Molecular Tumor Research Articles

Expert-Guided Large Language Models for Clinical Decision Support in Precision Oncology.

Rapidly expanding medical literature challenges oncologists seeking targeted cancer therapies. General-purpose large language models (LLMs) lack domain-specific knowledge, limiting their clinical utility. This study introduces the LLM system Medical Evidence Retrieval and Data Integration for Tailored Healthcare (MEREDITH), designed to support treatment recommendations in precision oncology. Built on Google's Gemini Pro LLM, MEREDITH uses retrieval-augmented generation and chain of thought. We evaluated MEREDITH on 10 publicly available fictional oncology cases with iterative feedback from a molecular tumor board (MTB) at a major German cancer center. Initially limited to PubMed-indexed literature (draft system), MEREDITH was enhanced to incorporate clinical studies on drug response within the specific tumor type, trial databases, drug approval status, and oncologic guidelines. The MTB provided a benchmark with manually curated treatment recommendations and assessed the clinical relevance of LLM-generated options (qualitative assessment). We measured semantic cosine similarity between LLM suggestions and clinician responses (quantitative assessment). MEREDITH identified a broader range of treatment options (median 4) compared with MTB experts (median 2). These options included therapies on the basis of preclinical data and combination treatments, expanding the treatment possibilities for consideration by the MTB. This broader approach was achieved by incorporating a curated medical data set that contextualized molecular targetability. Mirroring the approach MTB experts use to evaluate MTB cases improved the LLM's ability to generate relevant suggestions. This is supported by high concordance between LLM suggestions and expert recommendations (94.7% for the enhanced system) and a significant increase in semantic similarity from the draft to the enhanced system (from 0.71 to 0.76, P = .01). Expert feedback and domain-specific data augment LLM performance. Future research should investigate responsible LLM integration into real-world clinical workflows.

Hexokinase 2 as an independent risk factor for worse patient survival in esophageal adenocarcinoma and as a potential therapeutic target protein: A retrospective, single‑center cohort study.

Cancer cells exhibit a distinct metabolic profile that features an upregulation of less efficient glycolysis accompanied by lactate production for energy generation, in contract to the characteristic metabolism of normal cells. Consequently, cancer research has focused on the enzymes that participate in these cancer metabolic pathways. Among them, hexokinase 2 (HK2) has an important position as the initial enzyme in the glycolytic pathway. Increased expression levels of HK2 have been correlated with an increased risk of poor patient outcomes and advanced tumor stages in a number of malignant tumors, such as gastric carcinoma. The present study aimed to investigate the specific role of HK2 in patients diagnosed with esophageal adenocarcinoma. A total of 643 patients with esophageal adenocarcinoma were included. Immunohistochemical staining and HK2 mRNA in situ probes were used to investigate the association of HK2 expression levels with clinical and molecular tumor characteristics. Patients who exhibited high HK2 expression levels demonstrated significantly reduced overall survival (OS) times compared with patients who exhibited low HK2 expression levels (29.6 vs. 39.9 months, respectively; P=0.027). Furthermore, high HK2 expression levels were demonstrated to be an independent risk factor for reduced patient survival (hazard ratio, 1.65; 95% CI, 1.09-2.50; P=0.018). Significantly reduced patient survival was also demonstrated in the subgroups of male patients, patients with primarily resected tumors, patients with HER2-negative tumors and patients with tumors exhibiting Y chromosome loss. Elevated expression of HK2 was identified as a risk factor for unfavorable patient survival in esophageal adenocarcinoma. This revelation suggests the potential for future diagnostic and therapeutic avenues tailored to this specific patient subset. Identifying patients with high HK2 expression may pinpoint a higher-risk cohort, paving the way for comprehensive prospective studies that could advocate for intensified monitoring and more aggressive therapeutic regimens. Furthermore, the targeted inhibition of HK2 could hold promise as a strategy to potentially enhance patient outcomes.

Increasing access to biomarker-driven treatment for lung cancer in Alabama: The Alabama Access initiative.

159 Background: Lung cancer is the leading cause of cancer death in Alabama, with an estimated 2,550 deaths in 2024. Non-small cell lung cancer (NSCLC) represents 85% of these cases. Despite national guidelines recommending comprehensive biomarker testing (CBT) for metastatic NSCLC, significant disparities persist in the utilization of CBT and targeted therapies among Alabama residents. Methods: In March 2024, we launched the "Alabama Access" initiative – a partnership between the LUNGevity Foundation and the O’Neal Comprehensive Cancer Center at the University of Alabama at Birmingham – to foster academic and community oncology partnerships to increase access to biomarker-driven treatments. We used a population health science and geospatial mapping approach to visualize oncology practices serving counties with Alabama's highest lung cancer burden. Practices in Walker, Dothan, Marengo, Morgan, Jackson, Marshall, and Montgomery counties were identified as the highest priority based on annual mortality rates. Key interventions will include virtual molecular tumor boards and oncology navigation to facilitate the integration of resources and expertise and ensure that patients in nonacademic practices benefit from the latest advances in precision oncology. After roll-out, we will collect feasibility and acceptability data around program integration. Results: Our analysis revealed that 62.0% of the state’s population resides in Primary Care Health Professional Shortage Areas (HPSAs), and 58 out of 67 counties are classified as Medically Underserved Areas. The poverty rate in 89.6% of counties surpasses the national average, contributing to higher lung cancer incidence and mortality rates, with 62.0% of cases diagnosed at advanced stages. The state also shows a higher smoking prevalence, affecting 97.0% of counties compared to national figures. We will present practice-level testing data, including barriers to CBT. Conclusions: This pilot aims to mitigate disparities in CBT through enhanced collaboration between academic and community oncology settings. Integrating molecular navigation into community practices will be pivotal in disseminating program information and collecting data on current testing practices to improve overall lung cancer care quality in Alabama.

Diagnostic Utility of a 90-Gene Expression Assay (Canhelp-Origin) for Patients with Metastatic Cancer with an Unclear or Unknown Diagnosis.

Metastatic cancers with unclear or unknown origins pose significant challenges in diagnosis and management, frequently leading to suboptimal outcomes. Studies have demonstrated that a 90-gene expression assay is effective in predicting the primary origin and guiding the site-specific therapy to improve prognosis. This study aimed to evaluate the clinical effectiveness of a 90-gene expression assay in patients with unclear or unknown diagnoses. The study encompassed patients for whom a 90-gene expression assay was requested as part of standard care. Data on patient demographics, tumor characteristics, and clinical history were collected. The assay's performance was evaluated by comparing its predicted tumor type with the final histopathological diagnosis. Among 303 cases analyzed, a 90-gene expression assay successfully identified a molecular-based tumor type for 295 (97.4%) patients. Comparison with histopathological diagnosis revealed an overall agreement of 88.5% (170/192). In patients with a single suspected primary site (n = 140), the assay confirmed the suspected diagnosis in 90.7% of cases. For those with a differential diagnosis (n = 52), the assay narrowed down the possibilities in 82.7% of cases. Moreover, in cases where the histopathology report indicated cancer of unknown primary (n = 103), the assay offered a molecular tumor type prediction with potential clinical significance. This study demonstrates the significant impact of a 90-gene expression assay on diagnosis and potential treatment selection for difficult-to-diagnose patients, highlighting its clinical value as a standardized molecular approach to streamline further diagnostic testing for patients with metastatic cancer of unclear or unknown origin. Further prospective study is required to assess whether employing molecular diagnostic classifiers enhances clinical outcomes in these patients.

MicroRNA-506 as a tumor suppressor in prostate cancer by regulation of Hippo signaling pathway

IntroductionProstate cancer (PCa) is considered as one of the leading causes of cancer related deaths among males globally. There is a high rate of tumor relapse and metastasis in PCa patients that is associated with chemo-resistance. Beside the elimination of tumor cells, chemotherapy has an adverse effect in normal cells. Therefore, it is required to clarify the molecular tumor biology to introduce novel markers to predict the drug response in PCa patients. Hippo signaling pathway is an important regulator of cell proliferation, migration, and drug response that can be modulated by microRNAs (miRNAs). Since, miR-506 deregulation has been reported in PCs, in the present study we assessed a probable role of miR-506 in regulation of Hippo signaling pathway during prostate tumor cell migration and drug resistance. Materials and methodsThe mRNA expression levels of Hippo signaling components were assessed in miR-506 ectopic expressed in comparison with control PC3 cells. Apoptosis assay, drug response, and cell migration were also assessed to find the role of miR-506 in prostate tumor cell aggressiveness. ResultsMiR-506 promoted the Hippo signaling pathway via TAZ and CTGF up regulations, while BIRC5, FAT, and C-MYC down regulations in PC3 cells. MiR-506 significantly reduced prostate tumor cell migration (p = 0.019) and Paclitaxel (TXL) resistance (p = 0.0006), while promoted apoptosis (p < 0.0001). ConclusionmiR-506 exerted a tumor suppressor role during PCa progression by activation of Hippo pathway. MiR-506 targeted the FAT to activate the YAP/TAZ and nuclear translocation where it can bind with TEAD to up regulate the CTGF that resulted in reduced PCa cell migration. The WNT inhibition and C-MYC down regulation by the CTGF resulted in BIRC5 down regulation that induced apoptosis in PCa cells. Therefore, miR-506 can be introduced as a therapeutic marker in PCa following the confirmation by the animal studies and further clinical trials.

Actionable alterations in glioblastoma: Insights from the implementation of genomic profiling as the standard of care from 2016 to 2023

Abstract Background In 2016, genomic profiling was implemented for patients with grade 4 primary brain tumors at Rigshospitalet, Denmark. The aim of this study was to discover actionable alterations and to match these with targeted therapies. Methods Between January 2016 and December 2023, 483 brain tumor patients were profiled. We retrieved clinical data and molecular data. Whole exome, whole genome, or panel sequencing, along with SNP array analyses, and RNA-seq were performed on resected primary tumor tissue. Alterations were classified according to the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) following the European Association of Neuro-Oncology (EANO) guideline on rational molecular testing. Results A total of 200 (41.4%) patients’ tumors harbored an alteration of interest according to the EANO guideline. Twenty (4.1%) patients had an ESCAT high-tier alteration (tier I or II), while 155 patients (32.1%) had an alteration corresponding to ESCAT IIIA. Thirty-five patients (7.2%) had an actionable alteration, and 15 (3.1%) received targeted therapy. The treated targets were BRAFV600E mutations, FGFR alterations, NTRK fusions, PDGFRA fusions, PTPRZ1-MET fusions, and TMB-high. The overall response rate was 20%, with a median duration of response of 12 months, and 47% achieved stable disease as the best response. Conclusions Genomic profiling uncovers alterations of interest in a substantial number of patients, but only a minority are considered by the Danish National Molecular Tumor Board to have actionable alterations, and even fewer receive targeted therapy. Nevertheless, factors, such as promising targets and the increasing availability of trials, may contribute to a future increase in the number of patients benefiting from targeted therapies based on genomic profiling.

Abstract C008: Patient-derived organoids and precision medicine: Insights from the PASS-01 clinical trial in PDAC

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is challenging as most patients are diagnosed at an advanced stage with limited treatment options. Tailoring therapies for individual patients is paramount due to the aggressive nature of the disease. Our work explores patient- derived organoids (PDOs) as in vitro tumor models to dissect molecular signatures and conduct pharmacotyping, aiming to enhance precision medicine. Methods: In the PASS-01 stage IV PDAC clinical trial, biopsies were collected for molecular correlatives, including establishment of PDO models. Tissue samples were collected from patients at six institutes across the United States and Canada, highlighting our ability to integrate PDO models into a robust, multi- institutional clinical framework. Most biopsies were collected from liver metastases, followed by primary pancreas tumors, peritoneal, omental, lymph node, lung, and brain metastases. KRAS mutation status by ddPCR was used to validate neoplastic cells in the organoid cultures and identify pseudonormal outgrowth. Established PDO lines were subjected to high throughput drug screening for 120+ compounds, comprising both standard-of-care (as monotherapy and in combination therapies) and experimental agents. Subsequently, validated PDO lines were expanded, biobanked and harvested for RNA and DNA sequencing. Results: During the trial, 186 biopsies from 183 enrolled patients were shipped to CSHL for PDO establishment. The overall malignant PDO establishment rate was 50% across all biopsy sites and patients. Interestingly, PDOs could be generated more often from patients that rapidly progressed on therapy (p = 0.03). Furthermore, by comparing the characteristics of the primary biopsies to the established PDO, PDOs were more frequently generated from Moffitt subtype classical (64% establishment) compared to basal (35%), and from those with a KRASminor imbalance (67% establishment) compared with KRAS wild-type (36%), balanced (58%), and KRASmajor imbalance (52%). The average time from tissue receipt to first drug screen data was 65 days, with six PDOs screened in under 30 days. This turnaround time enabled PDO therapeutic data to be presented at monthly molecular tumor boards. Consequently, these data were considered alongside other clinical trial correlates to aid in selection of second-line therapies when patients progressed. Conclusions: The PASS-01 trial facilitated the real-time generation of PDO models and reporting of therapeutic results. We identified correlations between PDO establishment and patient characteristics, and improved the methods to detect pseudonormal outgrowth. PDO pharmacoptyping identified sensitivity that correlated with patient outcomes on GnP, while also highlighting challenges of using empiric drug testing for chemotherapy sensitivity. Moving forward we aim to continue incorporation of PDOs and tumor molecular profiling to aid in patient therapy selection. We anticipate this work to be crucial as targeted therapies, including KRAS inhibitors, become mainstream in PDAC care. Citation Format: Amber N. Habowski, Dennis Plenker, Hardik Patel, Caitlin Tsang, Luce St. Surin, Fatim Kouassi, Deepthi Budagavi, Grainne M O'Kane, Stephanie Ramotar, Kenneth H Yu, Faiyaz Notta, Andrew Aguirre, Brian Wolpin, Dan Laheru, Daniel A King, Elizabeth M Jaffee, Jennifer J Knox, David A Tuveson. Patient-derived organoids and precision medicine: Insights from the PASS-01 clinical trial in PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C008.

Abstract PR-17: Genomic and transcriptomic characterization of pancreatic cancer patients on the PASS-01 trial

Abstract Overall survival for patients with advanced PDAC remains less than 1 year. Biomarkers are needed to select chemotherapy regimens, either alone or in combination with novel agents. PASS-01 compared mFOLFIRINOX and Gemcitabine/nab-Paclitaxel in a phase II randomised control trial while prospectively exploring tissue, liquid and organoid biospecimens to interrogate putative biomarkers of chemotherapy response and resistance. Methods PASS-01 was conducted across 6 sites in North America. Patients with de novo metastatic disease and a lesion amenable to core biopsy were included. Cases with germline pathogenic variants in BRCA1/2 or PALB2 were excluded. Up to 6 core biopsies were obtained with priorities for clinical diagnosis, patient derived organoids (PDOs), and whole genome and transcriptome sequencing (WGTS). WGTS were performed at a single site following laser capture microdissection. WGS reports were clinically (CAP) accredited and annotated mutations, copy number alterations, mutational signatures, TMB and structural variant patterns. KRAS allelic states were documented with major imbalances in mutant KRAS (KRASmaj) defined as mutant: WT copy number &amp;gt;3. Transcriptomic subtypes (classical vs. basal-like) were classified as previously described (Moffitt et al., 2015). WGTS results were discussed at a molecular tumor board with PDO pharmacotyping to determine best second line options. Results: 160 patients were included in the intention to treat population, of these WGS was available in 127 (79%) and additional NGS reports in 20 (13%). RNA-seq was successful in 119 (74%) and the basal-like subtype accounted for 29% and was associated with inferior outcomes. KRASm were evident in 91% and KRASG12D represented 45%. Tumor suppressors TP53, CDKN2A and SMAD4 were lost in 81%, 76% and 39% respectively. MTAP deletion was present in 40%, largely synonymous with CDKN2A deletions. Commonly co-altered genes in the dataset included epigenetic regulators (ARID1A, KMT2C, KDM6A) and TGFBR2. KRASmaj was present in 30% of cases and polyploid tumors in 50%. 50% of basal-like PDAC harboured KRASmaj compared to 22% of classical PDAC, p&amp;lt;0.01. Dominant signatures (SBS) included age related SBS1, 5 and 8. Additionally, we saw a prevalence of SBS17 and APOBEC SBS2/13, signatures which occurred more frequently compared to a similarly characterised resected cohort. Unstable genotypes were present in 24% with somatic-HRD evident in 3%. Of KRASWT PDAC, 58% harboured class I-II BRAF variants. KRAS WT PDAC had fewer co-mutations and in one case where an NGS report did not find a driver, a novel fusion in SLC4A4-RASGRF2 was identified. 28 molecular tumor boards took place throughout the trial influencing 50% obtaining a 2nd-line treatment. Conclusion: The PASS-01 cohort exhibits a heterogeneous group of genotypes and molecular subgroups. Certain mutational processes are more evident in advanced compared to resected PDAC. The impact of subgroups on survival and chemotherapy response is ongoing with a planned data lock on July 15th. Results will be presented at the meeting. Citation Format: Grainne M O'Kane, Gunho Jang, Trevor J Pugh, Julie Wilson, Stephanie Ramotar, Daniel A King, Dan Laheru, Ken H Yu, Kimberly J Perez, Amber Habowski, Erica S Tsang, Robert C Grant, Andrew J Aguirre, Raymond W-J Jang, Craig E Devoe, Eileen M O'Reilly, Anna Dodd, Brian M Wolpin, Xiang Y Ye, Elizabeth M Jaffee, David Tuveson, Steven Gallinger, Jennifer J Knox, Faiyaz Notta. Genomic and transcriptomic characterization of pancreatic cancer patients on the PASS-01 trial [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr PR-17.

A triple hormone receptor ER, AR, and VDR signature is a robust prognosis predictor in breast cancer

BackgroundDespite evidence indicating the dominance of cell-of-origin signatures in molecular tumor patterns, translating these genome-wide patterns into actionable insights has been challenging. This study introduces breast cancer cell-of-origin signatures that offer significant prognostic value across all breast cancer subtypes and various clinical cohorts, compared to previously developed genomic signatures.MethodsWe previously reported that triple hormone receptor (THR) co-expression patterns of androgen (AR), estrogen (ER), and vitamin D (VDR) receptors are maintained at the protein level in human breast cancers. Here, we developed corresponding mRNA signatures (THR-50 and THR-70) based on these patterns to categorize breast tumors by their THR expression levels. The THR mRNA signatures were evaluated across 56 breast cancer datasets (5040 patients) using Kaplan–Meier survival analysis, Cox proportional hazard regression, and unsupervised clustering.ResultsThe THR signatures effectively predict both overall and progression-free survival across all evaluated datasets, independent of subtype, grade, or treatment status, suggesting improvement over existing prognostic signatures. Furthermore, they delineate three distinct ER-positive breast cancer subtypes with significant survival in differences—expanding on the conventional two subtypes. Additionally, coupling THR-70 with an immune signature identifies a predominantly ER-negative breast cancer subgroup with a highly favorable prognosis, comparable to ER-positive cases, as well as an ER-negative subgroup with notably poor outcome, characterized by a 15-fold shorter survival.ConclusionsThe THR cell-of-origin signature introduces a novel dimension to breast cancer biology, potentially serving as a robust foundation for integrating additional prognostic biomarkers. These signatures offer utility as a prognostic index for stratifying existing breast cancer subtypes and for de novo classification of breast cancer cases. Moreover, THR signatures may also hold promise in predicting hormone treatment responses targeting AR and/or VDR.

Multi‑omics identification of a signature based on malignant cell-associated ligand–receptor genes for lung adenocarcinoma

PurposeLung adenocarcinoma (LUAD) significantly contributes to cancer-related mortality worldwide. The heterogeneity of the tumor immune microenvironment in LUAD results in varied prognoses and responses to immunotherapy among patients. Consequently, a clinical stratification algorithm is necessary and inevitable to effectively differentiate molecular features and tumor microenvironments, facilitating personalized treatment approaches.MethodsWe constructed a comprehensive single-cell transcriptional atlas using single-cell RNA sequencing data to reveal the cellular diversity of malignant epithelial cells of LUAD and identified a novel signature through a computational framework coupled with 10 machine learning algorithms. Our study further investigates the immunological characteristics and therapeutic responses associated with this prognostic signature and validates the predictive efficacy of the model across multiple independent cohorts.ResultsWe developed a six-gene prognostic model (MYO1E, FEN1, NMI, ZNF506, ALDOA, and MLLT6) using the TCGA-LUAD dataset, categorizing patients into high- and low-risk groups. This model demonstrates robust performance in predicting survival across various LUAD cohorts. We observed distinct molecular patterns and biological processes in different risk groups. Additionally, analysis of two immunotherapy cohorts (N = 317) showed that patients with a high-risk signature responded more favorably to immunotherapy compared to those in the low-risk group. Experimental validation further confirmed that MYO1E enhances the proliferation and migration of LUAD cells.ConclusionWe have identified malignant cell-associated ligand–receptor subtypes in LUAD cells and developed a robust prognostic signature by thoroughly analyzing genomic, transcriptomic, and immunologic data. This study presents a novel method to assess the prognosis of patients with LUAD and provides insights into developing more effective immunotherapies.

KRASG 12C-inhibitor-based combination therapies for pancreatic cancer: insights from drug screening.

Pancreatic ductal adenocarcinoma (PDAC) has limited treatment options, emphasizing the urgent need for effective therapies. The predominant driver in PDAC is mutated KRAS proto-oncogene, KRA, present in 90% of patients. The emergence of direct KRAS inhibitors presents a promising avenue for treatment, particularly those targeting the KRASG12C mutated allele, which show encouraging results in clinical trials. However, the development of resistance necessitates exploring potent combination therapies. Our objective was to identify effective KRASG12C-inhibitor combination therapies through unbiased drug screening. Results revealed synergistic effects with son of sevenless homolog 1 (SOS1) inhibitors, tyrosine-protein phosphatase non-receptor type 11 (PTPN11)/Src homology region 2 domain-containing phosphatase-2 (SHP2) inhibitors, and broad-spectrum multi-kinase inhibitors. Validation in a novel and unique KRASG12C-mutated patient-derived organoid model confirmed the described hits from the screening experiment. Our findings propose strategies to enhance KRASG12C-inhibitor efficacy, guiding clinical trial design and molecular tumor boards.

Radiogenomic profiling of global DNA methylation associated with molecular phenotypes and immune features in glioma

BackgroundThe radiogenomic analysis has provided valuable imaging biomarkers with biological insights for gliomas. The radiogenomic markers for molecular profile such as DNA methylation remain to be uncovered to assist the molecular diagnosis and tumor treatment.MethodsWe apply the machine learning approaches to identify the magnetic resonance imaging (MRI) features that are associated with molecular profiles in 146 patients with gliomas, and the fitting models for each molecular feature (MoRad) are developed and validated. To provide radiological annotations for the molecular profiles, we devise two novel approaches called radiomic oncology (RO) and radiomic set enrichment analysis (RSEA).ResultsThe generated MoRad models perform well for profiling each molecular feature with radiomic features, including mutational, methylation, transcriptional, and protein profiles. Among them, the MoRad models have a remarkable performance in quantitatively mapping global DNA methylation. With RO and RSEA approaches, we find that global DNA methylation could be reflected by the heterogeneity in volumetric and textural features of enhanced regions in T2-weighted MRI. Finally, we demonstrate the associations of global DNA methylation with clinicopathological, molecular, and immunological features, including histological grade, mutations of IDH and ATRX, MGMT methylation, multiple methylation-high subtypes, tumor-infiltrating lymphocytes, and long-term survival outcomes.ConclusionsGlobal DNA methylation is highly associated with radiological profiles in glioma. Radiogenomic global methylation is an imaging-based quantitative molecular biomarker that is associated with specific consensus molecular subtypes and immune features.

TROP2 in colorectal carcinoma: associations with histopathology, molecular phenotype, and patient prognosis.

Antibody-drug conjugates (ADCs) directed to trophoblast cell surface antigen 2 (TROP2) have gained approval as a therapeutic option for advanced triple-negative breast cancer, and TROP2 expression has been linked to unfavourable outcomes in various malignancies. In colorectal carcinoma (CRC), there is still a lack of comprehensive studies on its expression frequency and its prognostic implications in relation to the main clinicopathological parameters. We examined the expression of TROP2 in a large cohort of 1,052 CRC cases and correlated our findings with histopathological and molecular parameters, tumour stage, and patient outcomes. TROP2 was heterogeneously expressed in 214/1,052 CRCs (20.3%), with only a fraction of strongly positive tumours. TROP2 expression significantly correlated with an invasive histological phenotype (e.g. increased tumour budding/aggressive histopathological subtypes), advanced tumour stage, microsatellite stable tumours, and p53 alterations. While TROP2 expression was prognostic in univariable analyses of the overall cohort (e.g. for disease-free survival, p < 0.001), it exhibited distinct variations among important clinicopathological subgroups (e.g. right- versus left-sided CRC, microsatellite stable versus unstable CRC, Union for International Cancer Control [UICC] stages) and lost its significance in multivariable analyses that included stage and CRC histopathology. In summary, TROP2 is quite frequently expressed in CRC and associated with an aggressive histopathological phenotype and microsatellite stable tumours. Future clinical trials investigating anti-TROP2 ADCs should acknowledge the observed intratumoural heterogeneity, given that only a subset of TROP2-expressing CRC show strong positivity. The prognostic implications of TROP2 are complex and show substantial variations across crucial clinicopathological subgroups, thus indicating that TROP2 is a suboptimal parameter to predict patient prognosis.

Molecular Markers, Immune Therapy, and Non-Small Cell Lung Cancer-State-of-the-Art Review for Surgeons.

Background: Lung cancer is a leading cause of cancer deaths in the United States. An increasing understanding of relevant non-small cell lung cancer (NSCLC) biomarkers has led to the recent development of molecular-targeted therapies and immune checkpoint inhibitors that have revolutionized treatment for patients with advanced and metastatic disease. The purpose of this review is to provide surgeons with a state-of-the-art understanding of the current medical and surgical treatment trends and their implications in the future of management of NSCLC. Materials and Methods: A systematic search of PubMed was conducted to identify English language articles published between January 2010 and March 2024 focusing on molecular markers, tumor targeting, and immunotherapy in the diagnosis and treatment of NSCLC. Case series, observational studies, randomized trials, guidelines, narrative reviews, systematic reviews, and meta-analyses were included. Results: There is now increasing data to suggest that molecular-targeted therapies and immune therapies have a role in the neoadjuvant setting. Advances in intraoperative imaging allow surgeons to perform increasingly parenchymal-sparing lung resections without compromising tumor margins. Liquid biopsies can noninvasively detect targetable mutations in cancer cells and DNA from a blood draw, potentially allowing for earlier diagnosis, personalized therapy, and long-term monitoring for disease recurrence. Conclusions: The management of NSCLC has advanced dramatically in recent years fueled by a growing understanding of the cancer biology of NSCLC. Advances in medical therapies, surgical techniques, and diagnostic and surveillance modalities continue to evolve but have already impacted current treatment strategies for NSCLC, which are encompassed in this review.

Mutations in the N-domain of aryl hydrocarbon receptor interacting protein affect interactions with heat shock protein 90β and phosphodiesterase 4A5

The aryl hydrocarbon receptor interacting protein (AIP) is a cytoplasmic molecular co-chaperone and tumour suppressor that assists in protein stability and complex formation involving the aryl hydrocarbon receptor. Germline mutations in the AIP gene predispose to pituitary tumourigenesis with patients exhibiting an aggressive clinical phenotype. Full length AIP proteins harbouring N-domain mutations (R9Q, R16H, V49 M and K103R) were purified from E.coli utilizing a methodology that maintained structural integrity and monomeric stability. Mutations did not significantly affect the thermal stability of the protein and caused no overall disruptive effect in the protein structure. The mutations studied lowered the binding affinity of AIP towards two of its binding partners; heat shock protein 90β and phosphodiesterase 4A5 (PDE4A5). The inhibition of phosphodiesterase activity by AIP was also greatly reduced by all mutants. While previously published data has mainly concentrated on the tetratricopeptide repeats of the C-domain of AIP, we present clear evidence that AIP N-domain mutations play a significant role in two protein:protein interactions with partner proteins. The complex interactome of AIP suggests that any observable change in one or more of its binding partners cannot be disregarded as it may have repercussions on other biochemical pathways.

407P Genomic profiling and prediction role of the molecular tumor burden index in advanced HR+HER2- breast cancer

407P Genomic profiling and prediction role of the molecular tumor burden index in advanced HR+HER2- breast cancer

122P Practice patterns and treatment outcomes of molecular tumour board (MTB)-based personalized cancer therapies: A single-center experience

122P Practice patterns and treatment outcomes of molecular tumour board (MTB)-based personalized cancer therapies: A single-center experience

Combined analysis of circulating tumor DNA and tumor tissue to overcome osimertinib resistance (OSIRIS); the second line osimertinib cohort

IntroductionOsimertinib resistance inevitably occurs in EGFR mutated NSCLC. We aimed to identify resistance mechanisms (RM) using paired plasma and tumor samples in patients that progressed on 2nd/3rd line osimertinib. MethodsFrom 09 to 2019 to 02-2021, 51 patients were enrolled. Plasma sequencing used AVENIO Expanded Panel (research use only), tumor biopsies underwent DNA and RNA sequencing and histological evaluation. Sequencing was regarded successful when the driver mutation was confirmed with a variant allele frequency of ≥ 0.10 %. Concordance between modalities was calculated for the driver mutation and RMs covered in both modalities. The Molecular Tumor Board formulated a treatment advice. ResultsThe driver mutation was detected in 42/51 plasma samples (82 %) and in 50/51 tumor samples (98 %), concordance rate was 80 %. In 41/51 (80 %) patients ≥ 1 RM was identified. Thirty-two RMs covered in both modalities were found in plasma (61.5 %), 39 in tumor (75 %), nineteen in both. RM concordance rate was 36.5 %. ConclusionCombined analysis of plasma and tumor samples post 2nd/3rd line osimertinib identifies additional RMs regardless of the comparative approach used. Plasma sequencing identified 61.5% of RMs, tumor analysis identified 75%. Combined, they provide a superior overview of osimertinib resistance, enabling more tailored treatment options.

80P Development of a next-generation sequencing diagnostics recommender tool in the framework of the molecular tumor board Freiburg

80P Development of a next-generation sequencing diagnostics recommender tool in the framework of the molecular tumor board Freiburg

120P A prospective comparative evaluation of automatic trial match tools in a molecular tumor board

120P A prospective comparative evaluation of automatic trial match tools in a molecular tumor board