JCO precision oncology最新文献

{"title":"Tumor Immune Microenvironment and Response to Preoperative Chemoradiotherapy in Locally Advanced Rectal Cancer: Results From the STAR-01 Study Cohort.","authors":"Francesca Negri, Lorena Bottarelli, Letizia Gnetti, Luca Boni, Nicoletta Campanini, Cinzia Azzoni, Stefano Tamberi, Francesca Bergamo, Michela Frisinghelli, Germana Chiaulon, Gianluca Masi, Angiolo Tagliagambe, Marija Petric, Alberto Morabito, Giovanni Luca Paolo Frassineti, Fabio Gelsomino, Domenico Corsi, Silvia Bozzarelli, Giulia Anna Carmen Vita, Gian Luigi de'Angelis, Enrico Maria Silini, Salvatore Siena, Luigi Laghi, Carlo Aschele","doi":"10.1200/PO-26-00278","DOIUrl":"https://doi.org/10.1200/PO-26-00278","url":null,"abstract":"<p><strong>Purpose: </strong>Preoperative chemoradiotherapy (CRT) can reshape the composition of the tumor immune microenvironment (TIME) in locally advanced rectal cancer (LARC), augmenting T-cell density and activation. As TIME may provide predictive insights, we analyzed the association of immune cell distribution and remodeling after CRT with pathologic response and clinical outcomes in patients with LARC derived from the STAR-01 (fluorouracil-based CRT plus/minus oxaliplatin) trial.</p><p><strong>Patients and methods: </strong>Tumor-infiltrating lymphocytes (TILs) were assessed by standard stains and immunostains (CD3, CD20, CD4, CD8, FOXP3, PD-1, and CD68). Immune cell populations in pretreatment biopsies and post-treatment surgical specimens were compared and associated with complete pathological response (ypT0N0) and overall (OS) and event-free (EFS) survival.</p><p><strong>Results: </strong>We retrieved 413 samples from 303 patients from the original cohort, including 110 paired pretreatment biopsies and post-treatment surgical tumor specimens. In pretreatment biopsies, CD20⁺ cell counts were associated with improved EFS (<i>P</i> = .051), independent of other prognostic factors. After therapy, intermediate-high TILs, CD3⁺ cells, low CD4⁺/CD8⁺ ratio, and CD68⁺ macrophage counts significantly increased, whereas FOXP3⁺ and CD20⁺ cells decreased. ypT0N0 was associated with low CD4⁺/CD8⁺ ratio (<i>P</i> < .001), reduced CD68⁺ (<i>P</i> = .001), and absence of eosinophils (<i>P</i> < .001) in post-treatment surgical specimens. In post-treatment specimens, low CD4⁺/CD8⁺ ratio and CD20⁺ cell counts were significantly associated with both improved EFS (CD4⁺/CD8⁺: <i>P</i> = .016; CD20⁺ cells: <i>P</i> = .002) and OS (CD4⁺/CD8⁺: <i>P</i> = .005; CD20⁺ cells: <i>P</i> = .014). This prognostic role was confirmed in a multivariable analysis for CD20⁺ cells.</p><p><strong>Conclusion: </strong>In LARC, CRT reshapes the type and amount of immune cell contents, and the effects on certain immune populations are associated with tumor regression and clinical outcome.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 9","pages":"e2600278"},"PeriodicalIF":4.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030652","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":"Longitudinal Clinical, Physiological, and Molecular Profiling of Female Patients With Metastatic Cancer: Protocol and Feasibility of a Multicenter High-Definition Oncology Study.","authors":"Leonardo D Garma, Sonia Pernas, David Vicente Baz, Rosario García Campelo, Josefa Terrasa, Berta Nasarre, Ruth Vera García, Begoña Bermejo, Santiago González Santiago, Bartomeu Fullana, Mario Rodríguez-Pérez, Manuel Fernandez Bruno, Cristina Reboredo Rendo, Antonia Perelló, Desirée Jiménez, Juan Antonio Guerra, Virginia Arrazubi, Susana de la Cruz, Juan Miguel Cejalvo, Cristina Tebar, Elena Núñez Berrueco, Berta Hernández-Marín, Jacobo Rogado, Pablo M Olmos, Leire P Arbaizar, Miguel A Villalba Oliva, Yolanda Madrid, Jon Sanz-Landaluze, Gustavo Moreno-Martín, Aída Morillas, Antonio Lopez-Alonso, Alfonso Rodríguez-Patón, Ramón Colomer, Antonio Artés-Rodríguez, Miguel Quintela-Fandino","doi":"10.1200/PO-25-01185","DOIUrl":"10.1200/PO-25-01185","url":null,"abstract":"<p><strong>Purpose: </strong>A substantial proportion of patients receiving genomically matched therapies do not achieve clinical benefit, underscoring the influence of nongenetic factors on cancer outcomes. High-Definition Oncology (HDO) proposes integrating longitudinal, multimodal patient data-spanning clinical, molecular, physiological, and behavioral domains-to enable truly individualized cancer care. This manuscript describes the HDO study design, framework, and feasibility results in women with metastatic cancer.</p><p><strong>Methods: </strong>We initiated a prospective, multicenter observational study (HDO study; ClinicalTrials.gov identifier: NCT06590506) enrolling 300 female patients with newly diagnosed metastatic breast, lung, or colorectal cancer. Here, we report the study design, standardized workflows, prespecified feasibility criteria, and early internal pilot results. Eleven data modalities are collected longitudinally, including tumor and germline genomics, germline epigenomics, gut microbiome, blood and stool metabolomics and proteomics, exposome characterization, wearable-derived physiological monitoring, digital footprint assessment, medical imaging, and patient-reported outcomes. Standardized workflows govern clinical procedures, data acquisition, biospecimen processing, and quality control across all participating sites.</p><p><strong>Results: </strong>Feasibility was evaluated in the first 30 participants (10% of planned accrual). Patients completed 100% of scheduled clinical visits, 97.4% of planned plasma collections, 80.7% of stool samples, and all tumor biopsies. Wearable devices captured activity, heart rate, sleep, and blood oxygen saturation data during 95.0%, 84.2%, 90.6%, and 70.7% of total patient-days, respectively. Biospecimens met predefined quality control metrics across all molecular modalities. Engagement with mobile applications for pain and emotion reporting exceeded 80%.</p><p><strong>Conclusion: </strong>The HDO study demonstrates the feasibility of comprehensive, longitudinal, multimodal data collection in women with metastatic cancer. This internal pilot establishes an integrated framework for future analyses aimed at characterizing disease trajectories, defining molecular and physiological determinants of outcomes, and developing patient-specific computational models.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 9","pages":"e2501185"},"PeriodicalIF":4.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148990068","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":"Predicting Targeted and Immunotherapeutic Response Outcomes in Melanoma With Single-Cell Raman Spectroscopy and Artificial Intelligence.","authors":"Kai Chang, Mamatha Serasanambati, Baba Ogunlade, Hsiu-Ju Hsu, James Agolia, Ariel Stiber, Jeffrey Gu, Jay Chadokiya, Grayson E Rodriguez, Prabhjeet Singh, Saurabh Sharma, Amanda Gonçalves, Ojasvi Verma, Fareeha Safir, Nhat Vu, K Christopher Garcia, Daniel Delitto, Amanda Kirane, Jennifer A Dionne","doi":"10.1200/PO-25-00591","DOIUrl":"10.1200/PO-25-00591","url":null,"abstract":"<p><strong>Purpose: </strong>Identifying reliable predictors of immunotherapeutic response in melanoma remains an outstanding challenge. Existing transcriptomic and proteomic profiling methods for the tumor-immune microenvironment are costly and may not faithfully capture modifications actively affecting tumor behavior. Here, we present a nondestructive, single-cell approach combining Raman spectroscopy and machine learning (ML) that enables rapid cell profiling and therapeutic response prediction.</p><p><strong>Methods: </strong>We analyzed single-cell Raman spectra of mouse and human melanoma cell lines alongside nine samples derived from patients with melanoma with known resistance profiles to targeted and immunotherapeutic inhibitors bemcentinib, cabozantinib, dabrafenib, and nivolumab and a combination of nivolumab and relatlimab. We assessed cell phenotyping classification and treatment resistance using random forests and feature importance analysis. For patient samples, we constructed a two-stage evaluation workflow to determine clinical drug resistance through aggregated single-cell predictions and identified corresponding highly variant spectral signatures using computational methods adapted from single-cell RNA sequencing methods.</p><p><strong>Results: </strong>In cell lines, our approach achieved >96% differentiation accuracy across tumor microenvironment cell types and induced functional phenotypes. Persistent (drug-resistant) cells formed subclusters based on genetic mutations rather than sample origin, with Raman signatures reflecting biochemical changes relevant to therapeutic pathways. For patient samples, our workflow correctly inferred resistance likelihoods for 30 of 33 clinically relevant patient-drug combinations (91% accuracy).</p><p><strong>Conclusion: </strong>Single-cell Raman spectroscopy combined with ML offers a scalable, prognostic platform to predict therapeutic resistance likelihood, with further potential to advance clinical, multiomic biomarker efforts for melanoma. Our approach may improve first- and second-line therapy selection assessments for precision medicine by providing rapid, nondestructive prediction of therapeutic response based on cellular spectral profiles.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 9","pages":"e2500591"},"PeriodicalIF":4.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148919682","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":"Nationwide Fully Decentralized Telemedicine Therapeutic Trial for Advanced Pancreatic Cancer: Implementation and First Enrollment.","authors":"Zachary A Risch, Julie W Reeser, Michele R Wing, Claire Jackman, Brett Bushong, Amy Smith, Thuy Dao, Eric Samorodnitsky, Xueliang Pan, Arjun Gupta, Sameek Roychowdhury","doi":"10.1200/PO-26-00364","DOIUrl":"https://doi.org/10.1200/PO-26-00364","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 9","pages":"e2600364"},"PeriodicalIF":4.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148990087","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":"Clinicopathologic Features, Treatment Patterns, and Outcomes of Microsatellite Instability-High Gastric and Gastroesophageal Junction Adenocarcinoma: A Single-Institution Retrospective Analysis.","authors":"Dani Castillo, Pranati Shah, Natasha Setia, Sofia Guzman, Sadia Mlamba, Derek Tai, Fei Fei, Dalilah Perez, Cecilia Lau, Max Hazeltine, Yanghee Woo, Gagandeep Brar, Marwan Fakih, Shengyang Peter Wu, Rifat Mannan","doi":"10.1200/PO-26-00543","DOIUrl":"https://doi.org/10.1200/PO-26-00543","url":null,"abstract":"<p><strong>Purpose: </strong>Microsatellite instability-high (MSI-H) and deficient mismatch repair (dMMR) gastric or gastroesophageal junction (GEJ) adenocarcinomas are biologically distinct tumors with established sensitivity to immune checkpoint inhibitors (ICIs). However, real-world treatment patterns, response heterogeneity, and predictors of durable benefit remain poorly defined.</p><p><strong>Methods: </strong>We retrospectively analyzed patients with biopsy-confirmed MSI-H/dMMR gastric/GEJ adenocarcinoma treated at a single center. Clinicopathologic, genomic, treatment, and outcome data were collected. Molecular profiling included ARID1A, RNF43, TP53, PIK3CA, KRAS, TGFBR2, and human epidermal growth factor 2 (HER2). ICIs-treated patients were classified as achieving clinical benefit (complete response, partial response, or durable stable disease ≥16 weeks) or no clinical benefit using iRECIST v1.1 and clinical assessment. Overall survival (OS) was estimated by using the Kaplan-Meier method.</p><p><strong>Results: </strong>Thirty-four patients were identified (median age, 66 years; 53% male), including 21 with stage IV disease. Tumors were predominantly poorly differentiated (65%) and HER2-negative (94%), and 18% of patients had Lynch syndrome. Among 22 ICI-treated patients, 55% achieved clinical benefit, which was strongly associated with prolonged OS (<i>P</i> < .01). Most responses occurred at the first radiographic assessment (approximately 12 weeks). Elevated tumor mutational burden (TMB; ≥20 mutations/Mb) was present in 56% of patients but was not associated with clinical benefit (<i>P</i> = .40), and no individual genomic alteration significantly correlated with treatment outcome. Exploratory analyses suggested longer OS among patients with liver versus peritoneal metastases. Treatment was well tolerated, with predominantly low-grade immune-related adverse events. Baseline Eastern Cooperative Oncology Group performance status (0-1 <i>v</i> ≥ 2) was associated with clinical benefit (<i>P</i> = .049).</p><p><strong>Conclusion: </strong>Approximately half of the patients with MSI-H/dMMR gastric/GEJ adenocarcinoma cancers derived durable clinical benefit from ICIs, and treatment response was strongly associated with survival. Conventional genomic features, including TMB, did not predict clinical benefit, highlighting the need for additional biomarkers.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 9","pages":"e2600543"},"PeriodicalIF":4.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148990147","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":"Evaluation of a Tumor-Informed Molecular Residual Disease Assay in Early Triple-Negative Breast Cancer Treated With Neoadjuvant Chemotherapy, With or Without Atezolizumab.","authors":"Marija Balic, Gong Tang, Priya Rastogi, Gregory Young, Matthew Wallace, Joshua Acosta, Andreas Schneeweiss, Christie J Hilton, Tanner J Freeman, Jiahe Li, Carsten Denkert, Mattea Reinisch, Melanie R Palomares, Bradley A Arrick, Matthew Petitt, Sai K Maley, Saima Hassan, Sujatha Murali, Jean-François Boileau, Dominique Boudreau, Peter J Polewski, Sandeep Mashru, Jeffrey B Hargis, Joanne Mortimer, Michael Thirlwell, William Sikov, Antoinette R Tan, Jorge Garces, Gina Costa, Janine LoBello, João Mouta, Walter C Darbonne, Frederick L Baehner, Eleftherios P Mamounas, Norman Wolmark, Sibylle Loibl, Charles E Geyer","doi":"10.1200/PO-26-00114","DOIUrl":"10.1200/PO-26-00114","url":null,"abstract":"<p><strong>Purpose: </strong>Detection of molecular residual disease (MRD) using circulating tumor DNA (ctDNA) is strongly associated with recurrence risk in early triple-negative breast cancer (TNBC). Prior studies suggest that ctDNA clearance during neoadjuvant therapy (NAT) may predict pathologic complete response (pCR) and enhance the prognostic value of pCR. National Surgical Adjuvant Breast and Bowel Project (NSABP) B-59/German Breast Group-96-GeparDouze evaluated atezolizumab added to NAT and as adjuvant therapy in 1,550 patients with stage II/III TNBC. For prospective ctDNA substudy on serial blood samples, we used whole-exome sequencing of primary tumors to generate patient-specific tumor-informed assays to correlate ctDNA status with distant recurrence and clinical outcomes.</p><p><strong>Materials and methods: </strong>This substudy included NSABP B-59 patients with serial blood collections before NAT (baseline), after NAT before surgery, 3-6 weeks postsurgery, and 12 and 24 months after random assignment. The primary objective was to evaluate the association between ctDNA status postsurgery with distant recurrence-free interval, defined from the date of surgery to first distant metastasis or death from breast cancer. The median follow-up for the primary end point was 37 months.</p><p><strong>Results: </strong>At baseline, ctDNA was detected in 153 of 160 patients (96%). Among 147 patients with ctDNA assessment postsurgery, ctDNA was detected in nine (6%). Distant recurrence occurred in seven of nine (77.8%) patients with ctDNA-positive status postsurgery, compared with seven of 138 (5%) with ctDNA-negative status postsurgery (log-rank <i>P</i> < 1E-16; hazard ratio, 30.3 [95% CI, 10.4 to 88.7]). Among patients with residual invasive disease after NAT and surgery, five of 42 (11.9%) with negative ctDNA status developed distant recurrence versus six of seven (85.7%) in those with positive ctDNA status.</p><p><strong>Conclusion: </strong>The tumor-informed MRD assay demonstrated high baseline ctDNA prevalence, marked clearance with NAT, and strong prognostic utility of post-NAT and postsurgery ctDNA-positive status for distant recurrence in early TNBC.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 9","pages":"e2600114"},"PeriodicalIF":4.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13581298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148945018","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":"Triple-Negative Transformation in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: Tissue Versus Liquid Biopsy in Two Cases.","authors":"Shahla Abu Naib, Paul Ellis, Eisa Velicaria, Crispin Hiley, Neill Patani, Humaid Al-Shamsi, Xiwen Wang, Darshana Patil, Vineet Datta, Kefah Mokbel, Tim Crook","doi":"10.1200/PO-26-00060","DOIUrl":"10.1200/PO-26-00060","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 9","pages":"e2600060"},"PeriodicalIF":4.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13623062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030596","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":"Identification of an <i>ERCC2</i> Mutation-Associated Mutational Signature of Nucleotide Excision Repair Deficiency in Targeted Panel Sequencing Data.","authors":"Olivera Stojkova, Judit Börcsök, Zsofia Sztupinszki, Miklos Diossy, Aurel Prosz, Alexander Neil, Kent W Mouw, Claus S Sørensen, Zoltan Szallasi","doi":"10.1200/PO-26-00329","DOIUrl":"10.1200/PO-26-00329","url":null,"abstract":"<p><strong>Purpose: </strong>Next-generation sequencing-based mutational signatures are frequently used to identify tumors with specific DNA repair deficiencies for targeted therapeutic strategies. Although mutational signatures are commonly derived from whole-exome or whole-genome sequencing data, patients often undergo tumor sequencing using more limited targeted panels that typically encompass several hundred cancer-associated genes. Identifying clinically relevant mutational signatures from targeted panel data requires new approaches capable of deriving signatures from the more limited sequencing data.</p><p><strong>Methods: </strong>Using publicly available panel sequencing data, we derived and validated a panel sequencing-based composite mutational signature associated with nucleotide excision repair (NER) deficiency induced by inactivating <i>ERCC2</i> mutations in bladder cancer.</p><p><strong>Results: </strong>We found that <i>ERCC2</i> wild-type (WT) bladder cancer cases that have high levels of this mutational signature respond better to neoadjuvant platinum therapy and have improved overall survival compared with <i>ERCC2</i> WT cases with low levels of the signature. We also found that other solid tumor types with <i>ERCC2</i> mutations also show the characteristic mutational signature seen in NER-deficient <i>ERCC2</i>-mutant bladder cancers, suggesting a novel approach to therapeutically target these <i>ERCC2</i>-mutant solid tumors beyond bladder cancer.</p><p><strong>Conclusion: </strong>Mutational signature-based NER deficiency status can be determined in panel sequencing data of tumor biopsies. This could be used to investigate the connection between NER deficiency and response to neoadjuvant platinum-based chemotherapy.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 9","pages":"e2600329"},"PeriodicalIF":4.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074737","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":"Clinical and Proteomic Biomarkers of Trifluridine/Tipiracil in Fluoropyrimidine-Refractory Advanced Pancreatic Adenocarcinoma: A Single-Arm Phase II Trial.","authors":"Chi Leung Chiang, Sik Kwan Kenneth Chan, Ann Shing Francis Lee, Ka Ming Eric Lam, Chun Yin Edwin Wong, Chun Wan Dominic Chan, Kwan Shuen Kristy Chan, Stephen Li, Wing Hon Jason Wong, Wan Hang Keith Chiu, Cheuk Lam Regina Lo","doi":"10.1200/PO-26-00323","DOIUrl":"10.1200/PO-26-00323","url":null,"abstract":"<p><strong>Purpose: </strong>Patients with refractory pancreatic cancer have limited therapeutic option and dismal prognoses. This study aimed to evaluate the efficacy and safety of trifluridine/tipiracil (FTD/TPI) in patients with fluoropyrimidine-refractory pancreatic cancer and their predictive biomarkers.</p><p><strong>Methods: </strong>In this single-arm phase II clinical trial, patients of refractory pancreatic cancer were enrolled and administered with FTD/TPI on days 1-5 and 8-12 of a 28-day cycle. The primary end point was the 16-week progression-free survival (PFS) rate. Secondary end points included median PFS, median overall survival (OS), disease control rate (DCR), and toxicities. Clinical and proteomic biomarkers were assessed before treatment and correlated with PFS and OS.</p><p><strong>Results: </strong>Between March 2021 and June 2023, a total of 28 patients were enrolled. The median age was 64 years (range, 49-80), and 16 (57.1%) patients were male. All patients (100%) received prior fluoropyrimidine. Twenty-three patients (82.1%) received two or more lines of chemotherapy. After a median follow-up of 4.8 months, the 16-week PFS rate was 35.7% (95% CI, 17.8 to 53.2). The median PFS was 3.3 months (95% CI, 1.8 to 4.8) and the median OS was 4.6 months (95% CI, 3.8 to 5.4). The DCR was 50% (14/28; 95% CI, 30.7 to 69.4). The most common grade 3 or worse adverse events were neutropenia (n = 9, 32.1%) and anemia (n = 4, 14.3%) without new safety signals. Neutrophil-to-lymphocyte ratio (NLR) > 5 and high IL1RL1 level were poor prognostic factors, while high APOA4, MSTN, and LUM levels were associated with better prognoses.</p><p><strong>Conclusion: </strong>To our knowledge, this is the first prospective study to suggest the potential efficacy and acceptable safety of FTD/TPI in patients with pancreatic cancer refractory to fluoropyrimidine. Further randomized trials are needed to validate these findings. NLR, IL1RL1, APOA4, MSTN, and LUM levels are promising biomarkers that warrant further investigation.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 9","pages":"e2600323"},"PeriodicalIF":4.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030605","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":"Cross-Ancestry and Phenome-Wide Associations of Cancer-Specific Polygenic Risk Scores.","authors":"Louise Wang, Heena Desai, Craig Teerlink, Oliver Clark, Kathryn M Pridgen, Jennifer Lee, Kyong-Mi Chang, Rachel L Kember, Marijana Vujkovic, Julie A Lynch, Kara N Maxwell","doi":"10.1200/PO-25-00957","DOIUrl":"10.1200/PO-25-00957","url":null,"abstract":"<p><strong>Purpose: </strong>Genome-wide association studies have identified many common variants associated at low effect sizes with various cancers. Summing the effects of these variants into polygenic risk scores (PRS) can improve cancer risk prediction. However, cross-cancer and cross-phenotype pleiotropic associations of cancer-specific PRS are limited.</p><p><strong>Methods: </strong>Using logistic regression models, we tested the association of 13 cancer-specific PRS with curated phenotypes representing the same 13 cancers and 340 cancer and cardiometabolic phecodes in 560,287 individuals (114,255 African ancestry [AFR] and 446,032 European ancestry [EUR]) from the Million Veteran Program. Models were stratified by ancestry and used age, principal components, and cancer-specific PRS per standard deviation as independent variables, and correction was applied for multiple comparisons.</p><p><strong>Results: </strong>All 13 cancer-specific PRS were significantly associated with their respective cancers among EUR individuals with odds ratios per standard deviation of PRS (odds ratio [OR]) 1.05-1.70. Among AFR individuals, the effect sizes of the cancer PRS were lower, with OR 1.01-1.48, and cancer-specific PRS were significantly associated with their respective cancers for five of 13 cancers (bladder, breast in female patients, colorectal, prostate, and thyroid). In cancer-cancer pleiotropy studies, only the renal cancer-specific PRS was significantly associated with skin cancer (OR = 1.04, <i>P</i> = 4.5 × 10^-06) among EUR individuals. PheWAS demonstrated five positive pleotropic associations with cardiometabolic conditions (thyroid cancer PRS with thyroid goiter, oral cancer PRS with diabetes phenotypes, and hypothyroidism) and two negative associations (oral and lung cancer PRS separately with coronary artery disease).</p><p><strong>Conclusion: </strong>Cancer PRS have stronger associations per cancer among EUR versus AFR individuals. In contrast to PRS of other chronic diseases, the majority of cancer-related PRS are highly specific and pleiotropic associations with other cancers and cardiometabolic traits are uncommon.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 9","pages":"e2500957"},"PeriodicalIF":4.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148990113","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}