bims-preonc 2024-10-06 papers

bims-preonc

Biomed News

on Precision oncology

Issue of 2024–10–06
nineteen papers selected by
Ankita Daiya, OneCell Diagnostics Inc.

Liquid biopsy for early cancer detection: technological revolutions and clinical dilemma.
Deciphering resistance mechanisms in cancer: final report of MATCH-R study with a focus on molecular drivers and PDX development.
The Role of ctDNA and Liquid Biopsy in the Diagnosis and Monitoring of Head and Neck Cancer: Towards Precision Medicine.
Detection of the BRAFV600E Mutation in Circulating Free Nucleic Acids as a Biomarker of Thyroid Cancer: A Review.
Circulating Tumor Cells: Origin, Role, Current Applications, and Future Perspectives for Personalized Medicine.
Liquid biopsy for CNS lymphoma: CSF exosomes and CSF exosomal miR-15a, miR-21, miR-155, miR-210, and miR-19b are promising biomarkers for diagnosis.
Cell-Free DNA Hydroxymethylation in Cancer: Current and Emerging Detection Methods and Clinical Applications.
The Role of Circulating Tumor DNA in Ovarian Cancer.
The Role of Molecular Imaging in Precision Oncology.
Prospects and Current Challenges of Extracellular Vesicle-Based Biomarkers in Cancer.
Feasibility of Circulating Tumor DNA Detection in the Cerebrospinal Fluid of Patients With Central Nervous System Involvement in Large B-Cell Lymphoma.
Molecular and functional landscape of malignant serous effusions for precision oncology.
Genomic Landscape of Advanced Solid Tumors in Middle East and North Africa Using Circulating Tumor DNA (ctDNA) in Routine Clinical Practice.
Poor compliance with germline testing recommendations in colorectal cancer patients undergoing molecular residual disease testing.
MiRNAs in Extracellular Vesicles as Biomarkers in Plasma of Papillary Thyroid Cancer Patients: A Proof-of-Concept Study.
Circulating Polyploid Giant Cancer Cells, a Potential Prognostic Marker in Patients with Carcinoma.
Plasma EGFR mutation ctDNA dynamics in patients with advanced EGFR-mutated NSCLC treated with Icotinib: phase 2 multicenter trial result.
Whole-Exome Sequencing Reveals Novel Candidate Driver Mutations and Potential Druggable Mutations in Patients with High-Risk Neuroblastoma.
Rationale and Design of the COPERNIC Trial: A Study of On-treatment ctDNA Changes in Chemo-refractory Colorectal Cancer Patients.

Expert Rev Mol Diagn. 2024 Oct 03. 1-19

Liquid biopsy for early cancer detection: technological revolutions and clinical dilemma.

Sidney W Fu, Cong Tang, Xiaohui Tan, Sudhir Srivastava.

   INTRODUCTION: Liquid biopsy is an innovative advancement in oncology, offering a noninvasive method for early cancer detection and monitoring by analyzing circulating tumor cells, DNA, RNA, and other biomarkers in bodily fluids. This technique has the potential to revolutionize precision oncology by providing real-time analysis of tumor dynamics, enabling early detection, monitoring treatment responses, and tailoring personalized therapies based on the molecular profiles of individual patients.
AREAS COVERED: In this review, the authors discuss current methodologies, technological challenges, and clinical applications of liquid biopsy. This includes advancements in detecting minimal residual disease, tracking tumor evolution, and combining liquid biopsy with other diagnostic modalities for precision oncology. Key areas explored are the sensitivity, specificity, and integration of multi-omics, AI, ML, and LLM technologies.
EXPERT OPINION: Liquid biopsy holds great potential to revolutionize cancer care through early detection and personalized treatment strategies. However, its success depends on overcoming technological and clinical hurdles, such as ensuring high sensitivity and specificity, interpreting results amidst tumor heterogeneity, and making tests accessible and affordable. Continued innovation and collaboration are crucial to fully realize the potential of liquid biopsy in improving early cancer detection, treatment, and monitoring.

Keywords:  Circulating tumor cells; circulating tumor DNA; early cancer detection; extracellular vesicles; liquid biopsy; machine learning and large language model; multi-omics; regulatory

DOI:  https://doi.org/10.1080/14737159.2024.2408744
Mol Cancer. 2024 Oct 04. 23(1): 221

Deciphering resistance mechanisms in cancer: final report of MATCH-R study with a focus on molecular drivers and PDX development.

Damien Vasseur, Ludovic Bigot, Kristi Beshiri, Juan Flórez-Arango, Francesco Facchinetti, Antoine Hollebecque, Lambros Tselikas, Mihaela Aldea, Felix Blanc-Durand, Anas Gazzah, David Planchard, Ludovic Lacroix, Noémie Pata-Merci, Catline Nobre, Alice Da Silva, Claudio Nicotra, Maud Ngo-Camus, Floriane Braye, Sergey I Nikolaev, Stefan Michiels, Gérôme Jules-Clement, Ken André Olaussen, Fabrice André, Jean-Yves Scoazec, Fabrice Barlesi, Santiago Ponce, Jean-Charles Soria, Benjamin Besse, Yohann Loriot, Luc Friboulet.

   BACKGROUND: Understanding the resistance mechanisms of tumor is crucial for advancing cancer therapies. The prospective MATCH-R trial (NCT02517892), led by Gustave Roussy, aimed to characterize resistance mechanisms to cancer treatments through molecular analysis of fresh tumor biopsies. This report presents the genomic data analysis of the MATCH-R study conducted from 2015 to 2022 and focuses on targeted therapies.
METHODS: The study included resistant metastatic patients (pts) who accepted an image-guided tumor biopsy. After evaluation of tumor content (TC) in frozen tissue biopsies, targeted NGS (10 < TC < 30%) or Whole Exome Sequencing and RNA sequencing (TC > 30%) were performed before and/or after the anticancer therapy. Patient-derived xenografts (PDX) were established by implanting tumor fragments into NOD scid gamma mice and amplified up to five passages.
RESULTS: A total of 1,120 biopsies were collected from 857 pts with the most frequent tumor types being lung (38.8%), digestive (16.3%) and prostate (14.1%) cancer. Molecular targetable driver were identified in 30.9% (n = 265/857) of the patients, with EGFR (41.5%), FGFR2/3 (15.5%), ALK (11.7%), BRAF (6.8%), and KRAS (5.7%) being the most common altered genes. Furthermore, 66.0% (n = 175/265) had a biopsy at progression on targeted therapy. Among resistant cases, 41.1% (n = 72/175) had no identified molecular mechanism, 32.0% (n = 56/175) showed on-target resistance, and 25.1% (n = 44/175) exhibited a by-pass resistance mechanism. Molecular profiling of the 44 patients with by-pass resistance identified 51 variants, with KRAS (13.7%), PIK3CA (11.8%), PTEN (11.8%), NF2 (7.8%), AKT1 (5.9%), and NF1 (5.9%) being the most altered genes. Treatment was tailored for 45% of the patients with a resistance mechanism identified leading to an 11 months median extension of clinical benefit. A total of 341 biopsies were implanted in mice, successfully establishing 136 PDX models achieving a 39.9% success rate. PDX models are available for EGFR (n = 31), FGFR2/3 (n = 26), KRAS (n = 18), ALK (n = 16), BRAF (n = 6) and NTRK (n = 2) driven cancers. These models closely recapitulate the biology of the original tumors in term of molecular alterations and pharmacological status, and served as valuable models to validate overcoming treatment strategies.
CONCLUSION: The MATCH-R study highlights the feasibility of on purpose image guided tumor biopsies and PDX establishment to characterize resistance mechanisms and guide personalized therapies to improve outcomes in pre-treated metastatic patients.

Keywords:  Biopsy; Cancer; Metastatic; PDX; Resistance; Targeted therapy

DOI:  https://doi.org/10.1186/s12943-024-02134-4
Cancers (Basel). 2024 Sep 11. pii: 3129. [Epub ahead of print]16(18):

The Role of ctDNA and Liquid Biopsy in the Diagnosis and Monitoring of Head and Neck Cancer: Towards Precision Medicine.

Sami I Nassar, Amber Suk, Shaun A Nguyen, Dauren Adilbay, John Pang, Cherie-Ann O Nathan.

  Recent data have shown a continued rise in the worldwide annual incidence and mortality rates of head and neck cancers. The present standard for diagnosis and monitoring for disease recurrence or progression involves clinical examination, imaging, and invasive biopsy techniques of lesions suspected of being malignant. In addition to limitations relating to cost, time, and patient discomfort, these methodologies have inherent inaccuracies for detecting recurrence. In view of these limitations, the analysis of patient bodily fluid samples via liquid biopsy proposes a cost-effective and convenient alternative, which provides insight on the biogenetic and biomolecular underpinnings of oncologic disease processes. The monitoring of biomarkers for head and neck cancer via liquid biopsy, including circulating tumor DNA, circulating tumor cells, and circulating cell-free RNA, has shown clinical utility in the screening, diagnosis, prognostication, and monitoring of patients with various forms of head and neck cancer. The present review will provide an update on the current literature examining the use of liquid biopsy in head and neck cancer care and the clinical applicability of potential biomarkers, with a focus on viral and non-viral circulating tumor DNA. Possible future avenues for research to address specific shortcomings of liquid biopsy will be discussed.

Keywords:  cancer biomarkers; ctDNA; genetic mutations; genomic sequencing; head and neck cancer; liquid biopsy; nasopharyngeal carcinoma; oropharyngeal carcinoma; squamous cell carcinoma

DOI:  https://doi.org/10.3390/cancers16183129
J Clin Med. 2024 Sep 12. pii: 5396. [Epub ahead of print]13(18):

Detection of the BRAFV600E Mutation in Circulating Free Nucleic Acids as a Biomarker of Thyroid Cancer: A Review.

Emilia Niedziela, Łukasz Niedziela, Aldona Kowalska, Artur Kowalik.

  Background: Liquid biopsy is a method that could potentially improve the management of thyroid cancer (TC) by enabling the detection of circulating tumor DNA and RNA (ctDNA, ctRNA). The BRAFV600E mutation appears to be the most representative example of a biomarker in liquid biopsy, as it is the most specific mutation for TC and a target for molecular therapeutics. The aim of this review is to summarize the available data on the detection of the BRAFV600E mutation in liquid biopsy in patients with TC. Methods: A comprehensive analysis of the available literature on the detection of the BRAFV600E mutation in liquid biopsy in TC was performed. Thirty-three papers meeting the inclusion criteria were selected after full-text evaluation. Results: Eleven papers discussed correlations between BRAF mutation and clinicopathological characteristics. Nine studies tested the utility of BRAFV600E detection in the assessment of residual or recurrent disease. Seven studies investigated BRAF-mutated circulating tumor nucleic acids (ctNA) as a marker of response to targeted therapy. In seven studies the method did not detect the BRAFV600E mutation. Conclusions: This review shows the potential of BRAFV600E-mutated ctNA detection in monitoring disease progression, particularly in advanced TC. The diagnostic value of BRAFV600E-mutated ctNA detection appears to be limited to advanced TC. The choice of the molecular method (quantitative PCR [qPCR], droplet digital polymerase chain reaction [ddPCR], and next-generation sequencing [NGS]) should be made based on the turnaround time, sensitivity of the test, and the clinical indications. Despite the promising outcomes of some studies, there is a need to verify these results on larger cohorts and to unify the molecular methods.

Keywords:  BRAFV600E; ctDNA; liquid biopsy; molecular diagnostics; thyroid cancer

DOI:  https://doi.org/10.3390/jcm13185396
Biomedicines. 2024 Sep 20. pii: 2137. [Epub ahead of print]12(9):

Circulating Tumor Cells: Origin, Role, Current Applications, and Future Perspectives for Personalized Medicine.

Maria Cristina Rapanotti, Tonia Cenci, Maria Giovanna Scioli, Elisa Cugini, Silvia Anzillotti, Luca Savino, Deborah Coletta, Cosimo Di Raimondo, Elena Campione, Mario Roselli, Sergio Bernardini, Luca Bianchi, Anastasia De Luca, Amedeo Ferlosio, Augusto Orlandi.

  Circulating tumor cells (CTCs) currently represent a revolutionary tool offering unique insights for the evaluation of cancer progression, metastasis, and response to therapies. Indeed, CTCs, upon detachment from primary tumors, enter the bloodstream and acquire a great potential for their use for personalized cancer management. In this review, we describe the current understanding of and advances in the clinical employment of CTCs. Although considered rare and fleeting, CTCs are now recognized as key players favoring the development of cancer metastasis and disease recurrence, particularly in malignant melanoma, lung, breast, and colorectal cancer patients. To date, the advancements in technology and the development of several successful approaches, also including immunomagnetic enrichment allow for a reliable and reproducible detection and characterization of CTCs. Those innovative methodologies improved the isolation, quantification, and characterization of CTCs from the blood of cancer patients, providing extremely useful evidence and new insights into the nature of the tumor, its epithelial/mesenchymal profile, and its potential resistance to therapy. In fact, in addition to their prognostic and predictive value, CTCs could serve as a valuable instrument for real-time monitoring of treatment response and disease recurrence, facilitating timely interventions and thus improving patient outcomes. However, despite their potential, several challenges hinder the widespread clinical utility of CTCs: (i) CTCs' rarity and heterogeneity pose technical limitations in isolation and characterization, as well as significant hurdles in their clinical implementation; (ii) it is mandatory to standardize CTC detection methods, optimize the sample processing techniques, and integrate them with existing diagnostic modalities; and (iii) the need for the development of new techniques, such as single-cell analysis platforms, to enhance the sensitivity and specificity of CTC detection, thereby facilitating their integration into routine clinical practice. In conclusion, CTCs represent a potential extraordinary tool in cancer diagnostics and therapeutics, offering unprecedented opportunities for personalized medicine and precision oncology. Moreover, their ability to provide real-time insights into tumor biology, treatment response, and disease progression underlines a great potential for their clinical application to improve patients' outcomes and advance our understanding of cancer biology.

Keywords:  CTC prognostic and predictive value; circulating tumor cells; liquid biopsy; metastasis

DOI:  https://doi.org/10.3390/biomedicines12092137
Mol Biol Rep. 2024 Oct 03. 51(1): 1035

Liquid biopsy for CNS lymphoma: CSF exosomes and CSF exosomal miR-15a, miR-21, miR-155, miR-210, and miR-19b are promising biomarkers for diagnosis.

Mustafa Aziz Hatiboglu, Busra Karacam, Imran Khan, Kerime Akdur, Elif Burce Elbasan, Sadaf Mahfooz, Mehmet Hakan Seyithanoglu, Guven Cetin, Meliha Gundag Papaker, Mustafa Namik Oztanir.

   BACKGROUND: Central nervous system lymphoma (CNSL) is a devastating disease with a poor prognosis. Early diagnosis, monitoring of the treatment response, and outcome prediction carry the utmost importance in the management of patients with CNSL. Surgical biopsy is the gold standard for tissue diagnosis, however, this procedure has potential complications. Therefore, there is a need for a method that provides information about diagnosis and patient monitoring to avoid surgical risks. The study aimed to investigate potential diagnostic biomarkers for patients with CNSL.
METHODS AND RESULTS: Patients with secondary CNSL were included in this study. Serum and cerebrospinal fluid (CSF) samples were collected before treatment and after completion of the treatment. Cell-free DNA (cfDNA), exosomes, free and exosomal microRNA (miR)-15a, miR-21, miR-155, miR-210, and miR-19b in both serum and CSF were examined, and they were compared with the controls. Also, their levels before and after treatment were compared. Nine patients with the diagnosis of secondary CNSL were reviewed. cfDNA, miR-15a, and miR-155 in serum, and exosome in CSF were found to be significantly higher in CNSL patients compared to the controls. Exosomal miR-15a, miR-21, miR-155, miR-210, and miR-19b in CSF were found to be significantly higher in CNSL patients compared to controls, whereas their levels in serum were not significantly high.
CONCLUSIONS: Our findings suggested that exosomes and exosomal miR-15a, miR-21, miR-155, miR-210 and miR-19b in CSF would be promising biomarkers for the diagnosis of patients with CNSL. Further studies are needed to confirm our findings.

Keywords:  Biomarker; CNS lymphoma; Exosome; Liquid biopsy; cfDNA; miRNA

DOI:  https://doi.org/10.1007/s11033-024-09967-8
Genes (Basel). 2024 Sep 03. pii: 1160. [Epub ahead of print]15(9):

Cell-Free DNA Hydroxymethylation in Cancer: Current and Emerging Detection Methods and Clinical Applications.

Janice J N Li, Geoffrey Liu, Benjamin H Lok.

  In the era of precision oncology, identifying abnormal genetic and epigenetic alterations has transformed the way cancer is diagnosed, managed, and treated. 5-hydroxymethylcytosine (5hmC) is an emerging epigenetic modification formed through the oxidation of 5-methylcytosine (5mC) by ten-eleven translocase (TET) enzymes. DNA hydroxymethylation exhibits tissue- and cancer-specific patterns and is essential in DNA demethylation and gene regulation. Recent advancements in 5hmC detection methods and the discovery of 5hmC in cell-free DNA (cfDNA) have highlighted the potential for cell-free 5hmC as a cancer biomarker. This review explores the current and emerging techniques and applications of DNA hydroxymethylation in cancer, particularly in the context of cfDNA.

Keywords:  5-hydroxymethylcytosine; DNA hydroxymethylation; cancer biomarker; cell-free DNA; epigenetics; liquid biopsy

DOI:  https://doi.org/10.3390/genes15091160
Cancers (Basel). 2024 Sep 10. pii: 3117. [Epub ahead of print]16(18):

The Role of Circulating Tumor DNA in Ovarian Cancer.

Anna Golara, Mateusz Kozłowski, Aneta Cymbaluk-Płoska.

  Ovarian cancer is the deadliest of all gynecological diseases because its diagnosis and treatment still pose many problems. Surgical excision, hormone therapy, radiation, chemotherapy, or targeted therapy for eradicating the main tumor and halting the spread of metastases are among the treatment options available to individuals with ovarian cancer, depending on the disease's stage. Tumor DNA that circulates in a patient's bodily fluids has been studied recently as a possible novel biomarker for a number of cancers, as well as a means of quantifying tumor size and evaluating the efficacy of cancer therapy. The most significant alterations that we could find in the ctDNA of ovarian cancer patients-such as chromosomal instability, somatic mutations, and methylation-are discussed in this review. Additionally, we talk about the utility of ctDNA in diagnosis, prognosis, and therapy response prediction for these patients.

Keywords:  chromosomal instability; ctDNA; methylation; ovarian cancer; somatic mutations

DOI:  https://doi.org/10.3390/cancers16183117
J Nucl Med. 2024 Oct 03. pii: jnumed.124.268036. [Epub ahead of print]

The Role of Molecular Imaging in Precision Oncology.

James R Bading, Joanne E Mortimer.

DOI: https://doi.org/10.2967/jnumed.124.268036
Biology (Basel). 2024 Sep 04. pii: 694. [Epub ahead of print]13(9):

Prospects and Current Challenges of Extracellular Vesicle-Based Biomarkers in Cancer.

Samuel R Lawrence, Karan M Shah.

  Cancer continues to impose a substantial global health burden, particularly among the elderly, where the ongoing global demographic shift towards an ageing population underscores the growing need for early cancer detection. This is essential for enabling personalised cancer care and optimised treatment throughout the disease course to effectively mitigate the increasing societal impact of cancer. Liquid biopsy has emerged as a promising strategy for cancer diagnosis and treatment monitoring, offering a minimally invasive method for the isolation and molecular profiling of circulating tumour-derived components. The expansion of the liquid biopsy approach to include the detection of tumour-derived extracellular vesicles (tdEVs) holds significant therapeutic opportunity. Evidence suggests that tdEVs carry cargo reflecting the contents of their cell-of-origin and are abundant within the blood, exhibiting superior stability compared to non-encapsulated tumour-derived material, such as circulating tumour nucleic acids and proteins. However, despite theoretical promise, several obstacles hinder the translation of extracellular vesicle-based cancer biomarkers into clinical practice. This critical review assesses the current prospects and challenges facing the adoption of tdEV biomarkers in clinical practice, offering insights into future directions and proposing strategies to overcome translational barriers. By addressing these issues, EV-based liquid biopsy approaches could revolutionise cancer diagnostics and management.

Keywords:  biomarker; cancer diagnosis; extracellular vesicles; liquid biopsy

DOI:  https://doi.org/10.3390/biology13090694
Ann Lab Med. 2024 Sep 30.

Feasibility of Circulating Tumor DNA Detection in the Cerebrospinal Fluid of Patients With Central Nervous System Involvement in Large B-Cell Lymphoma.

Seok Jin Kim, Jin Ju Kim, Mi Ri Park, Bon Park, Kyung Ju Ryu, Sang Eun Yoon, Won Seog Kim, Saeam Shin, Seung-Tae Lee.

  We explored the utility of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) sequencing as a noninvasive diagnostic tool for detecting central nervous system (CNS) involvement in patients with diffuse large B-cell lymphoma (DLBCL). Secondary CNS involvement in DLBCL, although rare (~5% of cases), presents diagnostic and prognostic challenges during systemic disease progression or relapse. Effective treatment is impeded by the blood-brain barrier. This was a prospective cohort study (Samsung Lymphoma Cohort Study III) involving 17 patients with confirmed CNS involvement. High-throughput sequencing was conducted using targeted gene panels designed to detect low-frequency variants and copy number alterations pertinent to lymphomas in ctDNA extracted from archived CSF samples. Despite challenges such as low DNA concentrations affecting library construction, the overall variant detection rate was 76%. Detected variants included those in genes commonly implicated in CNS lymphoma, such as MYD88. The study highlights the potential of CSF ctDNA sequencing to identify CNS involvement in DLBCL, providing a promising alternative to more invasive diagnostic methods such as brain biopsy, which are not always feasible. Further validation is necessary to establish the clinical utility of this method, which could significantly enhance the management and outcomes of DLBCL patients with suspected CNS involvement.

Keywords:  Central nervous system; Cerebrospinal fluid; Circulating tumor DNA; Lymphoma; Relapse

DOI:  https://doi.org/10.3343/alm.2024.0257
Nat Commun. 2024 Oct 02. 15(1): 8544

Molecular and functional landscape of malignant serous effusions for precision oncology.

Rebekka Wegmann, Lorenz Bankel, Yasmin Festl, Kate Lau, Sohyon Lee, Fabian Arnold, Valentina Cappelletti, Aaron Fehr, Paola Picotti, Konstantin J Dedes, Daniel Franzen, Daniela Lenggenhager, Peter K Bode, Martin Zoche, Holger Moch, Christian Britschgi, Berend Snijder.

Personalized treatment for patients with advanced solid tumors critically depends on the deep characterization of tumor cells from patient biopsies. Here, we comprehensively characterize a pan-cancer cohort of 150 malignant serous effusion (MSE) samples at the cellular, molecular, and functional level. We find that MSE-derived cancer cells retain the genomic and transcriptomic profiles of their corresponding primary tumors, validating their use as a patient-relevant model system for solid tumor biology. Integrative analyses reveal that baseline gene expression patterns relate to global ex vivo drug sensitivity, while high-throughput drug-induced transcriptional changes in MSE samples are indicative of drug mode of action and acquired treatment resistance. A case study exemplifies the added value of multi-modal MSE profiling for patients who lack genetically stratified treatment options. In summary, our study provides a functional multi-omics view on a pan-cancer solid tumor cohort and underlines the feasibility and utility of MSE-based precision oncology.

DOI: https://doi.org/10.1038/s41467-024-52694-8
Oncology. 2024 Sep 27. 1-24

Genomic Landscape of Advanced Solid Tumors in Middle East and North Africa Using Circulating Tumor DNA (ctDNA) in Routine Clinical Practice.

Shaheenah Dawood, Nippun Sandhir, Marwan Akasheh, Maroun El Khoury, Sonia Otsmane, Muath Alnassar, Omalkhair Abulkhair, Fadi Farhat, Steve Olsen.

INTRODUCTION: Next-generation sequencing (NGS) of tumor DNA can detect actionable drivers and help guide therapy for patients with advanced-stage cancers. While tissue-based genotyping is considered standard of care, blood-based genotyping is emerging as a valid alternative. Tumor genomic profiles may vary by region, and data from the Middle East and North Africa (MENA) are not widely available. This study elucidates the genomic landscape of advanced solid cancers in patients from the MENA region by retrospectively analyzing results from NGS ctDNA testing.
METHODS: In routine clinical practice, 926 plasma samples from 767 patients with advanced cancers from the MENA region were profiled using a comprehensive NGS assay (Guardant360®). We conducted a pan-cancer analysis and sub-analyses focusing on lung, breast, and colorectal cancers.
RESULTS: In the pan-cancer group, TP53 (58.5%), EGFR (20.4%), and KRAS (18.9%) were the most frequently mutated genes. EGFR (10.2%), FGFR1 (4.9%), and PIK3CA (4.9%) showed the most amplifications, while fusions were observed in 2.7% of patients, including ALK, FGFR2, and RET. For lung adenocarcinoma, EGFR (30.5%), KRAS (19.3%), and ERBB2 (4.6%) were the most frequently identified alterations among the genes recommended for evaluation by the National Comprehensive Cancer Network (NCCN). In patients with breast cancer, PIK3CA (35.3%), ESR1 (21.7%), and BRCA1/2 (13.3%) had the most prevalent alterations among NCCN-recommended genes. In colorectal cancer, KRAS (39.0%), NRAS (8.0%), and BRAF (V600E, 4.0%) were the most observed mutations among genes recommended by the NCCN. Comparing this cohort to publicly available Western and Eastern datasets also indicated similarities (including PIK3CA in breast cancer) and variances (including EGFR in lung adenocarcinoma) in key genes of interest in the analyzed cancer types.
CONCLUSION: Overall, our findings provide insight into the genomic landscape of individuals with advanced solid organ malignancies from the MENA region and support the role of ctDNA in guiding therapeutic decisions.

DOI: https://doi.org/10.1159/000541571
Commun Med (Lond). 2024 Sep 30. 4(1): 185

Poor compliance with germline testing recommendations in colorectal cancer patients undergoing molecular residual disease testing.

Suzanne Schrock-Kelley, Vivienne Souter, Michael J Hall, Youbao Sha, Urmi Sengupta, Adam C ElNaggar, Minetta C Liu, Jeffrey N Weitzel.

BACKGROUND: Approximately 15% of colorectal cancers (CRCs) are associated with germline mutations. There is increasing adoption of DNA-based assays for molecular residual disease (MRD) and growing evidence supporting its clinical utility, particularly for CRC by oncologists in the U.S. We assessed the uptake of germline multi-gene panel testing (MGPT) for hereditary cancer in CRC patients receiving MRD analyses in community oncology settings.
METHODS: This retrospective study included 80 patients receiving care for CRC through community oncology practices who were referred for MRD testing at a commercial laboratory (January-March 2022). Clinical data, including test requisition forms, pathology reports, and clinical notes were reviewed. Documentation of tumor microsatellite instability and/or immunohistochemical (IHC) testing for mismatch repair (MMR) deficiency, age of CRC diagnosis, family history of cancer, and any order or recommendation for MGPT were assessed.
RESULTS: Overall, 5/80 (6.3%) patients in the study have documented germline MGPT; 65/80 (81.3%) patients have documented MMR testing of their colorectal tumor. Among the 5 cases with abnormal MMR IHC, 2 have MGPT. Of the 33 patients meeting the 2021 National Comprehensive Cancer Network (NCCN) criteria for genetic/familial high-risk assessment, only 2 have MGPT.
CONCLUSIONS: Our real-world data suggest that many CRC patients receiving MRD testing and meeting NCCN (v. 2021) criteria for germline MGPT may not be receiving evaluation beyond routine MMR status. Process and educational improvements are needed in community health settings to increase access and uptake of germline testing among CRC patients regardless of age at diagnosis or MMR status.

DOI: https://doi.org/10.1038/s43856-024-00608-6
Biology (Basel). 2024 Sep 22. pii: 743. [Epub ahead of print]13(9):

MiRNAs in Extracellular Vesicles as Biomarkers in Plasma of Papillary Thyroid Cancer Patients: A Proof-of-Concept Study.

Giuseppa D'Amico, Radha Santonocito, Godfrey Grech, Giuseppa Graceffa, Calogero Cipolla, Federica Scalia, Samuele Raccosta, Mauro Manno, Everly Conway de Macario, Alberto J L Macario, Francesco Cappello, Francesca Rappa, Celeste Caruso Bavisotto, Claudia Campanella.

   BACKGROUND: The incidence of various types of cancer, for example, papillary thyroid carcinoma (PTC), is on the rise. Since therapeutic success depends greatly on early diagnosis, reliable diagnostic biomarkers must be identified, and easy-to-apply tools for detecting them must urgently be standardized. Here, we contribute to solving this medical challenge by assessing miRNAs suspected of promoting carcinogenesis in extracellular vesicles (EVs) that can be routinely obtained via liquid biopsy. We profit from current progress in cancerology that provides innovations in liquid biopsy and EVs analysis, along with the identification of miRNAs and chaperone system (CS) components implicated in carcinogenesis.
METHODS: We measured in EVs obtained from circulating blood plasma from PTC patients the levels of three miRNAs implicated in thyroid cancer, hsa-miR-1-3p, hsa-miR-206, and hsa-miR-221-3p, and most likely involved in the regulation of two members of the CS, Hsp60 and CCT. EVs were isolated from the plasma of patients with PTC and controls with benign goiter (BG) and from the culture medium of a PTC cell line (MDAT32) and were appropriately characterized.
RESULTS: The levels of miRNAs determined by RT-qPCR were consistently higher in PTC patients and decreased down to control levels after thyroidectomy. Bioinformatics showed that the miRNAs target genes are associated with the molecular pathogenesis of PTC.
CONCLUSIONS: Our exploratory study reaffirms the potential in clinics of the selected miRNAs in EVs as useful biomarkers of PTC easily accessible via liquid biopsy, which is minimally invasive and amenable to periodic repetition, an improvement compared to the established fine-needle aspirate biopsy.

Keywords:  CCT; Hsp60; cancer biomarkers; chaperone system; extracellular vesicles; liquid biopsy; microRNAs; thyroid cancer

DOI:  https://doi.org/10.3390/biology13090743
Int J Mol Sci. 2024 Sep 11. pii: 9841. [Epub ahead of print]25(18):

Circulating Polyploid Giant Cancer Cells, a Potential Prognostic Marker in Patients with Carcinoma.

Ludmilla Thomé Domingos Chinen, Jacqueline Aparecida Torres, Vinicius Fernando Calsavara, Angelo Borsarelli Carvalho Brito, Virgílio Sousa E Silva, Roberto Gabriel Santiago Novello, Thaissa Carvalho Fernandes, Alessandra Decina, Roger Dachez, Patrizia Paterlini-Brechot.

  Polyploid Giant Cancer Cells (PGCCs) have been recognized as tumor cells that are resistant to anticancer therapies. However, it remains unclear whether their presence in the bloodstream can be consistently detected and utilized as a clinical marker to guide therapeutic anticancer regimens. To address these questions, we conducted a retrospective study involving 228 patients diagnosed with six different types of carcinomas (colon, gastric, NSCLC, breast, anal canal, kidney), with the majority of them (70%) being non-metastatic. Employing a highly sensitive liquid biopsy approach, ISET®, and cytopathological readout, we isolated and detected circulating PGCCs in the patients' blood samples. PGCCs were identified in 46 (20.18%) out of 228 patients, including in 14.47% of 152 non-metastatic and 29.85% of 67 metastatic cases. Patients were subsequently monitored for a mean follow up period of 44.74 months (95%CI: 33.39-55.79 months). Remarkably, the presence of circulating PGCCs emerged as a statistically significant indicator of poor overall survival. Our findings suggest that circulating PGCCs hold promise as a reliable prognostic indicator. They underscore the importance of further extensive investigations into the role of circulating PGCCs as a prognostic marker and the development of anti-PGCC therapeutic strategies to improve cancer management and patient survival.

Keywords:  cancer giant cells; colon cancer; gastric cancer; liquid biopsy; lung cancer; polyploid giant cancer cells; prognostic marker

DOI:  https://doi.org/10.3390/ijms25189841
Sci Rep. 2024 Oct 04. 14(1): 23115

Plasma EGFR mutation ctDNA dynamics in patients with advanced EGFR-mutated NSCLC treated with Icotinib: phase 2 multicenter trial result.

Yaping Hong, Wu Zhuang, Jinhuo Lai, Haipeng Xu, Yueming He, Jinlan Lin, Qin Shi, Shengjia Chen, Zhangzhou Huang, Shijie Chen, Dongzhu Lu, Gen Lin, Yunjian Huang.

  Plasma epidermal growth factor receptor mutation (EGFRm) circulating tumor DNA (ctDNA) dynamics exhibit promise in predicting outcomes in patients with EGFRm-advanced non-small cell lung cancer (NSCLC). However, there remains limited trial-level data on integrating ctDNA monitoring into clinical practice. We performed a prospective, multicenter trial to investigate the relationship between EGFRm ctDNA dynamic changes and clinical outcomes in NSCLC patients with EGFRm. Ninety-eight treatment-naive EGFRm-advanced NSCLC patients were recruited and administered icotinib until disease progression. Plasma samples were collected at baseline and four weeks after icotinib administration. ctDNA was analyzed using a droplet-digital polymerase chain reaction. At baseline, 71.4% of patients had detectable EGFRm ctDNA. Among them, 45.9% of patients' ctDNA became undetectable within four weeks of treatment. These patients demonstrated significantly longer progression-free survival (PFS) and overall survival (OS) than those with detectable ctDNA after treatment (P = 0.004 and < 0.001, respectively) and were comparable to those with undetectable ctDNA at both baseline and four weeks. ctDNA detectable at four weeks emerged as a poor independent risk factor for PFS and OS. Patients whose ctDNA became undetectable after treatment had outcomes similar to those with initially undetectable ctDNA, underscoring the predictive value of ctDNA dynamics in treatment efficacy.Registry and the Registration No. of the study/trial: ChiCTR-DDD-17013131. Date of registration: 2017-10-27.

Keywords:  Biomarker; Circulating tumor DNA; Digital PCR; Epidermal growth factor receptor; Non-small cell lung cancer

DOI:  https://doi.org/10.1038/s41598-024-73749-2
J Pers Med. 2024 Sep 08. pii: 950. [Epub ahead of print]14(9):

Whole-Exome Sequencing Reveals Novel Candidate Driver Mutations and Potential Druggable Mutations in Patients with High-Risk Neuroblastoma.

Natakorn Nokchan, Praewa Suthapot, Pongsakorn Choochuen, Natthapon Khongcharoen, Suradej Hongeng, Usanarat Anurathapan, Komwit Surachat, Surasak Sangkhathat, Thai Pediatric Cancer Atlas Tpca Consortium.

  Neuroblastoma is the most prevalent solid tumor in early childhood, with a 5-year overall survival rate of 40-60% in high-risk cases. Therefore, the identification of novel biomarkers for the diagnosis, prognosis, and therapy of neuroblastoma is crucial for improving the clinical outcomes of these patients. In this study, we conducted the whole-exome sequencing of 48 freshly frozen tumor samples obtained from the Biobank. Somatic variants were identified and selected using a bioinformatics analysis pipeline. The mutational signatures were determined using the Mutalisk online tool. Cancer driver genes and druggable mutations were predicted using the Cancer Genome Interpreter. The most common mutational signature was single base substitution 5. MUC4, MUC16, and FLG were identified as the most frequently mutated genes. Using the Cancer Genome Interpreter, we identified five recurrent cancer driver mutations spanning MUC16, MUC4, ALK, and CTNND1, with the latter being novel and containing a missense mutation, R439C. We also identified 11 putative actionable mutations including NF1 Q1798*, Q2616*, and S636X, ALK F1174L and R1275Q, SETD2 P10L and Q1829E, BRCA1 R612S, NOTCH1 D1670V, ATR S1372L, and FGFR1 N577K. Our findings provide a comprehensive overview of the novel information relevant to the underlying molecular pathogenesis and therapeutic targets of neuroblastoma.

Keywords:  cancer driver gene; druggable mutations; mutational signatures; neuroblastoma; somatic variants; tumor mutational burden; tumor-only; whole-exome sequencing

DOI:  https://doi.org/10.3390/jpm14090950
Clin Colorectal Cancer. 2024 Sep 03. pii: S1533-0028(24)00081-1. [Epub ahead of print]

Rationale and Design of the COPERNIC Trial: A Study of On-treatment ctDNA Changes in Chemo-refractory Colorectal Cancer Patients.

Irene Assaf, Giacomo Bregni, Geraldine Anthoine, Thomas Aparicio, Pascal Artru, Meher Ben Abdelghani, Marc Buyse, Benoist Chibaudel, Elisabeth Coart, Marie Diaz, Camille Evrard, Karen Geboes, François Ghiringhelli, Francesco Puleo, Judith Raimbourg, Timon Vandamme, Marc Van den Eynde, Alain Hendlisz, Francesco Sclafani.

   BACKGROUND: Evidence suggests that ctDNA may be a reliable biomarker to monitor metastatic colorectal cancer (CRC) evolution. Nevertheless, evidence on the potential of liquid biopsy in this setting is still low quality, mostly consisting of retrospective studies.
METHODS: COPERNIC is an international, multicenter clinical trial. The pilot study aims to confirm the predictive potential of early on-treatment ctDNA dynamics, and inform the design of a larger ctDNA-driven trial. Advanced CRC patients who are candidates for ≥3rd lines of systemic therapy undergo longitudinal blood sample collection during treatment (day 1, 15 and 29 for 2- or 4-weekly treatment regimens; day 1, 22 and 43 for 3-weekly treatment regimens) and at each imaging assessment. ctDNA analyses are carried out with the FoundationOne Liquid CDx and FoundationOneMonitor assays, and ctDNA changes during treatment are correlated with radiologic response (as assessed every 8-12 weeks by RECIST v1.1). The primary objective is to select the optimal timepoint and cut-off value for early ctDNA changes (at day 15/22) to predict progressive disease as best radiological response with a high positive predictive value. The cut-off value for ctDNA will be defined based on nonparametric ROC-curves with bootstrapping. Based on the expected rate of progressive disease and statistical assumptions, 109 patients are needed to be screened to have 87 assessable patients. COPERNIC is sponsored by the Institut Jules Bordet, and supported by Roche and Foundation Medicine. Recruitment is open in 13 centres across Belgium and France. The study is registered with clinicaltrials.gov (NCT05487248).

Keywords:  Circulating tumour DNA; Early treatment switch; Early tumour response assessment

DOI:  https://doi.org/10.1016/j.clcc.2024.08.004