Clinical Cancer Research最新文献

{"title":"Shared HLA-Bound Neoepitopes Are New Targets for Pancreatic Cancer Immunotherapy.","authors":"Hao Yuan, Qun Chen, Kuirong Jiang, Courtney W Houchen, Yuqing Zhang, Min Li","doi":"10.1158/1078-0432.CCR-24-4368","DOIUrl":"10.1158/1078-0432.CCR-24-4368","url":null,"abstract":"<p><p>The shared HLA-bound neoepitopes in pancreatic ductal adenocarcinoma (PDAC) represent a novel class of noncanonical antigens with single amino acid substitutions resulting from translational errors. These peptides, shared across patients with PDAC, showed higher immunogenicity than wild-type counterparts, offering potential candidates for specific immunotherapy development in PDAC. See related article by Zhang et al., p. 1956.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1821-1823"},"PeriodicalIF":10.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540408","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":"Validation of Diagnostic Utility of Washout CYFRA 21-1 in Lymph Node Metastasis of Thyroid Cancer.","authors":"Jeongmin Lee, Yuri Shin, Jeongun Kwak, Hye Lim Park, Sohee Lee, Mee Kyung Kim, Ja Seong Bae, Chan Kwon Jung, So Lyung Jung, Jung-Min Lee, Sang-Ah Chang, Dong-Jun Lim","doi":"10.1158/1078-0432.CCR-24-3562","DOIUrl":"10.1158/1078-0432.CCR-24-3562","url":null,"abstract":"<p><strong>Purpose: </strong>Traditional methods, fine-needle aspiration cytology (FNAC), and washout thyroglobulin (Tg) do not always provide sufficient accuracy for diagnosing lymph node (LN) metastasis in thyroid cancer. This study aimed to validate the diagnostic performance of washout cytokeratin fragment 21-1 (CYFRA 21-1) as a complementary biomarker for diagnosing metastatic LN in thyroid cancer and to explore its relationship with molecular analysis and distant metastasis.</p><p><strong>Experimental design: </strong>In this retrospective cohort study involving 230 LN in 224 patients with papillary thyroid carcinoma, FNAC, washout Tg, and washout CYFRA 21-1 levels were measured in suspicious LN. The final LN outcomes were confirmed by surgical histology.</p><p><strong>Results: </strong>Among the 230 LN, 145 (63.0%) were benign and 85 (37.0%) were metastatic. The optimal cutoff value for washout CYFRA 21-1 was established at 1.12 ng/mL (AUC, 0.959; 95% confidence interval, 0.936-0.982) with sensitivity of 93.4% and specificity of 97.8%. The cutoff value for washout Tg was 12.61 ng/mL (AUC, 0.832; 95% confidence interval, 0.772-0.892). The diagnostic performance of CYFRA 21-1 remained consistent across the preoperative (1.14 ng/mL) and postoperative assessment (1.10 ng/mL). The combination of FNAC and washout CYFRA 21-1 showed higher sensitivity (92.5%), specificity (95.9%), negative predictive value (93.7%), and diagnostic accuracy (95.1%) than the combination of FNAC and washout Tg. The washout CYFRA 21-1 level was associated with TERT mutations (OR, 3.35; P < 0.001), LN metastasis (OR, 5.43; P = 0.019), and distant metastasis (OR, 4.27; P = 0.019).</p><p><strong>Conclusions: </strong>Incorporating washout CYFRA 21-1 into the diagnostic process improves the accuracy of metastatic LN detection in thyroid cancer.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1922-1930"},"PeriodicalIF":10.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604005","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":"Correction: Sulforaphane, a Dietary Component of Broccoli/Broccoli Sprouts, Inhibits Breast Cancer Stem Cells.","authors":"Yanyan Li,Tao Zhang,Hasan Korkaya,Suling Liu,Hsiu-Fang Lee,Bryan Newman,Yanke Yu,Shawn G Clouthier,Steven J Schwartz,Max S Wicha,Duxin Sun","doi":"10.1158/1078-0432.ccr-25-0737","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0737","url":null,"abstract":"","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"68 1","pages":"2062"},"PeriodicalIF":11.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982428","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":"Protein Profiles Predict Treatment Responses to the PI3K Inhibitor Umbralisib in Patients with Chronic Lymphocytic Leukemia.","authors":"Yanping Yin, Haifeng Xu, Liye He, Jennifer R Brown, Anthony R Mato, Tero Aittokallio, Sigrid S Skånland","doi":"10.1158/1078-0432.CCR-24-2911","DOIUrl":"10.1158/1078-0432.CCR-24-2911","url":null,"abstract":"<p><strong>Purpose: </strong>The management of chronic lymphocytic leukemia (CLL) has significantly improved with targeted therapies. However, many patients experience a suboptimal response. To optimally select the best therapy, predictive biomarkers are necessary. In this study, we used the phosphoinositide 3-kinase (PI3K) inhibitor umbralisib as a model to (i) understand the impact of targeted treatment on cell signaling and immunophenotypes in responders and nonresponders, (ii) identify molecular features that predict individual treatment responses, and (iii) suggest alternative treatment options for the nonresponders.</p><p><strong>Experimental design: </strong>We performed functional phenotyping of CLL cells from patients enrolled in two clinical trials with umbralisib, administered either as a monotherapy (NCT02742090, n = 55) or in combination with the Bruton tyrosine kinase (BTK) inhibitor acalabrutinib (NCT04624633, n = 12).</p><p><strong>Results: </strong>We found that umbralisib monotherapy led to significant changes in (phospho)protein levels, including AKT (pS473), in responders but not in nonresponders. Furthermore, the proportion of cytotoxic natural killer (NK) cells increased at the end of the study but only in responders, suggesting a role in the antitumor response. To identify molecular predictors of response, we used the baseline levels of 30 (phospho)proteins in the monotherapy cohort as input features for a machine learning model, which achieved significant prediction accuracy in cross-validation and maintained its predictive power in the combination cohort. Drug sensitivity profiling of the CLL cells at baseline suggested that PI3K + Bcl-2 inhibitors are effective in umbralisib nonresponders.</p><p><strong>Conclusions: </strong>Functional phenotyping reveals differential cellular responses to umbralisib treatment in responders and nonresponders; predicts treatment response of individual patients with CLL; and suggests alternative treatment options for the nonresponders.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1943-1955"},"PeriodicalIF":10.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623693","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":"Editor's Note: RNA Interference Demonstrates a Novel Role for Integrin-Linked Kinase as a Determinant of Pancreatic Adenocarcinoma Cell Gemcitabine Chemoresistance.","authors":"Mark S Duxbury, Hiromichi Ito, Eric Benoit, Talat Waseem, Stanley W Ashley, Edward E Whang","doi":"10.1158/1078-0432.CCR-25-0820","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-25-0820","url":null,"abstract":"","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"31 10","pages":"2065"},"PeriodicalIF":10.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076389","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":"Synergistic Effects of Transarterial Chemoembolization and Lenvatinib on HIF-1α Ubiquitination and Prognosis Improvement in Hepatocellular Carcinoma.","authors":"Sung Won Chung, Jin Sun Kim, Won-Mook Choi, Jonggi Choi, Danbi Lee, Ju Hyun Shim, Young-Suk Lim, Han Chu Lee, Kang Mo Kim","doi":"10.1158/1078-0432.CCR-24-1228","DOIUrl":"10.1158/1078-0432.CCR-24-1228","url":null,"abstract":"<p><strong>Purpose: </strong>A recent trial has shown that adding transarterial chemoembolization (TACE) to lenvatinib therapy results in enhanced therapeutic efficacy in hepatocellular carcinoma (HCC). We aimed to assess the effectiveness of the lenvatinib and TACE combination in a real-world clinical context for managing HCC and to elucidate the molecular pathways involved.</p><p><strong>Experimental design: </strong>This retrospective analysis included 199 patients diagnosed with HCC and having intrahepatic lesions between 2018 and 2021. The cohort was divided into those who received lenvatinib plus TACE (n = 62, combination group) and those who received lenvatinib monotherapy (n = 137, monotherapy group). To further explore the underlying mechanisms, Huh-7 cells were exposed to lenvatinib or a vehicle for 48 hours under normoxic or hypoxic conditions.</p><p><strong>Results: </strong>Propensity score-matched analysis revealed a significant improvement in both overall survival (adjusted HR, 0.38; 95% confidence interval, 0.24-0.59; P < 0.001) and progression-free survival (adjusted HR, 0.41; 95% confidence interval, 0.26-0.64; P < 0.001) in the combination group compared with the monotherapy group. In laboratory experiments, under hypoxic conditions, lenvatinib notably attenuated hypoxia-inducible factor-1α (HIF-1α) protein levels in Huh-7 cells without altering its mRNA levels. Intriguingly, lenvatinib facilitated the mouse double minute 2 homolog-mediated ubiquitination and subsequent degradation of HIF-1α. Additionally, cell viability assays confirmed a significant decrease in Huh-7 cell survival following lenvatinib treatment under hypoxic conditions.</p><p><strong>Conclusions: </strong>The combination of lenvatinib and TACE significantly improved survival in patients with HCC. The mechanistic foundation seems to be the lenvatinib-triggered degradation of HIF-1α via the mouse double minute 2 homolog-dependent ubiquitination pathway, highlighting a potential therapeutic target in HCC treatment.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"2046-2055"},"PeriodicalIF":10.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482244","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":"A Systematic Review with a Demonstrative Case of KIT and DOG-1 Expressing Gastrointestinal Stromal Tumors Harboring ETV6-NTRK3 Fusions.","authors":"Tannaz Ranjbarian, Mark Antkowiak, Robert J Mallory, Terence M Doherty, Mojgan Hosseini, Jill P Mesirov, Paul T Fanta, Jason K Sicklick","doi":"10.1158/1078-0432.CCR-24-3203","DOIUrl":"10.1158/1078-0432.CCR-24-3203","url":null,"abstract":"<p><strong>Purpose: </strong>Previous reports have described ETV6-NTRK3 fusion-positive gastrointestinal stromal tumors (GIST) in cases lacking KIT, PDGFRA, RAS pathway, or SDHx alterations. However, some investigators have questioned the rigor of these reports and the true existence of NTRK rearrangements in GIST. This study aims to (i) resolve whether NTRK gene rearrangements exist in GIST; (ii) review the relevant literature; and (iii) demonstrate a case of GIST with NTRK fusion.</p><p><strong>Experimental design: </strong>A comprehensive literature review using PubMed identified additional NTRK fusion-reported cases. Under an institutional review board-approved protocol, we describe a patient with biopsy-proven GIST who underwent genomic and transcriptomic Clinical Laboratory Improvement Amendments-certified testing, precision-matched therapy, surgical resection, and pathologic analysis.</p><p><strong>Results: </strong>We identified 17 reported cases of GIST with NTRK fusions. Five studies reported GIST with KIT/DOG-1 expression by IHC, wild-type KIT/PDGFRA, and an ETV6-NTRK3 fusion, consistent with GIST. We demonstrate a case of a 72-year-old female after resection of a high-risk gastric GIST followed by 45 months of adjuvant imatinib. She developed recurrent disease, and biopsy revealed mixed epithelioid and spindleoid GIST with IHC expression of KIT (CD117) and DOG-1. Imatinib was reinitiated, but her disease progressed, prompting molecular testing for the first time. RNA sequencing identified an in-frame fusion of ETV6 with NTRK3. Larotrectinib, a pan-NTRK inhibitor, was initiated at a dose of 100 mg twice daily for 7 months, resulting in shrinkage in five tumors (range, 4.2%-77%). Surgical cytoreduction demonstrated a pathologic near-complete response (1% viable tumor cells).</p><p><strong>Conclusions: </strong>Our findings confirm the existence of GIST with ETV6-NTRK3 fusion and demonstrate that these imatinib-resistant GIST may be exquisitely sensitive to tropomyosin receptor kinase inhibitors, although radiologic partial response may not be commensurate with pathologic responses.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"2056-2061"},"PeriodicalIF":10.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12081180/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481840","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":"Editor's Note: Blockade of Deubiquitylating Enzyme USP1 Inhibits DNA Repair and Triggers Apoptosis in Multiple Myeloma Cells.","authors":"Deepika Sharma Das, Abhishek Das, Arghya Ray, Yan Song, Mehmet Kemal Samur, Nikhil C Munshi, Dharminder Chauhan, Kenneth C Anderson","doi":"10.1158/1078-0432.CCR-25-0818","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-25-0818","url":null,"abstract":"","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"31 10","pages":"2063"},"PeriodicalIF":10.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076387","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":"TOP1 Mutations and Cross-Resistance to Antibody-Drug Conjugates in Patients with Metastatic Breast Cancer.","authors":"Rachel O Abelman, Bogang Wu, Haley Barnes, Arielle Medford, Bryanna Norden, Annika Putur, Elena Bitman, Win Thant, Ting Liu, Caroline Weipert, Geoffrey Fell, Laura M Spring, Seth A Wander, Beverly Moy, Neelima Vidula, Steven J Isakoff, Andreas Varkaris, Dejan Juric, Ryan B Corcoran, Leif W Ellisen, Aditya Bardia","doi":"10.1158/1078-0432.CCR-24-2771","DOIUrl":"10.1158/1078-0432.CCR-24-2771","url":null,"abstract":"<p><strong>Purpose: </strong>Antibody-drug conjugates (ADC) harboring topoisomerase I (TOP1) inhibitor payloads have improved survival for patients with metastatic breast cancer. However, knowledge of ADC resistance mechanisms and potential impact on the sequential use of ADCs is limited. In this study, we report the incidence and characterization of TOP1 mutations arising in the setting of ADC resistance in metastatic breast cancer.</p><p><strong>Experimental design: </strong>Patients with metastatic breast cancer treated with ADCs with available posttreatment plasma-based genotyping were included. TOP1 mutation incidence, mutant allele frequency, and functional characterization were assessed, and incidence was compared with that in patients with metastatic breast cancer not receiving ADC treatment and in The Cancer Genome Atlas.</p><p><strong>Results: </strong>Plasma-based genotyping identified distinct TOP1 mutations (S57C, R364H, W401C, and G359E) in 12.9% of patients (4/31) at the time of disease progression on ADC, compared with 0.7% (3/420) in non-ADC-treated patients with metastatic breast cancer and 0.5% in The Cancer Genome Atlas. The appearance of mutations was associated with clinical cross-resistance, as median duration on the first ADC was 455 versus 52 days for the second ADC. The functional characterization of three novel TOP1-mutant proteins demonstrated that all exhibited reduced enzymatic activity, attenuated covalent DNA binding, and resistance to TOP1 inhibitor ADC payloads SN38 and deruxtecan.</p><p><strong>Conclusions: </strong>We describe the recurrent emergence of functionally altered, resistance-associated TOP1 mutations in vivo under selective pressure from ADCs and the potential impact on mediating cross-resistance to sequential ADCs. TOP1 mutation may represent a biomarker of resistance in this setting, and additional work is needed to optimize biomarkers and ADC payload design to improve outcomes for the sequential use of ADCs. See related commentary by Gwin and Hurvitz, p. 1824.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1966-1974"},"PeriodicalIF":10.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12079096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913864","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":"Update on Cancer Screening Recommendations for Individuals with Li-Fraumeni Syndrome.","authors":"Maria Isabel Achatz, Anita Villani, Alison A Bertuch, Gaëlle Bougeard, Vivian Y Chang, Andrea S Doria, Bailey Gallinger, Lucy A Godley, Mary-Louise C Greer, Junne Kamihara, Payal P Khincha, Wendy K Kohlmann, Christian P Kratz, Suzanne P MacFarland, Luke D Maese, Kara N Maxwell, Sarah G Mitchell, Yoshiko Nakano, Stefan M Pfister, Jonathan D Wasserman, Emma R Woodward, Judy E Garber, David Malkin","doi":"10.1158/1078-0432.CCR-24-3301","DOIUrl":"10.1158/1078-0432.CCR-24-3301","url":null,"abstract":"<p><p>Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition condition characterized by a high lifetime risk for a wide spectrum of malignancies associated with germline pathogenic/likely pathogenic variants in the TP53 tumor suppressor gene. Secondary malignant neoplasms are particularly common. Early cancer detection through surveillance enables early intervention and leads to improved clinical outcomes with reduced tumor-related mortality and treatment-related morbidity. Since the 2017 publication of LFS tumor surveillance guidelines from the inaugural American Association for Cancer Research Childhood Cancer Predisposition Workshop, understanding the genotype-phenotype relationships in LFS has evolved, and adaptations of the guidelines have been implemented in institutions worldwide. The \"Toronto Protocol\" remains the current standard for lifelong surveillance; however, as outlined in this perspective, modifications should be considered about the use of certain modalities to target organs in an age-dependent manner. The Working Group's recommendations have also been extended to include a more detailed outline for surveillance in the adult TP53 pathogenic/likely pathogenic variant carrier population, based on the recognition that early education of both practitioners and patients on what to expect after the transition from childhood/adolescence to young adulthood is important in preparing them for changes in surveillance strategies. In this perspective, we provide an up-to-date clinical overview of LFS and present our updated consensus tumor surveillance recommendations from the 2023 American Association for Cancer Research Childhood Cancer Predisposition Workshop.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1831-1840"},"PeriodicalIF":10.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603928","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}