JCO precision oncology最新文献

{"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}

{"title":"Risk Assessment With Ultra-Low-Pass Whole-Genome Sequencing of Cell-Free DNA for Large B-Cell Lymphoma.","authors":"Davidson Zhao, Noémie Lang, Ting Liu, Victoria Shelton, Juan Rangel-Patiño, Inna Y Gong, Michael Hong, Anthea Travas, Vanessa Murad, Ibrahim Alrekhais, Ur Metser, Anca Prica, Vishal Kukreti, Sita Bhella, Abi Vijenthira, Michael Crump, John Kuruvilla, Andrea Arruda, Mark D Minden, Bernard Lam, Robert Kridel","doi":"10.1200/PO-25-00200","DOIUrl":"10.1200/PO-25-00200","url":null,"abstract":"<p><strong>Purpose: </strong>Although deep targeted DNA sequencing of liquid biopsies has shown prognostic utility in large B-cell lymphoma (LBCL), the routine clinical adoption of these assays remains limited because of their high costs.</p><p><strong>Materials and methods: </strong>Here, leveraging a well-annotated cohort encompassing both frontline and relapsed/refractory (R/R) LBCL, we profiled patient plasma samples with two complementary modalities-ultra-low-pass whole-genome sequencing (ULP-WGS) and deep targeted DNA sequencing, the former being a cost-effective method to profile large scale chromosomal abnormalities and estimate tumor burden.</p><p><strong>Results: </strong>Our findings revealed a strong association of high cell-free tumor burden by both genomic profiling modalities with established measures of tumor burden and patient survival. Notably, the associations with survival remained statistically significant after accounting for international prognostic index scoring. Furthermore, we showed that del(17p) in circulating tumor DNA as detected by ULP-WGS was strongly associated with <i>TP53</i> mutation status and predicted for significantly inferior outcome in frontline LBCL patients but not in patients with R/R LBCL.</p><p><strong>Conclusion: </strong>Our study demonstrates that ULP-WGS can provide robust prognostic biomarkers for both frontline and R/R LBCL, highlighting its broad applicability for risk stratification.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500200"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12258806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600462","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":"Prognostic Role of <i>MTAP</i> Loss in Cholangiocarcinoma.","authors":"James Lyon, Soravis Osataphan, Vaibhav Birda, Brian Russell, Charly Edmiston, Rodrigo Paredes, Ahmed Rattani, Mary Linton Peters","doi":"10.1200/PO-24-00842","DOIUrl":"https://doi.org/10.1200/PO-24-00842","url":null,"abstract":"<p><strong>Purpose: </strong>Methylthioadenosine phosphorylase (<i>MTAP</i>) loss is a common genomic event in cancer and is associated with an immunologically cold phenotype. Recent research has highlighted a synthetic lethality of <i>MTAP</i> loss when combined with PMRT5 or MAT2A inhibition. Although contemporary somatic genomic testing now routinely includes <i>MTAP</i> status, the clinicogenomic characteristics of <i>MTAP</i> loss in cholangiocarcinoma (CCA) remain largely undefined. In this study, we examine the genomic profiles, clinical features, and survival outcomes of <i>MTAP</i> loss CCA.</p><p><strong>Methods: </strong>This is a single-center retrospective cohort study of patients with CCA from December 2017 to January 2024. Somatic genomics alterations were assessed using targeted next-generational sequencing with FoundationOne CDx. Patient demographics, tumor characteristics, treatment history, and overall survival (OS) were retrospectively collected. Genomics coalterations were assessed using the Fisher exact test. Multivariate Cox proportional hazards regression analysis was used to assess the relationship between <i>MTAP</i> status and OS.</p><p><strong>Results: </strong>Among 94 CCA samples, 89 were successfully sequenced, uncovering 339 genomic alterations, with <i>MTAP</i> loss identified in 16% of cases. It commonly co-occurred with <i>CDKN2A</i> and <i>B</i> loss (93% and 86%, respectively) and was not associated with <i>FGF2R</i> rearrangement, <i>IDH1</i> mutation, or <i>human epidermal growth factor receptor 2</i> (<i>ERBB2</i>) amplification. Tumor mutational burden were similar between <i>MTAP</i> status. <i>MTAP</i> loss was associated with lower OS (hazard ratio, 3.95 [95% CI, 1.43 to 10.9]; <i>P</i> = .008) after adjustment for key covariates including age, Eastern Cooperative Oncology Group performance status, nodal stage, metastatic spread, resectability, histologic, and line of therapy.</p><p><strong>Conclusion: </strong><i>MTAP</i> loss is common CCA, co-occurred with <i>CDKN2A</i> and <i>CDKN2B</i> loss, and was associated with poor OS. Future effort to exploit this therapeutic vulnerability in <i>MTAP</i>-loss CCA is critical to improve the care of this population.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2400842"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608398","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: NTRK Fusion-Positive Thyroid Carcinoma: From Diagnosis to Targeted Therapy.","authors":"Vicente R Marczyk, Sasan Fazeli, Ramona Dadu, Naifa L Busaidy, Priyanka Iyer, Mimi I Hu, Steven I Sherman, Sarah Hamidi, Sayed Mohsen Hosseini, Michelle D Williams, Salmaan Ahmed, Mark J Routbort, Raja Luthra, Sinchita Roy-Chowdhuri, Francis Anthony San Lucas, Keyur P Patel, David S Hong, Mark Zafereo, Jennifer R Wang, Anastasios Maniakas, Steven G Waguespack, Maria E Cabanillas","doi":"10.1200/PO-25-00552","DOIUrl":"10.1200/PO-25-00552","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500552"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600459","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":"Polygenic Score Complements Family History and Lynch Syndrome Genes for Predicting Colorectal Cancer Risk.","authors":"Talia Y Helfand, Jun Wei, Ashley J Mulford, Huy Tran, Zhuqing Shi, Chi-Hsiung Wang, Andrew S Rifkin, Annabelle Ashworth, S Lilly Zheng, Brian T Helfand, Henry M Dunnenberger, David Duggan, Peter J Hulick, Allison DePersia, Alan R Sanders, Jianfeng Xu","doi":"10.1200/PO-25-00081","DOIUrl":"10.1200/PO-25-00081","url":null,"abstract":"<p><strong>Purpose: </strong>Family history (FH) and pathogenic variants (PVs) in Lynch syndrome (LS) genes are established risk factors of colorectal cancer (CRC). This study evaluates whether newly published polygenic scores (PGSs) improve CRC prediction of known risk factors.</p><p><strong>Methods: </strong>The associations of CRC risk with FH, PVs in LS genes (<i>MSH2</i>, <i>MLH1</i>, <i>MSH6</i>, <i>PMS2</i>), and PGS were investigated in the UK Biobank (UKB) using population attributable risk percentage (PAR%) and Cox regression. Model performance was assessed using Concordance Index (C-index) in UKB and validated in the Genomic Health Initiative (GHI), a US health care biobank with more diverse ancestry populations.</p><p><strong>Results: </strong>In UKB, 18.99%, 11.43%, and 0.42% of participants were positive for PGS, FH, and PVs, respectively, with corresponding PAR% of 29.97%, 6.27%, and 1.25%. In multivariable analysis adjusting for age, sex, and genetic background, each genetic factor independently predicted CRC risk (<i>P</i> < .001). Significant interactions between PVs and FH (<i>P</i> < .001) and PVs and PGS (<i>P</i> = .04) were found; hazard ratio (95% CI) of PVs was significantly higher in those with FH (7.90 [6.27 to 9.94]) than without FH (2.89 [2.32 to 3.60]) and that of PGS was significantly lower in PV carriers (1.69 [1.18 to 2.42]) than noncarriers (2.85 [2.73 to 2.98]). The combined genetic model had a significantly higher C-index (0.677) than models with PVs (0.573), FH (0.578), and PGS (0.669) alone (<i>P</i> < .001). This enhanced performance was validated in GHI across European and non-European ancestries.</p><p><strong>Conclusion: </strong>PGS complements FH and PVs of LS genes in predicting CRC risk and improves prediction performance beyond traditional genetic factors across diverse populations.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500081"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12233176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553623","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":"Liquid Biopsy and Solid Standards: Charting the Path to the Clinical Translation of Cerebrospinal Fluid Biomarkers.","authors":"Cecile Riviere-Cazaux, Terry C Burns","doi":"10.1200/PO-25-00360","DOIUrl":"https://doi.org/10.1200/PO-25-00360","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500360"},"PeriodicalIF":5.3,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144505720","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":"Precision Treatment of Patients With GI Cancer Using Pre-emptive <i>DPYD</i> Genotyping/Phenotyping Plus Pharmacokinetic-Guided Dosing of 5-Fluorouracil.","authors":"Helle-Brit Fiebrich-Westra, Christina Haroun, Remco van der Galiën, Daphne den Besten-Bertholee, Maarten J Deenen, Dirk Jan A R Moes, Pierre M Bet, Jan Willem B de Groot, Richard M Brohet, André B P van Kuilenburg, Jan Gerard Maring","doi":"10.1200/PO-25-00062","DOIUrl":"10.1200/PO-25-00062","url":null,"abstract":"<p><strong>Purpose: </strong>The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends screening for four common <i>DPYD</i> variants to prevent severe toxicity in patients with cancer treated with fluoropyrimidines. A 50% starting dose followed by toxicity-based dose titration is advised for patients heterozygous for these variants. In this study, the appropriateness of the CPIC-recommended 5-fluorouracil (5-FU) starting dose was evaluated.</p><p><strong>Patients and methods: </strong>Patients were grouped into four variant categories (<i>DPYD</i>*2A [c.1905+1G>A], <i>DPYD</i>*13 [c.1679T>G], c.2846A>T [p.D949V], c.1236G>A/HapB3 [p.E412E]) and a <i>DPYD</i> wild-type control group. Uracil loading tests were used for phenotyping. Variant patients started on a 50% reduced 5-FU dose. On the basis of steady-state 5-FU plasma concentrations, dose adjustments were made during cycles 2-4 until an 5-FU target AUC_0-46h of 20-30 mg × h/L was achieved, if tolerated.</p><p><strong>Results: </strong>Twenty-six wild-type controls and 34 <i>DPYD</i> variant patients were included: 16 with c.1236G>A/HapB3, eight with c.1905+1G>A, eight with p.D949V, and two with c.1679T>G. Heterozygous carriers of c.1905+1G>A (<i>DPYD</i>*2A) and c.1679T>G (<i>DPYD*</i>13) displayed significant reduced uracil metabolism. The impact on uracil clearance was highly variable in p.D949V but only minor in c.1236G>A/HapB3 variants. In all, 65% of wild-type controls had 5-FU exposure within target range on a 100% dose (mean, 23.2; IQR, 6.6). In 97% of all variant patients, the 50% reduced dose resulted in 5-FU underexposure, with a median AUC of 10.6 mg × h/L (IQR, 3.2). Dose escalation to 70% or higher was tolerated in most patients, reaching the target AUC in 68% of patients.</p><p><strong>Conclusion: </strong>The current CPIC guidelines are overly conservative for c.1236G>A/HapB3 and most p.D949V variants. A 75% starting dose is more appropriate for most c.1236G>A/HapB3 carriers. We recommend 5-FU therapeutic drug monitoring in all patients with <i>DPYD</i> variants to achieve optimal 5-FU exposure.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500062"},"PeriodicalIF":5.3,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247956","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}