JCO precision oncology最新文献

{"title":"Cancer Testis Antigen Expression Correlates With Immune Activation and Survival in Small Bowel Neuroendocrine Tumors.","authors":"Reed I Ayabe, Y David Seo, Brenda Melendez, Brittany C Fields, Laurence P Diggs, Rossana Lazcano, Bharat B Singh, Khalida Wani, Davis Ingram, Sarah Johnson, Manoj Chelvanambi, Courtney Hudgens, Sharia D Hernandez, Nadim J Ajami, Jennifer A Wargo, Alexander J Lazar, Mark Knafl, Scott Woodman, Daniel M Halperin, Jeannelyn S Estrella, Jessica E Maxwell","doi":"10.1200/PO-25-00107","DOIUrl":"https://doi.org/10.1200/PO-25-00107","url":null,"abstract":"<p><strong>Purpose: </strong>Small bowel neuroendocrine tumors (SBNET) frequently present with metastatic disease, and the efficacy of available systemic therapies, especially immune checkpoint blockade, is limited. Toward developing novel immunomodulatory strategies, we interrogated the tumor immune microenvironment of SBNETs using bulk transcriptional and digital spatial profiling (DSP).</p><p><strong>Methods: </strong>Patients with SBNET who underwent resection from 2003 to 2016 were retrospectively evaluated. Overall survival (OS) was assessed using the Kaplan-Meier method. The Cox proportional hazards model was used for multivariable analysis (MVA). Bulk transcriptional profiling was performed using the NanoString PanCancer-Immune Panel. Whole human transcriptome DSP was performed using PanCK to segment tumor and adjacent stroma.</p><p><strong>Results: </strong>Unsupervised clustering of gene expression in resected SBNET from 42 patients demonstrated dichotomization by cancer testis antigen (CTA) expression. CTA^high patients (12/42, 29%) demonstrated elevated interleukin expression and had significantly improved OS (hazard ratio, 0.211, 95% CI, 0.059 to 0.751). Increased CTA expression was also associated with objective response to atezolizumab/bevacizumab in patients with neuroendocrine tumors (<i>P</i> = .003). Spatial profiling revealed upregulation of genes involved in immune activation and epigenetic modification in CTA^high tumor regions (all <i>P</i> < .05). Immune deconvolution identified a trend toward increased CD8 T cells, NK cell activation, and dendritic cells in CTA^high tumor regions, whereas T-cell receptor (TCR) profiling revealed marked differences in TCR segment expression between CTA^high and CTA^low regions (<i>P</i> < .001).</p><p><strong>Conclusion: </strong>High CTA expression in resected SBNET is independently associated with improved survival. Epigenetic dysregulation and immune activation in CTA-enriched tumor regions highlight the potential for combination epigenetic modifiers and immunotherapy in future trials.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500107"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608395","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":"Pansarcoma Analysis of Cyclin-Dependent Kinase and Cyclin Outlier Gene Expression Highlights CDK7 as a Potential Therapeutic Target in Chordoma.","authors":"Daniel S Lefler, Andrew Elliott, Wei Jiang, Ubaldo Martinez-Outschoorn, Jude Al-Sabah, Daniel M Freed, Caitlin M King, Robert G Maki, Richard F Riedel, Jaime F Modiano, Daniel Hübschmann, Hanno Glimm, Stefan Fröhling, Matthew Oberley, Sosipatros A Boikos, Atrayee Basu Mallick","doi":"10.1200/PO-25-00149","DOIUrl":"https://doi.org/10.1200/PO-25-00149","url":null,"abstract":"<p><strong>Purpose: </strong>Cyclin-dependent kinase (CDK)4/6 inhibitors are approved for the treatment of breast cancer, and they have more recently been used in patients with well-differentiated/dedifferentiated liposarcomas (WD-LPSs/DD-LPSs). However, targeting of these and other CDKs, including transcriptional CDKs, remains a promising avenue of investigation for various cancers. Therefore, we sought to characterize outlier overexpression of CDK and cyclin genes in sarcomas. On the basis of the initial results, further studies were undertaken to investigate the roles of CDK7 and CDK18 in chordomas.</p><p><strong>Materials and methods: </strong>An initial analysis of CDK/cyclin gene expression involved an American national biomarker database of deidentified patients (Caris Life Sciences, Phoenix, AZ; n = 3,757) using novel, strict definitions to identify outlier overexpressing samples across subtypes. Results were validated with a German national database (Molecularly Aided Stratification for Tumor Eradication Research [MASTER]; n = 943). Outlier overexpression for <i>CDK7/18</i> in chordoma was compared with immunohistochemical (IHC) expression using tissue microarrays, and a selective investigational CDK7 inhibitor was tested against four chordoma cell lines.</p><p><strong>Results: </strong>Initial analysis identified expected findings (eg, outlier overexpression of <i>CDK4</i> in 39%-66% of WD-LPSs/DD-LPSs), clinical correlates of fundamental scientific work (eg, <i>CCND1</i> in 29% of Ewing sarcomas), and novel associations (eg, <i>CDK7/CDK18</i> in 42%/37% of chordomas). Outlier overexpression for <i>CDK7</i> and <i>CDK18</i> in chordomas was corroborated in the MASTER database (40% and 26% of patients, respectively). IHC analysis confirmed strong and diffuse expression of both CDK7 and CDK18 in chordoma samples. Furthermore, CDK7 inhibition was highly effective in four chordoma cell lines.</p><p><strong>Conclusion: </strong>This study supports further investigation into targeting of CDKs and cyclins in select sarcoma subtypes, and it specifically suggests a therapeutic approach inhibiting CDK7 in chordoma.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500149"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553622","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":"Geneva Homologous Recombination Deficiency Test Is Predictive of Survival Benefit From Olaparib and Bevacizumab Maintenance in Ovarian Cancer.","authors":"Yann Christinat, Intidhar Labidi-Galy, Liza Ho, Sophie Clément, Catherine Genestie, Jalid Sehouli, Saverio Cinieri, Antonio Gonzalez-Martin, Vassiliki Kolovetsiou-Kreiner, Keiichi Fujiwara, Toon Von Gorp, Germana Tognon, Sakari Hietanen, Viola Heinzelmann-Schwarz, Isabelle Ray-Coquard, Eric Pujade-Lauraine, Thomas A McKee","doi":"10.1200/PO-24-00825","DOIUrl":"10.1200/PO-24-00825","url":null,"abstract":"<p><strong>Purpose: </strong>The ability of the Geneva homologous recombination deficiency (HRD) test to predict progression-free survival (PFS) in patients with high-grade ovarian cancer treated with poly (ADP-ribose) polymerase inhibitors has been demonstrated. Its performance with respect to overall survival (OS) has not been assessed yet.</p><p><strong>Methods: </strong>Using the final results of the PAOLA-1/ENGOT-ov25 phase III clinical trial with a median follow-up of 5 years, we evaluated the Geneva HRD test on 468 samples as part of the ENGOT HRD European Initiative. Results were evaluated in terms of final PFS and OS in the olaparib + bevacizumab and placebo + bevacizumab arms and compared with the Myriad MyChoice HRD test.</p><p><strong>Results: </strong>Final PFS was consistent with previously published data and confirmed the predictive value of the Geneva HRD test with a hazard ratio (HR) of 0.41 (95% CI, 0.30 to 0.57) for HRD-positive patients. The results for OS showed a HR of 0.56 (95% CI, 0.37 to 0.85) for HRD-positive patients and 1.6 (95% CI, 1.1 to 2.3) for HRD-negative patients. These results are consistent with those observed with the Myriad test, including the negative OS trend in the HRD-negative subgroup treated with olaparib + bevacizumab (HR, 1.2 [95% CI, 0.83 to 1.8]). A subgroup analysis of patients with intermediate HRD scores showed that the normalized large-scale state transition score used by the Geneva HRD test had both predictive and prognostic value.</p><p><strong>Conclusion: </strong>The Geneva HRD test predicts PFS and OS benefit from olaparib + bevacizumab. The potential detrimental effect of olaparib + bevacizumab on OS in the HRD-negative population is hypothesis-generating and needs to be confirmed prospectively.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2400825"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12233177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553621","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":"Complete Response in Hairy Cell Leukemia to Anti-CD22 CAR T-Cell Therapy.","authors":"Robert J Kreitman, Brett Schroeder, Evgeny Arons, Constance Yuan, Hao-Wei Wang, Mark Raffeld, Liqiang Xi, Stefania Pittaluga, Hong Zhou, Mory Gould, Isaac Shpilman, Evrim Turkbey, Katherine R Calvo, Lacey James, Olena Sierra Ortiz, Steve Highfill, David Stroncek, Bonnie Yates, Ira Pastan, Nirali N Shah","doi":"10.1200/PO-25-00269","DOIUrl":"10.1200/PO-25-00269","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500269"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12270311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649492","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":"Real-World Germline BRCA Testing, Poly(ADP-ribose) Polymerase Inhibitor Utilization, and Survival Outcomes in Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer.","authors":"Siddhartha Yadav, Fergus J Couch, Sam Hillman, Linlin Luo, Weiyan Li, Qixin Li, Jennifer Fallas Hayes, Jagadeswara R Earla, Xiaoqing Xu","doi":"10.1200/PO-24-00814","DOIUrl":"10.1200/PO-24-00814","url":null,"abstract":"<p><strong>Purpose: </strong>Testing for germline <i>BRCA1</i> and/or <i>BRCA2</i> mutations (gBRCAm) is recommended for patients with human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC) to guide treatment selection with poly (ADP-ribose) polymerase inhibitors (PARPis). However, real-world data on germline <i>BRCA1</i> and/or <i>BRCA2</i> (gBRCA) testing and PARPi treatment patterns in metastatic BC (mBC) are limited.</p><p><strong>Methods: </strong>Deidentified patient data from adults diagnosed with HER2- mBC between 2014 and 2022 were captured from electronic health records in the US Flatiron Health database. gBRCA testing patterns and prevalence were examined by tumor subtype (hormone receptor-positive [HR+]/triple-negative) and disease stage at diagnosis. Demographic and clinical characteristics were described by receipt of gBRCA testing and PARPi. PARPi treatment patterns were assessed, and real-word overall survival (OS) was estimated in patients with gBRCAm diagnosed with mBC after January 1, 2018.</p><p><strong>Results: </strong>Of the 15,006 total patients, 4,654 (31.0%) received a gBRCA test. gBRCA testing rates mostly increased from 2014 to 2022 and were lower in patients with HR+ than triple-negative tumors. Of the patients who underwent gBRCA testing, 337 (7.2%) had gBRCAm. From 2018 to 2022, PARPi was initiated in 94 (45.6%) of 206 patients with gBRCAm. With a median follow-up of 22.8 months across patients with available first-line treatment start dates, real-world OS was numerically longer among 94 patients with gBRCAm who received PARPi (32.3 months [95% CI, 22.7 to 47.4]) than among 99 patients who did not (21.9 months [95% CI, 18.4 to not reached]).</p><p><strong>Conclusion: </strong>Although gBRCA testing increased over time, testing and PARPi utilization rates remained suboptimal in potentially eligible patients with HER2- mBC. Exploratory analysis showed numerically longer OS in patients who received PARPi. Wider and timelier gBRCA testing is warranted to inform potentially optimal treatment decisions.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2400814"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12278751/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649496","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":"Germline <i>POT1</i> Variants in a Pan-Cancer Cohort.","authors":"Pamela L Brock, Morgan Webster, Sandya Liyanarachchi, Lindsey Byrne, Dale J Hedges, Pat Gulhati, J Kevin Hicks, Carlos H F Chan, Kenan Onel, Leigh Anne Stout, Whitney Maxwell, Justine Cooper Pickarski, Juvianee Estrada-Veras, Bodour Salhia, Lisen Axell, Laura L Holman, Mohamed H Abdel-Rahman, Matthew D Ringel","doi":"10.1200/PO-24-00946","DOIUrl":"10.1200/PO-24-00946","url":null,"abstract":"<p><strong>Purpose: </strong>Germline likely pathogenic and pathogenic variants (LPV/PVs) in <i>POT1</i> have been associated with an increased risk of various cancers including angiosarcoma, melanoma, glioma, thyroid cancer, and chronic lymphocytic leukemia (CLL). However, to date, most of the published data regarding <i>POT1</i> PVs involve cohorts of patients selected for specific cancer types, or stem from commercial laboratory cohorts from patients selected for germline clinical testing, which may cause ascertainment biases. The objective was to identify germline <i>POT1</i> variants in a pan-cancer cohort and describe the associated phenotypes.</p><p><strong>Methods: </strong>Germline exome data available for 19,315 patients with cancer from the Oncology Research Information Exchange Network (ORIEN) were assessed for <i>POT1</i> LPV/PV. Data regarding cancer diagnoses were obtained for those with and without <i>POT1</i> variants. Associations were assessed.</p><p><strong>Results: </strong><i>POT1</i> LPV/PVs were identified in 23 patients. The cancer types seen in more than one patient include CLL (n = 7), papillary thyroid cancer (PTC, n = 5), colorectal cancer (n = 3), lung cancer (n = 3), glioblastoma (n = 2), and neuroendocrine tumors (n = 2). Compared with <i>POT1</i>-negative patients, those with <i>POT1</i> LPV/PVs were 5.5-fold more likely to be diagnosed with PTC (95% CI, 1.9 to 15.1; <i>P</i> = .004) and 16.6-fold more likely to be diagnosed with CLL (95% CI, 6.4 to 41.9; <i>P</i> < .001). Patients with <i>POT1</i> LPV/PVs had a younger median age of first cancer diagnosis compared with <i>POT1</i>-negative patients (<i>P</i> = .008).</p><p><strong>Conclusion: </strong>To our knowledge, this study is the largest investigation of <i>POT1</i> germline variants in a pan-cancer cohort. We identify and confirm specific associations with CLL and PTC in this cohort. Differences in results between analysis of largely unselected cohorts compared with clinical testing cohorts highlight the need to study gene-cancer associations in more unselected populations.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2400946"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12243956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600460","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":"Case of <i>KRAS</i> G12C-Mutated AML Treated With Sotorasib.","authors":"Dimitrios Drekolias, Todd C Knepper, Quan Lovette, David A Sallman","doi":"10.1200/PO-25-00368","DOIUrl":"https://doi.org/10.1200/PO-25-00368","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500368"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144715075","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":"LODESTAR: A Single-Arm Phase II Study of Rucaparib in Solid Tumors With Pathogenic Germline or Somatic Variants in Homologous Recombination Repair Genes.","authors":"Sriram Anbil, Nicholas J Seewald, E Gabriela Chiorean, Maen Hussein, Pashtoon Murtaza Kasi, Doug E Laux, Gary K Schwartz, Geoffrey I Shapiro, Kevin K Lin, Marcia Craib, Lara Maloney, Karen McLachlan, Hanna Tukachinsky, Alexa B Schrock, Shuoguo Wang, Ethan S Sokol, Brennan Decker, Katherine L Nathanson, Susan M Domchek, Kim A Reiss","doi":"10.1200/PO-25-00090","DOIUrl":"10.1200/PO-25-00090","url":null,"abstract":"<p><strong>Purpose: </strong>To explore poly (ADP-ribose) polymerase inhibitor utility across solid tumors and identify biomarkers that predict sensitivity.</p><p><strong>Patients and methods: </strong>This single-arm phase II study assessed rucaparib monotherapy in patients with solid tumors and pathogenic variants (PVs) in <i>BRCA1</i>, <i>BRCA2</i>, <i>PALB2</i>, <i>RAD51C</i>, and <i>RAD51D</i> (cohort A) or <i>BARD1</i>, <i>BRIP1</i>, <i>FANCA</i>, <i>NBN</i>, and <i>RAD51B</i> (cohort B). The primary end point was overall response rate (ORR) in cohort A. Secondary end points included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. A scar-based homologous recombination deficiency signature (HRDsig) and platinum sensitivity status were explored post hoc.</p><p><strong>Results: </strong>Fifty-one patients in cohort A and 12 in cohort B were evaluable for efficacy. ORR of cohort A was 18% (95% CI, 10 to 30). A significantly higher ORR was observed with HRDsig+ tumors compared with HRDsig- tumors (32%; 95% CI, 15 to 54 <i>v</i> 0%; 95% CI, 0 to 14; <i>P</i> < .01). In the entire study population, DCR was 65% (95% CI, 53 to 76), median PFS (mPFS) 5.5 months (95% CI, 3.68 to 7.82), and median OS 12.1 months (95% CI, 10.6 to inferred). PFS and hazard of death from any cause was significantly better for platinum-sensitive tumors (mPFS: 7.8 months <i>v</i> 3.5 months; <i>P</i> = .02; hazard ratio, 0.11 [95% CI, 0.02 to 0.55]). Tumor histology was not independently predictive of outcome. Tumors with PVs in cohort A genes were more likely to be HRDsig+ than tumors with PVs in cohort B genes. Analysis of a large commercial database showed that in noncanonical tumors with <i>BRCA</i> PVs, 30.2% were HRDsig+.</p><p><strong>Conclusion: </strong>Rucaparib has activity in HRDsig+ solid tumors with PVs in homologous recombination repair genes, regardless of histology. Platinum sensitivity correlated with improved outcomes.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500090"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600461","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":"Feasibility of Personalized and Tumor-Informed Circulating Tumor DNA Assay for Early Recurrence Detection in Patients With Hepatocellular Carcinoma.","authors":"Maen Abdelrahim, Alejandro Mejia, Abdullah Esmail, Juan Carlos Barrera Gutierrez, Mahmoud Ouf, Joseph W Franses, Irun Bhan, Sudha Kodali, Ashish Saharia, Amit Mahipal, Nikolas Naleid, Catherine Bridges, Antony Tin, Chris M Brewer, Vasily N Aushev, Arkarachai Fungtammasan, Charuta C Palsuledesai, J Bryce Ortiz, Adham Jurdi, Minetta C Liu, R Mark Ghobrial, Aiwu Ruth He","doi":"10.1200/PO-24-00934","DOIUrl":"10.1200/PO-24-00934","url":null,"abstract":"<p><strong>Purpose: </strong>Hepatocellular carcinoma (HCC) has high relapse rates after standard-of-care (SOC) resection or liver transplantation (LT). We evaluated the utility of circulating tumor DNA (ctDNA) to predict relapse/progression risk in patients with HCC.</p><p><strong>Materials and methods: </strong>This retrospective analysis examined real-world data from ctDNA testing on 125 patients with HCC (721 plasma samples) undergoing curative-intent treatments and SOC management. Patients were divided into four subcohorts: cohort A (n = 64) and B (n = 52) comprised patients under recurrence monitoring after LT or resection, respectively. Cohort C (n = 4) and D (n = 5) comprised patients under treatment response monitoring with known recurrence or inoperable disease, respectively. A personalized, tumor-informed 16-plex polymerase chain reaction next-generation sequencing assay (Signatera, Natera, Inc, Austin, TX) was used for ctDNA testing. The molecular residual disease (MRD) window was defined as 2-12 weeks post-LT/resection (cohorts A/B), before starting adjuvant therapy (AT). Surveillance window was defined as post-MRD window or 2 weeks post-AT (cohort B) or during ongoing treatment (cohorts C/D).</p><p><strong>Results: </strong>The median follow-up was 40 (1.5-60) months. In cohort A, 97.2% (35/36) of patients with ctDNA negativity in the MRD window remained negative during surveillance. In cohort B, ctDNA was detected in 29.4% (10/34) of patients within the MRD window, all of whom experienced clinical recurrence (hazard ratio [HR], 7.2 [95% CI, 2.6 to 20]; <i>P</i> < .0001). In the surveillance window (cohort B), the ctDNA detection rate was 32.3% (10/31), and all experienced recurrence (HR, 18.0 [95% CI, 3.9 to 85]; <i>P</i> < .0001). In cohorts C/D, on-treatment ctDNA dynamics were concordant with treatment response as measured by imaging. Compared with alpha-fetoprotein, ctDNA had higher sensitivity and a significantly longer lead time (7.9 <i>v</i> 2.2 months) for recurrence detection.</p><p><strong>Conclusion: </strong>Serial ctDNA testing effectively identified HCC recurrence early, postresection and post-LT. ctDNA was also useful for treatment response monitoring and could help resolve ambiguous imaging results.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2400934"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12233179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553620","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":"Real-World Clinical Utility of Tumor Next-Generation Sequencing in Adolescent and Young Adult Patients With Sarcoma.","authors":"Karan Gupta, Peter Grimison, Karl Fernandez, Victoria Choi, Vivek Bhadri","doi":"10.1200/PO-25-00228","DOIUrl":"https://doi.org/10.1200/PO-25-00228","url":null,"abstract":"<p><strong>Purpose: </strong>Tumor next-generation sequencing (NGS) enables molecular profiling to identify actionable mutations and guide targeted therapy. Adolescent and young adults (AYAs) with advanced sarcoma often face poor prognosis and limited systemic options. This study evaluated the clinical utility of tumor NGS in this population.</p><p><strong>Materials and methods: </strong>A retrospective cohort study was conducted at Chris O'Brien Lifehouse, Sydney, including consecutive AYA patients with sarcoma who underwent tumor NGS between 2015 and 2025. Sequencing was performed through four molecular screening programs: Molecular Screening and Therapeutics, Cancer Screening Program, Personalized Rare and Infrequent Solid Malignancies, Zero Childhood Cancer Program, and commercial platform Foundation Medicine (FoundationOne CDx). Platforms used whole-genome sequencing, whole-exome sequencing, or targeted panels, assessing between 324 and 523 genes. Analyzed biomarkers included somatic mutations, gene fusions, tumor mutational burden (TMB), and microsatellite instability. Key end points included frequency of actionable mutations, treatment changes, and outcomes from NGS-guided therapies.</p><p><strong>Results: </strong>NGS was successfully performed in 108 of 115 patients (94%). Actionable mutations were identified in 28 patients (24.4%), with molecular confirmation of diagnosis in four (3.5%). TMB was reported in 93 cases: 88 (94.6%) had low TMB (<10 mut/MB) and five (5.4%) had high TMB (≥10 mut/MB). Sixteen patients (14.8%) received NGS-directed therapy, mostly through clinical trials. Of them, 12 (75%) experienced disease progression, and only five (4.4%) derived clinical benefit (stable disease, partial response, or complete response). Among high TMB patients accessing immune checkpoint inhibitors, all but one progressed.</p><p><strong>Conclusion: </strong>Although few AYA patients with sarcoma derived clinical benefit from NGS-directed therapy (<5%), NGS proved useful for diagnosis and trial access. The absence of routine RNA sequencing may have limited the detection of fusion-driven sarcomas. Future integration of broader molecular techniques and collaborative infrastructure is essential to fully realize the potential of NGS in rare and high-risk sarcomas.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500228"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553632","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}