Oncology and Therapy最新文献

{"title":"Gastroenteropancreatic Neuroendocrine Carcinoma (GEP-NEC): An Aggressive Disease Course and Limitations for Personalized Oncology.","authors":"Celine Oanæs, Herish Garresori, Dordi Lea, Marcus T T Roalsø, Torjan M Haslerud, Cato Brede, Kjetil Søreide","doi":"10.1007/s40487-026-00454-7","DOIUrl":"https://doi.org/10.1007/s40487-026-00454-7","url":null,"abstract":"<p><p>Neuroendocrine carcinoma (NEC) is a rare, aggressive malignancy with limited treatment options and poor prognosis. We report a male patient diagnosed with a gastroenteropancreatic (GEP)-NEC with synchronous liver metastasis at the time of surgery who underwent a radical resection attempt. Despite radical-intent surgery followed by adjuvant carboplatin/etoposide, early recurrence developed with progression through multiple subsequent chemotherapy lines. During the treatment process, genetic profiling was performed twice to identify actionable genomic targets, with inclusion in the national IMPRESS study as a last resort. Comprehensive genomic profiling revealed TP53 mutation and RB1 loss but no actionable alterations. A patient-derived organoid (PDO) was successfully established from resected tumor tissue and retained key neuroendocrine and proliferative features, with partial genomic concordance to the primary tumor. Differences between the primary and subsequent PDO in variant allele frequencies suggest clonal selection during culture. Exploratory metabolomic profiling of tryptophan pathway metabolites in patient serum and PDO-culture media indicated tumor-associated metabolic alterations. We present clinical and translational efforts in difficult-to-treat NEC, illustrating both the translational challenges and the potential role of PDOs in advancing personalized treatment strategies for a cancer with very limited treatment options.</p>","PeriodicalId":44205,"journal":{"name":"Oncology and Therapy","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148333255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-World Outcomes Among Medicare Beneficiaries Treated with Bruton Tyrosine Kinase Inhibitors for Treatment-Naïve CLL.","authors":"Daniel A Ermann, Deborah M Stephens, Xiaoliang Wang, Irene Varghese, Heidi De Souza, Caitlin Sheetz, Qianhong Fu, Gregory A Maglinte, Rhys Williams, Erlene K Seymour, Derrick van Beuge, Mazyar Shadman, Ryan Jacobs","doi":"10.1007/s40487-026-00452-9","DOIUrl":"https://doi.org/10.1007/s40487-026-00452-9","url":null,"abstract":"<p><strong>Introduction: </strong>There is a dearth of head-to-head studies comparing covalent Bruton tyrosine kinase (cBTK) inhibitors in adults with chronic lymphocytic leukemia (CLL). Real-world evidence may complement clinical trial data by assessing relative effectiveness in routine practice. This retrospective observational study used a de-identified Medicare Fee-For-Service database to compare real-world outcomes associated with first-line cBTKi monotherapies in older adults with CLL.</p><p><strong>Methods: </strong>Patients aged ≥ 65 years with CLL initiating first-line ibrutinib, acalabrutinib, or zanubrutinib monotherapy between January 1, 2020 and September 30, 2025 were included. Real-world time to treatment discontinuation (rwTTD), time to next treatment (rwTTNT), and overall survival (rwOS) were evaluated using Kaplan-Meier analyses and Cox proportional hazards models. Subgroup analyses were performed by age group.</p><p><strong>Results: </strong>Among 10,523 patients included, 3006 (28.6%) received zanubrutinib (median follow-up 15.8 months), 4309 (40.9%) received acalabrutinib (20.7 months), and 3208 (30.5%) received ibrutinib (34.9 months). Median rwTTD was not reached (NR) for zanubrutinib, compared with 24 months for acalabrutinib and 14 months for ibrutinib. Median rwTTNT was NR for zanubrutinib, 40 months for acalabrutinib, and 20 months for ibrutinib. After adjustments for age, sex, race, CCI, and year of index, zanubrutinib had significantly longer rwTTD (hazard ratio [HR] 0.57 [95% CI 0.51-0.61]), rwTTNT (HR 0.63 [0.55-0.71]), and rwOS (HR 0.64 [0.54-0.77]) compared to ibrutinib. Zanubrutinib also had significantly improved rwTTD (HR 0.86 [0.78-0.94]), rwTTNT (HR 0.87 [0.78-0.96]), and rwOS (HR 0.77 [0.66-0.88]) compared to acalabrutinib. Similar patterns were observed when stratified by age group over 65.</p><p><strong>Conclusions: </strong>These findings demonstrate that zanubrutinib is associated with improved real-world outcomes compared with other cBTK inhibitors.</p>","PeriodicalId":44205,"journal":{"name":"Oncology and Therapy","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148296707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-World Actionability Analysis of Comprehensive Genomic Profiling Versus Single/Small-Gene Panels.","authors":"Paul Spin, Bela Bapat, Chad Moretz, Robert Dumanois, Adrienne M Gilligan, Mostafa Shokoohi, Emily Borgundvaag, John Fox, Carlo Bifulco, David Bartlett","doi":"10.1007/s40487-026-00453-8","DOIUrl":"https://doi.org/10.1007/s40487-026-00453-8","url":null,"abstract":"<p><strong>Introduction: </strong>Comprehensive genomic profiling (CGP) enables identification of patients eligible for targeted treatments, making it essential in the management of advanced cancer. This retrospective real-world study compared actionable mutations in CGP-tested patients with advanced/metastatic solid tumors to those who received single-gene/small-panel (SP) tests.</p><p><strong>Methods: </strong>Patients aged > 18 years with advanced/metastatic solid tumors (including non-small cell lung cancer (NSCLC), colorectal cancer, prostate cancer, breast cancer, or melanoma) with a CGP or SP test reported between 1 January 2018, and 31 December 2022, were included. OncoKB-derived actionability was compared between the two cohorts. Inverse probability of treatment weighting (IPTW) was used to adjust for baseline characteristics. A weighted generalized linear model with log link was used to report actionability ratio (AR) and 95% confidence intervals (CI).</p><p><strong>Results: </strong>Among 406 patients (CGP-tested cohort: 202, SP-tested cohort: 204), approximately half were diagnosed with NSCLC. After adjusting for baseline characteristics, CGP testing detected more actionable alterations than SP: OncoKB level 1 (50.0% versus 31.4%; AR 1.76 [95% CI: 1.24, 2.51]; p = 0.002), OncoKB level 2 (22.8% versus 10.3%; AR 2.53 [95% CI: 1.17, 5.48]; p = 0.018), and OncoKB level 1 or level 2 or level R1 (55.9% versus 41.2%; AR 1.5 [95% CI: 1.11, 2.01]; p = 0.008).</p><p><strong>Conclusions: </strong>CGP testing identified more actionable genetic alterations compared with SP testing methods for patients with advanced/metastatic NSCLC, colorectal cancer, prostate cancer, breast cancer, or melanoma. Expanding reimbursement and coverage for CGP testing as well as expanding CGP use can facilitate equitable treatment access for patients with advanced/metastatic cancer.</p>","PeriodicalId":44205,"journal":{"name":"Oncology and Therapy","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148296745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abemaciclib in HR+, HER2- Breast Cancer: A Narrative Review of the Clinical Evidence.","authors":"Miguel Martin, Alexandru Rosca, Alexandra Searles Vitko, Monique Coersmeyer, Katheryn Moreira, Huiping Li, Erica L Mayer","doi":"10.1007/s40487-026-00449-4","DOIUrl":"https://doi.org/10.1007/s40487-026-00449-4","url":null,"abstract":"<p><p>Hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2-) breast cancer comprises approximately 70% of all breast cancer cases. In early-stage breast cancer, adjuvant endocrine therapy (ET) reduces recurrence and mortality, while in advanced/metastatic breast cancer (MBC), ET prolongs survival and delays the use of chemotherapy. However, there remains a need for agents that further improve outcomes across the spectrum of breast cancer presentations. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, such as abemaciclib, ribociclib, and palbociclib, are used in combination with ET as a standard of care first-line option in HR+, HER2- advanced disease to improve survival outcomes. Moreover, the addition of abemaciclib and ribociclib to adjuvant ET reduces risk of cancer recurrence, with abemaciclib also improving overall survival. Here, we provide a comprehensive analysis of the clinical trials that have demonstrated the efficacy of abemaciclib across the HR+, HER2- breast cancer continuum, improving outcomes in both high-risk, node-positive early breast cancer as well as in advanced disease. Abemaciclib has also been shown to be effective when combined with a variety of ET options, including aromatase inhibitors, tamoxifen, fulvestrant, imlunestrant, or as monotherapy, and has shown efficacy regardless of prior CDK4/6 inhibitor exposure, ESR1 or PI3K pathway mutational status, menopausal status, and in both endocrine-sensitive and endocrine-resistant breast cancer. Importantly, the safety profile of abemaciclib has been consistent across trials and allows the administration of the drug over long periods of time when needed, particularly if dose-reduction strategies are employed. Together, the data summarized in this publication help inform clinical decision making regarding the role of abemaciclib in the treatment of patients with both early and metastatic HR+, HER2- breast cancer.</p>","PeriodicalId":44205,"journal":{"name":"Oncology and Therapy","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148253829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of Drug-Drug Interactions Using Drug-PIN® in Patients Receiving Avelumab Maintenance for Advanced Urothelial Carcinoma: Evidence from the MALVA Study (Meet-URO 25).","authors":"Giandomenico Roviello, Mattia Alberto Di Civita, Daniele Santini, Elisabetta Gambale, Lidia Strigari, Simone Scagnoli, Laura Pappalardo, Andrea Torchia, Andrea Botticelli, Serena Pillozzi, Lorenzo Antonuzzo","doi":"10.1007/s40487-026-00448-5","DOIUrl":"https://doi.org/10.1007/s40487-026-00448-5","url":null,"abstract":"<p><strong>Introduction: </strong>Polypharmacy is common in patients with advanced urothelial carcinoma (UC) receiving avelumab maintenance therapy, raising concerns about potential drug-drug interactions (DDIs).</p><p><strong>Methods: </strong>We retrospectively analyzed patients enrolled in the multicenter MALVA study treated with avelumab maintenance. Concomitant medications were assessed using the Drug Interaction and Pharmacogenomics Information Network (Drug-PIN®). Drug-PIN® scores were calculated with and without avelumab and correlated with overall survival (OS) and progression-free survival (PFS).</p><p><strong>Results: </strong>Among 115 patients, Drug-PIN® scores showed wide inter-patient variability but were not significantly influenced by inclusion of avelumab. No significant differences in OS or PFS were observed across Drug-PIN® risk categories.</p><p><strong>Conclusion: </strong>In this real-world cohort, polypharmacy and Drug-PIN® score did not impact survival outcomes, suggesting that, within the limitations of this exploratory analysis, Drug-PIN®-assessed DDI burden was not associated with survival outcomes in patients receiving avelumab maintenance therapy.</p>","PeriodicalId":44205,"journal":{"name":"Oncology and Therapy","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148253903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond the BCG Paradox: Biological Rationale and Clinical Evidence for Combining Intravesical BCG with Immune Checkpoint Inhibitors in High-Risk Non-muscle-Invasive Bladder Cancer.","authors":"Michele Musone, Biagio Barone, Stefano Chianese, Paolo Conforti, Antonio Madonna, Silvestro Imperatore, Fabrizio Dinacci, Raffaele Balsamo, Giuseppe Lucarelli, Roberto Falabella, Vincenzo Francesco Caputo, Antonio Luigi Pastore, Andrea Fuschi, Matteo Ferro, Lorenzo Romano, Marco Fabiano, Celeste Manfredi, Gian Maria Busetto, Valerio Santarelli, Francesco Del Giudice, Felice Crocetto","doi":"10.1007/s40487-026-00445-8","DOIUrl":"https://doi.org/10.1007/s40487-026-00445-8","url":null,"abstract":"<p><p>Bladder cancer (BC) is the most common malignancy of the urinary tract, with more than 75% of cases diagnosed as non-muscle-invasive bladder cancer (NMIBC). Intravesical Bacillus Calmette-Guérin (BCG) remains the gold standard adjuvant treatment for high-risk NMIBC owing to its ability to induce a robust local immune response within the bladder tumor microenvironment. Nevertheless, a substantial proportion of patients experience disease recurrence or progression, highlighting the need for improved therapeutic strategies. This narrative review examines the biological rationale and available clinical evidence supporting the combination of intravesical BCG with immune checkpoint inhibitors (ICIs) in high-risk NMIBC. A literature review was conducted to analyze the immunological mechanisms underlying BCG-induced antitumor activity, adaptive immune resistance, and the potential role of ICIs in modulating the tumor microenvironment. Clinical trials were evaluated with particular attention to patient populations, study design, safety profiles, and efficacy end points. From a biological perspective, BCG acts as an immunological primer by recruiting and activating innate and adaptive immune cells, while immune checkpoint inhibitors may counteract functional exhaustion of BCG-induced antitumor responses. However, translation of this rationale into consistent clinical benefit remains challenging. Early-phase studies have reported variable response rates in selected patient populations, particularly in BCG-unresponsive disease. In contrast, recent phase III data have shown that upfront combination strategies do not necessarily translate into improved oncological outcomes. Overall, while the combination of BCG and immune checkpoint inhibition is supported by a strong immunological rationale, current clinical evidence remains heterogeneous and largely derived from early-phase or ongoing trials, precluding definitive conclusions regarding long-term oncological benefit and durable bladder preservation. Despite a strong immunological rationale, the combination of BCG with immune checkpoint inhibitors remains investigational. Its adoption into routine clinical practice will require mature phase III evidence, validated predictive biomarkers, and a clear demonstration of superiority over established bladder-preserving treatment strategies.</p>","PeriodicalId":44205,"journal":{"name":"Oncology and Therapy","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148228738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Publisher Correction: Perioperative Treatment Patterns for Muscle-Invasive Bladder Cancer Patients Undergoing Radical Cystectomy in the Adjuvant Immunotherapy Era: A Retrospective Analysis of US Community Oncology Practice.","authors":"Patrick Squires, Ke Meng, Xiaohan Hu, Vladimir Turzhitsky, Yu-Han Kao, Jennifer Stuart, Chethan Ramamurthy, Haojie Li, Ronac Mamtani","doi":"10.1007/s40487-026-00451-w","DOIUrl":"10.1007/s40487-026-00451-w","url":null,"abstract":"","PeriodicalId":44205,"journal":{"name":"Oncology and Therapy","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148206075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine Learning-Guided Survival Prediction and Treatment Sequencing in Advanced Soft Tissue Sarcoma Beyond Second-Line Therapy: A Retrospective Cohort Study.","authors":"Michael Hoberger, Dorit Di Gioia, Romy L Zuber, Michael Völkl, Sinan E Güler, Vindi Jurinovic, Markus Albertsmeier, Alexander Klein, Hans Roland Dürr, Nina-Sophie Schmidt-Hegemann, Thomas Knösel, Wolfgang G Kunz, Michael von Bergwelt-Baildon, Lars H Lindner, Anton Burkhard-Meier, Luc M Berclaz","doi":"10.1007/s40487-026-00446-7","DOIUrl":"https://doi.org/10.1007/s40487-026-00446-7","url":null,"abstract":"<p><strong>Introduction: </strong>Evidence guiding the optimal sequencing of later-line systemic therapy in advanced soft tissue sarcoma (STS) remains limited. The aim of this study was to identify prognostic factors for overall survival (OS) beyond second-line treatment and to explore therapy sequencing in routine clinical practice.</p><p><strong>Methods: </strong>A total of 90 patients with advanced STS receiving third-line or later systemic therapy were retrospectively analyzed. Extreme gradient boosting (XGBoost) was used to identify clinical predictors of 1-year OS. The most influential variables were subsequently evaluated in multivariable Cox models for OS from the start of third- and fourth-line therapy. Sequencing analyses compared OS according to the line of administration of commonly used later-line agents.</p><p><strong>Results: </strong>In the third-line cohort (n = 88), inferior OS was independently associated with progression on second-line therapy (hazard ratio [HR] 2.31, p = 0.005). In contrast, lipo-/leiomyosarcoma histology was associated with improved survival (HR 0.37, p = 0.002), as was a time to progression ≥ 12 months on first-line therapy (HR 0.43, p = 0.007). Findings were largely consistent in the fourth-line cohort (n = 57). Sequencing analyses suggested sustained activity of trabectedin in later lines (p = 0.023), greater benefit of earlier pazopanib use (p = 0.022), and no significant impact of treatment line for gemcitabine + docetaxel combination therapy (p = 0.12).</p><p><strong>Conclusions: </strong>Machine learning-guided variable selection identified clinically relevant predictors of survival in later-line STS. Prior treatment response and histology strongly influence outcomes, and exploratory sequencing analyses suggest differential timing effects across systemic therapy agents.</p>","PeriodicalId":44205,"journal":{"name":"Oncology and Therapy","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148165036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gain and Loss of FLT3 Mutations in Patients with Acute Myeloid Leukemia: A Noninterventional Cohort Study (CLEVO).","authors":"Cristina Papayannidis, Irina Amitai, Pascal Turlure, Ann De Becker, Felix Mensah, Dina Elsouda, Ioanna Vardounioti, Jose Alejandro Palacios-Fabrega, Paresh Vyas, Blanca Boluda","doi":"10.1007/s40487-026-00427-w","DOIUrl":"10.1007/s40487-026-00427-w","url":null,"abstract":"<p><strong>Introduction: </strong>FMS-like tyrosine kinase 3 (FLT3) mutations show variable detectability in relapse/refractory acute myeloid leukemia (AML) with unclear clonal evolution dynamics.</p><p><strong>Methods: </strong>This prospective noninterventional study examined clonal evolution and outcomes from AML diagnosis to relapse/refractory disease occurrences.</p><p><strong>Results: </strong>Of 650 patients included, 172 were FLT3-positive (FLT3^pos) and 472 were FLT3-negative (FLT3^neg; 99.1% testing rate; unknown FLT3 status, six patients). At first occurrence, the FLT3 testing rate decreased (57.0% [166/291]). Among tested patients, 45 had FLT3^pos and 121 had FLT3^neg AML. A gain or loss of mutations was seen in 15.6% (7/45) of patients with FLT3^pos AML and 14.9% (18/121) of patients with FLT3^neg AML. Median (95% confidence interval [CI]) overall survival was 22.8 (19.6, not estimable [NE]) months across patients (FLT3^pos, NE;FLT3^neg, 20.3 [15.2-23.7] months; hazard ratio [HR] [95% CI] 0.6 [0.5-0.8]). Median (95% CI) disease-free survival across patients was NE (26.3-NE) (FLT3^pos, NE;FLT3^neg, NE; HR [95% CI] 0.8 [0.6-1.1]). Median event-free survival (95% CI) was 11.8 (10.0-15.5) months in all patients (FLT3^pos, 17.2 [11.0-NE] months;FLT3^neg, 10.4 [8.4-13.2] months; HR [95% CI] 0.8 [0.6-1.0]).</p><p><strong>Conclusions: </strong>Dynamic changes in FLT3 mutation status were observed during these patients' disease course. FLT3^pos status at baseline, but not at first occurrence, was associated with improved outcomes; other confounders should be considered. Timelier FLT3 mutation retesting may aid in personalizing treatment. Graphical abstract available for this article.</p>","PeriodicalId":44205,"journal":{"name":"Oncology and Therapy","volume":" ","pages":"655-670"},"PeriodicalIF":3.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13304035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147436262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of Variants in Candidate Pharmacogenes with Response to Mercaptopurine and Methotrexate in Pediatric Acute Lymphoblastic Leukemia: A Single-Center Experience from Croatia.","authors":"Isidora Curic, Nikola Kotur, Bojan Ristivojevic, Djordje Pavlovic, Marina Jelovac, Katarina Krstajic, Mia Radosevic, Ana Djordjevic, Sonja Pavlovic, Jelena Roganovic, Branka Zukic","doi":"10.1007/s40487-026-00440-z","DOIUrl":"10.1007/s40487-026-00440-z","url":null,"abstract":"<p><strong>Introduction: </strong>Interindividual variability in the efficacy and toxicity of 6-mercaptopurine (6-MP) and methotrexate (MTX) drugs remains a major challenge in the treatment of pediatric acute lymphoblastic leukemia (ALL). Germline variation in pharmacogenes involved in drug metabolism, transport, and folate pathways may contribute to this variability.</p><p><strong>Methods: </strong>In this retrospective cohort study, 43 pediatric patients with ALL treated at a tertiary referral center in Croatia according to ALL IC-BFM 2002 or 2009 protocols were genotyped for eleven variants in TPMT, ITPA, NUDT15, PACSIN2, MTHFR, TYMS, SLC19A1, and SLCO1B1 genes. Associations with average 6-MP dose during maintenance therapy, MTX pharmacokinetics during consolidation and MTX-related toxicity were analyzed. A polygenic risk score (PRS) was constructed to assess cumulative genetic risk of developing toxicity when administering these two drugs.</p><p><strong>Results: </strong>Carriers of the ITPA rs1127354 variant required significantly lower average 6-MP doses compared with wild-type carriers. The NUDT15 rs61973267 variant was associated with higher tolerated 6-MP doses after exclusion of outliers. No significant associations were observed between individual variants and MTX clearance. A trend toward reduced risk of oral mucositis was observed in carriers of the SLCO1B1 rs4149056 variant. PRS analyses that included carriers of the TPMT rs1142345 and ITPA rs1127354 variants showed a borderline association with the requirement for 6-MP dose reduction.</p><p><strong>Conclusions: </strong>Our findings support a role for ITPA and NUDT15 variants in modulating 6-MP dose requirements, while single-variant associations with MTX pharmacokinetics and toxicity were limited and not supported. These results underscore the complexity of antimetabolite pharmacogenetics and suggest that integrative polygenic approaches may better capture clinically relevant pharmacogenetic risk.</p>","PeriodicalId":44205,"journal":{"name":"Oncology and Therapy","volume":" ","pages":"791-809"},"PeriodicalIF":3.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13305058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147989416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}