JCO precision oncology最新文献

{"title":"Histologic Subvariants of Retroperitoneal Well-Differentiated Liposarcoma Show Evidence of Clinical and Genomic Progression Toward Dedifferentiated Liposarcoma.","authors":"George Z Li, Jay Lee, Karissa Whiting, Evan Seffar, Li-Xuan Qin, Edmund K Bartlett, Aimee M Crago, Murray Brennan, Meera R Hameed, Samuel Singer","doi":"10.1200/PO-25-00316","DOIUrl":"10.1200/PO-25-00316","url":null,"abstract":"<p><strong>Purpose: </strong>Several histologic subvariants of retroperitoneal well-differentiated liposarcoma (WDLS) have been described, but their associations with clinical outcomes, underlying genomic differences, and transformation to dedifferentiated liposarcoma (DDLS) are not well-defined.</p><p><strong>Methods: </strong>We identified 276 patients with primary retroperitoneal WDLS and 353 patients with primary retroperitoneal DDLS who underwent resection between July 1982 and July 2021 at our institution. WDLS histology was reviewed by a sarcoma pathologist and divided into three subvariants: lipoma-like, sclerosing/myxoid, or incipient/early dedifferentiated WDLS. We also performed an exploratory genomic analysis on a subset of 140 patients with available next-generation targeted sequencing data generated using the MSK-IMPACT platform.</p><p><strong>Results: </strong>Compared with the lipoma-like subvariant, the sclerosing/myxoid (hazard ratio [HR], 3.2) and incipient/early dedifferentiated subvariants (HR, 5.3) and DDLS (HR, 9.6) were independently associated with higher incidence of disease-specific death after controlling for other prognostic factors such as tumor size and resection margins. Both the sclerosing/myxoid (HR, 2.9) and incipient/early dedifferentiated (HR, 5.4) subvariants were also associated with a higher incidence of subsequent dedifferentiation compared with the lipoma-like subvariant. On genomic exploratory analysis, compared with the lipoma-like samples, the sclerosing/myxoid and incipient/early dedifferentiated samples had significantly higher copy number log ratios (CNLRs) of <i>MDM2</i> and <i>CDK4</i>, with the incipient/early dedifferentiated samples having similar CNLRs of <i>MDM2</i> and <i>CDK4</i> to DDLS samples.</p><p><strong>Conclusion: </strong>WDLS subvariants exhibit both a morphological and genomic progression along the WDLS to DDLS disease spectrum. Distinguishing between them is clinically meaningful for accurate patient counseling and enrollment and stratification in future clinical trials.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500316"},"PeriodicalIF":5.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137780","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":"Immunoprofiling at an Institutional Scale Reveals That High Numbers of Intratumoral CD8⁺ and PD-1⁺ Cells Predict Superior Patient Survival Across Major Cancer Types Independent of Major Risk Factors.","authors":"Joao V Alessi, James R Lindsay, Anita Giobbie-Hurder, Bijaya Sharma, Kristen Felt, Priti Kumari, Tali Mazor, Ethan Cerami, William Lotter, Jennifer Altreuter, Jason Weirather, Ian Dryg, Katharina Hoebel, Michael Manos, Elio Adib, Jennifer D Curtis, Biagio Ricciuti, Alessandro Di Federico, Fatme Ghandour, Eddy Saad, Xin-An Wang, Federica Pecci, Marta Holovatska, Malini M Gandhi, Melissa E Hughes, Tess A O'Meara, Sabrina J Chan, Kathleen Pfaff, Panagiotis A Konstantinopoulos, F Stephan Hodi, Margaret A Shipp, Sabina Signoretti, Toni Choueiri, Xiao X Wei, Sandro Santagata, Glenn J Hanna, Nancy U Lin, Sara M Tolaney, Joyce Liu, Peter K Sorger, Neal Lindeman, Lynette M Sholl, Jonathan A Nowak, David Barbie, Mark M Awad, Bruce E Johnson, Scott J Rodig","doi":"10.1200/PO-25-00240","DOIUrl":"10.1200/PO-25-00240","url":null,"abstract":"<p><strong>Purpose: </strong>Retrospective studies have found associations between the number of intratumoral immune cells and patient outcomes for specific cancers treated with targeted therapies. However, the clinical value of routinely quantifying intratumoral immune biomarkers using a digital pathology platform in the pan-cancer setting within an active clinical laboratory has not been established.</p><p><strong>Methods: </strong>We developed ImmunoProfile, a daily clinical workflow that integrates automated multiplex immunofluorescence tissue staining, digital slide imaging, and machine learning-assisted scoring to quantify intratumoral CD8⁺, PD-1⁺, CD8⁺PD-1⁺, and FOXP3⁺ immune cells and PD-L1 expression in formalin-fixed, paraffin-embedded tissue samples in a standardized and reproducible manner. We prospectively applied ImmunoProfile to biopsies collected from 2,023 unselected patients with cancer over a 3-year period in the clinical laboratory and correlated the results with patient survival.</p><p><strong>Results: </strong>In the pan-cancer cohort, patients with high numbers of intratumoral CD8⁺ or PD-1⁺ cells in had significantly lower risks of death compared with those with low numbers (CD8⁺: high <i>v</i> low hazard ratio [HR], 0.62 [95% CI, 0.48 to 0.81], Wald <i>P</i> = .002; PD-1⁺: high <i>v</i> low HR, 0.65 [95% CI, 0.51 to 0.83]; <i>P</i> = .0009) after adjusting for risk factors, including cancer type. In subset analyses, patients with high numbers of intratumoral CD8⁺, PD-1⁺, and/or CD8⁺PD-1⁺ cells showed lower risks of death from non-small cell lung, colorectal, breast, esophagogastric, head and neck, pancreatic, and ovarian cancers after considering clinical risk factors, including American Joint Committee on Cancer stage, and despite varying therapies (all <i>P</i> < .05).</p><p><strong>Conclusion: </strong>Routinely quantifying intratumoral CD8⁺ and PD-1⁺ cells with a clinically validated digital pathology platform predicts patient survival across major cancer types, independent of clinical stage and despite diverse treatment regimens.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500240"},"PeriodicalIF":5.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12419029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000589","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 Findings From Tumor-Only Comprehensive Genomic Profiling in the RATIONAL Study: A Missed Opportunity?","authors":"Riziero Esposito Abate, Alessandro Morabito, Michele Milella, Fabrizio Tabbò, Valentina Guarneri, Giacomo Pelizzari, Ilario G Rapposelli, Rossana Berardi, Lucio Buffoni, Elisa Bennicelli, Francesca Zanelli, Carlo Tondini, Laura Attademo, Tiziana P Latiano, Salvatore Corallo, Giancarlo Pruneri, Federica Marmorino, Orazio Caffo, Lorenzo Antonuzzo, Simona Tessitore, Silvia Novello, Giuseppe Curigliano, Carmine Pinto, Nicola Normanno, Antonella De Luca","doi":"10.1200/PO-25-00399","DOIUrl":"10.1200/PO-25-00399","url":null,"abstract":"<p><strong>Purpose: </strong>Tumor comprehensive genomic profiling (CGP) may detect potential germline pathogenic/likely pathogenic (P/LP) alterations as secondary findings. We analyzed the frequency of potentially germline variants and large rearrangements (LRs) in the RATIONAL study, an Italian multicenter, observational clinical trial that collects next-generation sequencing-based tumor profiling data, and evaluated how these findings were managed by the enrolling centers.</p><p><strong>Patients and methods: </strong>Patients prospectively enrolled in the pathway-B of the RATIONAL study and undergoing CGP with the FoundationOne CDx assays were included in the analysis. Potentially germline variants detected in 40 cancer susceptibility genes (CSGs) were classified in three classes with different actionability, most (MA), high (HA), and standard (SA), on the basis of penetrance, mutational spectrum, and intervention for prevention/early detection.</p><p><strong>Results: </strong>On the basis of the European Society of Medical Oncology recommendations, we identified 225 potentially germline P/LP variants in 193/1,339 (14.4%) enrolled patients. In particular, 62/225 (27.5%) variants were detected in genes classified as MA-CSG class, 53/225 (23.6%) in genes belonging to the HA-CSG class, and 110/225 (48.9%) in the SA-CSG class. In addition, we detected 58 LRs in the 16/40 CSGs in 53/1,339 (3.95%) patients. Information about germline-focused analysis and follow-up was available for 99 patients with potentially germline variants. Surprisingly, 95/99 (96%) patients were not referred to oncogenetic consultation and follow-up, including 30/32 (93.75%) patients with variants in the MA-CSG class.</p><p><strong>Conclusion: </strong>Our data confirm the utility of CGP for the identification of potentially germline variants in CSGs, highlighting the importance of reporting LRs in addition to single-nucleotide variants and insertions/deletions. However, our findings also demonstrate a relative lack of knowledge of the implications of germline findings detected on tumor-only sequencing among oncologists and underline the need for specific training in this area.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500399"},"PeriodicalIF":5.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12419028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033281","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":"Clinical and Pathologic Landscapes of Delta-Like Ligand 3 and Seizure-Related Homolog Protein 6 Expression in Neuroendocrine Carcinomas.","authors":"Jessica S Ross, Rohit Thummalapalli, Kristine Lacuna, Rania G Aly, Marina K Baine, Natasha Rekhtman, Andrea Arfè, Mark Y Jeng, Mark G Kris, Gregory J Riely, Mark M Awad, Charles M Rudin, Alissa J Cooper","doi":"10.1200/PO-25-00464","DOIUrl":"https://doi.org/10.1200/PO-25-00464","url":null,"abstract":"<p><strong>Purpose: </strong>Delta-like ligand 3 (DLL3) and seizure-related homolog protein 6 (SEZ6) are appealing drug targets in neuroendocrine carcinomas (NECs) given their preferential expression on the tumor cell surface compared with normal cells. We aimed to describe the landscape of these proteins across NECs from eight different primary sites.</p><p><strong>Patients and methods: </strong>We used immunohistochemistry to assess 124 NEC tumor samples from any primary site for DLL3 and 53 for SEZ6 and defined positivity as ≥1% staining.</p><p><strong>Results: </strong>DLL3 and SEZ6 were commonly expressed in our cohort (97 of 124, 78% and 43 of 53, 81% positivity rates, respectively) and frequently coexpressed when both tested (35 of 53, 66%). NECs of the breast, prostate, and GI system had the highest rates of DLL3 positivity (2 of 2, 100%; 15 of 16, 94%; and 14 of 17, 82%, respectively); all primary sites except lung exhibited 100% positivity rates for SEZ6. DLL3 expression and SEZ6 expression were seen in transformed NECs (12 of 17, 71% and 3 of 4, 75%, respectively) and in brain metastases (5 of 7, 71% and 1 of 2, 50%, respectively). Expression of both proteins tended to remain stable among 10 patients with serial biopsies. DLL3 expression did not affect progression-free survival (PFS) on first-line platinum/etoposide with or without immunotherapy among patients with metastatic lung NEC (median PFS 5.3 <i>v</i> 5.7 months in DLL3⁺ <i>v</i> DLL3^-, <i>P</i> = .9) but was associated with longer overall survival (median 12.5 <i>v</i> 2.6 months, <i>P</i> = .03).</p><p><strong>Conclusion: </strong>We describe the landscape of DLL3 and SEZ6 coexpression across NECs, establishing a broad-based cohort of patients who might derive benefit from therapeutics in development targeting these cell surface determinants.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500464"},"PeriodicalIF":5.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137726","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":"Recurrent and Refractory Ewing Sarcoma Phase I/II Trials: Current Perspective From the Euro-Ewing Consortium.","authors":"Antonio Juan Ribelles, Arthur Felix, Nuria Benavent, Josep Escrivá-Fernández, Mehdi Brahmi, Nathalie Gaspar, Susanne A Gatz, Thomas Grünewald, Christina Linder-Stragliotto, Emanuela Palmerini, Pan Pantziarka, Sandra Strauss, Didier Surdez, Pablo Berlanga, Martin G McCabe","doi":"10.1200/PO-25-00377","DOIUrl":"10.1200/PO-25-00377","url":null,"abstract":"<p><strong>Purpose: </strong>Updated analysis of phase I/II trials in recurrent/refractory (R/R) Ewing sarcoma (EwS) over the past 11 years.</p><p><strong>Methods: </strong>A systematic review was performed to identify phase I/II trials for R/R EwS in three databases (WHO, US National Library of Medicine, and European Clinical Trials Database) and/or published in PubMed/ASCO/European Society for Medical Oncology websites from 2014 to 2024. The search criteria included EwS OR bone sarcoma OR sarcoma AND Phase-I OR Phase-II. Eligibility and data extraction were performed independently by three reviewers, with priority given to trials with EwS specified data. Trials were categorized by therapeutic intervention, including targeted therapies, immunotherapy, chemotherapy, and combined therapies.</p><p><strong>Results: </strong>One hundred eight trials met inclusion criteria, predominantly academic (70%) and multicenter (81.5%), with significant US and European collaboration. Trial designs were mainly single-arm, with an increase in multiarm trials in the recent years and increased focus on the pediatric population. Trial modalities emphasized targeted therapies with tyrosine kinase, poly-ADP ribose polymerase, EWSR1::FLI1, and cell cycle inhibitors. Immunotherapy with monoclonal antibodies and CAR-T cells as primary agents is also under investigation. The COVID-19 pandemic coincided with a marked reduction in trial initiation in 2020. Among evaluable data, disease control rates averaged 44% and response rates 8%.</p><p><strong>Conclusion: </strong>This review highlights evolving therapeutic directions in R/R EwS, with increased emphasis on targeted therapies and immunotherapies. Despite pandemic-related delays, trials have progressed in exploring novel targets, including EWSR1::FLI1 oncogenic fusion and DNA repair pathways. These findings underscore ongoing global efforts to address critical unmet needs in EwS treatment, offering a foundation for future trial designs, especially international, randomized phase-II trials across all age ranges.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500377"},"PeriodicalIF":5.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091833","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":"Fibroblast Growth Factor Receptor 3 Alteration Status and Outcomes on Immune Checkpoint Inhibitors in Patients With Metastatic Urothelial Carcinoma.","authors":"Shilpa Gupta, Jessica K Lee, Jerry Mitchell, Richard S P Huang","doi":"10.1200/PO-25-00257","DOIUrl":"10.1200/PO-25-00257","url":null,"abstract":"<p><strong>Purpose: </strong>The use of immune checkpoint inhibitors (ICPIs) has expanded in the treatment of metastatic urothelial carcinoma (mUC), but response rates are variable, highlighting the need for predictive biomarkers. Tumor mutational burden (TMB) has been shown to predict response to ICPI, but Fibroblast Growth Factor Receptor 3 (<i>FGFR3</i>) alterations are common drivers in mUC and there is preclinical and anecdotal evidence that they may predict less favorable outcomes to ICPIs, similar to <i>ALK</i> and <i>ROS1</i> fusions in lung cancer. We sought to explore the effect of <i>FGFR3</i> alterations alone and with TMB on response to ICPI in mUC.</p><p><strong>Methods: </strong>A total of 1,416 patients with mUC who received hybrid-capture next-generation sequencing (NGS)-based genomic profiling were evaluated for their response to ICPI and chemotherapy based on the presence of <i>FGFR3</i> alterations and TMB. A nationwide deidentified real-world clinicogenomic database (CGDB) of NGS results linked to deidentified electronic health record-derived clinical data was used to assess treatment patterns and real-world overall survival (rwOS) and real-world progression-free survival (rwPFS).</p><p><strong>Results: </strong>Among 819 patients with mUC who received ICPI, there were no significant differences in rwOS or rwPFS between <i>FGFR3</i>-altered (alt) and wild-type (wt) patients. However, among patients with TMB ≥10 mut/Mb, <i>FGFR3</i>-alt patients trended toward longer rwOS and rwPFS than <i>FGFR3</i>-wt patients. Comparing first-line ICPI versus chemotherapy and adjusting for imbalances, patients with TMB ≥10 and <i>FGFR3</i>-alt who received ICPI also trended toward longer rwPFS than patients who received chemotherapy although no significant difference in rwOS was observed.</p><p><strong>Conclusion: </strong>While <i>FGFR3</i> status alone is not predictive of response to ICPI, <i>FGFR3</i> combined with TMB emerged as a biomarker that may be predictive of response to ICPI in mUC. Further studies involving larger patient populations are warranted to confirm these findings.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500257"},"PeriodicalIF":5.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12442780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075232","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":"Incorporating Continuous Mammographic Density Into the BOADICEA Breast Cancer Risk Prediction Model.","authors":"Lorenzo Ficorella, Mikael Eriksson, Kamila Czene, Goska Leslie, Xin Yang, Tim Carver, Adam E Stokes, Douglas F Easton, Per Hall, Antonis C Antoniou","doi":"10.1200/PO-25-00203","DOIUrl":"https://doi.org/10.1200/PO-25-00203","url":null,"abstract":"<p><strong>Purpose: </strong>Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA v7) predicts future breast cancer (BC) risk using data on cancer family history (FH), genetic markers, questionnaire-based risk factors, and mammographic density (MD) measured using the four-category Breast Imaging Reporting and Data System (BIRADS) classification. However, BIRADS requires manual reading, which is impractical on a large scale and may cause information loss. We extended BOADICEA to incorporate continuous MD measurements, calculated using the automated Volpara and STRATUS tools.</p><p><strong>Methods: </strong>We used data from the Karolinska Mammography Project for Risk Prediction of Breast Cancer cohort (60,276 participants; 1,167 incident BC). Associations between MD measurements and BC risk were estimated in a randomly selected training subset (two thirds of the data set). Percent MD residuals were calculated after regressing on age at mammography and BMI. Hazard ratios (HRs) were estimated using a Cox proportional hazards model, adjusting for FH and BOADICEA risk factors, and were incorporated into BOADICEA. The remaining one third of the cohort was used to assess the performance of the extended BOADICEA (v7.2) in predicting 5-year risks.</p><p><strong>Results: </strong>The BC HRs per standard deviation of residual STRATUS density were estimated to be 1.48 (95% CI, 1.33 to 1.64) and 1.41 (95% CI, 1.27 to 1.56) for pre- and postmenopausal women, respectively. The corresponding estimates for Volpara density were 1.27 (95% CI, 1.15 to 1.40) and 1.38 (95% CI, 1.25 to 1.54). The extended BOADICEA showed improved discrimination in the testing data set over using BIRADS, with a 1%-4% increase in AUC across different combinations of risk factors. On the basis of 5-year BC risk with MD as the sole input, approximately 11% of the women were reclassified into lower risk categories and 18% into higher risk categories using the extended model.</p><p><strong>Conclusion: </strong>Incorporating continuous MD measurements into BOADICEA enhances BC risk stratification and facilitates the use of automated MD measures for risk prediction.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500203"},"PeriodicalIF":5.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145175572","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":"Activity of Platinum Monotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer and DNA Damage Repair Gene Alterations.","authors":"Mihaela Aldea, Emeline Orillard, Alice Bernard-Tessier, Luigi Cerbone, Casilda Llacer, Kira-Lee Koster, Guilhem Roubaud, Ugo De Giorgi, Florence Joly, François Cherifi, Adrien Rochand, Aurelius Omlin, Himisha Beltran, Rafael Morales-Barrera, Mylene Annonay, Diletta Bianchini, Johann de Bono, Elena Castro, Giulia Baciarello, Silke Gillessen, Antoine Thiery-Vuillemin, Karim Fizazi","doi":"10.1200/PO-25-00310","DOIUrl":"10.1200/PO-25-00310","url":null,"abstract":"<p><strong>Purpose: </strong>Up to 30% of patients with metastatic castration-resistant prostate cancer (mCRPC) have DNA damage repair (DDR) gene alterations, mainly in <i>BRCA2</i>. PARP inhibitors (PARPi) are standard treatments for <i>BRCA1/2</i>-altered patients with mCRPC, and evidence for platinum agents is limited. This study assesses single-agent platinum therapy in patients with mCRPC with and without DDR alterations.</p><p><strong>Methods: </strong>This multicenter, retrospective study included patients with mCRPC with known DDR status treated with platinum monotherapy. DDR-positive (DDR+) patients had deleterious germline or somatic alterations in DDR genes (<i>BRCA1</i>, <i>BRCA2</i>, <i>CDK12</i>, <i>ATM</i>, <i>CHEK2</i>, <i>PALB2</i>, or <i>FANCA</i>), whereas DDR-negative (DDR-) patients had no such alterations. Prostate-specific antigen (PSA) response, progression-free survival (PFS, PSA/clinical/radiographic), and overall survival (OS) were assessed in DDR+ and DDR- groups.</p><p><strong>Results: </strong>Among 129 patients, 81 had DDR+ and 48 had DDR- cancers. A PSA decline of ≥50% was demonstrated in 48% in BRCA, 9% in DDR+ non-BRCA, and 13% in DDR- patients (<i>P</i> < .0001). Objective responses occurred in 37.5% in BRCA, 11% in DDR+ non-BRCA, and 13% in DDR- patients (<i>P</i> = .017). No response was reported in DDR+ patients who had received previous PARPi (n = 16). The median PSA response was 5 months for BRCA, 2 months for DDR+ non-BRCA, and 1.7 months for DDR- patients, respectively (<i>P</i> = .015), whereas the median clinical/radiographic PFS was 4.7 months, 2.8 months, and 2 months, respectively (<i>P</i> = .2). In PARPi-naïve patients, the median OS was 13.7 months for BRCA, 8.7 months for DDR+ non-BRCA, and 6.1 months for DDR- patients (<i>P</i> = .013).</p><p><strong>Conclusion: </strong>Single-agent platinum agents show significant anticancer activity in <i>BRCA</i>-mutated patients with mCRPC without previous PARPi exposure. With their low cost and broad availability, platinum agents offer a practical alternative, particularly in regions where PARPi are inaccessible.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500310"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799089","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":"BRCA To the Future: Platinum Chemotherapy in Biomarker-Selected Metastatic Castrate Resistant Prostate Cancer.","authors":"Peter D Zang, Koral Shah, Hedyeh Ebrahimi, Alexander Chehrazi-Raffle","doi":"10.1200/PO-25-00576","DOIUrl":"https://doi.org/10.1200/PO-25-00576","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500576"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799090","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 Significance of Extrachromosomal DNA in <i>FGFR2</i>-Amplified Gastric Cancer: Therapeutic Implications From Clinical Experience.","authors":"Yu Aoki, Tadayoshi Hashimoto, Nobuyuki Takahashi, Mashiro Okunaka, Saori Mishima, Daisuke Kotani, Akihito Kawazoe, Yoshiaki Nakamura, Izuma Nakayama, Yasutoshi Kuboki, Hideaki Bando, Takashi Kojima, Nobuyuki Nakamura, Naoya Sakamoto, Genichiro Ishii, Takao Fujisawa, Takayuki Yoshino, Yasuhito Arai, Tatsuhiro Shibata, Kohei Shitara","doi":"10.1200/PO-25-00033","DOIUrl":"10.1200/PO-25-00033","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500033"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12369511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873274","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}