2%, p = 0.0003). Moreover, TMB-positive hmILC samples were mostly HRD-negative.Genetic alterations in genes like FANCA , FANCD2 and PALB2 were more frequently enriched in hmILC tumors compared to hmNST (p < 0.1). Furthermore, hmILC subset with high HRD scores frequently harbored additional DNA repair gene mutations (e.g., BRCA2 ) compared to the subset with low HRD scores (p = 0.02). Conclusions: This study revealed macroscale genomic alterations, such as unique CNV patterns, altered distributions of HRD- and TMB-positive cases and increased APOBEC-driven mutational processes, in the hmILC BC subset. These distinct genomic architectures highlight the need for innovative trials using inhibitors of DNA repair and related pathways for hmILC BC patients, particularly in those with high HRD-high tumors.

Toward a rational therapeutic for elastin related disease: Key considerations for elastin based regenerative medicine strategies.

Toward a rational therapeutic for elastin related disease: Key considerations for elastin based regenerative medicine strategies.

Multigene NGS assay for biomarker identification in 621 colorectal cancer cases.

e15168 Background: Colorectal cancer (CRC), a major cause of cancer-related mortality, is driven by diverse genetic and molecular alterations. Advances in next-generation sequencing (NGS) enabled comprehensive genomic profiling, transforming CRC diagnosis and treatment. In this study molecular profiling was performed on 621 CRC cases, including 4 actionable biomarkers: microsatellite instability (MSI), KRAS , NRAS , BRAF and PIK3CA. Methods: DNA was extracted from embedded paraffin tissue samples using the Qiasymphony DSP DNA Mini Kit (Qiagen). RNA was extracted using the RNeasy FFPE Kit (Qiagen). Μutation hotspot regions of 27 genes were amplified using an Ion AmpliSeq Panel (Thermo Fisher Scientific). Copy number variations, SNPs, and indels were analysed. Additionally, ALK, ROS1, RET, NTRK1, NTRK2 & NTRK3 fusions were tested using an Ion AmpliSeq RNA Fusion Panel (Thermo Fisher Scientific). Sequencing was carried out using the Next Generation Sequencing platform Ion GeneStudio S5 Prime System (Thermo Fisher Scientific). Results: Based on our findings 62% of patients were eligible for on-label therapy. Mutations in KRAS and NRAS, were found in 36% of CRC cases and among these, the KRAS G12C mutation, was detected in 3% of them. Furthermore, the BRAF V600E mutation, was detected in approximately 11% of cases. Additionally, PIK3CA mutations are present in 15% of CRC cases. In 8% of tumors, High microsatellite instability (MSI-H) was observed. Notably, 4% of metastatic CRC cases exhibited co-occurrence of MSI-H and BRAF V600E mutation while for the remaining MSI-H/BRAF wt cases should be referred for Lynch syndrome testing. Conclusions: The results emphasize the pivotal role of NGS in guiding treatment decisions, including stratification for therapies and identifying hereditary CRC syndromes. This study underscores the transformative potential of precision oncology in optimizing therapeutic outcomes, decision impact and advancing personalized care for CRC patients.

Revisiting the relevance of sidedness in colonic tumor molecular profiling.

3531 Background: Colorectal cancer (CRC) is a heterogeneous disease with distinct molecular and clinical differences between right- and left-sided tumors. This study analyzes these variations to understand their impact on tumor behavior and treatment strategies. Methods: A total of 445 colonic tumor samples (132 right-sided, 313 left-sided) were profiled to assess mutations, amplifications, and fusions in key cancer-related genes along with targeted transcriptome analysis of 20,802 genes in a subset using semiconductor based next-generation sequencing (NGS) platform at Datar Cancer Genetics. Immunotherapy biomarkers (TMB, MSI, and PD-L1 22C3 TPS) were analyzed in a subset. Results: Right-sided and left-sided colon cancers exhibit substantial molecular heterogeneity, driven by distinct genetic and epigenetic alterations (Table 1). Right-sided tumors were more frequently associated with MSI and had statistically significant higher incidence of BRAF mutations. KRAS mutations were frequently observed in both right-sided and left-sided tumors at equal rates. ERBB2 amplifications were exclusive to left side tumors, whereas oncogenic ERBB2 mutations were equally distributed. Located around ERBB2, PGAP3 gene co‐amplification too was exclusive to left sided tumors. TFE3 alterations were absent from left sided tumors and common on right side. TP53 mutations, though more common in left-sided tumors, the difference was not statistically significant. Gene expression profiling of a subset, including 103 left-sided and 41 right-sided colon tumors, revealed activation of the Wnt / β-catenin signalling pathway, RAS/MAPK pathway, TGF-β signalling pathway, and immune-related pathways, though these differences were not statistically significant, suggesting that while specific drivers may differ—such as the predominance of APC mutations in left-sided tumors (56.8% vs 37.9%) leading to WNT activation and the higher incidence of RSPO2/3 fusions (7.1% vs 1.7%) in right-sided tumors -eventually some pathways are commonly implicated in colorectal cancer biology. Conclusions: Existing therapies like ICIs, HER2 inhibitors, and emerging molecules such as RSPO2/RSPO3 inhibitors could have differing impact based on tumor sidedness. Integrating these distinctions into drug development and clinical trials holds potential to optimize treatment outcomes. Molecular profiles of right- and left-sided colon tumors. Gene Right (%) Left (%) p-Value(Chi-square test) TP53 64.5% 73.2% 0.075644 APC 37.9% 56.8% 0.001354 KRAS 50.0% 43.6% 0.220194 BRAF 18.8% 3.0% 0.00001 TFE3 9.5% 0% 0.109087 ERBB2 mutation 2.3% 2.0% 0.80941 ERBB2 amplification 0% 5.9% 0.023006 PGAP3 amplification 0% 7.1% 0.673427 RSPO2/3 fusion 7.1% 1.7% 0.827207 Immunotherapy Biomarkers TMB 10-14 24.7% 29.3% 0.458066 TMB ³15 15.6% 7.6% 0.059925 MSI-High 8.1% 3.4% 0.066213 PD-L1 Positive 15% 5.6% 0.012571

Demographic characteristics of inflammatory bowel disease patients in Saudi Arabia and their relation to gastrointestinal cancers: An observational, prospective cohort study.

e15691 Background: Inflammatory Bowel Diseases (IBD), including Crohn’s disease (CD), ulcerative colitis (UC), and fistulizing CD (FCD), are chronic conditions that can increase the risk of gastrointestinal (GIT) cancers. IBD, particularly when diagnosed early, is associated with an increased risk of developing GIT cancers, including colorectal cancer (CRC). Long-standing inflammation in IBD patients can lead to genetic mutations and alterations, such as changes in the p53 tumor suppressor protein, which are early events in the progression to cancer. This study aims to evaluate the demographic characteristics of IBD patients in Saudi Arabia treated with Infliximab biosimilar. Methods: This observational, prospective cohort study was conducted across four medical centers in Saudi Arabia. The study included 154 patients, with 62 naïve and 92 switched from infliximab. Patients were followed for 48 weeks, with demographic data collected at baseline. Results: The study population had a mean age of 29.6 years (SD 10.1), with 57.7% males and 42.3% females. The majority of patients (87.8%) were Saudi nationals. Among the patients, 37.6% had moderate to severe active CD, 36.3% had fistulizing CD, and 26.1% had moderate to severe active UC. Naïve patients constituted 39.5% of the cohort, while 60.5% were switched from infliximab. The study sites included King Abdul Aziz University Hospital (28.2%), King Saud Medical City (21.2%), National Guard Hospital in Riyadh (31.4%), and National Guard Hospital in Jeddah (19.2%). Conclusions: The demographic profile of IBD patients in Saudi Arabia is consistent with regional data, showing a relatively young population with a higher prevalence of CD. The association between early IBD and the development of GIT cancers underscores the importance of early diagnosis, regular screening, and monitoring to manage and mitigate cancer risk in IBD patients. Patients’ disposition per site. Naïve patients Switched Patients Naïve patients Switched Patients Naïve patients Switched Patients KAUH 7(35.0) 14(35.9) 2(8.0) 5(16.1) 6(35.3) 10(41.7) 44 NGHA-Jeddah 5(25.0) 12(30.8) - 3(9.7) 3(17.6) 7(29.2) 30 NGH-Riyadh 4(20.0) 13(33.3) 3(12.0) 22(71.0) - 7(29.2) 49 KSMC 4(20.0) - 20(80.0) 1(3.2) 8(47.1) - 33 Total patients/ disease/ dynamic group 33.9% 66.1% 44.6% 55.4% 41.5% 58.5% - Total patients/ disease 12.8% 25.0% 16.0% 19.9% 10.9% 15.4% - Total Patients 20 39 25 31 17 24 156

Actionable insights: Liquid NGS in community oncology practice.

e15081 Background: Liquid-based next-generation sequencing (NGS) is an integral test alongside tissue biopsy for identifying actionable mutations in various cancers. Currently, most practicing oncologists order liquid NGS when tissue biopsy is not feasible or concurrently with tissue biopsy to guide management with targeted therapies. However, concurrent testing can increase healthcare costs. We aim to explore whether liquid NGS has the same clinical utility as tissue biopsy in certain malignancies in a community-based oncology practice. Methods: A retrospective analysis was conducted at a community-based practice in Wichita, Kansas from 2022-2024. Data was collected through chart review and entered into a REDCap database. Adult patients with solid tumors who underwent Guardant360 liquid biopsy were included in the study. The primary objective was to compare and evaluate efficacy and assess concordance of genetic alterations identified by liquid NGS and tissue NGS. Descriptive statistics were used for data summarization. Results: The study analyzed 168 adult patients (90 males, 78 females). The cohort consisted of Caucasians (85.3%), African Americans (7.7%), Hispanics (3.2%), and Asians (3.8%). Twenty-two cancer subtypes were represented, including prostate (29.9%), lung (27.5%), breast (12%), colon (9.6%), and other malignancies (21%). The most common histologic type was adenocarcinoma (74.4%), with the majority of patients having metastatic disease. Comparing liquid NGS (n = 168) to tissue NGS (n = 89), liquid NGS demonstrated a shorter median turnaround time (8 vs. 13 days) and identified more genes overall (27 vs. 18 actionable, and 572 vs. 153 other variants). The average number of genes identified per patient was higher with liquid NGS (8.76 vs. 1.66). In 13 cases with repeated liquid biopsies, 3 patients had new actionable mutations identified. In subgroup analysis, liquid-based NGS outperformed tissue NGS in detecting actionable mutations, particularly in prostate (70% vs. 16%) and lung cancers (64.4% vs. 31.1%). Concordance rates between liquid and tissue NGS were 40% for lung and 33% for prostate cancer. Conclusions: Liquid-based NGS can be a reliable and effective tool for identifying targetable mutations. In our dataset, for specific cancer subtypes like prostate and lung cancer, it can be used as a first-line test for finding actionable mutations without the need for tissue NGS, potentially reducing the overall financial burden in oncology care.

Assessing a tumor-agnostic circulating tumor DNA assay for uveal melanoma surveillance and metastatic disease monitoring.

e15037 Background: Uveal melanoma (UM) is a rare and aggressive intraocular malignancy, with up to half of patients developing metastatic disease. Surveillance approaches depend on gene expression profiling and radiographic imaging, but these methods do not address detection of subclinical disease. Circulating tumor DNA (ctDNA), derived from tumor nucleic acids in plasma, has emerged as a tumor marker for disease burden and treatment response, but currently limited in UM to matched tumor-informed assays in the metastatic setting. Here we assess the utility of a novel tumor-agnostic ctDNA assay, to be used for early detection in the surveillance setting as well as for metastatic disease monitoring. Methods: We conducted a prospective study of 42 UM patients at Columbia University Irving Medical Center, stratifying them into surveillance (n = 24) and metastatic (n = 18) cohorts. The Columbia University Division of Personalized Genomic Medicine developed blood based ctDNA assay using genetic alterations common to uveal melanoma (a 30 gene panel including GNAQ, GNA11, BAP1, and PLCB4). ctDNA level was measured in copies/mL and variant allele frequency (VAF %). Surveillance patients had ctDNA collected at 3-6 month intervals, while metastatic patients were sampled throughout a variety of investigational and standard treatments including liver-directed therapy. Results: In the surveillance cohort, all 24 patients had negative ctDNA at baseline and follow-up. This included two patients with undetectable ctDNA, both of whom developed radiographic evidence of liver metastasis, confirmed by biopsy within 2 weeks of a negative ctDNA. In the metastatic cohort, 10 of 18 (56%) patients had detectable ctDNA. ctDNA VAF correlated with imaging and clinical treatment responses in 6 of 7 (86%) patients in whom longitudinal samples were collected. As example, 3 patients showed rising ctDNA levels during radiographic disease progression; 1 patient exhibited decrease in ctDNA with positive treatment response on targeted clinical trial; 2 demonstrated stable disease by all metrics; and 1 exhibited stability in ctDNA levels despite rapid and overt disease progression while on trametinib. Overall, GNAQ Q209 were the most common mutations detected by ctDNA. Conclusions: Our findings show that tumor-agnostic ctDNA represents a useful biomarker for active disease monitoring in metastatic UM, in conjunction with radiographic and clinical assessment. Within the surveillance setting, our assay showed limited sensitivity for early disease detection with common false negative results. Additional development of novel, noninvasive biomarker driven assays are necessary to improve early detection of metastatic UM.

Molecular signatures of intrahepatic cholangiocarcinoma: role in targeted therapy selection.

Molecular signatures of intrahepatic cholangiocarcinoma: role in targeted therapy selection.

Intracranial Disease Control and Survival among Patients with KRAS-mutant Lung Adenocarcinoma and Brain Metastases Treated with Stereotactic Radiosurgery.

Intracranial Disease Control and Survival among Patients with KRAS-mutant Lung Adenocarcinoma and Brain Metastases Treated with Stereotactic Radiosurgery.

Analysis and characterization of chondroitin/dermatan sulfate composition of lung adenocarcinoma tissues with different types of genetic alterations in ALK, EGFR and KRAS oncogenes

Analysis and characterization of chondroitin/dermatan sulfate composition of lung adenocarcinoma tissues with different types of genetic alterations in ALK, EGFR and KRAS oncogenes

Real-world prognostic factors for first-line EGFR-TKI efficacy in advanced NSCLC patients harboring EGFR 21L858R mutation.

This study aimed to investigate the prognostic factors for the treatment efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC) patients with EGFR exon 21 L858R mutation. The study enrolled patients with advanced EGFR L858R-mutant NSCLC who received first-line EGFR-TKI treatment between January 2019 and April 2024. Cox regression analyses were performed to identify the prognostic factors from clinical characteristics and concomitant genetic alterations that influenced progression-free survival (PFS) and overall survival (OS). According to the study of a cohort of 120 patients, we found that more metastatic organs (≥3 organs), specific metastatic patterns (liver and bone involvement), concurrent TP53 mutations, and worse Eastern Cooperative Oncology Group Performance Status (ECOG PS) were associated with shorter PFS. And ECOG PS was an independent predictive factor for PFS. Similarly, metastatic organs ≥3 (HR, 2.719; 95% CI, 1.386-5.333; p=0.004), ECOG PS of 2 (HR, 10.756; 95% CI, 4.002-28.906; p<0.001), and body mass index (BMI)＞24kg/m2 (HR, 0.335; 95% CI, 0.147-0.760; p=0.009) were associated with worse OS. We also observed that patients harboring TP53 co-mutations demonstrated significantly inferior PFS compared with their TP53 wild-type counterparts (13.7 months vs. 18.8 months; p=0.006). This studyidentified several factors significantly associated with worse response to EGFR-TKIs in NSCLC patients with EGFR L858R mutation and respective independent predictive factors for PFS and OS. These findings could enable personalized therapeutic efficacy assessment to facilitate clinical decision-making for EGFR L858R-mutant NSCLC patients treated with EGFR-TKIs.