bims-preonc 2024-07-28 papers

bims-preonc

Biomed News

on Precision oncology

Issue of 2024–07–28
nine papers selected by
Ankita Daiya, OneCell Diagnostics Inc.

Understanding the treatment response and resistance to targeted therapies in non-small cell lung cancer: clinical insights and perspectives.
Circulating tumor DNA mutation analysis: advances in its application for early diagnosis of hepatocellular carcinoma and therapeutic efficacy monitoring.
The Role of Circulating Tumor DNA for Management of Patients With Rectal Cancer: Challenges and Opportunities.
Confirmation of Recurrent Lung Cancer Following Resection Using Liquid Biopsy, a Proof-of-Concept Real-World Study.
A Locally Advanced NSCLC Patient Harboring a Rare KIF13A-RET Fusion Benefited from Pralsetinib: A Case Report.
Circulating Liquid Biopsy Biomarkers in Glioblastoma: Advances and Challenges.
Cervical Cancer Genetic Profile through Circulating Tumor DNA: What Can We Learn from Blood?
Empowering effective biomarker-driven precision oncology: A call to action.
Tissue- and liquid-biopsy based NGS profiling in advanced non-small-cell lung cancer in a real-world setting: the IMMINENT study.

Front Oncol. 2024 ;14 1387345

Understanding the treatment response and resistance to targeted therapies in non-small cell lung cancer: clinical insights and perspectives.

Hang Zhang, Yingying Zhang, Yingying Zhu, Tian Dong, Zheng Liu.

  Lung cancer remains the leading cause of mortality worldwide. Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer with a generally poor prognosis. In recent years, advances in targeted therapy and sequencing technology have brought significant improvement in the therapeutic outcomes of patients with advanced NSCLC. Targeted inhibitors directed against specific mutated or rearranged oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and receptor tyrosine kinase ROS proto-oncogene 1(ROS1) among others, exhibit promising anti-tumor activity. Unfortunately, some patients develop acquired resistance and disease progression soon after initial remission. Despite the continuous development of new drugs and strategies to overcome drug resistance, it is still a major challenge in the treatment of NSCLC. The landscape of targeted therapy for NSCLC is evolving rapidly in response to the pace of scientific research. This study aimed to provide a comprehensive review of tumor target antigens and agents related to targeted therapy in NSCLC.

Keywords:  drug resistance; non-small cell lung cancer; targeted therapy; treatment response; tyrosine kinase inhibitor

DOI:  https://doi.org/10.3389/fonc.2024.1387345
Aging (Albany NY). 2024 Jul 19. 16

Circulating tumor DNA mutation analysis: advances in its application for early diagnosis of hepatocellular carcinoma and therapeutic efficacy monitoring.

Jing Yang, Na Lin, Miaomiao Niu, Boshu Yin.

  In recent years, the detection and analysis of circulating tumor DNA (ctDNA) have emerged as a new focus in the field of cancer research, particularly in the early diagnosis of hepatocellular carcinoma (HCC) and monitoring of therapeutic efficacy. ctDNA, which refers to cell-free DNA fragments released into the bloodstream from tumor cells upon cell death or shedding, carries tumor-specific genetic and epigenetic alterations, thereby providing a non-invasive approach for cancer diagnosis and prognosis. The concentration of ctDNA in the blood is higher compared to that in healthy individuals or other liquid biopsies from early-stage cancers, which is closely associated with the early diagnosis and comprehensive sequencing studies of HCC. Recent studies have indicated that sequential ctDNA analysis in patients receiving primary or adjuvant therapy for HCC can detect treatment resistance and recurrence before visible morphological changes in the tumor, making it a valuable basis for rapid adjustment of treatment strategies. However, this technology is continuously being optimized and improved. Challenges such as enhancing the accuracy of ctDNA sequencing tests, reducing the burden of high-throughput sequencing on a large number of samples, and controlling variables in the assessment of the relationship between ctDNA concentration and tumor burden, need to be addressed. Overall, despite the existing challenges, the examination and analysis of ctDNA have opened up new avenues for early diagnosis and therapeutic efficacy monitoring in hepatocellular carcinoma, expanding the horizons of this field.

Keywords:  circulating tumor DNA; early diagnosis; hepatocellular carcinoma; high-throughput sequencing; therapeutic efficacy monitoring

DOI:  https://doi.org/10.18632/aging.205980
Cancer J. 2024 Jul-Aug 01;30(4):30(4): 290-296

The Role of Circulating Tumor DNA for Management of Patients With Rectal Cancer: Challenges and Opportunities.

Ibrahim Halil Sahin, Rami Yanes, Turcin Saridogan, Jennifer Holder-Murray, Arvind N Dasari.

ABSTRACT: Recently, organ preservation with total neoadjuvant therapy resulted in substantial progress in the management of locally advanced rectal cancer (LARC). The PROSPECT trial showed noninferiority of de-escalation of radiotherapy for patients with low-risk LARC who do not need abdominoperineal resection. Although these escalation and de-escalation approaches offer more personalized therapeutic approaches, the current state of care for patients with rectal cancer is far from individualized management. Circulating tumor DNA (ctDNA) is known to be one of the most powerful prognostic factors for early relapse and has been investigated in several interventional clinical trials to offer more precise treatment algorithms. In this review article, we discuss recent updates from studies examining the role of ctDNA for the prediction of treatment response and recurrence for patients with rectal cancer. We also elaborate on the future potential use of ctDNA in treatment escalation and de-escalation approaches for more personalized therapeutic interventions.

DOI: https://doi.org/10.1097/PPO.0000000000000731
Curr Oncol. 2024 Jul 17. 31(7): 4052-4062

Confirmation of Recurrent Lung Cancer Following Resection Using Liquid Biopsy, a Proof-of-Concept Real-World Study.

Julia R Naso, Stephen Yip, Curtis Hughesman, Barb Melosky, Tanner Dowhy, Melissa K McConechy, John C English, Penelope M A Brasher, James Choi, Kyle Grant, John Yee, Stephen Lam, Anna McGuire.

  Appropriate management requires timely and accurate confirmation of non-small cell lung cancer (NSCLC) recurrence in patients who have had curative-intent surgical resection. We assessed the association between circulating tumor DNA (ctDNA) identified using amplicon sequencing and evidence of recurrence on CT surveillance. A prospective cohort study of NSCLC patients with early-stage disease undergoing curative-intent resection was conducted. Surveillance was performed post-operatively at pre-defined intervals with both liquid biopsy and chest CT imaging. Amplicon panel next-generation sequencing was performed on DNA and RNA from tumor tissue and on plasma cell-free DNA for tumor-informed ctDNA detection. Resected tumors from 78 NSCLC patients were analyzed. Alterations were detected on the DNA assay for 65 tumors and only on the RNA assay for 4 tumors. Of the 65 patients with alterations detected on the tumor DNA assay, 29 completed post-operative liquid biopsy testing. Four of those 29 patients had evidence of recurrence on imaging, of whom two had biopsy confirmation of recurrence and detectable ctDNA at the 12-month follow-up. Molecular confirmation of NSCLC recurrence can be provided through amplicon sequencing of plasma cell-free DNA in cases with imaging evidence of recurrence. Invasive tissue diagnosis may be avoidable in patients with ctDNA confirmation of recurrence that is suspected based on imaging. Further study of ctDNA assessment technologies in the setting of suspected recurrence is necessary to inform post-operative lung cancer surveillance guidelines.

Keywords:  biomarker; lung cancer; next-generation sequencing; targeted therapy

DOI:  https://doi.org/10.3390/curroncol31070302
Curr Oncol. 2024 Jun 30. 31(7): 3808-3814

A Locally Advanced NSCLC Patient Harboring a Rare KIF13A-RET Fusion Benefited from Pralsetinib: A Case Report.

Zenghao Chang, Tengfei Zhu, Hao Jiang, Wei Ou, Siyu Wang.

  The application of adjuvant treatment has significantly enhanced the survival of patients with resectable non-small cell lung cancer (NSCLC) carrying driver gene mutations. However, adjuvant-targeted therapy remains controversial for some NSCLC patients carrying rare gene mutations such as RET, as there is currently a lack of confirmed randomized controlled trials demonstrating efficacy. In this report, we describe the case of a 58-year-old man with stage IIIA NSCLC who underwent complete lobectomy with selective lymph node dissection. Postoperative next-generation sequencing revealed that the patient harbored a rare KIF13A-RET fusion. The patient elected to receive adjuvant treatment with pralsetinib monotherapy and underwent serial circulating tumor DNA (ctDNA) monitoring after surgery. During follow-up, despite experiencing dose reduction and irregular medication adherence, the patient still achieved a satisfactory disease-free survival (DFS) of 27 months. Furthermore, ctDNA predicted tumor recurrence 4 months earlier than imaging techniques. The addition of bevacizumab to the original regimen upon recurrence continued to be beneficial. Pralsetinib demonstrated promising efficacy as adjuvant therapy, while ctDNA analysis offered a valuable tool for early detection of tumor recurrence. By leveraging targeted therapies and innovative monitoring techniques, we aim to improve outcomes and quality of life for NSCLC patients in the future.

Keywords:  NSCLC; RET fusion; adjuvant treatment; case report; ctDNA; pralsetinib

DOI:  https://doi.org/10.3390/curroncol31070281
Int J Mol Sci. 2024 Jul 21. pii: 7974. [Epub ahead of print]25(14):

Circulating Liquid Biopsy Biomarkers in Glioblastoma: Advances and Challenges.

Attila A Seyhan.

  Gliomas, particularly glioblastoma (GBM), represent the most prevalent and aggressive tumors of the central nervous system (CNS). Despite recent treatment advancements, patient survival rates remain low. The diagnosis of GBM traditionally relies on neuroimaging methods such as magnetic resonance imaging (MRI) or computed tomography (CT) scans and postoperative confirmation via histopathological and molecular analysis. Imaging techniques struggle to differentiate between tumor progression and treatment-related changes, leading to potential misinterpretation and treatment delays. Similarly, tissue biopsies, while informative, are invasive and not suitable for monitoring ongoing treatments. These challenges have led to the emergence of liquid biopsy, particularly through blood samples, as a promising alternative for GBM diagnosis and monitoring. Presently, blood and cerebrospinal fluid (CSF) sampling offers a minimally invasive means of obtaining tumor-related information to guide therapy. The idea that blood or any biofluid tests can be used to screen many cancer types has huge potential. Tumors release various components into the bloodstream or other biofluids, including cell-free nucleic acids such as microRNAs (miRNAs), circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), proteins, extracellular vesicles (EVs) or exosomes, metabolites, and other factors. These factors have been shown to cross the blood-brain barrier (BBB), presenting an opportunity for the minimally invasive monitoring of GBM as well as for the real-time assessment of distinct genetic, epigenetic, transcriptomic, proteomic, and metabolomic changes associated with brain tumors. Despite their potential, the clinical utility of liquid biopsy-based circulating biomarkers is somewhat constrained by limitations such as the absence of standardized methodologies for blood or CSF collection, analyte extraction, analysis methods, and small cohort sizes. Additionally, tissue biopsies offer more precise insights into tumor morphology and the microenvironment. Therefore, the objective of a liquid biopsy should be to complement and enhance the diagnostic accuracy and monitoring of GBM patients by providing additional information alongside traditional tissue biopsies. Moreover, utilizing a combination of diverse biomarker types may enhance clinical effectiveness compared to solely relying on one biomarker category, potentially improving diagnostic sensitivity and specificity and addressing some of the existing limitations associated with liquid biomarkers for GBM. This review presents an overview of the latest research on circulating biomarkers found in GBM blood or CSF samples, discusses their potential as diagnostic, predictive, and prognostic indicators, and discusses associated challenges and future perspectives.

Keywords:  biomarkers; cell-free DNA (cfDNA); circulating microRNAs (miRNAs); circulating tumor DNA (ctDNA); circulating tumor cells (CTCs); diagnosis; extracellular vesicles (EVs) and exosomes; glioblastoma; metabolomics; prognosis; proteomics

DOI:  https://doi.org/10.3390/ijms25147974
Biomolecules. 2024 Jul 10. pii: 825. [Epub ahead of print]14(7):

Cervical Cancer Genetic Profile through Circulating Tumor DNA: What Can We Learn from Blood?

Sevastiani Antonouli, Valentina Di Nisio, Nikoletta Daponte, Athina-Ioanna Daponte, Alexandros Daponte.

  Cervical cancer (CC) is one of the deadliest gynecological cancers worldwide. Human papillomavirus is the main etiological agent responsible for the initiation and development of most CC cases. The standard method utilized for CC screening in the global population is the cytological Pap smear test. Despite its effective validity in detecting precancerous lesions and its response to layer stages of this disease, greater screening and diagnostic reliability are needed, as well as an improvement in specificity and sensitivity. In this context, the use of liquid biopsies, like blood, for the isolation of circulating tumor DNA (ctDNA) in CC screening, diagnosis, prognosis, and surveillance could fill the gaps that still exist. In the present review, we aim to study the literature in order to collect knowledge on blood-based liquid biopsy based on descriptions of its precious molecular content and its utilization as a potential tool for CC patients' management. We will mainly focus on the important role of the novel ctDNA and the unique possibilities to additionally use HPV-ctDNA in CC at various stages of clinical application.

Keywords:  HPV; cervical cancer; ctDNA; liquid biopsy

DOI:  https://doi.org/10.3390/biom14070825
Eur J Cancer. 2024 Jul 15. pii: S0959-8049(24)00881-5. [Epub ahead of print]209 114225

Empowering effective biomarker-driven precision oncology: A call to action.

Mark Lawler, Peter Keeling, Olga Kholmanskikh, Warnyta Minnaard, Heike Moehlig-Zuttermeister, Nicola Normanno, Reena Philip, Claudia Popp, Roberto Salgado, Ademi E Santiago-Walker, Ana Trullas, Sahar B van Waalwijk van Doorn-Khosrovani, Richard Vart, Jessica Vermeulen, Marianna Vitaloni, Jaap Verweij.

  Precision oncology has a significant role to play in delivering optimal patient care. Biomarkers are critical enablers for precision oncology across the continuum of cancer diagnosis, in defining patient prognosis, and in predicting the response to treatments and their potential toxicities, as well as delineating the risk of hereditary cancer syndromes. Biomarkers also potentiate cancer drug development, accelerating patient access to safe and effective therapies. However, despite an accurate and timely diagnosis being critical to patient survival, advances in genomic testing are not being fully exploited in daily clinical practice, leading to missed opportunities to deliver the most effective treatments for patients. Biomarker testing availability and implementation often lag behind approvals of respective biomarker-informed therapies, limiting prompt patient access to these life-saving drugs. Multiple factors currently impede the routine adoption of biomarker testing including, but not limited to, cost, lack of test reimbursement, limited access, regulatory hurdles, lack of knowledge, insufficient cooperation on assay development, and the urgent need to harmonize and validate testing assays, all leading to inefficient diagnostic pathways. Clinical guidelines increasingly include genomic profiling, and recent evidence suggests that precision oncology can be delivered in a cost-effective way for financially-challenged health systems. Therefore, precision genomic testing for cancer biomarkers must be embedded into the clinical practice of oncology care delivery going forward. We articulate a series of recommendations and a call to action to underpin the mainstreaming of a biomarker-informed precision oncology approach to enhance patient outcomes and deliver cost effective 21st century cancer care.

Keywords:  Biomarkers; Comprehensive genomic profiling; Cost effectiveness; In vitro diagnostics; Precision oncology

DOI:  https://doi.org/10.1016/j.ejca.2024.114225
Front Oncol. 2024 ;14 1436588

Tissue- and liquid-biopsy based NGS profiling in advanced non-small-cell lung cancer in a real-world setting: the IMMINENT study.

Marco Sposito, Lorenzo Belluomini, Riccardo Nocini, Jessica Insolda, Ilaria Mariangela Scaglione, Jessica Menis, Michele Simbolo, Antonio Lugini, Federica Buzzacchino, Francesco Verderame, Francesca Spinnato, Giuseppe Aprile, Lorenzo Calvetti, Mario Occhipinti, Daniele Marinelli, Antonello Veccia, Fiorella Lombardo, Hector José Soto Parra, Francesco Ferraù, Clementina Savastano, Camilla Porta, Lorenzo Pradelli, Emilia Sicari, Silvia Castellani, Umberto Malapelle, Silvia Novello, Emilio Bria, Sara Pilotto, Michele Milella.

   Introduction: To date, for all non-small cell lung cancer (NSCLC) cases, it is recommended to test for driver alterations to identify actionable therapeutic targets. In this light, comprehensive genomic profiling (CGP) with next generation sequencing (NGS) has progressively gained increasing importance in clinical practice. Here, with the aim of assessing the distribution and the real-world frequency of gene alterations and their correlation with patient characteristics, we present the outcomes obtained using FoundationOne (F1CDx) and FoundationLiquid CDx (F1L/F1LCDx) NGS-based profiling in a nationwide initiative for advanced NSCLC patients.
Methods: F1CDx (324 genes) was used for tissue samples, and F1L (70 genes) or F1LCDx (324 genes) for liquid biopsy, aiming to explore the real-world occurrence of molecular alterations in aNSCLC and their relationship with patients' characteristics.
Results: Overall, 232 advanced NSCLC patients from 11 Institutions were gathered [median age 63 years; never/former or current smokers 29.3/65.9%; adenocarcinoma/squamous 79.3/12.5%; F1CDx/F1L+F1LCDx 59.5/40.5%]. Alterations were found in 170 different genes. Median number of mutated genes per sample was 4 (IQR 3-6) and 2 (IQR 1-3) in the F1CDx and F1L/F1LCDx cohorts, respectively. TP53 (58%), KRAS (22%), CDKN2A/B (19%), and STK11 (17%) alterations were the most frequently detected. Actionability rates (tier I and II) were comparable: 36.2% F1CDx vs. 34% ctDNA NGS assays (29.5% and 40.9% F1L and F1LCDx, respectively). Alterations in KEAP1 were significantly associated with STK11 and KRAS, so as TP53 with RB1. Median tumor mutational burden was 6 (IQR 3-10) and was significantly higher in smokers. Median OS from metastatic diagnosis was 23 months (IQR 18.5-19.5) and significantly lower in patients harboring ≥3 gene mutations. Conditional three-year survival probabilities increased over time for patients profiled at initial diagnosis and exceeded those of individuals tested later in their clinical history after 12 months.
Conclusion: This study confirms that NGS-based molecular profiling of aNSCLC on tissue or blood samples offers valuable predictive and prognostic insights.

Keywords:  liquid biopsy; next generation sequencing; non-small cell lung cancer; precision medicine; target therapy

DOI:  https://doi.org/10.3389/fonc.2024.1436588