Clinical Cancer Research最新文献

{"title":"Nerve Types and Classification of Neurons Innervating Oral Cancer.","authors":"Cindy G Perez-Pacheco,Laura A Gonzalez-Maldonado,Allison Furgal,Ligia B Schmitd,Brian S C Constantinescu,Yihan Li,Noam Gannot,Sienna K Perry,Laura Rozek,Greg Wolf,Joshua J Emrick,Peng Li,Nisha J D'Silva","doi":"10.1158/1078-0432.ccr-24-2375","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2375","url":null,"abstract":"PURPOSEAlthough the association between neural invasion and poor survival in oral cavity squamous cell carcinoma (OSCC) is known, innervating nerve types have not been definitively established; this has confounded mechanistic and translational studies. Therefore, we investigated innervation in human OSCC and further explored these findings in mice.EXPERIMENTAL DESIGNSensory, sympathetic, and parasympathetic nerves were identified by immunohistochemistry and linked to neural phenotypes in 71 patients. Additionally, we investigated sensory innervation of OSCC using neuronal tracing with transcriptomic profiling, and transgenic mice.RESULTSIn OSCC, most nerves are exclusively sensory or sensory mixed with other types. The presence of exclusively sensory nerves and mixed sensory and sympathetic nerves was significantly increased within the tumor bulk compared to the margin, whereas mixed sympathetic and parasympathetic nerves were decreased. The proportion of exclusively sensory, and mixed sensory and sympathetic PNI+ (perineural invasion) nerves was significantly higher, whereas the proportion of mixed sympathetic and parasympathetic nerves was significantly lower than PNI(-) nerves. Classification of tumor-innervating trigeminal sensory neurons in mice revealed an increase in Calca+ peptidergic nociceptors and reduction in low-threshold mechanoreceptors. Using transgenic reporter mice to verify innervation, we identified that mouse tongue SCC is innervated by Pirt+ and Calca+ nociceptors.CONCLUSIONSThis study is the first comprehensive characterization of nerve types in OSCC with classification of innervating trigeminal sensory neurons. Our findings emphasize the importance of sensory innervation in OSCC and are highly relevant for mechanistic and translational studies on treatment strategies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"1 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143897428","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":"Metabolic Tumor Volume and Immunotherapy in NSCLC-Letter.","authors":"Nicolas Aide,Egesta Lopci,Laurent Dercle","doi":"10.1158/1078-0432.ccr-24-4107","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-4107","url":null,"abstract":"","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"133 1","pages":"1812-1813"},"PeriodicalIF":11.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143897442","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":"Safety and Tolerability of Lete-cel in NSCLC-Letter.","authors":"Di Zhao,Jie Liu","doi":"10.1158/1078-0432.ccr-24-3948","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3948","url":null,"abstract":"","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"1 1","pages":"1809"},"PeriodicalIF":11.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143897439","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":"Presurgical ablative radiation is associated with local control and immune response in pancreatic cancer","authors":"Peter Q. Leung, Eslam A. Elghonaimy, Ahmed M. Elamir, Megan Wachsmann, Song Zhang, Neha Barrows, Hollis Notgrass, Ethan Johnson, Cheryl M. Lewis, Rachel von Ebers, Cassandra Hamilton, Samy Castillo-Flores, Ricardo E. Nunez-Rocha, Grace Josephson, Zhikai Chi, Salwan Al Mutar, Patricio M. Polanco, Nina N. Sanford, Syed M. Ali Kazmi, Matthew R. Porembka, David Hsiehchen, Adam C. Yopp, John C. Mansour, Muhammad S. Beg, Herbert J. Zeh, Todd A. Aguilera","doi":"10.1158/1078-0432.ccr-24-3582","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3582","url":null,"abstract":"Purpose: To compare outcomes and molecular characteristics of patients who had surgery after neoadjuvant chemotherapy, with and without ablative radiotherapy (SAbR) for pancreas cancer. Insight could clarify the benefits of SAbR and provide molecular guidance for future therapeutic regimens. Experimental Design: This single-institution, tertiary care academic center cohort study included all patients diagnosed with pancreatic cancer between 2012–2023 treated with neoadjuvant chemotherapy, with or without SAbR. We compared therapeutic responses, performed patient matching, and conducted Cox modeling to identify differences between groups. We assessed molecular response using RNA sequencing to identify SAbR-induced biologic differences. Results: Among 133 patients receiving chemotherapy and 48 receiving chemotherapy + SAbR, RNA sequencing was available for 29 and 14 patients, respectively. Despite more advanced baseline disease, the SAbR group showed better post-treatment pathology and similar overall survival (HR = 0.97, 95% CI = 0.58–1.60, P = .9). Patient matching indicated that SAbR improved locoregional recurrence-free survival (HR = 0.24, 95% CI = 0.07–0.88, P = .009). Arterial involvement raised local failure risk with chemotherapy alone (HR = 3.37, 95% CI = 1.74–6.54, P < .001), which was significantly reduced with SAbR (HR = 0.28; 95% CI = 0.12–0.68; P = .005). Gene set enrichment analysis showed immune activation, with CD8 and NK/NKT cell signatures associated with local control and Treg signatures associated with worse control. Conclusion: Neoadjuvant SAbR is associated with improved pathological outcomes, enhanced local control, and maintained survival while inducing a distinct immune response. Well-powered studies are needed to clarify its clinical benefits.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"44 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143898272","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":"Metabolic Tumor Volume and Immunotherapy in NSCLC-Reply.","authors":"Filippo Dall'Olio,Benjamin Besse,Camilo Garcia","doi":"10.1158/1078-0432.ccr-25-0202","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0202","url":null,"abstract":"","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"114 1","pages":"1814"},"PeriodicalIF":11.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143897438","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":"Safety and Tolerability of Lete-cel in NSCLC-Reply.","authors":"Mehmet Altan,Gilberto Lopes,T Jeroen N Hiltermann,Ramaswamy Govindan,Liza C Villaruz,Emiliano Calvo,Martin J Edelman,Muhammad Furqan,Joel Neal,Enriqueta Felip,Jennifer W Carlisle,John V Heymach,Róisín Eilish O'Cearbhaill,Marjorie Zauderer,Michael Chisamore,Ellie Corigliano,Ioanna Eleftheriadou,Stefan Zajic,Ben Jenkins,Sophia Goodison,Sunil Suchindran,Natalia Ramos-Hernandez,Nidale Tarek,Adam J Schoenfeld","doi":"10.1158/1078-0432.ccr-25-0070","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0070","url":null,"abstract":"","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"53 1","pages":"1810-1811"},"PeriodicalIF":11.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143897443","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":"Liquid and tissue biopsies for identifying MET exon 14 skipping NSCLC: Analyses from the Phase II VISION study of tepotinib.","authors":"Christian Rolfo,Aurora O'Brate,Christoph Menzel,Rolf Bruns,Dilafruz Juraeva,Christopher Stroh,Andreas Johne,Paul K Paik","doi":"10.1158/1078-0432.ccr-24-4097","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-4097","url":null,"abstract":"PURPOSEThe VISION trial of tepotinib, a selective MET inhibitor, enrolled patients with NSCLC and prospectively detected MET exon 14 skipping (METex14) in liquid biopsies (LBx) and/or tissue biopsies (TBx). We evaluated patient characteristics and outcomes according to METex14 positivity in LBx (LBx-positive) or TBx (TBx-positive).METHODSMETex14 was centrally assessed by next-generation sequencing of ctDNA from LBx (Guardant360®/Archer®MET) and/or RNA from TBx (Oncomine Focus/Archer®MET) or, in Japan only, local TBx polymerase chain reaction. Parallel LBx/TBx testing was recommended but not mandatory. Eligibility required LBx-positive or TBx-positive status. ctDNA burden was analyzed in patients with baseline Guardant360® data.RESULTSMETex14 was detected in 469/7,937 prescreened/screened patients, of whom 313 were enrolled (TBx-positive, n=208; LBx-positive, n=178). LBx-positive patients had higher radiographic tumor burden than TBx-positive patients, including higher median sum of target lesion diameters per RECIST v1.1 (67.1 vs 55.2 mm), and more patients with ≥3 target lesions (27.5% vs 18.8%). In 180 TBx-positive patients with matching LBx results, objective response rates were slightly higher in TBx-positive/LBx-positive patients, but TBx-positive/LBx-negative patients had longer duration of response, progression-free survival (PFS), and overall survival (OS). In ctDNA analysis (n=165), detectable baseline ctDNA burden was associated with shorter PFS and OS.CONCLUSIONTepotinib had robust, durable activity in TBx-positive/LBx-negative and TBx-positive/LBx-positive patients. While LBx is a complementary method to TBx for detecting METex14, it may preferentially select patients with higher tumor burden and poorer prognosis. Undetectable METex14 in baseline ctDNA (due to low ctDNA shedding) may define more favorable treatment outcomes.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"70 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143897427","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":"Targeting the MAP kinase pathway in colorectal cancer: A journey in personalized medicine.","authors":"Jordan W Appleyard,Christopher J M Williams,Paolo Manca,Filippo Pietrantonio,Jenny F Seligmann","doi":"10.1158/1078-0432.ccr-25-0107","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0107","url":null,"abstract":"The anti-EGFR agents, cetuximab and panitumumab, were the first targeted agents to be licensed in colorectal cancer and marked a significant advancement in personalized care. Initial biomarkers provided poor discrimination between responders and non-responders. Through hypothesis-led translational studies, tumor genomic negative predictive markers were identified, and treatment is now limited to patients with RAS and BRAF wild-type disease. Guidelines further recommend treatment limitation to those with left-primary tumor location (PTL). Despite such progress, anti-EGFR response remains variable within the biomarker-selected population, indicating the presence of additional mechanisms of resistance and underscoring the need for novel positive predictive biomarkers, and novel targeted agents. This review explores established and emerging predictive biomarkers of anti-EGFR efficacy, including tumor genetic alterations beyond RAS and BRAF, as well as the EGFR ligands, amphiregulin (AREG) and epiregulin (EREG). To date, biomarker discovery and validation have largely been performed within post hoc analyses of existing clinical trial datasets. We highlight ongoing prospective clinical trials aiming to validate earlier findings and describe how novel biomarkers are being used to re-evaluate anti-EGFR agents in treatment settings where earlier trials, among non-biomarker selected populations, yielded negative results - including right-PTL, locally advanced disease, and anti-EGFR rechallenge strategies. Additionally, we discuss how our improved understanding of the molecular mechanisms underpinning anti-EGFR response and resistance is being leveraged to develop novel targeted agents.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"36 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143897437","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":"Amplification of extrachromosomal MYC paralogs shapes immunosuppressive tumor microenvironment in small cell lung cancer","authors":"Jingwei Zhang, Yueqi Jin, Haodong Lin, Jiaming Deng, Yan Ju, Xueyan Hu, Jianqi She, Zhijian Liang, Kongxu Dai, Mantang Qiu, Kunkun Sun, Jun Wang, Fan Yang, Jian Chen, Ence Yang, Xiao Li","doi":"10.1158/1078-0432.ccr-24-3399","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3399","url":null,"abstract":"Purpose: Immunotherapy has demonstrated promise in small cell lung cancer (SCLC), but certain patients encounter limited benefits, highlighting the need for immunosuppressive biomarkers. Extrachromosomal circular DNA (ecDNA) promotes amplification of MYC-paralogs (MYC, MYCN and MYCL), driving cross-resistance in SCLC. Here, we aim to investigate whether ecDNA-mediated MYC-paralogs amplification (ecMYC+) represents immunosuppressive features in SCLC. Experimental Design: Bulk RNA sequencing data were retrieved from public database and paraffin-embedded samples. The overexpression and amplification of MYC-paralogs were identified using immunohistochemistry and fluorescence in situ hybridization. Imaging mass cytometry and multiplex immunohistochemistry were used to characterize spatial distribution of tumor immune microenvironment (TIME). The copy number of MYC-paralogs was investigated using real-time polymerase chain reaction. RNA-sequencing and flow cytometry were performed in SCLC cell lines. Results: The mean copy number of ecDNAs and the frequency of ecMYC+ cell lines were higher in SCLC than that in the other lineages (SCLC 22/47 vs others 15/282). In ecMYC+ SCLC, multiple immune-related pathways were downregulated while nucleotide metabolism processes were upregulated. Inhibition of nucleotide metabolism induced ecDNA elimination, along with activated antigen presenting pathways. Highly dispersed MYC-paralogs amplifications were detected in resected treatment-naïve SCLC samples. Through the resolution of 103,341 cells from 24 pathological regions, we observed higher expression of MKI67, VEGFA, FAP and FOXP3 and reduced T cell infiltration in ecMYC+ samples. Moreover, ecMYC+ samples exhibited elevated cellular neighborhoods dominated by Ki67+ tumors, with reduced spatial interaction with immune cells. Conclusions: Extrachromosomal amplification of MYC-paralogs shapes suppressive TIME, identifying potential subgroup of immunotherapy resistant patients.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"61 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889620","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 Phase II Randomized Study of Paclitaxel alone or combined with Pelareorep with or without Avelumab in Metastatic Hormone Receptor Positive Breast Cancer: the BRACELET-01/PrE0113 study","authors":"Amy S. Clark, Fengmin Zhao, Paula Klein, Alberto J. Montero, Carla Falkson, Elisa Krill-Jackson, Kendrith Rowland, Sagar Sardesai, Jason Incorvati, Patrick Dillon, Antonio C. Wolff, Richard Trauger, Thomas C. Heineman, Matthew C. Coffey, Kathy D. Miller","doi":"10.1158/1078-0432.ccr-24-2701","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2701","url":null,"abstract":"Purpose: Pelareorep (Pel) is a type 3 oncolytic reovirus that upregulates PD-L1 expression. We determined the objective response rate (ORR) with paclitaxel (Pac), Pac + Pel, or Pac + Pel + avelumab (Ave). Patients and Methods: Patients with hormone receptor positive (HR+) HER2 negative metastatic breast cancer (MBC) who had progressed on at least one line of endocrine therapy with a CDK 4/6 inhibitor and had not received chemotherapy for MBC were eligible. Patients were randomized 1:1:1 to Pac, Pac/Pel or Pac/Pel/Ave after a three-patient run-in confirmed safety of the triplet. Response was assessed every 8 weeks until week 16 and then every 12 weeks using RECIST v1.1. The primary endpoint was 16-week ORR. Statistical comparison across arms was not planned. Results: 48 patients enrolled with 45 randomized, 16-week ORR was 20%, 31% and 14% in the Pac, Pac/Pel and Pac/Pel/Ave arms, respectively. Median progression-free survival (PFS) was 6.4 months (m), 12.1m and 5.8m in the Pac, Pac/Pel and Pac/Pel/Ave arms respectively. There were more adverse events, particularly infusion reactions, in the combination arms than the Pac arm. Expansion of peripheral T cell clones were observed by cycle (C)4 in Pac/Pel but not the Pac or Pac/Pel/Ave arms. Conclusions: The addition of Pel to Pac was associated with increased toxicity, expanded peripheral T-cell clones, and numerically increased ORR and PFS compared to Pac; Pac/Pel/Ave further increased toxicity and blunted T cell responses without obvious increase in efficacy. Investigation of the Pac/Pel combination warrants consideration with careful attention to acute toxicity.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"43 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889617","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}