The Journal of Liquid Biopsy最新文献

{"title":"ESR1 analysis of liquid biopsy in breast cancer, one-year routine experience of an Italian clinical referral center","authors":"Thais Maloberti ,&nbsp;Laura Poppi ,&nbsp;Giulia Ciccimara ,&nbsp;Sara Coluccelli ,&nbsp;Floriana Jessica Di Paola ,&nbsp;Giulia Calafato ,&nbsp;Viviana Sanza ,&nbsp;Elisa Gruppioni ,&nbsp;Annalisa Altimari ,&nbsp;Sara Quercia ,&nbsp;Alessandra Bernardi ,&nbsp;Claudio Zamagni ,&nbsp;Roberta Minari ,&nbsp;Antonio De Leo ,&nbsp;Giovanni Tallini ,&nbsp;Dario de Biase","doi":"10.1016/j.jlb.2025.100331","DOIUrl":"10.1016/j.jlb.2025.100331","url":null,"abstract":"<div><h3>Background</h3><div>Activating mutations in the <em>ESR1</em> gene are a known mechanism of secondary resistance to endocrine therapy in metastatic estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancers. Liquid biopsy has become a non-invasive tool for molecularly characterizing these neoplasms and allows for dynamic monitoring through the analysis of circulating tumor DNA (ctDNA).</div></div><div><h3>Methods</h3><div>We analyzed 161 plasma samples from patients with metastatic ER+/HER2− breast cancer who had previously undergone treatment with endocrine therapy and CDK4/6 inhibitors. <em>ESR1</em> mutation analysis was performed using two NGS panels: Oncomine™ Breast cfDNA Assay v2 (n = 102) and Oncomine™ Precision Assay GX (n = 59). The sensitivity threshold (Limit of Detection - LOD) for variant detection was set at ≤0.5 %.</div></div><div><h3>Results</h3><div>Twenty-one samples (12.4 %) did not meet the quality criteria for <em>ESR1</em> analysis. <em>ESR1</em> mutations were identified in 29.1 % (n = 41) of the remaining 141 cases. The most frequent <em>ESR1</em> variant was the p.Asp538Gly (53.7 %). Multiple <em>ESR1</em> mutations were observed in 29.3 % of mutated cases, and co-mutations were detected in 61 % of cases, mainly with <em>PIK3CA</em> (36.6 %) and <em>TP53</em> (12.2 %). The median variant allele frequency (VAF) of <em>ESR1</em> mutations was 1.46 %. No statistically significant difference in mutation frequency emerged between the two panels (p = 0.6993).</div></div><div><h3>Conclusions</h3><div><em>ESR1</em> mutations are detectable in approximately one-third of ER+/HER2− metastatic patients undergoing liquid biopsy. NGS platforms allow for sensitive and in-depth analysis, highlighting co-mutations of potential clinical and therapeutic relevance.</div></div>","PeriodicalId":101235,"journal":{"name":"The Journal of Liquid Biopsy","volume":"10 ","pages":"Article 100331"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145325950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Chemotherapy response monitoring with DNA methylation-based ctDNA tumor fraction: Evidence from a real-world cohort of patients with advanced common solid malignancies” [J Liq Biopsy, 10 (2025), 100442]","authors":"Christian D. Rolfo ,&nbsp;Moh'd M. Khushman ,&nbsp;Alessandro Russo ,&nbsp;Roberto Borea ,&nbsp;Bernard Herrman ,&nbsp;Jing Wang ,&nbsp;Jiemin Liao ,&nbsp;Carin R. Espenschied ,&nbsp;Sean Gordon ,&nbsp;Katie Quinn ,&nbsp;Kimberly C. Banks ,&nbsp;Arielle J. Medford","doi":"10.1016/j.jlb.2025.100448","DOIUrl":"10.1016/j.jlb.2025.100448","url":null,"abstract":"","PeriodicalId":101235,"journal":{"name":"The Journal of Liquid Biopsy","volume":"10 ","pages":"Article 100448"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145799753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating tumor DNA as part of the routine work-up for patients with suspected advanced lung cancer","authors":"Emma Holjak ,&nbsp;Tia Brasoveanu ,&nbsp;Saurav Verma ,&nbsp;Saqib Khan ,&nbsp;Morgan Black ,&nbsp;Inderdeep Dhaliwal ,&nbsp;Michael Mitchell ,&nbsp;Rahul Nayak ,&nbsp;Mehdi Qiabi ,&nbsp;Richard Inculet ,&nbsp;Dalilah Fortin ,&nbsp;Richard Malthaner ,&nbsp;Matthew Cecchini ,&nbsp;Anna Lapuk ,&nbsp;Daniel Breadner","doi":"10.1016/j.jlb.2025.100443","DOIUrl":"10.1016/j.jlb.2025.100443","url":null,"abstract":"<div><div>Liquid biopsy (LB) is a useful tool in patients with advanced non-small cell lung cancer (aNSCLC) to detect actionable molecular alterations and thereby allow genotype-matched therapies. Currently, LB is recommended for individuals diagnosed with aNSCLC who have an insufficient tissue sample or difficult-to-reach tumour tissue. Despite the potential advantages of LB, its incorporation into the standard diagnostic work-up for all newly diagnosed patients with aNSCLC is lacking. Our study aimed to evaluate whether addition of plasma circulating tumor DNA (ctDNA) next generation sequencing (NGS) testing early in the diagnostic work-up for patients with aNSCLC can improve the time to molecular results and treatment initiation. This was a single-centre quality improvement initiative with two cohorts of patients. Patients in the ‘ctDNA cohort’ had plasma ctDNA testing in addition to the standard diagnostic work-up. The ‘reference cohort' was a parallel group of patients who had the standard work-up (no LB). Tissue biopsy and reflex tissue NGS testing were done in both cohorts. ctDNA testing shortened the time to molecular results in the ctDNA cohort compared to the reference cohort (median, 14 vs 35 days; p = 0.01), the time from first respirology/thoracic surgery consult to molecular results (median, 22 vs 48 days respectively; p = 0.01), and the time from medical oncology consultation to initiation of first-line treatment (median, 12 vs 22 days; p = 0.01). In conclusion, in a publicly funded and single-payer healthcare system, ctDNA testing as part of the standard work-up for patients with aNSCLC provides molecular results significantly faster than tissue-based testing and shortens the time to treatment initiation.</div></div>","PeriodicalId":101235,"journal":{"name":"The Journal of Liquid Biopsy","volume":"10 ","pages":"Article 100443"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145528295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BLOODPAC's collaborations with European Union liquid biopsy initiatives","authors":"Jennifer Dickey ,&nbsp;Elaine Katrivanos ,&nbsp;Lauren C. Leiman ,&nbsp;Abde M. Abukhdeir ,&nbsp;Antonella Cardone ,&nbsp;Banu Saritas-Yildirim ,&nbsp;Carlos Galamba ,&nbsp;Cheyenne Jankiewicz ,&nbsp;Christian Rolfo ,&nbsp;Deepshikha Bhandari ,&nbsp;Emily Finnegan ,&nbsp;Francesca Fenizia ,&nbsp;Haydar Celik ,&nbsp;Ingrid Mehlhorn ,&nbsp;Jillian Walker ,&nbsp;Jose Luis Costa ,&nbsp;Kathy Williams ,&nbsp;Mark Sewart ,&nbsp;Matias Olsen ,&nbsp;Michael Wierzba ,&nbsp;Veronica Gonzales","doi":"10.1016/j.jlb.2025.100321","DOIUrl":"10.1016/j.jlb.2025.100321","url":null,"abstract":"<div><div>The adoption of liquid biopsy into clinical practice has revolutionized the landscape of cancer diagnostics and treatment monitoring. In the U.S., the Blood Profiling Atlas in Cancer (BLOODPAC) has significantly supported the advancement of these technologies through consensus building [<span><span>1</span></span>]. In collaboration with the United States (US) Food and Drug Administration (FDA), BLOODPAC has developed minimum technical data elements (MTDEs) and analytical validation protocols to streamline the assay development and regulatory assessment of liquid biopsy-based technologies. Additionally, BLOODPAC has established a pre-competitive data sharing model to support clinical implementation.</div><div>The European Union faces regulatory and access challenges that hinder widespread adoption of liquid biopsy technologies. Complexities under the In Vitro Diagnostic Regulation (IVDR) and Clinical Trials Regulation (CTR) have introduced variability and delays across member states. While recognizing Europe's strengths in developing robust frameworks and high standards for advancing precision oncology, this paper explores how BLOODPAC's efforts—particularly in standardization, validation, and data sharing—could inform and complement EU initiatives. BLOODPAC's experience in developing fit-for-purpose validation frameworks and fostering regulatory-industry dialogue offers particularly relevant insights for addressing EU-specific challenges. This paper proposes opportunities for collaboration and guidance development that could enhance European access to liquid biopsy-based tests for precision medicine, ultimately improving patient access and outcomes for cancer care and management.</div></div>","PeriodicalId":101235,"journal":{"name":"The Journal of Liquid Biopsy","volume":"10 ","pages":"Article 100321"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145108654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenotype independent capture of circulating tumor cell using magnetic platelet decoys","authors":"Kenise Morris ,&nbsp;Colette Li ,&nbsp;Sasmit Sarangi ,&nbsp;Anne-Laure Papa","doi":"10.1016/j.jlb.2025.100326","DOIUrl":"10.1016/j.jlb.2025.100326","url":null,"abstract":"<div><div>Circulating tumor cells (CTCs) are an essential biomarker for metastatic disease as they provide valuable information regarding the primary tumor, metastatic potential, potential prognosis, as well as aid in patient monitoring and guiding personalized therapy. Successful detection, isolation, and enumeration of CTCs remains a challenge due to their rarity in blood and biological heterogeneity. Though traditionally known for their roles in maintaining hemostasis and promoting wound healing, platelets significantly contribute to cancer metastasis by interacting with CTCs in the bloodstream. These interactions protect CTCs from shear stress and immune detection, facilitate their arrest in blood vessels, and ultimately promote metastatic spread to distant tissues. We describe a system that leverages platelet-cancer cell interactions to target and retrieve CTCs from a liquid biopsy sample by engineering magnetic platelet decoys. Conventional techniques typically rely on specific markers on the CTC surface (most commonly EpCAM). Our approach begins with engineering platelet decoys that lose their functional ability but retain some functional surface receptors that enable their ability to interact with other cells, followed by ION (iron oxide nanoparticle) loading which permits CTC capture <em>via</em> magnetic retrieval. Because our non-antibody-based approach relies on magnetic platelet decoy-CTC interactions, we infer that our system is applicable to CTCs of various origins and phenotypes. We have characterized and shown that our system can effectively interact with various cell lines (MDA-MB-231, MCF-7, A549) and capture these cells in spiked whole blood with a retrieval rate of at least 58.5%. This study has also demonstrated that the magnetic platelet decoys remain stable and effective after cryopreservation. While experiments used freshly prepared magnetic platelet decoys, stability assessment demonstrated that magnetic platelet decoys stored for one month at −20 °C with cryoprotectant retain their activity and ability to interact with other cells, supporting their practical use in future applications.</div></div>","PeriodicalId":101235,"journal":{"name":"The Journal of Liquid Biopsy","volume":"10 ","pages":"Article 100326"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145222212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating tumour DNA (ctDNA) as a predictor of progression-free and overall survival in non-resectable pancreatic cancer: a systematic review and meta-analysis","authors":"Mette M. Steiniche ,&nbsp;Louise B. Callesen ,&nbsp;Elizabeth H. Vlk ,&nbsp;Lise Ventzel ,&nbsp;Signe Timm ,&nbsp;Rikke F. Andersen ,&nbsp;Sidsel C. Lindgaard ,&nbsp;Torben F. Hansen ,&nbsp;Morten Ladekarl ,&nbsp;Karen-Lise G. Spindler","doi":"10.1016/j.jlb.2025.100441","DOIUrl":"10.1016/j.jlb.2025.100441","url":null,"abstract":"<div><h3>Background</h3><div>This systematic review and meta-analysis synthesised current evidence on circulating tumour DNA (ctDNA) for predicting clinical outcomes in patients with non-resectable pancreatic ductal adenocarcinoma (PDAC).</div></div><div><h3>Methods</h3><div>PubMed, Embase, and Cochrane databases were searched up to 31/01/2025. Eligible studies reported prognostic value of ctDNA in patients with non-resectable PDAC. Meta-analyses evaluated associations between baseline ctDNA and changes in ctDNA during treatment (ctDNA kinetics) and survival outcomes. Risk of bias was assessed using the Quality in Prognosis Studies (QUIPS) tool.</div></div><div><h3>Results</h3><div>Sixty-four studies involving 5652 patients with non-resectable PDAC were included, with 24 studies contributing to meta-analyses. High baseline ctDNA level implied shorter overall survival (OS; HR = 2.3, 95 % CI 1.9–2.8; n = 1883) and progression-free survival (PFS; HR = 2.1, 95 % CI 1.8–2.4; n = 1196). Unfavourable ctDNA kinetics were associated with shorter OS (HR = 3.1, 95 % CI 2.3–4.3; n = 269) and PFS (HR = 4.3, 95 % CI 2.6–7.2; n = 244). Thirty-three studies had high risk of bias in at least one QUIPS domain.</div></div><div><h3>Conclusion</h3><div>Baseline ctDNA and ctDNA kinetics demonstrate strong prognostic value in non-resectable PDAC. However, clinical translation is limited by methodological heterogeneity, notably the use of study-specific, non-validated thresholds. Standardised, externally validated thresholds for interpreting ctDNA changes are needed to support clinical implementation.</div></div><div><h3>Prospero</h3><div>CRD42023438774.</div></div>","PeriodicalId":101235,"journal":{"name":"The Journal of Liquid Biopsy","volume":"10 ","pages":"Article 100441"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145466249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An innovative nuclear antigen-based approach for single-cell isolation of circulating tumor cells in adrenal cortical carcinoma","authors":"Giulia Cantini ,&nbsp;Francesca Salvianti ,&nbsp;Roberta Armignacco ,&nbsp;Arianna Pia Propato ,&nbsp;Letizia Canu ,&nbsp;Tonino Ercolino ,&nbsp;Anna Aurora Dedonno ,&nbsp;Chiara Lepri ,&nbsp;Massimo Mannelli ,&nbsp;Gabriella Nesi ,&nbsp;Serena Pillozzi ,&nbsp;Giuseppe Defazio ,&nbsp;Pamela Pinzani ,&nbsp;Michaela Luconi","doi":"10.1016/j.jlb.2025.100447","DOIUrl":"10.1016/j.jlb.2025.100447","url":null,"abstract":"<div><div>Adrenal cortical carcinoma (ACC) is a rare and aggressive endocrine tumor that originates from the adrenal cortex. Radical tumor resection remains the most effective therapy since survival dramatically drops when metastases are present at diagnosis. Hence, there is an urgent need for reliable biomarkers to enable early diagnosis, monitor minimal residual disease (MRD), and assess chemotherapy response. Circulating tumor cells (CTCs) detected via blood liquid biopsy may represent a valuable oncological marker in ACC patients. However, CTC isolation methods so far applied to ACC patients lack specificity, reproducibility and standardization, thus preventing the potential application of CTCs in the management of these patients.</div><div>In this study, we present a novel method for the specific and reproducible detection and analysis of single CTCs in ACC patients. This approach combines size- and mechanical property-based enrichment via the Parsortix® system with immunofluorescent detection and isolation of single CTCs using DEPArray® technology, targeting the steroidogenic factor-1 (SF1) nuclear adrenal cortex marker. Isolated CTCs undergo low-pass copy number alteration (CNA) analysis. This is the first report of a nuclear antigen-based method for isolating single CTCs in suspension, overcoming the limitations of membrane and cytokeratin markers commonly used in other solid tumors. By exploiting the large nuclear size of CTCs, this strategy provides an alternative and more standardized approach for single-cell isolation in tumors lacking specific surface markers.</div></div>","PeriodicalId":101235,"journal":{"name":"The Journal of Liquid Biopsy","volume":"10 ","pages":"Article 100447"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145579312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liquid biopsy biomarkers in cervical cancer: A systematic review and meta-analysis","authors":"Isaac Kinyua Njangiru ,&nbsp;Bizhar Ahmed Tayeb ,&nbsp;Hazhmat Ali ,&nbsp;Rafl M. Kamil","doi":"10.1016/j.jlb.2025.100328","DOIUrl":"10.1016/j.jlb.2025.100328","url":null,"abstract":"<div><h3>Background/objectives</h3><div>Liquid biopsy biomarkers are emerging as vital tools for cancer screening and diagnosis, offering a noninvasive and accurate approach to early malignancy detection. This study aimed to assess the diagnostic performance of circulating biomarkers in cervical cancer (CC).</div></div><div><h3>Methods</h3><div>A comprehensive literature search was conducted across the Cochrane Library, PubMed, SCOPUS, and Web of Science, identifying 130 studies, of which 11 met the inclusion criteria. Data on true and false positives and negatives were extracted to calculate pooled sensitivity, specificity, likelihood ratios, diagnostic odds ratios (DORs), and 95 % confidence intervals (CIs). Study quality and risk of bias were evaluated using the QUADAS-2 tool, while publication bias was assessed via Deeks’ funnel plot.</div></div><div><h3>Results</h3><div>The meta-analysis included 1301 patients, 670 healthy controls, and 438 individuals with benign or precancerous lesions. Pooled sensitivity was 0.68 (95 % CI: 0.65–0.70), and specificity was 0.84 (95 % CI: 0.81–0.86). The DOR was 61.10 (95 % CI: 32.20–115.9), with an area under the curve (AUC) of 0.95. Most studies demonstrated a low risk of bias, and no significant publication bias was observed (P = 0.06). Plasma-based liquid biopsies and miRNA biomarkers exhibited superior diagnostic performance.</div></div><div><h3>Conclusions</h3><div>These findings suggest that liquid biopsy biomarkers may substantially enhance the accuracy of cervical cancer detection, representing a promising strategy for early diagnosis.</div></div>","PeriodicalId":101235,"journal":{"name":"The Journal of Liquid Biopsy","volume":"10 ","pages":"Article 100328"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145222210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping the stage-specific plasma p53 interactome reveals colorectal cancer progression signatures and therapeutic vulnerabilities","authors":"Raajesh Anand Natarajan ,&nbsp;Siva Kaliyamoorthy ,&nbsp;Vinoth Boopathi ,&nbsp;Jawahar Ramasamy ,&nbsp;Ravikumar Sambandam","doi":"10.1016/j.jlb.2025.100329","DOIUrl":"10.1016/j.jlb.2025.100329","url":null,"abstract":"<div><div>Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide, yet the molecular changes that occur in the bloodstream as the disease advances remain poorly understood. In particular, how p53—a key tumor suppressor—interacts with circulating proteins at different stages of CRC has not been well characterized. In this discovery-phase study, we analyzed plasma samples from patients with CRC stages I–IV using high-resolution LC–MS/MS. Stage-specific proteins were identified and cross-validated with transcriptomic data, revealing TP53 as a central hub in multiple functional networks. Enrichment analyses highlighted progressive changes in pathways linked to immune surveillance, complement activation, and cellular stress responses. Early-stage disease showed signals consistent with tumor suppression and immune regulation, while advanced stages were enriched in proteins associated with metastasis and therapy resistance. Notably, KLHL40 (Stage I) and FKBP1A (Stage III) emerged as potential stage-specific circulating biomarkers with functional links to p53 signaling. These findings outline a plasma-based molecular map of p53-associated protein networks across CRC progression and point to candidate biomarkers that warrant validation in larger, independent, and longitudinal studies.</div></div>","PeriodicalId":101235,"journal":{"name":"The Journal of Liquid Biopsy","volume":"10 ","pages":"Article 100329"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145417370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cerebrospinal fluid ctDNA clarifies clonal divergence: leptomeningeal flare of EGFR-mutant disease after switch to selpercatinib for acquired RET fusion","authors":"Kei Kunimasa ,&nbsp;Motohiro Tamiya ,&nbsp;Takako Inoue ,&nbsp;Nobuaki Mamesaya ,&nbsp;Tsunehiro Tanaka ,&nbsp;Kiyohide Komuta ,&nbsp;Shun Futamura ,&nbsp;Keiichiro Honma ,&nbsp;Kazumi Nishino","doi":"10.1016/j.jlb.2025.100450","DOIUrl":"10.1016/j.jlb.2025.100450","url":null,"abstract":"<div><div>Liquid biopsy can expose spatially segregated resistance biology that is invisible to single-site tissue testing, particularly across the blood–brain barrier. We report how cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) clarified therapeutic direction in <em>EGFR</em>-mutated non-small-cell lung cancer (NSCLC) with leptomeningeal involvement. A 67-year-old woman with <em>EGFR</em> exon 19–deleted adenocarcinoma received afatinib followed by long-term osimertinib. After three years, progression of the primary lesion prompted rebiopsy, which revealed a <em>CCDC6-RET</em> fusion with strong RET immunoreactivity. Selpercatinib monotherapy yielded minor thoracic shrinkage at 1 month but was followed by dizziness and MRI evidence of leptomeningeal enhancement at 3 months. CSF analysis showed pleocytosis without malignant cells. Critically, CSF ctDNA demonstrated the <em>EGFR</em> E746_A750 deletion at 29.2 % variant allele frequency by amplicon sequencing, whereas the <em>CCDC6–RET</em> fusion was undetectable by targeted sequencing and highly sensitive single-plex qPCR using junction-specific primers. Re-challenging with osimertinib rapidly improved symptoms and led to resolution of leptomeningeal enhancement. These data indicate clonal divergence at acquired resistance: a <em>RET</em>-fusion clone dominated the thoracic compartment while <em>EGFR</em>-addicted clones predominated in the leptomeninges. The leptomeningeal flare after discontinuing EGFR inhibition highlights the risk of switching to RET inhibitor monotherapy when CNS disease is driven by the original <em>EGFR</em> mutant clone. CSF liquid biopsy provided actionable, compartment-specific genotyping that outperformed cytology and guided effective retreatment. Incorporating CSF ctDNA into routine evaluation may improve therapeutic alignment across sanctuary sites; when feasible, maintaining EGFR blockade should be considered when CNS involvement is suspected in <em>EGFR</em>-mutated NSCLC in routine practice.</div></div>","PeriodicalId":101235,"journal":{"name":"The Journal of Liquid Biopsy","volume":"10 ","pages":"Article 100450"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145750061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}