Clinical Cancer Research最新文献

{"title":"Missense Mutations in Myc Box I Influence Nucleocytoplasmic Transport to Promote Leukemogenesis.","authors":"Nancy B J Arthur, Keegan A Christensen, Kathleen Mannino, Marianna B Ruzinova, Ashutosh Kumar, Agata Gruszczynska, Ryan B Day, Petra Erdmann-Gilmore, Yiling Mi, Robert Sprung, Conner R York, Robert R Townsend, David H Spencer, Stephen M Sykes, Francesca Ferraro","doi":"10.1158/1078-0432.CCR-24-0926","DOIUrl":"10.1158/1078-0432.CCR-24-0926","url":null,"abstract":"<p><strong>Purpose: </strong>Somatic missense mutations in the phosphodegron domain of the MYC gene (MYC Box I or MBI) are detected in the dominant clones of a subset of patients with acute myeloid leukemia (AML), but the mechanisms by which they contribute to AML are unknown.</p><p><strong>Experimental design: </strong>To investigate the effects of MBI MYC mutations on hematopoietic cells, we employed a multi-omic approach to systematically compare the cellular and molecular consequences of expressing oncogenic doses of wild type, threonine-58 and proline-59 mutant MYC proteins in hematopoietic cells, and we developed a knockin mouse harboring the germline MBI mutation p.T58N in the Myc gene.</p><p><strong>Results: </strong>Both wild-type and MBI mutant MYC proteins promote self-renewal programs and expand highly selected subpopulations of progenitor cells in the bone marrow. Compared with their wild-type counterparts, mutant cells display decreased cell death and accelerated leukemogenesis in vivo, changes that are recapitulated in the transcriptomes of human AML-bearing MYC mutations. The mutant phenotypes feature decreased stability and translation of mRNAs encoding proapoptotic and immune-regulatory genes, increased translation of RNA binding proteins and nuclear export machinery, and distinct nucleocytoplasmic RNA profiles. MBI MYC mutant proteins also show a higher propensity to aggregate in perinuclear regions and cytoplasm. Like the overexpression model, heterozygous p.T58N knockin mice displayed similar changes in subcellular MYC localization, progenitor expansion, transcriptional signatures, and develop hematopoietic tumors.</p><p><strong>Conclusions: </strong>This study uncovers that MBI MYC mutations alter RNA nucleocytoplasmic transport mechanisms to contribute to the development of hematopoietic malignancies.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11326984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141283162","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":"Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma.","authors":"Flurina A M Saner, Kazuaki Takahashi, Timothy Budden, Ahwan Pandey, Dinuka Ariyaratne, Tibor A Zwimpfer, Nicola S Meagher, Sian Fereday, Laura Twomey, Kathleen I Pishas, Therese Hoang, Adelyn Bolithon, Nadia Traficante, Kathryn Alsop, Elizabeth L Christie, Eun-Young Kang, Gregg S Nelson, Prafull Ghatage, Cheng-Han Lee, Marjorie J Riggan, Jennifer Alsop, Matthias W Beckmann, Jessica Boros, Alison H Brand, Angela Brooks-Wilson, Michael E Carney, Penny Coulson, Madeleine Courtney-Brooks, Kara L Cushing-Haugen, Cezary Cybulski, Mona A El-Bahrawy, Esther Elishaev, Ramona Erber, Simon A Gayther, Aleksandra Gentry-Maharaj, C Blake Gilks, Paul R Harnett, Holly R Harris, Arndt Hartmann, Alexander Hein, Joy Hendley, Brenda Y Hernandez, Anna Jakubowska, Mercedes Jimenez-Linan, Michael E Jones, Scott H Kaufmann, Catherine J Kennedy, Tomasz Kluz, Jennifer M Koziak, Björg Kristjansdottir, Nhu D Le, Marcin Lener, Jenny Lester, Jan Lubiński, Constantina Mateoiu, Sandra Orsulic, Matthias Ruebner, Minouk J Schoemaker, Mitul Shah, Raghwa Sharma, Mark E Sherman, Yurii B Shvetsov, T Rinda Soong, Helen Steed, Paniti Sukumvanich, Aline Talhouk, Sarah E Taylor, Robert A Vierkant, Chen Wang, Martin Widschwendter, Lynne R Wilkens, Stacey J Winham, Michael S Anglesio, Andrew Berchuck, James D Brenton, Ian Campbell, Linda S Cook, Jennifer A Doherty, Peter A Fasching, Renée T Fortner, Marc T Goodman, Jacek Gronwald, David G Huntsman, Beth Y Karlan, Linda E Kelemen, Usha Menon, Francesmary Modugno, Paul D P Pharoah, Joellen M Schildkraut, Karin Sundfeldt, Anthony J Swerdlow, Ellen L Goode, Anna DeFazio, Martin Köbel, Susan J Ramus, David D L Bowtell, Dale W Garsed","doi":"10.1158/1078-0432.CCR-23-3552","DOIUrl":"10.1158/1078-0432.CCR-23-3552","url":null,"abstract":"<p><strong>Purpose: </strong>The purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC).</p><p><strong>Experimental design: </strong>RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss.</p><p><strong>Results: </strong>RB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1.</p><p><strong>Conclusions: </strong>Co-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11325151/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141260601","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":"Rintatolimod in Advanced Pancreatic Cancer Enhances Antitumor Immunity through Dendritic Cell-Mediated T-Cell Responses.","authors":"Casper W F van Eijck, Hassana El Haddaoui, Songul Kucukcelebi, Disha Vadgama, Amine Fellah, Dana A M Mustafa, Joachim G J V Aerts, Casper H J van Eijck, Marcella Willemsen","doi":"10.1158/1078-0432.CCR-23-4085","DOIUrl":"10.1158/1078-0432.CCR-23-4085","url":null,"abstract":"<p><strong>Purpose: </strong>Amid the need for new approaches to improve survival in pancreatic ductal adenocarcinoma (PDAC), immune-based therapies have garnered interest. Rintatolimod, a Toll-like receptor 3 (TLR-3) agonist, is a potential candidate due to its dual impact on restraining PDAC cell functions and boosting the antitumor immune response. This study investigates the effect of TLR-3 activation through rintatolimod on the peripheral immune landscape of patients with advanced PDAC.</p><p><strong>Experimental design: </strong>Paired blood samples of 30 patients with advanced PDAC, collected at baseline and after 12 rintatolimod intravenous infusions, underwent comprehensive transcriptomic NanoString and proteomic flow cytometry profiling. The impact of rintatolimod and immunologic factors on survival outcomes was assessed through univariate Cox proportional hazards models.</p><p><strong>Results: </strong>Rintatolimod treatment enhances peripheral immune activity at the transcriptomic and proteomic levels, particularly involving type 1 conventional dendritic cells (cDC1) and T cells. Post-rintatolimod, the increased peripheral abundance of BTLA+ XCR1+ cDC1s and CD4+SELL+ T cells correlated with improved clinical outcomes. Patients with stable disease exhibited pronouncedDCand T-cell activation gene overexpression. Notably, the expression of immune checkpoints PD-L1 and PD-L2 decreased post-rintatolimod across all patients. However, those with progressive disease showed increased expression of genes encoding IDO1 and PD-1.</p><p><strong>Conclusions: </strong>This study presents compelling evidence of the immune-stimulatory properties linked to TLR-3 activation through rintatolimod. Rintatolimod may break immunologic tolerance by enhancing antitumor immunity through DC-mediated Th-cell responses. Furthermore, our findings lay the groundwork for investigating the potential synergy between TLR-3 activation and immune checkpoint inhibitor therapy to improve therapeutic outcomes. See related commentary by Martínez-Riaño et al., p. 3355.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140130867","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":"Early Evaluation of Risk Stratification and Clinical Outcomes for Patients with Advanced Breast Cancer through Combined Monitoring of Baseline Circulating Tumor Cells and DNA.","authors":"Qiang Zhang, Zheng Cai, Lorenzo Gerratana, Andrew A Davis, Paolo D'Amico, Akhil Chawla, Saya Jacob, Youbin Zhang, Jianhua Jiao, Weijun Qin, Carolina Reduzzi, Lisa Flaum, Ami Shah, William J Gradishar","doi":"10.1158/1078-0432.CCR-24-0535","DOIUrl":"10.1158/1078-0432.CCR-24-0535","url":null,"abstract":"<p><strong>Purpose: </strong>Early evaluation of tumor heterogeneity related to metastasis and outcomes is a major challenge in the management of advanced breast cancer (BCa) in the clinic. In this study, we introduced the value of baseline circulating tumor cells (CTC) and ctDNA for early differentiation of clinical stages, tumor heterogeneity, and prognosis in clinic.</p><p><strong>Experimental design: </strong>A total of 292 patients with BCa were enrolled in this study, including 254 Stage IV and 38 Stage III patients, and examined the baseline levels of CTCs, CTC-clusters, and plasma ctDNA before initiating therapies. Outcomes including progression-free survival (PFS) and overall survival were evaluated using proportional hazards regression analysis.</p><p><strong>Results: </strong>The baseline CTCs, including HER2+ CTCs, in Stage IV patients were approximately 9.5 times higher than those detected in Stage III patients. Baseline CTC counts with a cutoff of 5 were significantly associated with the prognosis. Within each stage, patients with <5 CTCs had significantly longer PFS. Stage III patients with no CTCs exhibited the longest survival compared with patients with ≥1 CTC. CTC-clusters were only found in Stage IV patients, among whom 15 Stage IV patients with ≥5 CTC-clusters had the worst PFS compared with the 239 Stage IV patients with <5 CTC-clusters. Similar outcomes were observed in 28 out of 254 Stage IV patients who had at least one CTC-cluster detected, as these patients had shorter PFS compared with CTC-cluster negative group. The major differences in ctDNA mutations between patients with Stage III and Stage IV BCa were in PIK3CA and ESR1, which were associated with specific organ metastasis and worse outcomes.</p><p><strong>Conclusions: </strong>Assessing the baseline levels of CTCs, CTC-clusters, and mutational ctDNA profile could reliably aid in differentiation of clinical stage and early prediction of metastasis and outcomes in advanced BCa.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199540","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":"FDA Approval Summary: Durvalumab and Pembrolizumab, Immune Checkpoint Inhibitors for the Treatment of Biliary Tract Cancer.","authors":"Sandra J Casak, Vaibhav Kumar, Chi Song, Mengdie Yuan, Anup K Amatya, Joyce Cheng, Pallavi S Mishra-Kalyani, Shenghui Tang, Steven J Lemery, Doris Auth, Gina Davis, Paul G Kluetz, Richard Pazdur, Lola A Fashoyin-Aje","doi":"10.1158/1078-0432.CCR-24-0517","DOIUrl":"10.1158/1078-0432.CCR-24-0517","url":null,"abstract":"<p><p>On September 2, 2022, the Food and Drug Administration (FDA) approved durvalumab in combination with cisplatin and gemcitabine, for the treatment of patients with unresectable or metastatic biliary tract cancers (BTC). On October 31, 2023, the FDA approved pembrolizumab in combination with cisplatin and gemcitabine for the same indication. Approvals were based on two randomized, multiregional, placebo-controlled trials that randomly allocated patients to receive durvalumab (TOPAZ-1) or pembrolizumab (KEYNOTE-966) in combination with chemotherapy or placebo in combination with chemotherapy. Overall survival (OS) was the primary endpoint in both studies. In both studies, a statistically significant and clinically meaningful improvement in OS was demonstrated. In the TOPAZ-1 trial, the median OS of patients receiving durvalumab was 12.8 months [95% confidence interval (CI), 11.1-14.0] and 11.5 months (95% CI, 10.1-12.5) in patients receiving placebo [hazard ratio (HR), 0.80 (95% CI, 0.66-0.97)]. In the KEYNOTE-966 trial, the median OS of patients receiving pembrolizumab was 12.7 months (95% CI, 11.5-13.6) and 10.9 months (95% CI, 9.9-11.6) in patients receiving placebo [HR, 0.83 (95% CI, 0.72-0.95)]. The addition of checkpoint inhibitors to standard of care chemotherapy for this indication did not reveal any new adverse event signals, and the safety profile was generally consistent with the known clinical experience with durvalumab, pembrolizumab, and the backbone chemotherapy regimen. The approvals of durvalumab and pembrolizumab in combination with standard of care cisplatin and gemcitabine for the treatment of unresectable or metastatic BTC add two new therapeutic options for these patients.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11326973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141295615","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":"Spatially Informed Gene Signatures for Response to Immunotherapy in Melanoma.","authors":"Thazin N Aung, Jonathan Warrell, Sandra Martinez-Morilla, Niki Gavrielatou, Ioannis Vathiotis, Vesal Yaghoobi, Harriet M Kluger, Mark Gerstein, David L Rimm","doi":"10.1158/1078-0432.CCR-23-3932","DOIUrl":"10.1158/1078-0432.CCR-23-3932","url":null,"abstract":"<p><strong>Purpose: </strong>We aim to improve the prediction of response or resistance to immunotherapies in patients with melanoma. This goal is based on the hypothesis that current gene signatures predicting immunotherapy outcomes show only modest accuracy due to the lack of spatial information about cellular functions and molecular processes within tumors and their microenvironment.</p><p><strong>Experimental design: </strong>We collected gene expression data spatially from three cellular compartments defined by CD68+ macrophages, CD45+ leukocytes, and S100B+ tumor cells in 55 immunotherapy-treated melanoma specimens using Digital Spatial Profiling-Whole Transcriptome Atlas. We developed a computational pipeline to discover compartment-specific gene signatures and determine if adding spatial information can improve patient stratification.</p><p><strong>Results: </strong>We achieved robust performance of compartment-specific signatures in predicting the outcome of immune checkpoint inhibitors in the discovery cohort. Of the three signatures, the S100B signature showed the best performance in the validation cohort (N = 45). We also compared our compartment-specific signatures with published bulk signatures and found the S100B tumor spatial signature outperformed previous signatures. Within the eight-gene S100B signature, five genes (PSMB8, TAX1BP3, NOTCH3, LCP2, and NQO1) with positive coefficients predict the response, and three genes (KMT2C, OVCA2, and MGRN1) with negative coefficients predict the resistance to treatment.</p><p><strong>Conclusions: </strong>We conclude that the spatially defined compartment signatures utilize tumor and tumor microenvironment-specific information, leading to more accurate prediction of treatment outcome, and thus merit prospective clinical assessment.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11326985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141260776","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":"Double-Stranded RNA to Mimic Viral Infection for Cancer Immunotherapy.","authors":"Ana Martínez-Riaño, Laura Mosteo, Paula Molero-Glez, Iván Márquez-Rodas, Ignacio Melero","doi":"10.1158/1078-0432.CCR-24-0938","DOIUrl":"10.1158/1078-0432.CCR-24-0938","url":null,"abstract":"<p><p>The presence of moieties denoting viral infection is crucial to mount powerful cytotoxic T-cell immune responses acting through innate receptors such as Toll-like receptor 3. For cancer immunotherapy, several safe analogues of viral double-stranded RNA are under clinical development following compelling evidence for efficacy in mouse models. See related article by van Eijck et al., p. 3447.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141310208","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":"Early On-Treatment Assessment of T Cells, Cytokines, and Tumor DNA with Adaptively Dosed Nivolumab + Ipilimumab: Final Results from the Phase 2 ADAPT-IT Study.","authors":"James W Smithy, Hannah L Kalvin, Fiona D Ehrich, Ronak Shah, Matthew Adamow, Vladislav Raber, Collen A Maher, Jenna Kleman, Deborah A G McIntyre, Alexander N Shoushtari, Allison Betof Warner, Margaret K Callahan, Parisa Momtaz, Omar Eton, Suresh Nair, Jedd D Wolchok, Paul B Chapman, Michael F Berger, Katherine S Panageas, Michael A Postow","doi":"10.1158/1078-0432.CCR-23-3643","DOIUrl":"10.1158/1078-0432.CCR-23-3643","url":null,"abstract":"<p><strong>Purpose: </strong>The Adaptively Dosed ImmunoTherapy Trial (ADAPT-IT;NCT03122522) investigated adaptive ipilimumab discontinuation in melanoma based on early radiographic assessment. Initial findings indicated similar effectiveness compared with conventional nivolumab-ipilimumab (nivo-ipi). Exploratory biomarker analyses and final clinical results are now reported.</p><p><strong>Patients and methods: </strong>Patients with unresectable melanoma received two doses of nivo-ipi. Radiographic assessment at Week 6 informed continuation of ipilimumab before nivolumab maintenance. The primary endpoint was overall response rate at Week 12. Plasma was assayed for circulating tumor DNA and 10 cytokines using a multiplex immunoassay. Flow cytometry of peripheral blood mononuclear cells was performed with an 11-color panel.</p><p><strong>Results: </strong>Among the treated patients, expansion of proliferating T-cell populations was observed in responders and nonresponders. Baseline IL6 levels were low in patients achieving an objective radiographic response (median 1.30 vs. 2.86 pg/mL; P = 0.025). High baseline IL6 levels were associated with short progression-free survival [PFS; HR = 1.24, 95% confidence interval (CI), 1.01-1.52; P = 0.041]. At Week 6, patients with response had lower average tumor variant allele fractions than nonresponders (median 0.000 vs. 0.019; P = 0.014). Greater increases in average variant allele fractions from baseline to Week 6 correlated with short PFS (HR = 1.11, 95% CI, 1.01-1.21; P = 0.023). Week 12 overall response rate was 47% (95% CI, 35%-59%) with a median follow-up of 34 months among survivors. Median PFS was 21 months (95% CI, 10-not reached); 76% of responses (95% CI, 64%-91%) persisted at 36 months.</p><p><strong>Conclusions: </strong>Adaptively dosed nivo-ipi responses are durable and resemble historical data for conventional nivo-ipi. Baseline IL6 and circulating tumor DNA changes during treatment warrant further study as biomarkers of nivo-ipi response.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11357703/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141064710","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":"T2-FLAIR Mismatch Sign Predicts DNA Methylation Subclass and CDKN2A/B Status in IDH-Mutant Astrocytomas.","authors":"Matthew D Lee, Rajan Jain, Kristyn Galbraith, Anna Chen, Evan Lieberman, Sohil H Patel, Dimitris G Placantonakis, David Zagzag, Marissa Barbaro, Maria Del Pilar Guillermo Prieto Eibl, John G Golfinos, Daniel A Orringer, Matija Snuderl","doi":"10.1158/1078-0432.CCR-24-0311","DOIUrl":"10.1158/1078-0432.CCR-24-0311","url":null,"abstract":"<p><strong>Purpose: </strong>DNA methylation profiling stratifies isocitrate dehydrogenase (IDH)-mutant astrocytomas into methylation low- and high-grade groups. We investigated the utility of the T2-fluid-attenuated inversion recovery (T2-FLAIR) mismatch sign for predicting DNA methylation grade and cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) homozygous deletion, a molecular biomarker for grade 4 IDH-mutant astrocytomas, according to the 2021 World Health Organization classification.</p><p><strong>Experimental design: </strong>Preoperative MRI scans of IDH-mutant astrocytomas subclassified by DNA methylation profiling (n = 71) were independently evaluated by two radiologists for the T2-FLAIR mismatch sign. The diagnostic utility of T2-FLAIR mismatch in predicting methylation grade, CDKN2A/B status, copy number variation, and survival was analyzed.</p><p><strong>Results: </strong>The T2-FLAIR mismatch sign was present in 21 of 45 (46.7%) methylation low-grade and 1 of 26 (3.9%) methylation high-grade cases (P < 0.001), resulting in 96.2% specificity, 95.5% positive predictive value, and 51.0% negative predictive value for predicting low methylation grade. The T2-FLAIR mismatch sign was also significantly associated with intact CDKN2A/B status (P = 0.028) with 87.5% specificity, 86.4% positive predictive value, and 42.9% negative predictive value. Overall multivariable Cox analysis showed that retained CDKN2A/B status remained significant for progression-free survival (P = 0.01). Multivariable Cox analysis of the histologic grade 3 subset, which was nearly evenly divided by CDKN2A/B status, copy number variation, and methylation grade, showed trends toward significance for DNA methylation grade with overall survival (P = 0.045) and CDKN2A/B status with progression-free survival (P = 0.052).</p><p><strong>Conclusions: </strong>The T2-FLAIR mismatch sign is highly specific for low methylation grade and intact CDKN2A/B in IDH-mutant astrocytomas.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11326959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199542","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":"Oxygen-enhanced MRI detects incidence, onset and heterogeneity of radiation-induced hypoxia modification in HPV-associated oropharyngeal cancer.","authors":"Michael J Dubec, James Price, Michael Berks, John Gaffney, Ross A Little, Nuria Porta, Nivetha Sridharan, Anubhav Datta, Damien J McHugh, Christina J Hague, Susan Cheung, Prakash Manoharan, Marcel van Herk, Ananya Choudhury, Julian C Matthews, Geoff J M Parker, David L Buckley, Kevin J Harrington, Andrew McPartlin, James P B O'Connor","doi":"10.1158/1078-0432.CCR-24-1170","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-1170","url":null,"abstract":"<p><strong>Purpose: </strong>Hypoxia mediates treatment resistance in solid tumors. We evaluated if oxygen-enhanced (OE)-MRI-derived hypoxic volume (HVMRI) is repeatable and can detect radiotherapy-induced hypoxia modification in HPV-associated oropharyngeal head and neck squamous cell cancer (HNSCC).</p><p><strong>Experimental design: </strong>27 patients were recruited prospectively between March 2021 and January 2024. HVMRI was measured in primary and nodal tumors prior to standard-of-care (chemo)radiotherapy then at weeks 2 and 4 (W2, W4) into therapy. Two pre-treatment scans assessed biomarker within-subject coefficient of variation (wCV) and repeatability coefficient (RC). Cohort treatment response was measured using mixed-effects modelling. Responding lesions were identified by comparing HVMRI change to RC limits of agreement (LOA).</p><p><strong>Results: </strong>OE-MRI identified hypoxia in all lesions. HVMRI wCV was 24.6% and RC LOA were -45.7% to 84.1%. Cohort median pre-treatment HVMRI of 11.3 cm3 reduced to 6.9 cm3 at W2 and 5.9 cm3 at W4 (both p < 0.001). HVMRI was reduced in 54.5% of individual lesions by W2 and in 88.2% by W4. All lesions with W2 hypoxia reduction showed persistent modification at W4. HVMRI reduced in some lesions that showed no overall volume change. Hypoxia modification was discordant between primary and nodal tumors in 50.0% of patients.</p><p><strong>Conclusions: </strong>Radiation-induced hypoxia modification can occur as early as W2, but onset varies between patients and was not necessarily associated with overall size change. Half of all patients had discordant changes in primary and nodal tumors. These findings have implications for patient selection and timing of dose de-escalation strategies in HPV-associated oropharyngeal carcinoma.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981852","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}