bims-preonc 2024-11-03 papers

bims-preonc

Biomed News

on Precision oncology

Issue of 2024–11–03
eightteen papers selected by
Ankita Daiya, OneCell Diagnostics Inc.

Liquid Biopsy in Pancreatic Ductal Adenocarcinoma: A Review of Methods and Applications.
ctDNA in the reading room: A guide for radiologists.
From photonic technologies to microfluidics-A review on the techniques which revolutionize liquid biopsy, opening a new era in cancer therapy.
A Novel AKT1, ERBB2, ESR1, KRAS, PIK3CA, and TP53 NGS Assay: A Non-Invasive Tool to Monitor Resistance Mechanisms to Hormonal Therapy and CDK4/6 Inhibitors.
Highly Multiplexed Tissue Imaging in Precision Oncology and Translational Cancer Research.
Circulating Tumor Cells in Cancer Diagnosis, Therapy, and Theranostics Applications: An Overview of Emerging Materials and Technologies.
Clinical value of comprehensive genomic profiling on clinical trial enrollment for patients with advanced solid tumors.
Prospective study of the real impact of fusion centered genomic assays in patient management in a national collaborative group: the GETHI-XX-16 study.
Mutant KRAS in Circulating Tumor DNA as a Biomarker in Localized Pancreatic Cancer in Patients Treated with Neoadjuvant Chemotherapy.
Molecular tumor board in patients with metastatic breast cancer.
Potential Transcriptomic Biomarkers for Predicting Platinum-based Chemotherapy Resistance in Patients With High-grade Serous Ovarian Cancer.
Advancements in nanotheranostics for glioma therapy.
Circular RNA landscape in extracellular vesicles from human biofluids.
H3K27me3 Loss in Central Nervous System Tumors: Diagnostic, Prognostic, and Therapeutic Implications.
De-Escalating Treatment Strategies for Patients with Human Epidermal Growth Factor Receptor-2 (HER2)-Positive Early-Stage Breast Cancer.
The potential clinical utility of Whole Genome Sequencing for patients with cancer: evaluation of a regional implementation of the 100,000 Genomes Project.
Pathologic complete response (pCR) rates for patients with HR+/HER2- high-risk, early-stage breast cancer (EBC) by clinical and molecular features in the phase II I-SPY2 clinical trial.
Expert consensus on the optimal management of BRAFV600E-mutant metastatic colorectal cancer in the Asia-Pacific region.

Int J Mol Sci. 2024 Oct 13. pii: 11013. [Epub ahead of print]25(20):

Liquid Biopsy in Pancreatic Ductal Adenocarcinoma: A Review of Methods and Applications.

Genia Dubrovsky, Alison Ross, Pooya Jalali, Michael Lotze.

  Pancreatic ductal adenocarcinoma (PDAC) remains a malignancy with one of the highest mortality rates. One limitation in the diagnosis and treatment of PDAC is the lack of an early and universal biomarker. Extensive research performed recently to develop new assays which could fit this role is available. In this review, we will discuss the current landscape of liquid biopsy in patients with PDAC. Specifically, we will review the various methods of liquid biopsy, focusing on circulating tumor DNA (ctDNA) and exosomes and future opportunities for improvement using artificial intelligence or machine learning to analyze results from a multi-omic approach. We will also consider applications which have been evaluated, including the utility of liquid biopsy for screening and staging patients at diagnosis as well as before and after surgery. We will also examine the potential for liquid biopsy to monitor patient treatment response in the setting of clinical trial development.

Keywords:  ctDNA; exosomes; liquid biopsy; pancreatic cancer

DOI:  https://doi.org/10.3390/ijms252011013
Eur J Radiol. 2024 Oct 21. pii: S0720-048X(24)00512-6. [Epub ahead of print]181 111796

ctDNA in the reading room: A guide for radiologists.

Hayes Pearce, Yu-Cherng Chang, Marcia C Javitt, Jashodeep Datta, Agustin Pimentel, Steven Bialick, Peter J Hosein, Francesco Alessandrino.

  Liquid biopsy with sequencing of circulating tumor DNA (ctDNA) is a minimally invasive method for sampling body fluids and offers a promising alternative to tissue biopsies that involve greater risks, costs, and time. ctDNA not only identifies actionable targets by revealing unique molecular signatures in cancer, but also may assess treatment response, treatment resistance and progression, and recurrence. Imaging correlates of these applications are already being identified and utilized for various solid tumors. Radiologists have new challenges in interpreting oncologic imaging. Given their integral role in cancer surveillance, they must become familiar with the importance of ctDNA in detecting recurrence and minimal residual disease, measuring treatment response, predicting survival and metastatic patterns, and identifying new molecular therapeutic targets. In this review, we provide an overview of ctDNA testing, and a snapshot of current clinical guidelines from the National Comprehensive Cancer Network and the European Society of Molecular Oncology on the use of ctDNA in lung, breast, colorectal, pancreatic, and hepatobiliary cancers. For each cancer type, we also highlight current research applications of ctDNA that are relevant to the field of diagnostic radiology.

Keywords:  Breast cancer; Colorectal cancer; Hepatobiliary cancer; Lung cancer; Pancreatic cancer; ctDNA

DOI:  https://doi.org/10.1016/j.ejrad.2024.111796
Health Sci Rep. 2024 Nov;7(11): e70147

From photonic technologies to microfluidics-A review on the techniques which revolutionize liquid biopsy, opening a new era in cancer therapy.

Subham Sarkar, Soubhagya Ghosh, Samraggi Chakraborty, Jenifer Rajak, Ekanansha R Chowdhury, Arup K Mitra, Ajoy Kumer, Bikram Dhara.

   Background and Aims: Cancer therapy is one of the most researched upon medical field in the world. Non invasive technologies such as liquid biopsy are gaining more importance in cancer therapy because of their manifold advantages over traditional invasive biopsy methods. Liquid biopsy is used to analyze nucleic acids such as ctDNA, cfDNA and RNA, cellular and subcellular components such as proteins, extracellular vesicles and circulating tumor cells in various biological fluids such as blood, urine, cerebrospinal fluid, pleural fluid and ascites fluid for diagnosis of cancer.
Methods: Liquid biopsy has a wide range of applications such as assessment of residual diseases and tumors which cannot be biopsied easily and prediction of CAR-T response and response to immune checkpoint inhibitors. It can also be used to know the efficacy of cancer drugs in a patient by analyzing multiple samples. Liquid biopsy is becoming more popular as it allows biopsy of those samples in which solid tumor biopsies are challenging or impracticable.
Techniques and Results: To achieve comprehensive insight on the status of cancer in a patient, various cutting edge liquid biopsy techniques have been developed. Microfluidics and photonic technologies, along with PCR, next generation sequencing, advanced and innovative molecular and cell biology approaches and imaging techniques have expanded the domain of liquid biopsy and elevated the accuracy of liquid biopsy results.
Conclusion: This review discusses about the contributions of some widely used methods along with microfluidics and photonic technologies in detection of cancer biomarkers by liquid biopsy.

Keywords:  cancer biomarkers; liquid biopsy; microfluidics; photonic technologies

DOI:  https://doi.org/10.1002/hsr2.70147
Biomedicines. 2024 Sep 26. pii: 2183. [Epub ahead of print]12(10):

A Novel AKT1, ERBB2, ESR1, KRAS, PIK3CA, and TP53 NGS Assay: A Non-Invasive Tool to Monitor Resistance Mechanisms to Hormonal Therapy and CDK4/6 Inhibitors.

Alessandra Virga, Caterina Gianni, Michela Palleschi, Davide Angeli, Filippo Merloni, Roberta Maltoni, Paola Ulivi, Giovanni Martinelli, Ugo De Giorgi, Sara Bravaccini.

  Background: Patients with hormone receptor-positive (HR+)/HER2- metastatic breast cancer (mBC) generally receive hormonal therapy (HT) combined with CDK4/6 inhibitors (CDK4/6i). Despite this treatment, resistance mechanisms to CDK4/6i emerge and the majority of these patients experience disease progression (PD). This highlight the necessity to uncover the resistance mechanism to CDK4/6i through the identification of specific biomarkers. The primary objective is to assess the accuracy and feasibility of a novel multi-gene target panel NGS assay on circulating tumor DNA (ctDNA) to detect molecular alterations of AKT1, ERBB2, ESR1, KRAS, PIK3CA, and TP53 genes in women with BC undergoing HT plus CDK4/6i treatment. Secondarily, the study aims to explore the relationship between genomic profiling and clinical outcomes. Materials and Methods: Plasma samples were collected from 16 patients diagnosed with advanced/locally advanced HR+/HER2- BC at 2 time points: T0 (baseline) and at T1 (3 months after CDK4/6i treatment). Starting from 2 mL of plasma, ctDNA was isolated and libraries were set up using the Plasma-SeqSensei (PQS)® Breast Cancer IVD Kit, sequenced on Nextseq 550 and analyzed using the Plasma-SeqSensei™ IVD Software®. Results: Among the five patients who presented PD, three had PIK3CA mutations and, of these, two showed a higher mutant allele frequency (MAF) at T1. In three patients with stable disease and in eight patients with partial response, the MAF of the detected alterations decreased dramatically or disappeared during CDK4/6i treatment. Conclusions: Based on our findings, the liquid biopsy analysis using the PQS panel seems to be both feasible and accurate, demonstrating a strong sensitivity in detecting mutations. This exploratory analysis of the clinical outcome associated to the mutational status of patients highlights the potential of molecular analysis on liquid biopsy for disease monitoring, although further validation with a larger patient cohort is necessary to confirm these preliminary observations.

Keywords:  CDK4/6 inhibitors resistance; hormone receptor-positive metastatic breast cancer patients; novel multi-gene target panel NGS assay

DOI:  https://doi.org/10.3390/biomedicines12102183
Cancer Discov. 2024 Nov 01. 14(11): 2071-2088

Highly Multiplexed Tissue Imaging in Precision Oncology and Translational Cancer Research.

Alina Bollhagen, Bernd Bodenmiller.

Precision oncology tailors treatment strategies to a patient's molecular and health data. Despite the essential clinical value of current diagnostic methods, hematoxylin and eosin morphology, immunohistochemistry, and gene panel sequencing offer an incomplete characterization. In contrast, highly multiplexed tissue imaging allows spatial analysis of dozens of markers at single-cell resolution enabling analysis of complex tumor ecosystems; thereby it has the potential to advance our understanding of cancer biology and supports drug development, biomarker discovery, and patient stratification. We describe available highly multiplexed imaging modalities, discuss their advantages and disadvantages for clinical use, and potential paths to implement these into clinical practice. Significance: This review provides guidance on how high-resolution, multiplexed tissue imaging of patient samples can be integrated into clinical workflows. It systematically compares existing and emerging technologies and outlines potential applications in the field of precision oncology, thereby bridging the ever-evolving landscape of cancer research with practical implementation possibilities of highly multiplexed tissue imaging into routine clinical practice.

DOI: https://doi.org/10.1158/2159-8290.CD-23-1165
Curr Pharm Des. 2024 Oct 29.

Circulating Tumor Cells in Cancer Diagnosis, Therapy, and Theranostics Applications: An Overview of Emerging Materials and Technologies.

Sina Soleymani, Seyed Morteza Naghib, M R Mozafari.

  In recent years, immunotherapy, namely immune checkpoint inhibitor therapy, has significantly transformed the approach to treating various forms of cancer. Simultaneously, the adoption of clinical oncology has been sluggish due to the exorbitant expense of therapy, the adverse effects experienced by patients, and the inconsistency in treatment response among individuals. As a reaction, individualized methods utilizing predictive biomarkers have arisen as novel strategies for categorizing patients to achieve successful immunotherapy. Recently, the identification and examination of circulating tumor cells (CTCs) have gained attention as predictive indicators for the treatment of cancer patients undergoing chemotherapy and for personalized targeted therapy. CTCs have been found to exhibit immunological checkpoints in several types of solid tumors, which has contributed to our understanding of managing cancer immunotherapy. Circulating tumor cells (CTCs) present in the bloodstream have a crucial function in the formation of metastases. Nevertheless, the practical usefulness of existing CTC tests is mostly restricted by methodological limitations.

Keywords:  Circulating tumor cells ; immunotherapy; materials; technologies; theranosis; therapy

DOI:  https://doi.org/10.2174/0113816128328459241009191933
Oncologist. 2024 Oct 29. pii: oyae293. [Epub ahead of print]

Clinical value of comprehensive genomic profiling on clinical trial enrollment for patients with advanced solid tumors.

Richard S P Huang, Jessica K Lee, Katherine T Lofgren.

  The use of biomarker testing to inform treatment decisions has emerged as a standard of care in multiple cancer types. However, the rates of patients with genomic testing results in hand to inform treatment decision-making remain variable. Here, we studied the impact of comprehensive genomic profiling (CGP) on clinical trial enrollment rates in patients with advanced-stage non-small cell lung, colorectal, breast, and prostate cancer using a real-world clinicogenomic database. On average, clinical trial enrollment in the therapy line immediately after CGP report receipt was 5.4%, which represents a 3.0 percentage point increase compared to therapy lines preceding CGP report receipt, supporting a meaningful association between CGP report availability and increased clinical trial enrollment.

Keywords:  CGP; advanced solid tumor; clinical trial enrollment; clinical value

DOI:  https://doi.org/10.1093/oncolo/oyae293
Clin Transl Oncol. 2024 Nov 01.

Prospective study of the real impact of fusion centered genomic assays in patient management in a national collaborative group: the GETHI-XX-16 study.

Paloma Navarro, Carmen Beato, Juan Francisco Rodriguez-Moreno, Sergio Ruiz-Llorente, Xabier Mielgo, Estela Pineda, Miguel Navarro, Gema Bruixola, Tatiana P Grazioso, Antonio Viudez, Jose Fuster, Esther Nogueron, Maria Dolores Mediano, Carmen Balaña, Carlos Mendez, Rosa María Rodriguez, Sonia Del Barco Berron, Beatriz Gongora, Alberto Carmona-Bayonas, Jesus Garcia-Donas.

   PURPOSE: Precision medicine represents a paradigm shift in oncology. Access to genetic testing and targeted therapies is frequently limited. Assays based on DNA sequencing can miss druggable alterations. We aimed to determine the impact of a free access program to RNA tests in patient management.
METHODS: We designed a multicenter prospective observational study within the Spanish National Group for Translational Oncology and Rare and Orphan Tumors (GETTHI). Eligible patients were adults with solid cancers that had progressed on standard therapies. Tumor samples were analyzed using two RNA sequencing assays (Trailblaze PharosTM and Archer FusionPlex Solid TumorTM). A central committee evaluated the actionability of genetic alterations and reported the findings to attending physicians, who made the final clinical management decisions.
RESULTS: Between November 2016 and April 2019, 395 patients with 41 different tumors across 30 hospitals were included. Molecular analysis revealed actionable genetic alterations in 57 individuals (14.4%). Targeted therapies were advised for 23 and seven received a matched targeted therapy: two lung cancers (EML4-ALK and CD74-ROS1 fusion), three glioblastomas (EGFR point mutations), one oligodendroglioma (FGFR3-TACC3 fusion) and a prostate cancer (SND1-BRAF fusion). The outcomes included two tumor responses, one disease stabilization, one early withdrawal due to toxicity, one progression, and one unknown.
CONCLUSION: Despite the growing knowledge of cancer biology and its translation to drug development, the overall impact of personalized treatments remains low. Access to comprehensive molecular tests covering properly all known actionable alterations and programs for a wide access to targeted therapies seem to be critical steps.

Keywords:  Advanced cancer; Fusion; Mutation; NGS; Precision medicine

DOI:  https://doi.org/10.1007/s12094-024-03745-5
Ann Surg. 2024 Oct 14.

Mutant KRAS in Circulating Tumor DNA as a Biomarker in Localized Pancreatic Cancer in Patients Treated with Neoadjuvant Chemotherapy.

Dominic J Vitello, Dhavan Shah, Amy Wells, Larissa Masnyk, Madison Cox, Lauren M Janczewski, John Abad, Kevin Dawravoo, Arlene D'Souza, Grace Suh, Robert Bayer, Massimo Cristofanilli, David Bentrem, Yingzhe Liu, Hui Zhang, Lucas Santana-Santos, Lawrence J Jennings, Qiang Zhang, Akhil Chawla.

OBJECTIVE: The primary objective was to determine the prognostic significance of circulating tumor DNA (ctDNA) in patients receiving neoadjuvant chemotherapy (NAC) for localized pancreatic ductal adenocarcinoma (PDAC) using digital droplet polymerase chain reaction (ddPCR).
SUMMARY AND BACKGROUND DATA: Increasingly, ctDNA is being used for clinical decision-making in a variety of solid malignancies. However, the detection and prognostic value of KRAS ctDNA as assessed by ddPCR during NAC has yet to be characterized.
METHODS: Patients with localized PDAC eligible to receive NAC were prospectively enrolled. Peripheral blood samples were obtained at diagnosis, after NAC, and after resection and analyzed for ctDNA using ddPCR. Log-rank tests and Cox proportional hazards model were used to assess for association with OS.
RESULTS: 84 patients were included in the analysis. Mutant KRAS ctDNA was detected in 49.3% of patients at diagnosis, 69.6% of patients after NAC, and 69.7% of patients after resection, respectively. There were 15 (17.9%) patients that cleared mutational ctDNA over the course of treatment. Clearance of ctDNA during NAC was associated with improved overall survival (OS) (18.4 mo. vs NR, P<0.05). Detection of mutant KRAS G12V after NAC and resection was associated with shorter OS (18.0 versus NR months, P<0.031). Detection of the KRAS G12V mutation after resection was associated with reduced OS (aHR 36.75, 95% CI 2.93-461.38).
CONCLUSIONS: Throughout treatment, KRAS ctDNA is detectable by ddPCR in patients with localized PDAC treated with NAC. Detection of mutant KRAS G12V after resection was associated with reduced OS.

DOI: https://doi.org/10.1097/SLA.0000000000006562
Breast Cancer Res Treat. 2024 Oct 30.

Molecular tumor board in patients with metastatic breast cancer.

Luca Boscolo Bielo, Elena Guerini Rocco, Edoardo Crimini, Matteo Repetto, Mariano Lombardi, Cristina Zanzottera, Gaetano Aurilio, Massimo Barberis, Carmen Belli, Yinxiu Zhan, Elena Battaiotto, Jalissa Katrini, Renato Marsicano, Paola Zagami, Beatrice Taurelli Salimbeni, Angela Esposito, Dario Trapani, Carmen Criscitiello, Nicola Fusco, Antonio Marra, Giuseppe Curigliano.

   PURPOSE: Comprehensive genomic profiling is becoming increasingly important in the management of patients with metastatic breast cancer (mBC). Real-world clinical outcomes from applying molecular tumor boards (MTBs) recommendations in this context remain limited. Accordingly, we conducted a retrospective, single-institution analysis to evaluate the clinical impact of discussing patients affected by mBC at the MTB.
METHODS: Clinicogenomic data of patients affected by mBCs referred to the European Institute of Oncology MTB between August 2019 and December 2023 were reviewed. Genomic alterations were classified by ESCAT framework. Clinical outcomes of patients showing actionable alterations and receiving molecular-matched therapy (MMT) were compared to those receiving standard therapy (ST).
RESULTS: Ninety-six patients were included. Following MTB discussion, genetic counseling was recommended in 27% (n = 26) of patients, while additional molecular analyses were requested in 25% (n = 24) cases. Fifty-six patients (58%) displayed at least one actionable alteration. For patients with available follow-up (n = 50), 32 (64%) received MMTs and 18 (36%) ST. No differences in real-world progression-free survival (rwPFS) (4.07 months [95% CI 2.14-8.28] vs. 3.12 months [95% CI 1.51-NE], P = 0.8) and 12-month overall survival (OS) (58% [95%CI 43-78] vs. 57% [95%CI 34-97), P = 0.9) were observed between the MMT- and ST-group. Level I ESCAT alterations yielded longer rwPFS (5.82 months [95% CI 3.12-8.41]) compared to ESCAT II (2.14 months [95%CI 1.61-NE]) and ESCAT III (2.10 months [95% CI 2.04-NE]; P = 0.03). Twenty-four percent of patients showed a PFS2/PFS1 ratio > 1.3 from MMT.
CONCLUSION: Molecular tumor boards can provide additional treatment options for patients affected by mBC. Besides treatment recommendations, MTBs also have the utility to assess the validity of discussed genomic reports and to identify alterations worthy of genetic counseling.

Keywords:  Breast cancer; MTB; Molecular tumor board; Precision medicine; Precision oncology

DOI:  https://doi.org/10.1007/s10549-024-07535-z
Anticancer Res. 2024 Nov;44(11): 4691-4707

Potential Transcriptomic Biomarkers for Predicting Platinum-based Chemotherapy Resistance in Patients With High-grade Serous Ovarian Cancer.

Sara Cocchi, Joanna Lopacinska-Jørgensen, Estrid V Høgdall.

   BACKGROUND/AIM: Due to the absence of screening protocols, high-grade serous ovarian cancer (HGSOC) patients are frequently diagnosed at an advanced stage, which significantly reduces the survival rate. Moreover, relapse occurs in approximately 70% of HGSOC patients after primary treatment. Predicting resistance to primary chemotherapy remains a challenge. In the research setting, transcriptomic analyses have emerged as powerful tools for predicting which HGSOC patients are likely to benefit from primary treatment. The aim of this review was to investigate the literature demonstrating the potential of transcriptomic signatures as biomarkers for assessing the risk of resistance to platinum-based chemotherapy.
MATERIALS AND METHODS: We conducted a three-step search process on PubMed to systematically review English-language articles published between 2020 and 2024. From the 123 articles retrieved, we included 11 articles that investigated transcriptomic signatures by RNA sequencing in tissues from chemo-sensitive and -resistant HGSOC patients.
RESULTS: We report the clinicopathological data of 727 patients in the experimental cohorts, transcriptomic signatures, and technical aspects. Finally, the review lists 15 publicly available datasets used in the included studies. Furthermore, we investigated the overlap of 167 differentially expressed genes retrieved across the various articles.
CONCLUSION: We believe this review might offer valuable insights for further studies focusing on predicting platinum resistance and personalized treatments. In addition to discussing the latest findings and potential candidates, we highlight the challenges of validating biomarkers across studies and publicly available datasets. Transcriptomic signatures represent a potential tool for patient stratification, prognosis, and the potential adoption of long-term therapies, such as poly (ADP-ribose) polymerase inhibitors (PARPis).

Keywords:  High-grade serous ovarian cancer; chemotherapy; resistance; review; transcriptomic analysis

DOI:  https://doi.org/10.21873/anticanres.17296
Naunyn Schmiedebergs Arch Pharmacol. 2024 Oct 31.

Advancements in nanotheranostics for glioma therapy.

Liza Sahoo, Safal Kumar Paikray, Nigam Sekhar Tripathy, Donald Fernandes, Fahima Dilnawaz.

  Gliomas are brain tumors mainly derived from glial cells that are difficult to treat and cause high mortality. Radiation, chemotherapy, and surgical excision are the conventional treatments for gliomas. Patients who have surgery or have undergone chemotherapy for glioma treatment have poor prognosis with tumor recurrence. In particular, for glioblastoma, the 5-year average survival rate is 4-7%, and the median survival is 12-18 months. A number of issues hinder effective treatment such as, poor surgical resection, tumor heterogeneity, insufficient drug penetration across the blood-brain barrier, multidrug resistance, and difficulties with drug specificity. Nanotheranostic-mediated drug delivery is becoming a well-researched consideration, and an efficient non-invasive method for delivering chemotherapeutic drugs to the target area. Theranostic nanomedicines, which incorporate therapeutic drugs and imaging agents for personalized therapies, can be used for preventing overdose of non-responders. Through the identification of massive and complicated information from next-generation sequencing, machine learning enables for precise prediction of therapeutic outcomes and post-treatment management for patients with cancer. This article gives a thorough overview of nanocarrier-mediated drug delivery with a brief introduction to drug delivery challenges. In addition, this assessment offers a current summary of preclinical and clinical research on nanomedicines for gliomas. In the future, nanotheranostics will provide personalized treatment for gliomas and other treatable cancers.

Keywords:  Blood–brain barrier; Central nervous system; Drug delivery systems; Glioma; Precision medicine; Theranostic nanomedicine

DOI:  https://doi.org/10.1007/s00210-024-03559-w
Genome Med. 2024 Oct 31. 16(1): 126

Circular RNA landscape in extracellular vesicles from human biofluids.

Jingjing Zhao, Qiaojuan Li, Jia Hu, Hongwu Yu, Youmin Shen, Hongyan Lai, Qin Li, Hena Zhang, Yan Li, Zhuting Fang, Shenglin Huang.

   BACKGROUND: Circular RNAs (circRNAs) have emerged as a prominent class of covalently closed single-stranded RNA molecules that exhibit tissue-specific expression and potential as biomarkers in extracellular vesicles (EVs) derived from liquid biopsies. Still, their characteristics and applications in EVs remain to be unveiled.
METHODS: We performed a comprehensive analysis of EV-derived circRNAs (EV-circRNAs) using transcriptomics data obtained from 1082 human body fluids, including plasma, urine, cerebrospinal fluid (CSF), and bile. Our validation strategy utilized RT-qPCR and RNA immunoprecipitation assays, complemented by computational techniques for analyzing EV-circRNA features and RNA-binding protein interactions.
RESULTS: We identified 136,327 EV-circRNAs from various human body fluids. Significantly, a considerable amount of circRNAs with a high back-splicing ratio are highly enriched in EVs compared to linear RNAs. Additionally, we discovered brain-specific circRNAs enriched in plasma EVs and cancer-associated EV-circRNAs linked to clinical outcomes. Moreover, we demonstrated that EV-circRNAs have the potential to serve as biomarkers for evaluating immunotherapy efficacy in non-small cell lung cancer (NSCLC). Importantly, we identified the involvement of RBPs, particularly YBX1, in the sorting mechanism of circRNAs into EVs.
CONCLUSIONS: This study unveils the extensive repertoire of EV-circRNAs across human biofluids, offering insights into their potential as disease biomarkers and their mechanistic roles within EVs. The identification of specific circRNAs and the elucidation of RBP-mediated sorting mechanisms open new avenues for the clinical application of EV-circRNAs in disease diagnostics and therapeutics.

Keywords:  Biomarker; Cancer; Circular RNAs; Extracellular vesicles; RNA-binding proteins

DOI:  https://doi.org/10.1186/s13073-024-01400-w
Cancers (Basel). 2024 Oct 11. pii: 3451. [Epub ahead of print]16(20):

H3K27me3 Loss in Central Nervous System Tumors: Diagnostic, Prognostic, and Therapeutic Implications.

Giuseppe Angelico, Manuel Mazzucchelli, Giulio Attanasio, Giordana Tinnirello, Jessica Farina, Magda Zanelli, Andrea Palicelli, Alessandra Bisagni, Giuseppe Maria Vincenzo Barbagallo, Francesco Certo, Maurizio Zizzo, Nektarios Koufopoulos, Gaetano Magro, Rosario Caltabiano, Giuseppe Broggi.

  Central nervous system (CNS) tumors represent a formidable clinical challenge due to their molecular complexity and varied prognostic outcomes. This review delves into the pivotal role of the epigenetic marker H3K27me3 in the development and treatment of CNS tumors. H3K27me3, specifically the trimethylation of lysine 27 on the histone H3 protein, plays a crucial role in regulating gene expression and maintaining chromatin architecture (e.g., in X-chromosome inactivation). Notably, a reduction in H3K27me3 levels, frequently tied to mutations in the H3 gene family such as H3F3A and HIST1H3B, is evident in diverse brain tumor variants, including the diffuse midline glioma characterized by the H3K27M mutation and certain pediatric high-grade gliomas. The loss of H3K27me3 has been linked to more aggressive behavior in meningiomas, with the trimethylation loss associated with significantly shorter recurrence-free survival (RFS) among grade 2 meningiomas, albeit not within grade 1 tumors. Pediatric posterior fossa ependymomas characterized by a lowered H3K27me3 and DNA hypomethylation exhibit poor prognosis, underscoring the prognostic significance of these epigenetic alterations in CNS tumors. Comprehending the role of H3K27me3 in CNS tumors is vital for advancing diagnostic tools and therapeutic interventions, with the goal of enhancing patient outcomes and quality of life. This review underscores the importance of ongoing investigations into H3K27me to refine and optimize management strategies for CNS tumors, paving the way for improved personalized medicine practices in oncology.

Keywords:  H3K27me3 loss; central nervous system; diffuse midline glioma; immunohistochemistry; tumor

DOI:  https://doi.org/10.3390/cancers16203451
Cancers (Basel). 2024 Oct 14. pii: 3478. [Epub ahead of print]16(20):

De-Escalating Treatment Strategies for Patients with Human Epidermal Growth Factor Receptor-2 (HER2)-Positive Early-Stage Breast Cancer.

Hikmat Abdel-Razeq.

  Almost one-fifth of breast cancer cases express Human Epidermal Growth Factor-2 (HER2), and such expression is associated with highly proliferative tumors and poor prognosis. The introduction of anti-HER2 therapies has dramatically changed the natural course of this aggressive subtype of breast cancer. However, anti-HER2 therapy can be associated with substantial toxicities, mostly cardiac, and high cost. Over the past few years, there has been growing interest in de-escalation of anti-HER2 therapies to minimize adverse events and healthcare costs, while maintaining the efficacy of treatment. Data from clinical observations and single-arm studies have eluted to the minimal impact of anti-HER2 therapy in low-risk patients, like those with node-negative and small tumors. Though single-arm, the APT trial, in which patients with node-negative, small tumors received single-agent paclitaxel for 12 cycles plus trastuzumab for 1 year, was a practice-changing study. Several other recently published studies, like the PERSEPHONE trial, have shown more convincing data that 6 months of trastuzumab is not inferior to 12 months, in terms of disease-free survival (DFS), suggesting that de-escalating strategies with shorter treatment may be appropriate for some low-risk patients. Other de-escalating strategies involved an adaptive, response-directed approach, and personalized therapy that depends on tumor genomic profiling.

Keywords:  HER2; adjuvant therapies; breast cancer; de-escalation; neoadjuvant therapies; personalized medicine; pertuzumab; targeted therapies; trastuzumab

DOI:  https://doi.org/10.3390/cancers16203478
Br J Cancer. 2024 Oct 30.

The potential clinical utility of Whole Genome Sequencing for patients with cancer: evaluation of a regional implementation of the 100,000 Genomes Project.

Elaine Y L Leung, Helen L Robbins, Shafquat Zaman, Neeraj Lal, Dion Morton, Lisa Dew, Anthony P Williams, Yvonne Wallis, Jennie Bell, Manoj Raghavan, Gary Middleton, Andrew D Beggs.

BACKGROUND: The 100,000 Genomes Project established infrastructure for Whole Genome Sequencing (WGS) in the United Kingdom.
METHODS: A retrospective study of cancer patients recruited to the 100,000 Genomes Project by the West Midlands Genomics Medicine Centre, evaluating clinical relevance of results.
RESULTS: After excluding samples with no sequencing data (1678/4851; 34.6%), 3166 sample sets (germline and somatic) from 3067 participants were sequenced. Results of 1256 participants (41.0%) were interpreted (excluding participants who died (308/3067; 10.0%) or were clinically excluded (1503/3067; 49.0%)). Of these, 323 (25.7%) had no variants in genes which may alter management (Domain 1 genes). Of the remaining 933 participants, 552 (59.2%) had clinical recommendations made (718 recommendations in total). These included therapeutic recommendations (377/933; 40.4%), such as clinical trial, unlicensed or licensed therapies or high TMB recommendations, and germline variants warranting clinical genetics review (85/933; 9.1%). At the last follow up, 20.2% of all recommendations were followed (145/718). However, only a small proportion of therapeutic recommendations were followed (5.1%, 25/491).
CONCLUSIONS: The 100,000 Genomes Project has established infrastructure and regional experience to support personalised cancer care. The majority of those with successful sequencing had actionable variants. Ensuring GTAB recommendations are followed will maximise benefits for patients.

DOI: https://doi.org/10.1038/s41416-024-02890-6
Ann Oncol. 2024 Oct 28. pii: S0923-7534(24)04070-5. [Epub ahead of print]

Pathologic complete response (pCR) rates for patients with HR+/HER2- high-risk, early-stage breast cancer (EBC) by clinical and molecular features in the phase II I-SPY2 clinical trial.

L A Huppert, D Wolf, C Yau, L Brown-Swigart, G L Hirst, C Isaacs, L Pusztai, P R Pohlmann, A DeMichele, R Shatsky, D Yee, A Thomas, R Nanda, J Perlmutter, D Heditsian, N Hylton, F Symmans, L J van 't Veer, L Esserman, H S Rugo.

   BACKGROUND: Hormone receptor positive (HR+), HER2- early-stage breast cancer (EBC) is a heterogenous disease. Identification of better clinical and molecular biomarkers is essential to guide optimal therapy for each patient.
PATIENTS AND METHODS: We analyzed rates of pathologic complete response (pCR) and distant recurrence-free survival (DRFS) for patients with HR+/HER2- EBC in 8 neoadjuvant arms in the I-SPY2 trial by clinical/molecular features: age, stage, histology, percentage ER positivity, ER/PR status, MammaPrint (MP)-High1 (0 to -0.57) versus MP-High2 (<-0.57), BluePrint (BP)-Luminal-type versus BP-Basal-type, and ImPrint immune signature. We quantified the clinical/molecular heterogeneity, assessed overlap among these biomarkers, and evaluated associations with pCR and DRFS.
RESULTS: 379 patients with HR+/HER2- EBC were included in this analysis, with an observed pCR rate of 17% across treatment arms. pCR rates were higher in patients with stage II versus III disease (21% versus 9%, p=0.0013), ductal versus lobular histology (19% versus 11%, p=0.049), lower %ER positivity (≤66% versus >66%) (35% versus 9%, p=3.4E-09), MP-High2 versus MP-High1 disease (31% versus 11%, p=1.1E-05), BP-Basal-type versus BP-Luminal-type disease (34% versus 10%, p=1.62E-07), and ImPrint positive versus negative disease (38% versus 10%, p=1.64E-09). Patients with lower %ER were more likely to have MP-High2 and BP-Basal-type disease. At a median follow-up of 4.8 years, patients who achieved pCR had excellent outcomes irrespective of clinical/molecular features. Among patients who did not achieve pCR, DRFS events were more frequent in patients with MP-High2 and BP-Basal-type disease than those with MP-High1 and BP-Luminal-type disease.
CONCLUSION: Among patients with high molecular-risk HR+/HER2- EBC, the MP-High2, BP-Basal-type, and ImPrint positive signatures identified a partially overlapping subset of patients who were more likely to achieve pCR in response to neoadjuvant chemotherapy +/- targeted agents or immunotherapy compared to patients with MP-High1, BP-Luminal-type, and ImPrint negative disease. I-SPY2.2 is incorporating the use of these biomarkers to molecularly define specific patient populations and optimize treatment selection.

Keywords:  MammaPrint; Neoadjuvant therapy; basal; intrinsic subtype; luminal; molecular subtype

DOI:  https://doi.org/10.1016/j.annonc.2024.10.018
Asia Pac J Clin Oncol. 2024 Oct 25.

Expert consensus on the optimal management of BRAFV600E-mutant metastatic colorectal cancer in the Asia-Pacific region.

Oliver Piercey, Lorraine Chantrill, Hung-Chih Hsu, Brigette Ma, Timothy Price, Iain Beehuat Tan, Hao-Wei Teng, Jeanne Tie, Jayesh Desai.

  The burden of colorectal cancer (CRC) is high in the Asia-Pacific region, and several countries in this region have among the highest and/or fastest growing rates of CRC in the world. A significant proportion of patients will present with or develop metastatic CRC (mCRC), and BRAFV600E-mutant mCRC represents a particularly aggressive phenotype that is less responsive to standard chemotherapies. In light of recent therapeutic advances, an Asia-Pacific expert consensus panel was convened to develop evidence-based recommendations for the diagnosis, treatment, and management of patients with BRAFV600E-mutant mCRC. The expert panel comprised nine medical oncologists from Australia, Hong Kong, Singapore, and Taiwan (the authors), who met to review current literature and develop eight consensus statements that describe the optimal management of BRAFV600E-mutant mCRC in the Asia-Pacific region. As agreed by the expert panel, the consensus statements recommend molecular testing at diagnosis to guide individualized treatment decisions, propose optimal treatment pathways according to microsatellite stability status, advocate for more frequent monitoring of BRAFV600E-mutant mCRC, and discuss local treatment strategies for oligometastatic disease. Together, these expert consensus statements are intended to optimize treatment and improve outcomes for patients with BRAFV600E-mutant mCRC in the Asia-Pacific region.

Keywords:  Asia‐Pacific; BRAFV600E mutation; immunotherapy; metastatic colorectal cancer; targeted therapy

DOI:  https://doi.org/10.1111/ajco.14132