Clinical Cancer Research最新文献

{"title":"The activity of EGFR CAR-NK and CAR-T cells against EGFR inhibitor-resistant NSCLC and drug-tolerant persister cells.","authors":"Yan Yang, Monique B Nilsson, Xiaoxing Yu, Alissa Poteete, Hong Jiang, Qian Huang, Junqin He, Simon Heeke, John V Heymach","doi":"10.1158/1078-0432.CCR-25-1693","DOIUrl":"10.1158/1078-0432.CCR-25-1693","url":null,"abstract":"<p><strong>Purpose: </strong>Patients with NSCLC harboring EGFR mutations typically have significant clinical benefits from EGFR tyrosine kinase inhibitors (TKIs) such as osimertinib. However, a residual population of drug-tolerant persister cells (DTPCs) inevitably remains, which ultimately gives rise to fully drug-resistant cells (DRCs). This study evaluates the activity of EGFR chimeric antigen receptor (CAR)-based therapies in this context.</p><p><strong>Experimental design: </strong>We developed EGFR CAR-T and CAR-NK cells and evaluated their antitumor activity against parental cells, DTPCs, and DRCs in vitro and in vivo. We investigated the mechanisms regulating the sensitivity of DTPCs and DRCs to CAR-T or CAR-NK cells, including NK-activating ligands, TGF-β signaling, and EGFR surface levels. Additionally, we developed strategies that included galunisertib treatment and the expression of dominant-negative TGF-β receptor II (DNR) in CAR-NK cells.</p><p><strong>Results: </strong>DTPCs demonstrated increased sensitivity to both EGFR CAR-T and CAR-NK. DRCs were relatively resistant to CAR-T cells but more sensitive to CAR-NK cells. DRCs and DTPCs had higher levels of NKp30 or NKG2D ligands, which enhance the effectiveness of CAR-NK. Elevated TGF-β levels in DRCs impaired CAR function, but this was reversed by co-expression of galunisertib or DNR in CAR-NK cells. Continued TKI treatment increased EGFR expression on DRCs, possibly contributing to the improved killing activity seen with TKI/CAR combinations compared to CARs alone in TKI-resistant cells.</p><p><strong>Conclusions: </strong>EGFR-directed cellular therapies, particularly EGFR CAR-NK cells, demonstrate activity against EGFR-mutant DTPCs and DRCs in vitro and in vivo, with enhanced activity observed when combined with EGFR TKIs or TGF-β pathway blockade.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic and Immune Landscape of Pancreatic Ductal Adenocarcinoma Associated with Germline Pathogenic Variants in ATM.","authors":"Siddhartha Yadav, Riyue Bao, Rondell P Graham, Chunling Hu, Steven N Hart, Jie Na, Nicholas Boddicker, Rohan D Gnanaolivu, James Smadbeck, Li Ding, Daniel D Billadeau, Aaron T Mayer, Shounak Majumder, Paulo Cilas Morais Lyra, Adrian V Lee, Alvaro N Monteiro, Jose C Villasboas, Robert McWilliams, Fergus J Couch","doi":"10.1158/1078-0432.CCR-24-4120","DOIUrl":"10.1158/1078-0432.CCR-24-4120","url":null,"abstract":"<p><strong>Background: </strong>Germline pathogenic variants (PVs) in ATM increase the risk of pancreatic ductal adenocarcinoma (PDAC) but the underlying tumor biology of PDAC associated with germline PVs in ATM have not been adequately explored.</p><p><strong>Experimental design: </strong>Whole-genome (WGS), whole-exome (WES), and RNA-sequencing were performed on PDAC tumors from 25 germline ATM PVs carriers diagnosed at Mayo Clinic between 2007 and 2017. Somatic and copy number alterations, mutational signatures, transcriptomic subtypes, and the immune landscape were evaluated.</p><p><strong>Results: </strong>High-quality WES and WGS sequencing were obtained from 21 and 15 tumors, respectively. Biallelic inactivation of ATM was observed in 87%, KRAS PVs in 90%, CDKN2A homozygous loss in 60%, and TP53 alterations in <10% of these tumors. A predominant clock-like mutational signature was present in all samples. Whole transcriptome analysis identified that the Aberrantly Differentiated Endocrine Exocrine (ADEX) subtype accounted for 18% of PDACs and was consistently associated with >5-year overall survival. In addition, a 28-gene expression-based signature associated with OS was identified and further validated in the TCGA cohort. Immune landscape analysis through CODEX identified enriched CD4 T-helper cell/tumor interactions and reduced B7H3 high cell/tumor interactions in ATM PV carriers compared to non-carriers.</p><p><strong>Conclusions: </strong>The observed absence of TP53 PVs and enrichment for CDKN2A alterations in ATM tumors, along with differences in the mutational signatures, transcriptomic subtypes and immune landscape, improve our understanding of the mechanistic pathways involved in PDAC development in germline ATM PV carriers and help identify potential targeted therapeutic strategies.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FDA Approval Summary: Nogapendekin Alfa Inbakicept-pmln with BCG for BCG-unresponsive carcinoma in situ.","authors":"Brian L Heiss, Elaine Chang, Hee-Koung Joeng, Mallorie H Fiero, Lingshan Wang, Salaheldin S Hamed, Haw-Jyh Chiu, Tiffany K Ricks, Eun Hee Koh, Teegan A Dellibovi-Ragheb, Min Wang, Christal Lee, William F Pierce, John K Leighton, Nam Atiqur Rahman, Shenghui Tang, Richard Pazdur, Laleh Amiri-Kordestani, Paul G Kluetz, Daniel L Suzman","doi":"10.1158/1078-0432.CCR-25-1231","DOIUrl":"10.1158/1078-0432.CCR-25-1231","url":null,"abstract":"<p><p>On April 22, 2024, the U.S. Food and Drug Administration (FDA) granted regular approval to nogapendekin alfa inbakicept-pmln (N-803) with Bacillus Calmette-Guerin (BCG) for the treatment of adult patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS), with or without papillary tumors. Substantial evidence of effectiveness for this application was obtained from Cohort A of the single-arm, multicenter QUILT-3.032 trial. Patients received N-803 400 μg administered intravesically with TICE BCG once a week for 6 weeks as induction therapy, a second induction course if complete response (CR) was not achieved at month 3, and maintenance N-803 with BCG weekly for 3 weeks at months 4, 7, 10, 13, and 19 (for a total of 15 maintenance doses). The major efficacy outcome measures were CR at any time (as defined by negative results for cystoscopy [with TURBT/biopsies as applicable] per local investigator assessment and urine cytology) and duration of response. The CR rate in the 77-patient efficacy population, per FDA review, was 62% (95% confidence interval [CI]: 51%, 73%). Of the 48 patients with a CR, 28 (58%; 95% CI: 26%, 55%) and 19 (40%; 95% CI: 16%, 36%) maintained a response for ≥12 months and ≥24 months, respectively. The most common adverse reactions were increased creatinine, dysuria, hematuria, urinary frequency, urinary urgency, and urinary tract infection. This article summarizes the data and FDA thought process supporting the approval of N-803 with BCG.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12363661/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Childhood Cancer Predisposition and Evolutionary Constraints: Novel lessons from Germline Genomes from 1,127 Children with Cancer.","authors":"Ulrik Kristoffer Stoltze,Thomas van Overeem Hansen,Jon Foss-Skiftesvik,Anna Byrjalsen,Kasper Amund Henriksen,Adrian Otamendi Laspiur,Anne-Marie Gerdes,Sisse Rye Ostrowski,Erik Sørensen,Mads Bak,Charlotte Kvist Lautrup,Karen Grønskov,Elena Papaleo,Henrik Hasle,Torben Stamm Mikkelsen,Peder Wehner,Astrid Brix Saksager,Mette Klarskov Andersen,Mimi Kjærsgaard,Tina Duelund Hjortshøj,Jane Hübertz Frederiksen,David Scheie,Tina Elisabeth Olsen,Ruta Tuckuviene,Marianne Olsen,Zeynep Tümer,Rene Mathiasen,Jesper Brok,Astrid Sehested,Bram L Gorissen,Simon Rasmussen,Konrad J Karczewski,Lisa L Hjalgrim,Karin A W Wadt,Kjeld Schmiegelow","doi":"10.1158/1078-0432.ccr-25-0153","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0153","url":null,"abstract":"BACKGROUNDCancer predisposition syndromes (CPSs) with pediatric onset are the leading known cause of childhood malignancies and are increasingly guiding clinical strategies in pediatric oncology. CPSs are placed under evolutionary negative selective pressure, but pediatric pancancer studies have so far failed to investigate genomic evolutionary metrics as a guide to predict penetrance and reveal novel CPSs.METHODGermline whole-genome sequencing (WGS) in a 5-year prospective, registry-validated, nationwide cohort of individuals diagnosed with cancer before 18 years of age. Evolution-guided burden analysis of private germline variants in constrained genes compared with 125,748 gnomAD exomes.RESULTSAcross a total of 1,127 participants, 16% carried a pathogenic variant in at least one CPS gene. After genotype-phenotype matching, 9 % of children in the prospective cohort (n=651) carried a variant considered causative, a rate deemed significantly higher than previous studies (RR=1.54,95%CI1.37-1.75,p=1e-14). As predicted for a disease subject to negative Darwinian selective pressure, compared to reference adults, we found a significant excess of loss-of-function (LoF) variants in the 1,500 most constrained genes (RR=1.54,99%CI 1.21-1.95,p=4e-6). Surprisingly, this excess was greater than expected, leaving a significant residual enrichment of pLoF variants in genes evolutionarily considered the least tolerant to damage (RR=1.41,99%CI1.09-1.80,p=4e-4).CONCLUSIONThe high frequency of LoF variants, including in known CPSs, emphasizes the need for systematic and extensive germline genomic mapping as part of the diagnostic work-up of childhood cancer patients and linkage of such data to disease and response phenotypes to guide future pediatric oncological care, and ultimately paving the way for pre-diagnostic interventional measures.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"23 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144851102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Solid Stress Estimations via Intraoperative 3D Navigation in Patients with Brain Tumors.","authors":"Hadi T Nia, Meenal Datta, Ashwin S Kumar, Saeed Siri, Gino B Ferraro, Sampurna Chatterjee, Jeffrey M McHugh, Patrick R Ng, Timothy R West, Otto Rapalino, Bryan D Choi, Brian V Nahed, Lance L Munn, Rakesh K Jain","doi":"10.1158/1078-0432.CCR-24-4159","DOIUrl":"10.1158/1078-0432.CCR-24-4159","url":null,"abstract":"<p><strong>Purpose: </strong>Physical forces exerted by expanding brain tumors-specifically the compressive stresses propagated through solid tissue structures-reduce brain perfusion and neurologic function but heretofore have not been directly measured in patients in vivo. Solid stress levels estimated from tumor growth patterns are negatively correlated with neurologic performance in patients. We hypothesize that measurements of solid stress can be used to inform clinical management of brain tumors.</p><p><strong>Experimental design: </strong>We developed an intraoperative technique to quantitatively estimate solid stress and brain replacement by the tumor. In 30 patients, we made topographic measurements of brain deformation through the craniotomy site with a neuronavigation system during surgical workflows immediately preceding tumor resection (<5 minutes in the operating room). Utilizing these measurements in conjunction with finite element modeling, we calculated solid stress within the tumor and brain and estimated the amount of brain tissue replaced, i.e., lost, by tumor growth.</p><p><strong>Results: </strong>Mean solid stresses were in the range of 10 to 600 Pa, and the amount of tissue replacement was up to 10% of the brain. Brain loss in patients delineated glioblastoma from brain metastatic tumors, and in mice, solid stress was a sensitive biomarker of chemotherapy response.</p><p><strong>Conclusions: </strong>We present in this study a quantitative approach to intraoperatively measure solid stress in patients that can be readily adopted into standard clinical workflows. Brain loss due to tumor growth is a novel mechanical-based biomarker that, in addition to solid stress, may inform personalized management in future clinical studies in brain cancer.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"3571-3580"},"PeriodicalIF":10.2,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12351280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Effectiveness of PARP Inhibitor Maintenance Therapy in Ovarian Cancer by BRCA1/2 and a Scar-Based HRD Signature in Real-World Practice.","authors":"Debra L Richardson, Julia C F Quintanilha, Natalie Danziger, Gerald Li, Ethan Sokol, Alexa B Schrock, Ericka Ebot, Neeru Bhardwaj, Tanesha Norris, Anosheh Afghahi, Anthony Frachioni, Christina Washington, Lauren Dockery, Julia Elvin, Ryon P Graf, Kathleen N Moore","doi":"10.1158/1078-0432.CCR-25-2196","DOIUrl":"10.1158/1078-0432.CCR-25-2196","url":null,"abstract":"","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"31 16","pages":"3599"},"PeriodicalIF":10.2,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12351271/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144844694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CH Mutations in 16,812 Advanced Cancer Patients-Letter.","authors":"Emmanuel S Antonarakis, Katherine L Nathanson, Kim A Reiss, Colin C Pritchard, Jacob E Berchuck, Kimberly Johnson, Derek W Brown, Hanna Tukachinsky","doi":"10.1158/1078-0432.CCR-25-0945","DOIUrl":"10.1158/1078-0432.CCR-25-0945","url":null,"abstract":"","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"31 16","pages":"3594-3596"},"PeriodicalIF":10.2,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12356489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144844692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GFH018 and Toripalimab Combination Therapy for Previously Treated Recurrent or Metastatic Nasopharyngeal Carcinoma: Results from a Phase Ib/II Study.","authors":"Lin-Quan Tang, Sai-Lan Liu, Muh-Hwa Yang, Hui-Ching Wang, Yu-Juan Zhou, Kun-Yu Yang, Qun Li, Mun Hui, Xiao-Zhong Chen, Yi-Shing Leu, Li-Tzong Chen, Li-Ting Liu, Shan-Shan Guo, Qiu-Yan Chen, Shuang Wang, Hua-Qiang Zhu, Hai-Ge Shen, Yu Wang, Ye Guo, Hai-Qiang Mai","doi":"10.1158/1078-0432.CCR-25-0085","DOIUrl":"10.1158/1078-0432.CCR-25-0085","url":null,"abstract":"<p><strong>Purpose: </strong>GFH018 is a novel TGF-β type I receptor inhibitor, which has been shown to potentiate the antitumor effect of anti-PD-1/PD-L1 blockade. This study aimed to evaluate the safety and efficacy of GFH018 plus toripalimab in patients with recurrent/metastatic (R/M) nasopharyngeal carcinoma (NPC).</p><p><strong>Patients and methods: </strong>This phase Ib/II study included patients with specific solid tumors who had failed at least one prior line of standard therapy. Patients received GFH018 (40 or 80 mg) twice a day for 14 days on/14 days off, combined with toripalimab (3 mg/kg) intravenously every 2 weeks on a 28-day cycle. Treatment continued until disease progression or intolerable toxicity. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), duration of response (DoR), and safety.</p><p><strong>Results: </strong>Forty-six patients with R/M NPC were accrued. The ORR was 26.1% [90% confidence interval (CI), 15.8%-38.8%], and the disease control rate (DCR) was 43.5% (90% CI, 31.0%-56.6%). The median PFS was 2.0 months (90% CI, 1.8-8.9), and the median DoR was 7.6 months (90% CI, 5.6-not reached). In patients without prior immune checkpoint inhibitor (ICI) treatment, the ORR was 40% (90% CI, 23.6%-58.3%) and the DCR was 60% (90% CI, 41.7%-76.4%). The median PFS was 9.0 months (90% CI, 1.9-not reached), and the median DoR was not reached. In patients previously exposed to ICIs, the ORR was 9.5% (90% CI, 1.7%-27.1%) and the DCR was 23.8% (90% CI, 9.9%-43.7%). High parenchymal CD8+ T-cell density correlated with better PFS in these patients. Data from other solid tumor cohorts will be reported in future analyses.</p><p><strong>Conclusions: </strong>The combination of GFH018 and toripalimab showed a manageable toxicity profile and durable antitumor activity in patients with R/M NPC, especially those without prior ICI exposure.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"3424-3432"},"PeriodicalIF":10.2,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic Analysis of Carboplatin and Fluorescein Brain Retention following Ultrasound-Based Blood-Brain Barrier Opening.","authors":"Karl J Habashy, Timothy W Synold, Ye Feng, Cristal Gomez, Christina Amidei, Rachel Ward, Sarah VanderMolen, Ashkan Zarrieneh, Kwang-Soo Kim, Mateo Gomez, Victor A Arrieta, Jawad Fares, Kirsten B Burdett, Hui Zhang, Crismita Dmello, Li Chen, John F Bebawy, Michael Canney, Roger Stupp, Behnam Badie, Jana Portnow, Adam M Sonabend","doi":"10.1158/1078-0432.CCR-25-0080","DOIUrl":"10.1158/1078-0432.CCR-25-0080","url":null,"abstract":"<p><strong>Purpose: </strong>The blood-brain barrier (BBB) impedes the passage of most circulating drugs into the brain. Low-intensity pulsed ultrasound with microbubbles (LIPU/MB) transiently opens the BBB, improving parenchymal drug penetration. Parenchymal drug retention following short-lived BBB opening is unknown. We investigated the effect of LIPU/MB on the concentration of carboplatin and fluorescein over time and compared the parenchymal retention of temozolomide (TMZ), carboplatin, and fluorescein in the nonsonicated brain.</p><p><strong>Experimental design: </strong>We analyzed four patients who underwent intraoperative LIPU/MB with intravenous administration of carboplatin and fluorescein in the NCT04528680 clinical trial. Microdialysis catheters were implanted into sonicated and nonsonicated brain regions, and drug levels were measured over 24 hours. Published microdialysis data of TMZ without LIPU/MB were used for comparison.</p><p><strong>Results: </strong>LIPU/MB led to sustained elevated parenchymal drug concentrations, achieving a 3.1-fold increase in brain-to-plasma AUC for carboplatin and fluorescein (P = 0.03). In the nonsonicated brain, TMZ concentrations remained below their plasma levels, as parenchymal drug clearance mirrored plasma clearance. In contrast, BBB-impermeable drugs such as carboplatin and fluorescein exhibited delayed parenchymal clearance, resulting in higher brain than plasma drug levels over time. Parenchymal drug clearance of carboplatin and fluorescein was not affected by sonication.</p><p><strong>Conclusions: </strong>Following LIPU/MB, BBB-impermeable drugs exhibit sustained elevated parenchymal concentrations surpassing their plasma levels, highlighting the bidirectional restriction of drug passage by the BBB. Future studies are warranted to explore drug trapping and the efficacy of sustained exposure to cytotoxic drugs for the treatment of brain-infiltrating tumors.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"3562-3570"},"PeriodicalIF":10.2,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12310118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular characterization of patients with metastatic invasive lobular carcinoma (ILC): using real-world data to describe this unique clinical entity.","authors":"Andrew A Davis,Ellen Jaeger,Ian S Hagemann,Amir Behdad,Kayla Viets Layng,Lorenzo Gerratana,Elizabeth Mauer,Ami N Shah,Paolo D'Amico,Lisa Flaum,Carolina Reduzzi,Katie Navo,William J Gradishar,Talal Ahmed,Calvin Chao,Massimo Cristofanilli","doi":"10.1158/1078-0432.ccr-25-0359","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0359","url":null,"abstract":"PURPOSEInvasive lobular carcinoma (ILC) is the second most common type of breast cancer, but distinct treatment strategies are limited. Better characterization of the genomic and transcriptomic landscape is critical to elucidate ILC tumor biology, improve histologic classification, and define precision medicine treatment approaches.MATERIALS AND METHODSWe retrospectively analyzed de-identified next-generation sequencing data of 4,613 metastatic patients from the Tempus database including 637 with ILC, 91 with mixed lobular/ductal histology, and 3,885 with invasive breast carcinoma of no special type (IBC-NST). Samples were profiled using the Tempus xT assays.RESULTSMutations in CDH1 occurred in 71% of ILC patients (453/637). The median tumor mutational burden was significantly higher in CDH1-mutant ILC samples compared to wild type (p=0.008). Mutations in PIK3CA (55% vs. 28%), ERBB2 (13% vs. 4.3%), and TBX3 (12% vs. 3.8%) were enriched in CDH1-mutant ILC versus CDH1-wild type ILC. CDH1 expression was similar between CDH1-mutant ILC and wild type ILC samples (p=0.11). Patients with CDH1-mutant mixed histology or IBC-NST had lower CDH1 expression than CDH1-wild type mixed histology or IBC-NST patients (p<0.001). ILC had a different distribution of PAM50 subtypes compared to IBC-NST and mixed (p<0.001).CONCLUSIONSOur real-world data illustrate the distinct molecular landscape of CDH1-mutant metastatic ILC, and therapies targeting ERBB2 and PIK3CA should be further investigated in CDH1-mutant ILC. ILC differs from mixed and IBC-NST at a transcriptional level, suggesting the possibility of using CDH1 RNA expression levels to improve classification of ILC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"18 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144850825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}