JCO precision oncology最新文献

{"title":"Limitations of Radiographic Response Assessments of Systemic Therapy for Advanced Hepatocellular Carcinoma.","authors":"Kelsey S Lau-Min, Joseph W Franses","doi":"10.1200/PO-25-00551","DOIUrl":"10.1200/PO-25-00551","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500551"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12363656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873275","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":"Comprehensive Comparison of Somatic, Germline, and Immune Cell Profiles in Upper Tract and Bladder Urothelial Carcinoma.","authors":"Kit Yuen, Margaret Meagher, Jacob Mercer, Binyam Yilma, Melissa Stoppler, Stamatina Fragkogianni, Nataliya Mar, Arash Rezazadeh Kalebasty, Shilpa Gupta, Petros Grivas, Aditya Bagrodia, Rana Mckay, Tyler Stewart, Amirali Salmasi","doi":"10.1200/PO-25-00289","DOIUrl":"https://doi.org/10.1200/PO-25-00289","url":null,"abstract":"<p><strong>Purpose: </strong>Molecular characterization of anatomically distinct urothelial carcinoma in the upper tract (UTUC) and bladder (UCB) has been challenging because of the rarity of UTUC. However, recent advances in real-world data curation have facilitated the generation of larger UTUC cohorts. In this study, we investigated the somatic, germline, and immunologic landscapes of UTUC compared with UCB.</p><p><strong>Methods: </strong>From the Tempus Database, we retrospectively analyzed 505 UTUC and 2,416 UCB cases. Tumors were sequenced using Tempus xT DNA and xR RNA assays. Pathogenic somatic mutations, immune cell infiltration, tumor mutational burden (TMB), PD-L1, microsatellite instability (MSI), and mismatch repair (MMR) were evaluated. Potential germline alterations were assessed in 46 genes for patients with tumor/normal matched sequencing (UTUC, n = 285; UCB, n = 1,359).</p><p><strong>Results: </strong>Alterations in <i>TERT, TP53, RB1, ERBB2,</i> and <i>CDKN1A</i> were more frequent in UCB, whereas <i>KMT2D, FGFR3, CDKN2B, KRAS</i>, and <i>MYC</i> were more frequent in UTUC. Germline variants were found in 4.8% of UCB and 5.6% of UTUC, with trends toward higher Lynch syndrome-associated gene alterations (<i>MLH1, MSH2, MSH6, PMS2</i>) in UTUC (0.6% <i>v</i> 1.8%, <i>P</i> = .059). The prevalence of TMB ≥10 mut/Mb was higher in UCB (17% <i>v</i> 11%, <i>P</i> < .001). UCB had higher PD-L1 positivity (<i>P</i> = .013), whereas UTUC had more MSI-high (UTUC = 3.2% <i>v</i> UCB = 1%, <i>P</i> = .001) and MMR-deficient (<i>P</i> = .020) cases. CD4⁺ and regulatory T-cell infiltrates were similar in both.</p><p><strong>Conclusion: </strong>By comprehensive molecular characterization of UC, we observed distinct genomic alterations and tumor microenvironment patterns in UTUC and UCB. Further research is warranted to elucidate the clinical implications of these findings. We compared the genetic and immune features of upper tract and bladder cancers. Our study found key differences that could affect treatment decisions, such as specific gene changes and immune markers. These insights may help doctors personalize therapies and improve patient care.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500289"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799091","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":"Circulating Tumor DNA Genotyping of Intrinsic and Acquired Gene Alterations in Patients With Advanced Breast Cancer Receiving Palbociclib: Biomarker Results From POLARIS Study.","authors":"Debu Tripathy, Joanne L Blum, Hong Zhang, Shibing Deng, Steven L McCune, Kamal Patel, Yao Wang, Shailendra Lakhanpal, Meghan S Karuturi, Zhe Zhang, Chetan Deshpande, Monica Z Montelongo, Eric Gauthier, Yuan Liu, Gabrielle B Rocque, Aditya Bardia","doi":"10.1200/PO-24-00810","DOIUrl":"10.1200/PO-24-00810","url":null,"abstract":"<p><strong>Purpose: </strong>To identify gene alterations in circulating tumor DNA (ctDNA) from palbociclib-treated patients with advanced or metastatic breast cancer (ABC) in POLARIS to identify potential mutagenic drivers of resistance.</p><p><strong>Methods: </strong>POLARIS was a prospective, real-world study of palbociclib in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) ABC in the United States and Canada. Patients who received ≥1 palbociclib dose and had ≥1 ctDNA measurement were included in the biomarker analysis. ctDNA samples were analyzed using the Guardant360 platform (73 genes) at baseline, cycle 2 day 1 (C2D1), and end of treatment (EOT). Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs.</p><p><strong>Results: </strong>A total of 344 patients were included in the biomarker analysis. Gene alterations were detected in 85% (286 of 336) of baseline samples, 72% (201 of 278) of C2D1 samples, and 85% (88 of 104) of EOT samples. The most frequently mutated genes were <i>ESR1</i>, <i>PIK3CA</i>, and <i>TP53</i>. <i>CCND1</i>, <i>FGFR1</i>, and <i>EGFR</i> were most frequently amplified. Real-world progression-free survival (rwPFS) was better in patients without baseline mutations in <i>ESR1</i> (HR, 0.42) or <i>PIK3CA</i> (HR, 0.60) and amplifications in <i>CCND1</i> (HR, 0.52) or <i>FGFR1</i> (HR, 0.62) versus altered genes. Patients with undetectable versus detectable mutations at C2D1 also had better rwPFS (HR, 0.57).</p><p><strong>Conclusion: </strong>Patients without altered <i>ESR1</i>, <i>PIK3CA</i>, <i>CCND1</i>, or <i>FGFR1</i> at baseline had better rwPFS than patients with altered genes. Genotyping analysis of ctDNA over time highlights the emergence of mutations in estrogen receptor and cell cycle pathways under selective therapeutic pressure and could guide monitoring and therapeutic sequencing for patients with HR+/HER2- ABC.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2400810"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12369510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873273","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":"Comprehensive Screening for Early Cancer Detection in Individuals With Genetic Predisposition.","authors":"Natalia A Bodunova, Airat I Bilyalov, Anastasiia M Danishevich, Gurami E Kvetenadze, Artem K Andronov, Andrey V Starshinin, Maria M Litvinova, Ludmila G Zhukova, Igor E Khatkov","doi":"10.1200/PO-25-00333","DOIUrl":"https://doi.org/10.1200/PO-25-00333","url":null,"abstract":"<p><strong>Purpose: </strong>To evaluate the effectiveness of a comprehensive screening program for individuals with genetic predisposition to cancer, focusing on early detection and improved treatment outcomes through systematic clinical, instrumental, and laboratory monitoring of pathogenic/likely pathogenic (P/LP) variant carriers.</p><p><strong>Materials and methods: </strong>The registry screening program included two groups: (1) patients with cancer with confirmed germline P/LP variants associated with cancer predisposition, and (2) healthy individuals carrying germline P/LP variants predisposing to cancer development. In total, 816 participants were included. Participants underwent routine screening, including medical history recording, and instrumental and laboratory investigations accompanied by consultations of different specialists. The study compared the age and stage of the disease at the time of cancer diagnosis between healthy P/LP variant carriers (Group A, n = 554) and patients with cancer (Group B, n = 262).</p><p><strong>Results: </strong>Among the 554 healthy P/LP variant carriers in Group A, 57 patients of cancer (10.2%) were identified, predominantly breast and ovarian cancers (Group A1). In Group A1, 96.4% of detected cancers were at stages I to II. The average age at diagnosis in Group A1 was 52 ± 12 years, with 35% of patients detected within 6 months, 58% within 1 year, and 7% within 1.5 years after inclusion of an individual into the screening program. In Group B1 (191 patients with breast cancer), 20.9% were diagnosed at stages III to IV. Notably, 27% of aggressive molecular biological subtypes of breast cancer (Luminal B and triple-negative) were identified at stage I in Group A1, and the most common <i>BRCA1</i> variant was c.5266dupC (rs80357906), accounting for 64.3% of such patients.</p><p><strong>Conclusion: </strong>The comprehensive screening program demonstrated the effectiveness of early detection of malignancies in individuals with genetic predisposition to cancer development. The identification of a significant proportion of early-stage cancers, particularly aggressive subtypes, highlights the importance of tailored screening strategies for the cohort of patients at high risk of cancer development.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500333"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12379788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955038","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":"Impact of <i>BRCA</i> Mutation on Treatment Outcomes of Endocrine Therapy ± CDK4/6 Inhibitors in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor-2-Negative Breast Cancer: A Systematic Review and Meta-Analysis.","authors":"Hamdy A Azim, Hagar Elghazawy, Kyrillus S Shohdy, Shaimaa Lasheen, Mahmoud Elghazawy, Ramy Mohamed Ghazy, Dalia Abdelnasser, Loay Kassem","doi":"10.1200/PO-24-00841","DOIUrl":"10.1200/PO-24-00841","url":null,"abstract":"<p><strong>Purpose: </strong>The prognostic significance of <i>BRCA1/2</i> mutation and <i>RB1</i> alteration (Alt) in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor-2-negative (HER2-) breast cancer (BC) treated with endocrine therapy (ET) ± cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) remains unresolved. This meta-analysis aimed to define their influence on therapy outcomes in the early and metastatic stages.</p><p><strong>Materials and methods: </strong>We systematically searched PubMed, Cochrane, and Google Scholar databases. Primary end points included disease-free (or progression-free) survival (DFS/PFS) and overall survival (OS) according to <i>BRCA1/2</i> mutation or <i>RB1 Alt</i> status. A separate analysis of individual-patient data for metastatic HR+/HER2- BC extracted from MSK-MET project was performed.</p><p><strong>Results: </strong>Twenty-two studies comprising 34,960 patients were eligible for meta-analysis. In the early setting, in eight studies (n = 7,857 patients with HR+ BC received ET), <i>BRCA1/2 mutant type</i> (<i>MT</i>) was associated with a marginally significant worse DFS (hazard ratio, 1.64 [95% CI, 1 to 2.69]; <i>P</i> = .05) and a significantly worse OS (hazard ratio, 1.52 [95% CI, 1.20 to 1.92]; <i>P</i> = .0006) versus <i>BRCA</i> wild-type (<i>WT</i>). In the metastatic setting, in 11 studies (n = 12,670 patients received ET+ CDK4/6i), <i>BRCA1/2</i> mutation was associated with a significantly worse PFS (hazard ratio, 1.87 [95% CI, 1.45 to 2.41]; <i>P</i> < .00001) and OS (hazard ratio, 1.38 [95% CI, 1.15 to 1.65]; <i>P</i> = .0005) versus <i>BRCA WT</i>. The individual-patient data confirmed the poorer prognosis of <i>BRCA2 MT</i> and <i>RB1 Alt</i>, but not <i>BRCA1 MT</i>, and a significant co-occurrence of <i>RB1</i> loss of heterozygosity (<i>LOH</i>) among <i>BRCA2 MT</i> carriers.</p><p><strong>Conclusion: </strong>The current analysis adds to the body of evidence supporting the inferior outcomes of ET± CDK4/6i in <i>BRCA MT</i> compared with <i>BRCA WT</i>. Given its significant coexistence with <i>RB1</i> LOH, <i>BRCA2 MT</i> BC seems uniquely resistant to ET± CDK4/6i, a point that is profoundly different from sporadic or even <i>BRCA1 MT</i> HR+/HER2- BC.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2400841"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794507","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":"Multi-Regional Profiling of Epidermal Growth Factor Receptor L858R Mutation-Positive Metastatic Renal Pelvic Cancer Successfully Treated With Osimertinib.","authors":"Yoshiyuki Yamamoto, Atsushi Kuwahara, Atsunari Kawashima, Daisuke Motooka, Yoshitake Iwamoto, Takehiro Yamamoto, Masako Kurashige, Daisuke Sakai, Yuki Horibe, Yu Ishizuya, Takuji Hayashi, Kentaro Takezawa, Taigo Kato, Koji Hatano, Yoichi Kakuta, Taroh Satoh, Eiichi Morii, Norio Nonomura","doi":"10.1200/PO-25-00434","DOIUrl":"10.1200/PO-25-00434","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500434"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12337946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794509","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":"Evaluating the Effect of <i>KRAS</i> Variants on Survival Outcomes and Therapy Response in Pancreatic Cancer.","authors":"Matthew I Ebia, Edik M Blais, Yujie Cui, Emanuel F Petricoin, Michael Pishvaian, Srinivas Gaddam, Jun Gong, Arsen Osipov, Andrew E Hendifar","doi":"10.1200/PO-24-00684","DOIUrl":"https://doi.org/10.1200/PO-24-00684","url":null,"abstract":"<p><strong>Purpose: </strong>Tumor molecular profiling is recommended in pancreatic ductal adenocarcinoma (PDAC). However, the predictive and prognostic value of <i>KRAS</i> variants on clinical outcomes including response to standard therapies remains unknown.</p><p><strong>Methods: </strong>In this retrospective analysis using real-world data from patients with early-stage (I to III) and metastatic PDAC who underwent molecular profiling via referrals to Perthera or the PanCAN Know Your Tumor program, patients included were 18 years and older, received standard chemotherapy in the first- and second-line setting, and had complete records. Main outcomes were overall survival (OS) and progression-free survival (PFS) measured from the date of diagnosis of metastatic/recurrent metastatic disease stratified by the <i>KRAS</i> variants and chemotherapy regimen. OS and PFS on first- or second-line therapies were analyzed using Cox regression. Outcomes from each subgroup were compared with reference cohort G12D/V using a Bonferroni-adjusted significance threshold of α = .00714 (0.05/7).</p><p><strong>Results: </strong>A total of 1359 patients (median [range] age, 64 [28-94] years; 689 [50.7%] male; 707 [52.0%] White) were included. <i>KRAS</i> wild type had significantly longer OS compared with G12D/V (2.1 <i>v</i> 1.4 years; hazard ratio [HR], 0.61 [95% CI, 0.48 to 0.77]; <i>P</i> < .0001). Q61 had shorter OS (1.1 <i>v</i> 1.5 years; HR, 2.28 [95% CI, 1.33 to 3.92]; <i>P</i> = .0027) and PFS (3.13 <i>v</i> 9.03 months; HR, 2.54 [95% CI, 1.43 to 4.52]; <i>P</i> = .0015) on first-line fluorouracil-based therapy compared with G12D/V. G12R had numerically longer OS (1.8 <i>v</i> 1.5 years; HR, 0.69 [95% CI, 0.48 to 0.98]; <i>P</i> = .0366) and PFS (12.17 <i>v</i> 9.03 months; HR, 0.6 [95% CI, 0.41 to 0.88]; <i>P</i> = .0091) on first-line fluorouracil-based therapy compared with G12D/V.</p><p><strong>Conclusion: </strong><i>KRAS</i> variants are associated with survival and may be predictive of response to standard therapies. A molecularly driven, variant-specific approach is recommended to guide PDAC treatment and better inform prognosis.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2400684"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12379785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic Indicators of Preoperative Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel Efficacy in Locally Advanced Gastroesophageal and Gastric Cancer: Integrating Biomarker Analysis and Clinicopathological Factors.","authors":"Amane Jubashi, Izuma Nakayama, Naoya Sakamoto, Shogo Takei, Yuki Matsubara, Yu Miyashita, Seiya Sato, Shinpei Ushiyama, Akinori Kobayashi, Ukyo Okazaki, Dai Okemoto, Kazumasa Yamamoto, Saori Mishima, Daisuke Kotani, Akihito Kawazoe, Tadayoshi Hashimoto, Yoshiaki Nakamura, Yasutoshi Kuboki, Hideaki Bando, Takashi Kojima, Takayuki Yoshino, Takeshi Kuwata, Kazuma Sato, Takeo Fujita, Mitsumasa Yoshida, Masahiro Yura, Takahiro Kinoshita, Kohei Shitara","doi":"10.1200/PO-24-00925","DOIUrl":"10.1200/PO-24-00925","url":null,"abstract":"<p><strong>Purpose: </strong>Perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) is a standard treatment for locally advanced gastric/gastroesophageal junction cancer (GC/GEJC). The impact of biomarker status on the efficacy of perioperative FLOT remains unclear. This study evaluated the association between clinicopathological features, including biomarker status, and the efficacy of perioperative FLOT in patients with resectable GC/GEJC.</p><p><strong>Patients and methods: </strong>A retrospective observational study was conducted by reviewing medical records of patients treated with perioperative FLOT between February 2020 and March 2024. Eligible patients had histologically confirmed adenocarcinoma, resectable disease at stages cT2-4a and/or N0-3, M0, and underwent biomarker testing.</p><p><strong>Results: </strong>Among 116 eligible patients, human epidermal growth factor receptor 2 (HER2) positivity was observed in 7.8%, whereas PD-L1 combined positive score (CPS) of ≥1, ≥5, and ≥10 was detected in 90.5%, 44.0%, and 15.5% of patients, respectively. Claudin-18 isoform 2 (CLDN18.2) positivity (2+/3+ in ≥75% of tumor cells) was observed in 30.2% of patients. Major pathological response (MPR) and pathological complete response (pCR) rates were 22.4% (95% CI, 15.3 to 31.0) and 8.6% (95% CI, 4.2 to 15.3), respectively. Diffuse-type histology was a negative indicator for pathological response. CLDN18.2 expression decreased significantly after preoperative FLOT, with the median H-score declining from 285.0 to 187.5 (<i>P</i> < .001) in patients with CLDN18.2 positivity at initiation. Maintained CLDN18.2 positivity was more frequently observed in patients without MPR compared with those with MPR (53.8% <i>v</i> 12.5%, <i>P</i> = .05).</p><p><strong>Conclusion: </strong>HER2, PD-L1, and CLDN18.2 statuses were not linked to pathological response to FLOT in resectable GC/GEJC. CLDN18.2 expression significantly decreased after preoperative FLOT but remained higher in patients without MPR, suggesting that CLDN18.2-targeted therapy may warrant investigation in the perioperative setting.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2400925"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12316131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764916","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":"Mucin 16-Directed Therapy in Pediatric Sarcomas: Case Evidence of Ubamatamab Efficacy in Epithelioid Sarcoma and Its Implications for Other Sarcoma Subtypes.","authors":"Denise M Connolly, Gabriel Revon-Rivière, Rose Chami, Denise Mills, Ailish C Coblentz, Thomas S Uldrick, David A Knorr, Priscila Goncalves, Michael Dobosz, Sumreen Jalal, Sarah Cohen-Gogo, Daniel A Morgenstern","doi":"10.1200/PO-25-00404","DOIUrl":"10.1200/PO-25-00404","url":null,"abstract":"<p><strong>Purpose: </strong>Epithelioid sarcoma (ES) and malignant rhabdoid tumor (MRT) are rare soft tissue sarcomas with poor prognoses. Although mucin 16 (MUC16) and its soluble form, cancer antigen 125 (CA125), are established as biomarkers and therapeutic targets in ovarian cancer, emerging data suggest MUC16 may also be expressed in ES and MRT. In this study, we present a patient with ES, who demonstrated a response to ubamatamab, a novel bispecific T-cell engager (MUC16xCD3), and analyze treatment resistance after disease progression. Additionally, we examine MUC16 expression across pediatric and adolescent and young adult (AYA) sarcomas, to evaluate the frequency of this target and explore the broader application of ubamatamab in this population.</p><p><strong>Materials and methods: </strong>We performed a retrospective clinical case review and immunohistochemical analysis of pediatric and AYA (0-25 years) sarcoma samples from 2015 to 2021, evaluating MUC16 expression using anti-CA125 immunohistochemistry (IHC) on the DAKO Omnis platform.</p><p><strong>Results: </strong>A 23-year-old female patient with multiply relapsed metastatic ES, harboring MUC16 expression by IHC and elevated serum CA125, received intravenous ubamatamab (250 mg) once per week as part of a single patient study. After 11 weeks of ubamatamab, a RECIST v1.1 partial response was demonstrated, along with serum CA125 normalization, lasting 43 weeks. During the initial step-up dosing, the patient experienced grade 2 cytokine release syndrome. Treatment-emergent adverse events included grade 2 pleural effusion, pericardial effusion, and palmar-plantar erythrodysesthesia, all resolving without intervention. IHC analysis of retrospective samples showed positive MUC16 staining in six of eight (75%) ES and two of four (50%) MRT samples, with no immunoreactivity observed in other pediatric/AYA sarcoma subtypes.</p><p><strong>Conclusion: </strong>MUC16 is frequently detected in ES and MRTs. Ubamatamab is an encouraging anti-MUC16 therapy, demonstrating clinical efficacy. Ongoing trials (ClinicalTrials.gov identifier: NCT06444880) are evaluating ubamatamab in other rare MUC16-positive tumors.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500404"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12316166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764915","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":"Impact of Baseline β-Catenin Comutations on Prognosis in EGFR-Mutant Lung Cancer.","authors":"Jonas Kulhavy, Katja Maurus, Miriam Blasi, Stephanie Brändlein, Simone Reu-Hofer, Julia Doll, Julia Böck, Albrecht Stenzinger, Daniel Kazdal, Jan Budczies, Valeria Roll, Volker Kunzmann, Elena Gerhard-Hartmann, Andreas Rosenwald, Ralf Bargou, Maria-Elisabeth Goebeler, Jens Kern, Pius Jung, Markus Krebs, Manik Chatterjee, Petros Christopoulos, Vivek Venkataramani, Horst-Dieter Hummel","doi":"10.1200/PO-24-00771","DOIUrl":"10.1200/PO-24-00771","url":null,"abstract":"<p><strong>Purpose: </strong>Epidermal growth factor receptor (EGFR) mutations are a main actionable driver in non-small cell lung cancer (NSCLC). However, the clinical significance of catenin beta-1 (CTNNB1) comutations remains unclear. This study evaluated outcomes of patients with EGFR/CTNNB1 comutated NSCLC in a dual-center cohort.</p><p><strong>Methods: </strong>A retrospective analysis of 1,804 patients with NSCLC undergoing next-generation sequencing (NGS) in 2019-2024 at University Hospital Würzburg (single-center cohort, including 15 patients with EGFR/CTNNB1 comutations) was complemented with patients with EGFR/CTNNB1 comutated NSCLC receiving first-line osimertinib at the Thoraxklinik Heidelberg (n = 11) to extend and validate initial findings. We assessed clinical outcomes after first-line osimertinib therapy in 90 EGFR-mutated patients with CTNNB1 wild-type (wt) status and 23 with CTNNB1 comutation.</p><p><strong>Results: </strong>CTNNB1 mutations were identified in 2.0% (36/1,804) of all patients with NSCLC from the single-center cohort, with 41.7% of these also harboring EGFR mutations. Among EGFR-mutant tumors, 7.7% (15/195) exhibited concurrent CTNNB1 mutations. In the dual-center cohort, the objective response rate with first-line osimertinib was 74.4% in CTNNB1-wt (n = 90) and 65.0% in CTNNB1-mutant patients (n = 23; <i>P</i> = .38). Notably, CTNNB1 mutations were associated with significantly longer progression-free survival (PFS; hazard ratio [HR], 0.32; <i>P</i> < .001) and overall survival (OS; HR, 0.33; <i>P</i> = .003). Multivariate analysis confirmed CTNNB1 comutation as an independent prognostic factor for improved PFS (HR, 0.31 [95% CI, 0.14 to 0.69]; <i>P</i> = .004) and OS (HR, 0.26 [95% CI, 0.10 to 0.65]; <i>P</i> = .004). Additionally, CTNNB1 mutations correlated with lower PD-L1 expression (<i>P</i> = .001) and TP53-wt status (<i>P</i> < .001).</p><p><strong>Conclusion: </strong>CTNNB1 comutations are associated with lower PD-L1 expression and TP53-wt status, correlating with improved outcomes in patients with EGFR-mutant NSCLC undergoing osimertinib therapy. These results suggest that CTNNB1 comutations may serve as a favorable prognostic biomarker in patients with EGFR-mutant NSCLC. Additional prospective studies are warranted to validate these results.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2400771"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12337941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794508","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}