JCO precision oncology最新文献

{"title":"Cobimetinib + Vemurafenib in Patients With <i>BRAF</i> V600E-Mutant Papillary Thyroid and Biliary Tract Cancers: Results From the TAPUR Study.","authors":"Samantha A Diamond-Rossi, Michael Rothe, Elizabeth Garrett-Mayer, Evan Pisick, Jonathan Bleeker, Apar Kishor Ganti, Funda Meric-Bernstam, Justin T Moyers, Suresh G Nair, Kunal C Kadakia, Nitin Rohatgi, Vaibhav Sahai, Namrata Vijayvergia, Philip J Gold, Manish R Sharma, Dominique C Hinshaw, Abigail Gregory, Gina N Grantham, Susan Halabi, Richard L Schilsky","doi":"10.1200/PO-26-00703","DOIUrl":"10.1200/PO-26-00703","url":null,"abstract":"<p><strong>Purpose: </strong>TAPUR is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations. Results of two cohorts of patients with advanced thyroid (TC) or biliary tract cancer (BTC) with <i>BRAF</i> V600E mutations treated with cobimetinib plus vemurafenib (C + V) are reported.</p><p><strong>Methods: </strong>Eligible patients had measurable disease (RECIST v1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. The primary end point was disease control (DC), defined as objective response (OR) or stable disease (SD) of at least 16+ weeks duration. Simon's two-stage design was based on a null DC rate of 15% versus 35% (power = 0.85; α = .10). Both cohorts expanded to stage II but closed before reaching the target sample size by pharmaceutical company request; inferences are based on thresholds set forth in the protocol to maintain the α level. Secondary end points included OR, progression-free survival, overall survival, duration of response, duration of SD, and safety.</p><p><strong>Results: </strong>Patients with TC (N = 22; n = 16 evaluable) or BTC (N = 18; n = 15 evaluable) with <i>BRAF</i> V600E mutations were enrolled. In the TC cohort, the DC and OR rates were 94% (one-sided 90% CI, 78 to 100) and 63% (95% CI, 35 to 85), respectively. In the BTC cohort, the DC and OR rates were 67% (one-sided 90% CI, 47 to 100) and 53% (95% CI, 27 to 79), respectively. The null hypothesis of 15% DC rate was rejected for both cohorts (<i>P</i> < .0001). Twenty-one patients (53%) had ≥1 treatment-related grade 3 to 4 adverse event (AE) or serious AE.</p><p><strong>Conclusion: </strong>The combination of C + V met the prespecified criteria to declare a signal of activity in patients with TC and BTC with <i>BRAF</i> V600E mutations.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 10","pages":"e2600703"},"PeriodicalIF":4.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding Treatment Response and Prognosis in Unresectable Locally Advanced Non-Small Cell Lung Cancer by Integrating Spatiotemporal Heterogeneity From ¹⁸F-FDG Positron Emission Tomography-Computed Tomography: A Multicenter Study.","authors":"Yu Ji, Jiaqi Wang, Meixia Zhou, Yaru Wang, Zhengjun Dai, Jingsong Zheng","doi":"10.1200/PO-26-00609","DOIUrl":"10.1200/PO-26-00609","url":null,"abstract":"<p><strong>Purpose: </strong>Treatment response in unresectable locally advanced non-small cell lung cancer (LA-NSCLC) is highly variable due to marked intratumoral heterogeneity, while existing predictive biomarkers lack accuracy. We aimed to develop and validate a pretreatment ¹⁸F-FDG positron emission tomography (PET)-computed tomography (CT)-derived spatiotemporal heterogeneity model to predict treatment response and prognosis in unresectable LA-NSCLC, and to explore its biological underpinnings.</p><p><strong>Materials and methods: </strong>In a multicenter cohort of 434 patients with unresectable LA-NSCLC (training: n = 215; internal validation: n = 93; external validation: n = 126), treatment response was classified as responsive or nonresponsive based on initial assessment. Four distinct habitats (PEThigh-CThigh, PETlow-CTlow, PETlow-CThigh, and PEThigh-CTlow) were generated via the Otsu algorithm. Temporal heterogeneity was quantified using metabolic hotspot displacement (normalized distance from the hotspot to the tumor centroid and normalized distance from the hotspot to the tumor periphery) and integrated with spatial radiomics to build a multidimensional spatiotemporal model. Model performance was evaluated against conventional metrics, with interpretability enhanced via nomogram and SHapley Additive exPlanations analysis. Survival outcomes were assessed using Kaplan-Meier curves, and public transcriptomic data were analyzed to characterize underlying pathways.</p><p><strong>Results: </strong>The spatiotemporal model accurately predicted treatment response with AUCs of 0.822 (training), 0.821 (internal validation), and 0.810 (external validation), significantly outperforming conventional whole-tumor PET-CT models. It maintained robust generalizability across treatment subgroups and effectively stratified patients by progression-free survival and overall survival (<i>P</i> < .01). PEThigh-CThigh habitat volume fraction correlated with treatment resistance, whereas PETlow-CTlow habitat correlated with better response. Exploratory pathway analysis highlighted key pathways involving drug metabolism, glycolytic reprogramming, and immune microenvironment remodeling.</p><p><strong>Conclusion: </strong>This study establishes a noninvasive spatiotemporal heterogeneity biomarker based on ¹⁸F-FDG PET-CT that reliably predicts treatment response and prognostic outcomes in unresectable LA-NSCLC. It offers valuable insights for personalized clinical decision making and supports precision oncology.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 10","pages":"e2600609"},"PeriodicalIF":4.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13657396/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149109457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tailoring Escalated Adjuvant Chemotherapy for Multifocal and Multicentric Breast Cancer With Low Tumor Burden.","authors":"Yonghui Su, Jiaqi Ying, Zhuozhao Zhan, Tingting Wu, Yena Yu, Wanxin Gao, Yizi Zheng","doi":"10.1200/PO-26-00177","DOIUrl":"10.1200/PO-26-00177","url":null,"abstract":"<p><strong>Purpose: </strong>The prognostic significance of multifocal and multicentric breast cancer (MMBC) with low tumor burden remains controversial, and adjuvant chemotherapy guidelines for these patients are lacking.</p><p><strong>Materials and methods: </strong>Female patients with cT1-T2 MMBC or unifocal breast cancer (UBC) diagnosed between 2010 and 2020 were identified from the SEER database. Propensity score matching (PSM) balanced baseline characteristics. Survival outcomes were evaluated using Kaplan-Meier and Cox proportional hazards models, with subgroup analyses stratified by tumor size in node-negative MMBC.</p><p><strong>Results: </strong>After PSM, 9,751 matched pairs of patients with MMBC and UBC were included. Analyses showed MMBC had significantly worse overall survival (OS) and breast cancer-specific survival (BCSS) than UBC (both <i>P</i> < .001). Multivariate Cox regression confirmed chemotherapy improved OS (hazard ratio [HR], 0.583 [95% CI, 0.522 to 0.652]) and BCSS (HR, 0.830 [95% CI, 0.702 to 0.980]) in MMBC. In eligible cases, 1,731 matched pairs with and without chemotherapy were identified. Subgroup analyses showed that in node-negative MMBC, chemotherapy improved OS only when tumors were ≥1 cm (tumor <1 cm: HR, 0.804 [95% CI, 0.506 to 1.275], <i>P</i> = .353; 1-2 cm: HR, 0.577 [95% CI, 0.414 to 0.806], <i>P</i> = .001; ≥2 cm: HR, 0.535 [95% CI, 0.399 to 0.717], <i>P</i> < .001).</p><p><strong>Conclusion: </strong>MMBC predicts poorer survival than UBC. In node-negative MMBC, chemotherapy confers benefit only when tumor size is ≥1 cm, suggesting multifocality and multicentricity should guide chemotherapy decisions. Prospective studies are warranted to confirm findings and refine guidelines.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 10","pages":"e2600177"},"PeriodicalIF":4.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13668041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149127618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Determining the Causal Effect of Neurotrophic Tropomyosin Receptor Kinase Gene Fusions on Survival Prognosis for Adult Patients With Advanced Cancers.","authors":"Emanuel Krebs, Nirupama Tamvada, Deirdre Weymann, Howard J Lim, Stephen Chia, Cheryl Ho, Dean A Regier","doi":"10.1200/PO-26-00281","DOIUrl":"10.1200/PO-26-00281","url":null,"abstract":"<p><strong>Purpose: </strong>Uncertainty about the prognostic significance of neurotrophic tropomyosin receptor kinase (<i>NTRK</i>) fusions complicates clinical decisions and interpretation of survival outcomes in oncology care. Drawing on the largest cohort of <i>NTRK</i> fusion-positive (<i>NTRK</i>+) patients, we establish the prognostic effect of <i>NTRK</i> fusions in adults with advanced cancers.</p><p><strong>Methods: </strong>We used a large real-world clinicogenomic research database from the United States to emulate a pragmatic randomized trial that determines the causal effect of harboring an <i>NTRK</i> gene fusion (<i>NTRK</i>+) on survival prognosis for adult patients with advanced solid tumors. We 1:1 matched <i>NTRK</i>+ patients to patients with no identified <i>NTRK</i> genomic alterations (<i>NTRK</i>-) using a machine learning matching approach. Excluding patients who received TRK inhibitors, we conducted stratified matching within common tumor groups. We used Kaplan-Meier and Weibull regression survival analyses and estimated the difference in restricted mean survival time (RMST) over 1-, 2-, 3-, and 5-year study periods.</p><p><strong>Results: </strong>We included 68,145 <i>NTRK-</i> patients for matching to 73 <i>NTRK</i>+ patients within seven tumor groups, including colorectal (n = 22), non-small cell lung (n = 13), sarcoma (n = 13), breast (n = 10), head and neck (n = 7), neuroendocrine (n = 4), and prostate (n = 4), and 14 <i>NTRK</i>+ patients representing eight other cancers. The difference in overall survival over 1 year was statistically significant using the Kaplan-Meier estimate (<i>P</i> = .008), Weibull regression (hazard ratio, 2.105 [95% CI, 1.207 to 3.673]), and RMST (-50 days [95% CI, -96 to -5]; <i>P</i> = .029). Differences were also statistically different at 2 years and 3 years. At 5 years, no survival differences were statistically significant.</p><p><strong>Conclusion: </strong>In this large real-world target trial emulation, <i>NTRK</i> gene fusions were associated with clinically meaningful reductions in overall survival among adults with advanced cancers not treated with TRK inhibitors. These findings clarify the prognostic role of <i>NTRK</i> fusions and inform clinical interpretation of outcomes in routine oncology.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 10","pages":"e2600281"},"PeriodicalIF":4.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13668040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149127594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic Analysis Using Liquid Biopsy: Considerations for Pretest Counseling in UK Practice.","authors":"David John McMahon, Elizabeth Bancroft, George J Burghel, Ellen Copson, Michael Hubank, Jennifer Wiggins, Katie Snape, Natalie Cook, Ian Frayling, Matthew J Murray, Alastair Greystoke, Matthew G Krebs, Sanjay Popat, Terri Patricia McVeigh","doi":"10.1200/PO-26-00366","DOIUrl":"10.1200/PO-26-00366","url":null,"abstract":"<p><p>Modern cancer diagnostics is heavily reliant on molecular data. Next-generation sequencing using liquid biopsy (LB) is primarily focused on identifying predictive and prognostic biomarkers to guide systemic therapy decision making. However, additional findings including genomic variants of possible or probable germline origin are detected in a significant minority of patients (3%-18%), with significant implications for patients and their families. Pretest information provision regarding both the purpose and potential benefits of the test and additional findings on LB varies in clinical practice, with little guidance for clinicians regarding the degree of detail required regarding possible additional findings. LB requires explicit disclosure of these aspects. Implementing a standardized, context-dependent approach to this discussion, with nationally standardized information provision tools, should be prioritized to enable patient-centered decision making regarding LB, without prioritizing the incidentalome over the primary purpose of the test-refining and optimizing treatment options.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 10","pages":"e2600366"},"PeriodicalIF":4.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13668035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149127558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>PIK3CA</i> Mutations in Advanced or Recurrent Endometrial Cancer: An Exploratory Molecular Profiling From the Phase II MITO END-3 Study.","authors":"Anna Passarelli, Giovanni Luca Scaglione, Daniela Califano, Michele Bartoletti, Domenica Lorusso, Sabrina Chiara Cecere, Anna Fagotti, Alberto Farolfi, Claudia Andreetta, Jole Ventriglia, Laura Arenare, Carmela Pisano, Daniela Russo, Maria Teresa Perri, Saverio Cinieri, Simona Scalone, Ugo De Giorgi, Valentina Arcangeli, Elena Zafarana, Maria Chiara Cannizzaro, Serafina Mammoliti, Tommaso Ambrosio, Rossella De Cecio, Clorinda Schettino, Francesco Perrone, Sandro Pignata","doi":"10.1200/PO-26-00484","DOIUrl":"10.1200/PO-26-00484","url":null,"abstract":"<p><strong>Purpose: </strong>Immunotherapy with chemotherapy significantly improves progression-free survival in advanced endometrial cancer (EC), especially in microsatellite instability-high (MSI-H) cases. Despite this, for recurrent EC in the postimmunotherapy setting, new treatment options are urgently needed. The PI3K pathway is frequently altered in gynecologic cancers, including EC, representing a potential treatment target.</p><p><strong>Patients and methods: </strong>In a preplanned translational analysis of the MITO END-3, we retrospectively analyzed the genomic abnormalities of 107 patients with samples eligible for next-generation sequencing (NGS) analysis (FoundationOne CDx) with a focus on <i>PIK3CA</i> mutational status.</p><p><strong>Results: </strong>In our analysis, the four most frequently mutated genes were <i>TP53</i>, <i>PIK3CA</i>, <i>ARID1A</i>, and <i>PTEN. PIK3CA</i> mutations were detected in 51.4% (55/107 patients) of tissue samples. A total of 68 different <i>PIK3CA</i> mutations were observed, of which 64 were considered pathogenic and four were classified as variants of unknown significance, with the co-occurrence of two different pathogenic mutations in 2 patients. The most frequent <i>PIK3CA</i> mutations were found in the kinase domain, most commonly H1047R (11/68) and H1047Y (3/68), and in the helical domain, including E545K (4/68) and E542K (3/68). Notably, 24 different <i>PIK3CA</i> mutations out of 68 reported in MITO END-3 are considered predictive of response to PI3K inhibition with alpelisib according to current literature in breast cancer. Interestingly, <i>PIK3CA</i> mutations were observed in all The Cancer Genome Atlas categories.</p><p><strong>Conclusion: </strong>In this post hoc analysis from the MITO END-3 trial, we confirmed the high frequency of <i>PIK3CA</i> mutations in EC, establishing this tumor as an ideal candidate for testing of PI3K inhibitors in clinical trials.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 10","pages":"e2600484"},"PeriodicalIF":4.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Latent Class Analysis-Derived Classification and Cancer-Specific Death in Endometrial Carcinoma: A Population-Based Cohort Study.","authors":"Suojian Zhao, Jing Cheng, Hua Wang, Qiuji Wu","doi":"10.1200/PO-26-00393","DOIUrl":"https://doi.org/10.1200/PO-26-00393","url":null,"abstract":"<p><strong>Purpose: </strong>Molecular classifications have advanced prognostic stratification in endometrial carcinoma (EC), but they do not explicitly account for cause-specific mortality (CSM) and host-clinical context. We aimed to derive a clinically accessible classification that links demographic/clinicopathologic features, CSM, and molecular landscapes and to test whether it refines molecular-based survival stratification.</p><p><strong>Methods: </strong>We conducted latent class analysis (LCA) on 46,772 cases of primary EC from the SEER program to identify latent characteristic lineages. The resulting LCA scheme was mapped to The Cancer Genome Atlas (TCGA) data. Cumulative incidence functions and Fine-Gray competing risks regression were used to estimate CSM. The Fisher test was employed to evaluate its association with TCGA subtypes. Transcriptomic differential expression analysis and pathway enrichment analysis were performed where data were accessible. Likelihood ratio tests assessed treatment-LCA interactions.</p><p><strong>Results: </strong>Five clinically interpretable classes emerged. Class 4 had significantly increased subdistribution hazard for CSM (1.34, <i>P</i> = .031); classes 3/5 trended higher. Classes were associated with TCGA subtypes (<i>P</i> < .001). Specifically, class 3 was associated with copy number (CN)-high enriched sybtype and class 1 was associated with CN-low subtype. Incorporating LCA labels into molecular survival models increased C-index and robustness of prognostic discrimination. Transcriptomics revealed class specific signatures implicating metabolic reprogramming, DNA repair, and immune pathways. Treatment benefit varied by class: compared with surgery alone, class 3 demonstrated the most significant survival advantage with surgery-radiotherapy-chemotherapy. Class 4 exhibited sensitivity to radiotherapy, while class 5 benefited exclusively from the triple therapy. Conversely, class 1/2 did not benefit from combined treatment.</p><p><strong>Conclusion: </strong>LCA of routine clinical variables identifies subgroups susceptible to CSM and complements TCGA molecular classification, improving survival stratification.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 10","pages":"e2600393"},"PeriodicalIF":4.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149109480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patient-Derived Organoids and the Next Phase of Functional Precision Oncology.","authors":"Eleftherios A Makris, Richard A Erali, Konstantinos I Votanopoulos","doi":"10.1200/PO-26-00363","DOIUrl":"https://doi.org/10.1200/PO-26-00363","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 10","pages":"e2600363"},"PeriodicalIF":4.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum: Clinicogenomic Landscape and Function of <i>PIK3CA</i>, <i>AKT1</i>, and <i>PTEN</i> Mutations in Breast Cancer.","authors":"Jacqueline J Tao, Saumya D Sisoudiya, Hanna Tukachinsky, Alexa B Schrock, Ericka M Ebot, Smruthy Sivakumar, Ethan S Sokol, Neil Vasan","doi":"10.1200/PO-26-01021","DOIUrl":"https://doi.org/10.1200/PO-26-01021","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 10","pages":"e2601021"},"PeriodicalIF":4.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor-Free Circulating Tumor DNA in Node-Negative Rectal Cancers Undergoing Neoadjuvant Chemotherapy, Excision, and Observation in the Phase II NEO Trial (CO.28).","authors":"Jonathan M Loree, Emma Titmuss, Carl J Brown, Thereasa Rich, Kimberly Banks, Vallerie Gordon, Sunil Patel, Marianne Krahn, Antonio Caycedo-Marulanda, Manoj Raval, Dongsheng Tu, Derek J Jonker, Christopher J O'Callaghan, Hagen F Kennecke","doi":"10.1200/PO-26-00459","DOIUrl":"10.1200/PO-26-00459","url":null,"abstract":"<p><strong>Purpose: </strong>Organ preservation is a priority in early-stage rectal cancer as total mesorectal excision (TME) can reduce quality of life. The Canadian Cancer Trials Group CO.28 trial demonstrated that neoadjuvant chemotherapy followed by transanal excision was effective in patients with cT1-3, node-negative (N0) rectal cancer. Here, we explored circulating tumor DNA (ctDNA) from the trial as a potential future decision aid to guide TME.</p><p><strong>Materials and methods: </strong>Fifty-three of 58 patients (91.4%) from CO.28 had at least one sample available for ctDNA analysis using the Guardant Reveal epigenomic assay from the following time points: prechemotherapy, postchemotherapy, pretransanal endoscopic surgery (TES), and on follow-up at months 12, 24, and 36.</p><p><strong>Results: </strong>ctDNA was detected in 45.8% of patients before neoadjuvant chemotherapy. Detection was similar by T-stage (<i>P</i> = .18). The rate of detectable ctDNA significantly decreased after chemotherapy (and pre-TES) to 8.7% (<i>P</i> < .0001), with 41.4% of evaluable patients moving from detectable ctDNA to completely undetectable following chemotherapy. ctDNA detection postchemotherapy and pre-TES was associated with poor response and persistent cancer (<i>P</i> = .03), with recommended TME for 100% (n = 4 of 4) of patients with ctDNA detected versus 38.1% (n = 16 of 42) of patients with undetectable ctDNA. Five patients had recurrence during follow-up (two local, three distant), 50% of whom (1 of 2, both local) had longitudinal plasma collected had detectable ctDNA at progression.</p><p><strong>Conclusion: </strong>ctDNA testing identified cancers with inadequate response to chemotherapy in patients for whom TME was recommended. A tissue-free assay may enable faster turnaround times compared with tumor-informed assays and provide a tool to support organ preservation. Further exploration of these assays in early-stage rectal cancers is warranted.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 10","pages":"e2600459"},"PeriodicalIF":4.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13657393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149109590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}