JCO precision oncology最新文献

{"title":"Prognostic Significance of Cell-Free DNA Derived 5-Hydroxymethylcytosine Signatures in Newly Diagnosed Multiple Myeloma.","authors":"Zhou Zhang, Benjamin Derman, Bei Wang, Krissana Kowitwanich, John Cursio, Lu Gao, Daniel Appelbaum, Chuan He, Andrzej Jakubowiak, Wei Zhang, Brian C Chiu","doi":"10.1200/PO-25-01121","DOIUrl":"10.1200/PO-25-01121","url":null,"abstract":"<p><strong>Purpose: </strong>While survival outcomes in multiple myeloma (MM) have improved with contemporary combination therapies, predicting disease trajectories for individual patients at diagnosis remains a significant challenge. We investigate the prognostic value of a noninvasive biomarker-cell-free DNA (cfDNA)‑derived 5-hydroxymethylcytosine (5hmC) signature-in newly diagnosed MM, aiming to improve risk stratification at diagnosis.</p><p><strong>Materials and methods: </strong>In this prospective cohort study, 321 patients with newly diagnosed MM were enrolled between 2010 and 2017, with follow-up through 2022. We profiled genome-wide 5hmC modifications (gene bodies) in cfDNA collected at diagnosis. We applied elastic net regularization to a Cox proportional hazards model to identify 5hmC signatures associated with overall survival (OS) and progression-free survival (PFS). A weighted prognostic score (wp-score), based on 18 key 5hmC-modified genes, was developed through machine learning and validated in the validation set, controlling for clinical prognostic factors.</p><p><strong>Results: </strong>During a median follow-up of 70.5 months, 127 deaths occurred. The cfDNA 5hmC at diagnosis reflected the 5hmC in bone marrow‑derived tumor cells and differed across clinical subgroups. The wp-score showed strong prognostic ability for OS (hazard ratio [HR], 2.9 [95% CI, 1.7 to 4.9]; <i>P</i> < .0001) and PFS (HR, 1.8 [95% CI, 1.3 to 2.5] <i>P</i> = .00014) in the validation set, controlling for known prognostic factors, including stage, lactate dehydrogenase levels, and treatment type. The wp-score calculated at diagnosis remained associated with OS and PFS at 24-, 48-, and 72-month follow-up periods.</p><p><strong>Conclusion: </strong>This prospective study suggests that cfDNA-derived 5hmC signatures at diagnosis provide independent prognostic information for OS and PFS in MM. These findings support further investigation and independent validation of noninvasive epigenomic biomarkers within contemporary MM risk stratification frameworks.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 7","pages":"e2501121"},"PeriodicalIF":4.7,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13418869/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148578829","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":"Rechallenge With Anti-Human Epidermal Growth Factor Receptor 2 Therapy Guided by Liquid Biopsy in <i>HER2</i>-Amplified Metastatic Colorectal Cancer.","authors":"Patricia Garcia-Pastor, Javier Ros, Iosune Baraibar, Francesc Salva, Clara Salva, Ariadna Garcia, Caterina Vaghi, Josep Tabernero, Ana Vivancos, Elena Elez","doi":"10.1200/PO-26-00515","DOIUrl":"10.1200/PO-26-00515","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 7","pages":"e2600515"},"PeriodicalIF":4.7,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13432965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148620192","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 Landscape of GNAQ and GNA11 Mutations in Metastatic Solid Tumors: A Real-World Data Analysis.","authors":"Minsuk Kwon, Yunjin Go, Ji Eun Shin, Sung Hee Lim, Jung Yong Hong, Se Hoon Park, Joon Oh Park, Young Suk Park, Kee-Taek Jang, Jeeyun Lee, Seung Tae Kim","doi":"10.1200/PO-26-00072","DOIUrl":"10.1200/PO-26-00072","url":null,"abstract":"<p><strong>Purpose: </strong>Activating mutations in <i>GNAQ</i> and <i>GNA11</i> are recognized oncogenic drivers in uveal melanoma (UM); however, their prevalence across various cancers and their genomic context remain inadequately characterized. This study aimed to elucidate the genomic landscape of these mutations across a range of metastatic solid tumors.</p><p><strong>Materials and methods: </strong>We conducted a pan-cancer analysis involving 5,416 patients with metastatic solid tumors who had undergone next-generation sequencing. Our evaluation encompassed mutational distribution, hotspot identification, tumor mutational burden (TMB), microsatellite instability (MSI), and coalterations.</p><p><strong>Results: </strong>Mutations in <i>GNAQ</i> (n = 10) or <i>GNA11</i> (n = 16) were detected in 26 patients (0.48%). Aside from UM, these mutations were most frequently observed in colorectal cancer (38.5%), melanoma (15.4%), gastric cancer (11.5%), and neuroendocrine tumors (7.7%). A notable subset exhibited an immunogenic profile, with 42.3% classified as TMB-High (≥10 Mut/Mb) and 19.2% as MSI-High. This immunogenic subgroup was primarily associated with nonhotspot mutations (eg, p.Gln88His, p.Ala231Val), suggesting that these may represent bystander events in hypermutated tumors. Conversely, canonical hotspots (Q209, R183) were predominantly identified in TMB-Low/microsatellite stable tumors, such as UM. Notable coalterations included <i>NOTCH3</i> (80%), <i>FAT1</i> (70%), and <i>TP53</i> (37.5%-40%). Exploratory survival analysis suggested favorable OS in the immunogenic subgroup, supported by cases with durable ICI benefit including a treatment-free remission exceeding 21 months.</p><p><strong>Conclusion: </strong>This real-world analysis demonstrates that GNAQ and GNA11 mutations are not exclusive to UM, occurring across diverse solid tumors, particularly colorectal cancer. The strong association between nonhotspot mutations and high TMB/MSI status defines a distinct immunogenic subgroup, underscoring the need to differentiate canonical hotspot drivers from bystander mutations when selecting targeted pathway inhibitors versus immune checkpoint blockade.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 7","pages":"e2600072"},"PeriodicalIF":4.7,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13361959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396325","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":"Erratum: Multi-Institutional Study Evaluating the Role of Early Circulating Tumor DNA Dynamics During Treatment With Immune Checkpoint Inhibitors in Patients With Advanced-Stage Melanoma.","authors":"Vincent T Ma, Alice Y Zhou, Amir Forati, Fauzia Hollnagel, Janmesh D Patel, Caroline Burkey, Alyssa Steimle, Deepak M Sahasrabudhe, Matthew C Mannino, Jennifer L Schehr, Alexander Birbrair, Shuang G Zhao, Joshua M Lang, Adrienne I Victor","doi":"10.1200/PO-26-00740","DOIUrl":"https://doi.org/10.1200/PO-26-00740","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 7","pages":"e2600740"},"PeriodicalIF":4.7,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148470785","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":"EMBER-Lung: Electronic Medical Record Boosting Molecular Testing in Early-Stage Non-Small Cell Lung Cancer.","authors":"Willdragon Wang, Dylan G Scholes, Alex C Watts, Megan A Roy, Sunil Singhal, John C Kucharczuk, Doraid Jarrar, Jarrod Predina, Taine T V Pechet, Lova L Sun, Aditi P Singh, Roger B Cohen, Corey J Langer, Charu Aggarwal, Melina E Marmarelis","doi":"10.1200/PO-25-01207","DOIUrl":"10.1200/PO-25-01207","url":null,"abstract":"<p><strong>Purpose: </strong>Adjuvant targeted therapies and perioperative chemoimmunotherapy have made it imperative to perform molecular testing in early-stage nonsquamous (NSq) non-small cell lung cancer (NSCLC). We present a prospective clinical trial evaluating an electronic medical record (EMR)-based nudge intervention to promote timely completion of comprehensive molecular testing (cMT) in patients with early-stage NSq NSCLC.</p><p><strong>Methods: </strong>The EMBER-Lung trial prospectively enrolled patients undergoing surgical resection. The intervention included an EMR-based nudge at the time of the first postoperative visit, prompting the clinician to accept an order for cMT if NSq NSCLC histology. Following completion of cMT, if an actionable alteration was found, a reflex alert summarizing therapeutic options was sent to the patient's care team. The primary end point was the proportion of patients who underwent cMT in the real-world control and nudge intervention cohorts. Clinical characteristics and outcomes of the control and nudge intervention cohorts were compared using Pearson Chi-squared test, Fisher exact test, or Z score.</p><p><strong>Results: </strong>Between July 2021 and November 2023, 460 patients were included (243 nudge and 217 control patients). The median age was 68.4 years, 64.3% female; 74.1% had a smoking history and mostly stage I (I/II/III; 75.9%, 14.1%, 10.0%, respectively). The proportion of patients with cMT increased in the nudge intervention (80/217, 36.9% <i>v</i> 197/243, 81.1%, <i>P</i> < .00001) across all stages (I to III). A greater proportion of patients with classical <i>EGFR</i> mutations and <i>KRAS</i> G12C mutations were detected in the nudge intervention setting (<i>EGFR</i>: 14/217, 6.5% <i>v</i> 41/243, 16.9%, <i>P</i> < .001; <i>KRAS</i> G12C: 12/217, 5.5%, <i>v</i> 33/243, 13.6%, <i>P</i> < .01).</p><p><strong>Conclusion: </strong>In well-matched control and nudge intervention cohorts, an EMR-based nudge after resection of early-stage NSq NSCLC was feasible and increased the proportion of patients with cMT. Future research will incorporate this earlier, at the time of biopsy, to inform neoadjuvant therapy.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 7","pages":"e2501207"},"PeriodicalIF":4.7,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148455886","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":"Multimodal Spatiotemporal Signature Integrating Pathomics and Longitudinal Magnetic Resonance Imaging Predicts Response to Neoadjuvant Therapy and Prognosis in Rectal Cancer.","authors":"Jianye Jia, Hongyan Xie, Xinkai Wang, Jiahao Wang, Hui Zhang, Mingxiang Wei, Lixue Xu, Dawei Yang, Shuai Mu, Yantao Niu","doi":"10.1200/PO-26-00124","DOIUrl":"10.1200/PO-26-00124","url":null,"abstract":"<p><strong>Purpose: </strong>The purpose of this study was to accurately identify patients with locally advanced rectal cancer (LARC) who are likely to achieve pathologic complete response (pCR) after neoadjuvant therapy (NAT). This study develops a Multimodal Spatiotemporal Attentive Fusion Network (MSTAF-Net) to predict pCR and derives a Multimodal Spatiotemporal Signature (MSTAF-MSS) for disease-free survival (DFS) and explored its association with immune-related transcriptomic features.</p><p><strong>Methods: </strong>This retrospective multicenter study included 642 patients with LARC. Longitudinal multiparametric magnetic resonance imaging (MRI) acquired before and after NAT and pretreatment hematoxylin and eosin-stained whole-slide images were collected. A dual-stream MSTAF-Net was designed to integrate longitudinal MRI features and pathomics features. Model performance was evaluated using receiver operating characteristic curves and survival analysis. Transcriptomic analyses were conducted to investigate the biologic correlates of the MSTAF-MSS and its association with immune-related transcriptomic features.</p><p><strong>Results: </strong>The multimodal transformer fusion model achieved AUC values of 0.894 (95% CI, 0.847 to 0.942) in the internal validation cohort and 0.865 (95% CI, 0.786 to 0.943) in the external validation cohort, outperforming single-modality model. The MSTAF-MSS enabled effective risk stratification, with low-risk patients showing significantly longer DFS than high-risk patients (log-rank <i>P</i> < .05). Cox regression analyses identified MSTAF-MSS as an independent predictor of DFS in multivariate models (hazard ratio, 0.31 [95% CI, 0.13 to 0.73], <i>P</i> = .007). Distinct patterns of immune cell infiltration were observed between MSTAF-MSS-defined groups.</p><p><strong>Conclusion: </strong>The proposed MSTAF-Net integrates pathomics and longitudinal multiparametric MRI to capture spatial heterogeneity and treatment-related temporal dynamics of tumors. It demonstrates robust performance in predicting response to NAT and enables prognostic risk stratification. Furthermore, transcriptomic analysis supports potential biologic relevance of the model in associations with immune-related tumor biology.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 7","pages":"e2600124"},"PeriodicalIF":4.7,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396409","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":"Patterns of Response to Immune Checkpoint Inhibitors in Sarcomas With High Tumor Burden and/or Mismatch Repair Deficiency.","authors":"Thierry Alcindor, David J Papke, Vinayak Venkataraman, Michael J Wagner, Priscilla Merriam, Candace L Haddox, Andrew J Wagner, Nicole L Solimini, Ashwini Jambhekar, Suzanne George","doi":"10.1200/PO-26-00414","DOIUrl":"10.1200/PO-26-00414","url":null,"abstract":"<p><strong>Purpose: </strong>Immune checkpoint inhibitors (ICIs) are frequently used to treat metastatic solid tumors characterized by high tumor mutational burden (TMB) and/or mismatch repair (MMR) deficiency. Most of the literature on their benefit is about carcinomas and melanomas, but little is known about their effects on sarcomas in these settings. In this study, we examined the response pattern to ICI-based therapy in sarcomas with those characteristics.</p><p><strong>Methods: </strong>Patients treated in our institution with ICI-based therapy for sarcomas with high TMB and/or MMR deficiency were identified. We analyzed the main outcome of interest, radiologic response to therapy, alongside clinical information including treatment type and duration, histologic diagnosis, germline and somatic MMR deficiency, and ultraviolet A (UVA) mutational signature.</p><p><strong>Results: </strong>Among 17 patients identified, TMB ranged from 9 to 151 mut/Mb. Radiologic response was observed in 6 patients. TMB of responding patients ranged from 15-75 mut/Mb. The only responding case of MMR deficiency was seen in the one patient diagnosed with Lynch syndrome. By contrast, none of the five cases of sporadic MMR deficiency responded. The three complete responses were seen in MMR-proficient tumors associated with UVA signature and high TMB.</p><p><strong>Conclusion: </strong>Overall, sarcomas with MMR deficiency and/or high TMB show a heterogeneous pattern of responses to ICI-based therapy. Other cellular and molecular factors, such as histology, germline factors, and mutation signatures, likely contribute to the response to ICI treatment in sarcomas.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 7","pages":"e2600414"},"PeriodicalIF":4.7,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13361952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396397","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":"Development and Validation of a Cytochrome C Oxidase Subunit 6B2-Based Risk Model for Cholangiocarcinoma Recurrence.","authors":"Meiru Chen, Xiaoli Xie, Jiaqi Wang, Lixian Zhang, Yun He, Jing Yang, Jinmei Tian, Dongqiang Zhao","doi":"10.1200/PO-26-00349","DOIUrl":"https://doi.org/10.1200/PO-26-00349","url":null,"abstract":"<p><strong>Purpose: </strong>Given the high postoperative recurrence rates and poor prognosis of cholangiocarcinoma (CCA), this study aimed to evaluate cytochrome C oxidase subunit 6B2 (COX6B2) as a potential biomarker for recurrence prediction and to develop a composite risk stratification model integrating clinicopathologic features for personalized treatment planning.</p><p><strong>Methods: </strong>We first performed an unbiased recurrence-oriented transcriptomic screening using TCGA-CHOL and GSE107943 data sets. Recurrence-upregulated genes were subjected to log-rank survival testing, univariate Cox regression, and cross-cohort intersection to identify candidate recurrence-associated genes. COX6B2 was then evaluated at the protein level by immunohistochemistry in a training cohort (N = 115) and an independent validation cohort (N = 48). A composite recurrence risk stratification model incorporating COX6B2 and routine clinicopathologic variables, including carbohydrate antigen 19-9, carcinoembryonic antigen, vascular invasion, and tumor size, was developed and validated.</p><p><strong>Results: </strong>Bioinformatics analysis revealed significant <i>COX6B2</i> upregulation in recurrent CCA (hazard ratio, 1.351; <i>P</i> = .034). COX6B2 alone demonstrated robust predictive performance with AUC values of 0.87 (training cohort) and 0.81 (validation cohort). The composite model achieved superior predictive accuracy (AUC, 0.93) and effectively stratified patients into high-risk (5-year recurrence rate: 90.62%-95.59%) and low-risk (recurrence-free rate: 85.11%-87.50%) groups. The model's negative predictive value improved by 11% compared with COX6B2 alone.</p><p><strong>Conclusion: </strong>COX6B2 may serve as a clinically useful tissue-based biomarker for postoperative recurrence prediction in CCA. By integrating COX6B2 with standard clinicopathologic features, the composite model provides a practical approach for recurrence risk assessment and individualized postoperative management.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 7","pages":"e2600349"},"PeriodicalIF":4.7,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148412082","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":"First-In-Human [¹⁷⁷Lu]Lu-FAPI-XT Therapy Combined With Anti-PD-1 Antibody in a Patient With Metastatic Colon Cancer Who Has Progressed on Multiple Prior Lines of Therapy.","authors":"Ru Jia, Yue Shi, Yao-Yue Zhang, Rui-Min Wang, Hong-Hong Liu, Sha-Sha Sun, Wan-Chen Zhao, Guang-Hai Dai","doi":"10.1200/PO-26-00126","DOIUrl":"https://doi.org/10.1200/PO-26-00126","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 7","pages":"e2600126"},"PeriodicalIF":4.7,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148421283","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":"Acquired <i>TSC1</i> Mutation as a Mechanism of Alectinib Resistance in <i>ALK</i>-Fused Leiomyosarcoma: Response to Combined ALK and Mammalian Target of Rapamycin Inhibition.","authors":"Alisa Posner, Carol Rosenberg, Katharine M Esselen, Andrew Kelly, Bruno Bockorny","doi":"10.1200/PO-26-00046","DOIUrl":"https://doi.org/10.1200/PO-26-00046","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 7","pages":"e2600046"},"PeriodicalIF":4.7,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148578771","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}