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Real-world performance analysis of a novel computational method in the precision oncology of pediatric tumors

World Journal of Pediatrics 2023年第10期19卷 992-1008页

作者： Barbara Vodicska Júlia Déri Dóra Tihanyi Edit Várkondi EnikőKispéter Róbert Dóczi Dóra Lakatos Anna Dirner Mátyás Vidermann Péter Filotás Réka Szalkai-Dénes István Szegedi Katalin Bartyik Krisztina Míta Gábor Réka Simon Péter Hauser György Péter Csongor Kiss Miklós Garami István Peták Oncompass Medicine Hungary Kft Retek Str.34Budapest 1024Hungary Division of Pediatric Hematology-oncology Department of PediatricsFaculty of MedicineUniversity of DebrecenDebrecenHungary Department of Pediatrics Albert Szent-Györgyi Medical SchoolUniversity of SzegedSzegedHungary Onco-Hematology Department Velkey LászlóPaediatric Health CentreMiskolcHungary Department of Paediatrics Semmelweis UniversityBudapestHungary Onco-Hematology Department Heim Pál Children’s HospitalBudapestHungary Department of Pharmacology and Pharmacotherapy Semmelweis UniversityBudapestHungary Department of Pharmaceutical Sciences University of Illinois at ChicagoChicagoUSA Genomate Health CambridgeMAUSA

Background The utility of routine extensive molecular profiling of pediatric tumors is a matter of debate due to the high number of genetic alterations of unknown significance or low evidence and the lack of standardized and personalized decision support *** drug assignment(DDA)is a novel computational method to prioritize treatment options by aggregating numerous evidence-based associations between multiple drivers,targets,and targeted *** has been validated to improve personalized treatment decisions based on the outcome data of adult patients treated in the SHIVA01 clinical *** aim of this study was to evaluate the utility of DDA in pediatric *** Between 2017 and 2020,103 high-risk pediatric cancer patients(precision oncology program,and samples from 100 patients were eligible for further *** or blood samples were analyzed by whole-exome(WES)or targeted panel sequencing and other molecular diagnostic modalities and processed by a software system using the DDA algorithm for therapeutic decision ***,a molecular tumor board(MTB)evaluated the results to provide therapy *** Of the 100 cases with comprehensive molecular diagnostic data,88 yielded WES and 12 panel sequencing *** identified matching off-label targeted treatment options(actionability)in 72/100 cases(72%),while 57/100(57%)showed potential drug *** reached 88%(29/33)by 2020 due to the continuous updates of the evidence *** approved the clinical use of a DDA-top-listed treatment in 56 of 72 actionable cases(78%).The approved therapies had significantly higher aggregated evidence levels(AELs)than dismissed *** of WES results for targeted panels missed important mutations affecting therapy *** DDA is a promising approach to overcome challenges associated with the interpretation of extensive molecular profiling in the routine car

关键词： Computational decision support Pediatric tumors precision oncology Tumor board

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Applications of RNA Indexes for precision oncology in Breast Cancer

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Genomics, Proteomics & Bioinformatics 2018年第2期16卷 108-119页

作者： Liming Ma Zirui Liang Hui Zhou Lianghu Qu Key Laboratory of Gene Engineering of the Ministry of Education State Key Laboratory of Biocontrol School of Life SciencesSun Yat-sen University

precision oncology aims to offer the most appropriate treatments to cancer patients mainly based on their individual genetic information. Genomics has provided numerous valuable data on driver mutations and risk loci; however, it remains a formidable challenge to transform these data into therapeutic agents. Transcriptomics describes the multifarious expression patterns of both mRNAs and non-coding RNAs （ncRNAs）, which facilitates the deciphering of genomic codes. In this review, we take breast cancer as an example to demonstrate the applications of these rich RNA resources in precision medicine exploration. These include the use of mRNA profiles in triple-negative breast cancer （TNBC） subtyping to inform corresponding candidate targeted therapies; current advancements and achievements of high-throughput RNA interference （RNAi） screening technologies in breast cancer; and microRNAs as functional signatures for defining cell identities and regulating the biological activities of breast cancer cells. We summarize the benefits of transcriptomic analyses in breast cancer management and propose that unscrambling the core signaling networks of cancer may be an important task of multiple-omic data integration for precision oncology.

关键词： precision oncology Transcriptomics RNA interference microRNA Breast cancer

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Machine intelligence for precision oncology

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World Journal of Translational Medicine 2021年第1期9卷 1-10页

作者： Nelson S Yee Department of Medicine The Pennsylvania State University College of MedicinePenn State Cancer InstitutePenn State Health Milton S.Hershey Medical CenterHersheyPA 17033-0850United States

Despite various advances in cancer research,the incidence and mortality rates of malignant diseases have remained *** risk assessment,prevention,detection,and treatment of cancer tailored to the individual are major challenges in clinical *** intelligence(AI),a field of applied computer science,has shown promising potential of accelerating evolution of healthcare towards precision *** article focuses on highlights of the application of data-driven machine learning(ML)and deep learning(DL)in translational research for cancer diagnosis,prognosis,treatment,and clinical *** algorithms in radiological and histological images have been demonstrated to improve detection and diagnosis of ***-based prediction models in molecular or multi-omics datasets of cancer for biomarkers and targets enable drug discovery and *** approaches combining radiomics with genomics and other omics data enhance the power of AI in improving diagnosis,prognostication,and treatment of *** and regulatory issues involving patient confidentiality and data security impose certain limitations on practical implementation of ML in clinical ***,the ultimate goal of application of AI in cancer research is to develop and implement multi-modal machine intelligence for improving clinical decision on individualized management of patients.

关键词： Artificial intelligence Deep learning Machine learning precision oncology Radiomics Radiogenomics

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Genomic profiling of colorectal cancer in large-scale Chinese patients:amplification and somatic mutations in ERBB2

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oncology Research 2024年第9期32卷 1429-1438页

作者： YUZHI LIU EVELYNE BISCHOF ZHIQIN CHEN JIAHUAN ZHOU BEI ZHANG DING ZHANG YONG GAO MING QUAN Department of oncology Shanghai East HospitalTongji University School of MedicineShanghaiChina State Key Laboratory of Oncogenes and Related Genes Shanghai Cancer InstituteDepartment of OncologyRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina Jiangsu Hengrui Pharmaceuticals Co. Ltd.ShanghaiChina D Medicines Inc. ShanghaiChina

Objectives:Human epidermal growth factor receptor 2(HER2)-targeted therapies have demonstrated potential benefits for metastatic colorectal cancer(mCRC)patients with HER2 amplification,but are not satisfactory in cases of HER2 mutant ***:Consequently,further elucidation of amplifications and somatic mutations in erythroblastic oncogene B-2(ERBB2)is *** genomic profiling was conducted on 2454 Chinese CRC cases to evaluate genomic alterations in 733 cancer-related genes,tumor mutational burden,microsatellite instability,and programmed death ligand 1(PD-L1)***:Among 2454 CRC patients,85 cases(3.46%)exhibited ERBB2 amplification,and 55 cases(2.24%)carried ERBB2 mutation.p.R678Q(28%),p.V8421(24%),and p.S310F/Y(12%)were the most prevalent of the 16 detected mutation *** comparison to the ERBB2 altered(alt)group,KRAS/BRAF mutations were more prevalent in ERBB2 wild-type(wt)samples(ERBB2wt ***2alt,KRAS:50.9%vs.25.6%,p<0.05;BRAF:8.5%vs.2.3%,p<0.05).32.7%(18/55)of CRCs with ERBB2 mutation exhibited microsatellite instability high(MSI-H),while no cases with HER2 amplification displayed *** genes varied between ERBB2 copy number variation(CNV)and ERBB2 single nucleotide variant(SNV);TP53 alterations tended to co-occur with ERBB2 amplification(92.3%)as opposed to ERBB2 mutation(58.3%).KRAS and PIK3CA alterations were more prevalent in ERBB2 SNV cases(KRAS/PIK3CA:45.8%/31.2%)compared to ERBB2 amplification cases(KRAS/PIK3CA:14.1%/7.7%).Conclusion:Our study delineates the landscape of HER2 alterations in a large-scale cohort of CRC patients from *** findings enhance our understanding of the molecular features of Chinese CRC patients and offer valuable implications for further investigation.

关键词： Colorectal cancer ERBB2 HER2 Human epidermal growth factor receptor 2 Genetic profiling precision oncology

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Hidden army within:Harnessing the microbiome to improve cancer treatment outcomes

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World Journal of Clinical Cases 2024年第28期12卷 6159-6164页

作者： Ippokratis Messaritakis Georgios Vougiouklakis Asimina Koulouridi Aris P Agouridis Nikolaos Spernovasilis Department of Microbiology German Oncology Center&Yiannoukas Labs LTDBioiatriki GroupLimassol 4108Cyprus Department of Internal Medicine German Oncology CenterLimassol 4108Cyprus Department of oncology German Oncology CenterLimassol 4108Cyprus School of Medicine European University CyprusNicosia 2404Cyprus Department of Infectious Diseases German Oncology CenterLimassol 4108Cyprus

The gut microbiome has emerged as a critical player in cancer pathogenesis and treatment ***,an imbalance in the gut microbial community,impacts tumor initiation,progression,and therapy *** bacterial species have been associated with either promoting or inhibiting tumor growth,offering potential targets for therapeutic *** gut microbiome in-fluences the efficacy and toxicity of conventional treatments and cutting-edge immunotherapies,highlighting its potential as a therapeutic target in cancer ***,translating microbiome research into clinical practice requires addres-sing challenges such as standardizing methodologies,validating microbial bio-markers,and ensuring ethical ***,we provide a comprehensive overview of the gut microbiome's role in cancer highlighting the need for on-going research,collaboration,and innovation to harness its full potential for im-proving patient outcomes in *** current editorial aims to explore these insights and emphasizes the need for standardized methodologies,validation of microbial biomarkers,and interdisciplinary collaboration to translate microbiome research into clinical ***,it underscores ethical consider-ations and regulatory challenges surrounding the use of microbiome-based ***,this article advocates for ongoing research,collaboration,and innovation to realize the full potential of microbiome-guided oncology in impro-ving patient care and outcomes.

关键词： Gut microbiome Cancer treatment Immunotherapy Microbiome-based interventions Dysbiosis precision oncology

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Glycoproteogenomics: Setting the Course for Next-generation Cancer Neoantigen Discovery for Cancer Vaccines

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Genomics, Proteomics & Bioinformatics 2021年第1期19卷 25-43页

作者： José Alexandre Ferreira Marta Relvas-Santos Andreia Peixoto AndréM.N.Silva Lúcio Lara Santos Experimental Pathology and Therapeutics Group Portuguese Institute of OncologyPorto 4200-072Portugal Institute of Biomedical Sciences Abel Salazar University of PortoPorto 4050-313Portugal Porto Comprehensive Cancer Center(P.ccc) Porto 4200-072Portugal REQUIMTE-LAQV Department of Chemistry and BiochemistryFaculty of Sciences of the University of PortoPorto 4169-007Portugal

Molecular-assisted precision oncology gained tremendous ground with high-throughput next-generation sequencing(NGS),supported by robust *** quest for genomicsbased cancer medicine set the foundations for improved patient stratification,while unveiling a wide array of neoantigens for *** pre-clinical and clinical studies have successfully used tumor-specific peptides in vaccines with minimal off-target ***,the low mutational burden presented by many lesions challenges the generalization of these solutions,requiring the diversification of neoantigen *** utilizing customized databases for protein annotation by mass spectrometry(MS)is a powerful tool toward this *** the concept toward exploring proteoforms originated from post-translational modifications(PTMs)will be decisive to improve molecular subtyping and provide potentially targetable functional nodes with increased cancer *** through the path of systems biology,we highlight that alterations in protein glycosylation at the cell surface not only have functional impact on cancer progression and dissemination but also originate unique molecular fingerprints for targeted ***,we discuss the outstanding challenges required to accommodate glycoproteomics in oncoproteogenomics *** envisage that such rationale may flag a rather neglected research field,generating novel paradigms for precision oncology and immunotherapy.

关键词： Glycoproteogenomics Oncoproteogenomics Cancer neoantigens Glycosylation precision oncology

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Cell-free DNA liquid biopsy for early detection of gastrointestinal cancers:A systematic review

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World Journal of Gastrointestinal oncology 2021年第11期13卷 1799-1812页

作者： Isabelle Uhe Monika Elisabeth Hagen Frederic Ris Jeremy Meyer Christian Toso Jonathan Douissard Abdominal Surgery Division Geneva University HospitalsGeneva 1211Switzerland

BACKGROUND Gastrointestinal tumors are among the most common cancer types,and early detection is paramount to improve their ***-free DNA(cfDNA)liquid biopsy raises significant hopes for non-invasive early *** To describe current applications of this technology for gastrointestinal cancer detection and *** A systematic review of the literature was performed across the PubMed *** reporting the use of cfDNA liquid biopsy in the screening or diagnosis of gastrointestinal cancers were included in the *** A total of 263 articles were screened for eligibility,of which 13 articles were *** investigated colorectal cancer(5 studies),pancreatic cancer(2 studies),hepatocellular carcinoma(3 studies),and multi-cancer detection(3 studies),including gastric,oesophageal,or bile duct cancer,representing a total of 4824 *** sensitivities ranged from 71% to 100%,and specificities ranged from 67.4% to 100%.Pre-cancerous lesions detection was less performant with a sensitivity of 16.9% and a 100% specificity in one *** study using a large biobank demonstrated a 94.9% sensitivity in detecting cancer up to 4 years before clinical symptoms,with a 61% accuracy in tissue-of-origin *** cfDNA liquid biopsy seems capable of detecting gastrointestinal cancers at an early stage of development in a non-invasive and repeatable manner and screening simultaneously for multiple cancer types in a single blood *** trials in clinically relevant settings are required to determine the exact place of this technology in gastrointestinal cancer screening and diagnosis strategies.

关键词： Cell-free DNA Tumor DNA Liquid biopsy Next-generation sequencing Cancer genomics Pancreatic cancer Colorectal cancer Hepatocellular carcinoma Multicancer detection Cancer screening Public health precision oncology

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Tumor organoids to study gastroesophageal cancer: a primer

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Journal of Molecular Cell Biology 2020年第8期12卷 593-606页

作者： Ramon U.Jin Jason C.Mills Division of oncology Department of Internal MedicineWashington University School of MedicineSt.LouisMO 63130USA Division of Gastroenterology Department of Internal MedicineWashington University School of MedicineSt.LouisMO 63130USA Department of Developmental Biology Washington University School of MedicineSt.LouisMO 63130USA Department of Pathology and Immunology Washington University School of MedicineSt.LouisMO 63130USA

Gastroesophageal cancers are leading causes of cancer *** attempts at adopting molecularly based treatment approaches have been slow and ineffective even though we begin to identify specific targetable gene mutations and *** is dear that we should no longer treat all gastroesophageal cancers as a homogeneous disease,which is what we do when we use nonspecific ***,we currently cannot monitor successful gene/pathway targeting,nor understand how/when tumors develop resistance,nor predict which patients will derive maximal *** improve outcomes,we must precisely detail the heterogeneity of these tumors to then individualize cancer therapy as well as develop novel avenues to study and predict treatment effects in individual *** this end,patient-derived organoids,in which tumor cells from individual patients are grown in a Petri dish,are a new versatile system that allows for timely expandability,detailed molecular characterization,and genetic manipulation with the promise of enabling predictive assessment of treatment *** this review,we will explore the development and basic techniques for organoid generation,and discuss the current and potential future applications of this exciting technology to study the basic science of carcinogenesis and to predict/guide cancer patient care in the clinics.

关键词： targeted therapy precision oncology cancer model tumor heterogeneity cancer evolution personalized medicine

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Emerging predictors of the response to the blockade of immune checkpoints in cancer therapy

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Cellular & Molecular Immunology 2019年第1期16卷 28-39页

作者： Xiaolei Li Wenhui Song Changshun Shao Yufang Shi Weidong Han The First Affiliated Hospital of Soochow University and State Key Laboratory of Radiation Medicine and Radioprotection Institutes for Translational MedicineSoochow UniversitySuzhouJiangsu 215123China Department of Molecular Biology Immunology and Bio-therapeuticInstitute of Basic MedicineChinese PLA General HospitalBeijing 100853China The Second Hospital of Shanxi Medical University TaiyuanShanxi 030001China

Checkpoint blockade-based immunotherapy offers new options and powerful weapons for the treatment of cancer,but its efficacy varies greatly among different types of cancer and across individual ***,the development of the right tools that can be used to identify patients who could benefit from this therapy is of utmost importance in order to maximize the therapeutic benefit,minimize risk of toxicities,and guide combination *** predictors have emerged that are based on checkpoint receptor ligand expression,tumor mutational burden,neoantigen and microsatellite instability,tumor-infiltrating immune cells,and peripheral blood *** this review,we discuss the current state and progress of predictors as aids in checkpoint blockadebased immunotherapy in cancer.

关键词： Cancer immunotherapy Checkpoint blockade immunotherapy Predictive biomarkers precision oncology

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Response to osimertinib in a colorectal cancer patient with an EGFR T790M mutation: A case report

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World Journal of Gastrointestinal oncology 2023年第10期15卷 1829-1834页

作者： Blake Buzard Lindsey Douglass Beth Gustafson Jennifer Buckley Marc Roth Lara Kujtan Dhruv Bansal Cancer Institute St.Luke's HospitalKansasMO 64111United States Department of Medical oncology University of Missouri-Kansas CityKansasMO 64108United States Department of Hematology/oncology St.Luke's Cancer InstituteKansasMO 64111United States

BACKGROUND Although common in lung cancer,somatic epidermal growth factor receptor(EGFR)mutations are rarely found in colorectal cancer,occurring in approximately 3%of *** with anti-EGFR antibodies is commonplace,but EGFR tyrosine kinase inhibitors are not standard treatments in colorectal *** we report a case of sustained response to osimertinib in a colorectal cancer patient with an EGFR T790M mutation on cell-free DNA *** SUMMARY A 72-year old woman with a past medical history of post-polio syndrome confined to a wheelchair,scoliosis and hypothyroidism presented with metastatic sigmoid colon adenocarcinoma with hepatic *** generation sequencing revealed a RAS/RAF wild-type,microsatellite stable,PD-L1 negative *** in TP3 and APC were also identified,as well as EGFR ***-free DNA analysis revealed an EGFR T790M *** was unable to tolerate first-line treatment with panitumumab,5-fluorouracil and leucovorin,progressed on second-line treatment with trifluridine/tipiracil plus bevacizumab,and was unable to tolerate third-line treatment with *** was started on fourth-line treatment with off-label osimertinib,with clinical response–decrease in size of hepatic metastases and a pericardial *** remained on treatment with osimertinib for seven *** This case shows the benefit of multi-gene sequencing assays to identify potential therapeutic options in patients with refractory disease.

关键词： Colorectal cancer Osimertinib Epidermal growth factor receptor T790M precision oncology Tyrosine kinase inhibitor Case report

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