Clinical Cancer Research最新文献

{"title":"Clinical and Genomic Features of Classical and Basal Transcriptional Subtypes in Pancreatic Cancer.","authors":"Harshabad Singh, Joanne Xiu, Kevin S Kapner, Chen Yuan, Raja R Narayan, Matthew Oberley, Alex Farrell, Rishi Surana, Brandon M Huffman, Kimberly Perez, James M Cleary, Alexander C Jordan, Andressa Dias Costa, Hannah L Williams, Srivatsan Raghavan, Benjamin Weinberg, Michael J Pishvaian, Rachna T Shroff, Sanjay Goel, Stephanie K Dougan, Jonathan A Nowak, David Spetzler, George Sledge, Brian M Wolpin, Andrew J Aguirre","doi":"10.1158/1078-0432.CCR-24-1164","DOIUrl":"10.1158/1078-0432.CCR-24-1164","url":null,"abstract":"<p><strong>Purpose: </strong>Transcriptional profiling of pancreatic cancers has defined two main transcriptional subtypes: classical and basal. Initial data suggest shorter survival for patients with basal tumors and differing treatment sensitivity to FOLFIRINOX and gemcitabine plus nab-paclitaxel by transcriptional subtype.</p><p><strong>Experimental design: </strong>We examined 8,743 patients with RNA sequencing from pancreatic cancers performed at Caris Life Sciences. Classical and basal subtypes were identified using purity independent subtyping algorithm on RNA sequencing, and two cohorts were analyzed: (i) the biomarker cohort included patients with complete molecular profiling data (n = 7,250) and (ii) the outcome cohort included patients with metastatic disease with available survival outcomes (n = 5,335). A total of 3,842 patients were shared between the two cohorts. Kaplan-Meier curves and Cox proportional hazards regression were used to assess patient survival.</p><p><strong>Results: </strong>In the biomarker cohort, 3,063 tumors (42.2%) were strongly classical (SC) and 2,015 tumors (27.8%) were strongly basal (SB). SC and SB tumors showed strong associations with histologic phenotypes and biopsy sites. SB tumors had higher rates of KRAS, TP53, and ARID1A mutations, lower rates of SMAD4 mutation, and transcriptional evidence of epithelial-mesenchymal transition. Sixty of 77 cases (78%) maintained their transcriptional subtype between temporally and/or spatially disparate lesions. In the outcome cohort, the SB subtype was associated with shorter overall survival time, regardless of whether they received FOLFIRINOX or gemcitabine plus nab-paclitaxel as first-line chemotherapy. The mutant KRAS allele type was prognostic of outcomes; however, this impact was restricted to SC tumors, whereas all mutant KRAS alleles had similarly poor outcomes in SB tumors.</p><p><strong>Conclusions: </strong>The SB subtype is a strong independent predictor of worse outcomes, regardless of the up-front chemotherapy regimen used. Clinical trials should further investigate pancreatic cancer transcriptional subtypes as a prognostic and predictive biomarker.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"4932-4942"},"PeriodicalIF":10.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281265","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":"Understanding and Overcoming Resistance to Selective FGFR Inhibitors across FGFR2-Driven Malignancies.","authors":"Francesco Facchinetti, Yohann Loriot, Floriane Brayé, Damien Vasseur, Rastislav Bahleda, Ludovic Bigot, Rémy Barbé, Catline Nobre, David Combarel, Stefan Michiels, Antoine Italiano, Cristina Smolenschi, Lambros Tselikas, Jean-Yves Scoazec, Santiago Ponce-Aix, Benjamin Besse, Fabrice André, Ken A Olaussen, Antoine Hollebecque, Luc Friboulet","doi":"10.1158/1078-0432.CCR-24-1834","DOIUrl":"10.1158/1078-0432.CCR-24-1834","url":null,"abstract":"<p><strong>Purpose: </strong>Understanding resistance to selective FGFR inhibitors is crucial to improve the clinical outcomes of patients with FGFR2-driven malignancies.</p><p><strong>Experimental design: </strong>We analyzed sequential ctDNA, ± whole-exome sequencing, or targeted next-generation sequencing on tissue biopsies from patients with tumors harboring activating FGFR2 alterations progressing on pan-FGFR-selective inhibitors, collected in the prospective UNLOCK program. FGFR2::BICC1 Ba/F3 and patient-derived xenograft models were used for functional studies.</p><p><strong>Results: </strong>Thirty-six patients were included. In cholangiocarcinoma, at resistance to both reversible inhibitors (e.g., pemigatinib and erdafitinib) and the irreversible inhibitor futibatinib, polyclonal FGFR2 kinase domain mutations were frequent (14/27 patients). Tumors other than cholangiocarcinoma shared the same mutated FGFR2 residues, but polyclonality was rare (1/9 patients). At resistance to reversible inhibitors, 14 residues in the FGFR2 kinase domain were mutated-after futibatinib, only the molecular brake N550 and the gatekeeper V565. Off-target alterations in PI3K/mTOR and MAPK pathways were found in 11 patients, often together with on-target mutations. At progression to a first FGFR inhibitor, 12 patients received futibatinib or lirafugratinib (irreversible inhibitors), with variable clinical outcomes depending on previous resistance mechanisms. Two patients with TSC1 or PIK3CA mutations benefited from everolimus. In cell viability assays on Ba/F3 and in pharmacologic studies on patient-derived xenografts, irreversible inhibitors retained better activity against FGFR2 kinase domain mutations, with lirafugratinib active against the recalcitrant V565L/F/Y.</p><p><strong>Conclusions: </strong>At progression to FGFR inhibitors, FGFR2-driven malignancies are characterized by high intra- and interpatient molecular heterogeneity, particularly in cholangiocarcinoma. Resistance to FGFR inhibitors can be overcome by sequential, molecularly oriented treatment strategies across FGFR2-driven tumors.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"4943-4956"},"PeriodicalIF":10.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7616615/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125006","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":"A Phase 1 First-in-Human Study of the MCL-1 Inhibitor AZD5991 in Patients with Relapsed/Refractory Hematologic Malignancies.","authors":"Pinkal Desai, Sagar Lonial, Amanda Cashen, Manali Kamdar, Ian Flinn, Susan O'Brien, Jacqueline S Garcia, Neha Korde, Javid Moslehi, Margaret Wey, Patricia Cheung, Shringi Sharma, Damilola Olabode, Hong Chen, Firasath Ali Syed, Mary Liu, Jamal Saeh, Marcio Andrade-Campos, Tapan M Kadia, James S Blachly","doi":"10.1158/1078-0432.CCR-24-0028","DOIUrl":"10.1158/1078-0432.CCR-24-0028","url":null,"abstract":"<p><strong>Purpose: </strong>AZD5991, a human MCL-1 inhibitor, was assessed for safety, tolerability, pharmacokinetics, and antitumor activity as monotherapy and in combination with venetoclax in patients with relapsed or refractory hematologic malignancies.</p><p><strong>Patients and methods: </strong>In the monotherapy cohort (n = 61), patients with hematologic malignancies received AZD5991 intravenously in escalating doses either once or twice weekly, following intrapatient dose escalation, during a 3-week cycle. In the combination cohort (n = 17), patients with acute myeloid leukemia and myelodysplastic syndrome received escalating doses of AZD5991 and venetoclax during either a 3- or 4-week cycle. Primary objectives were safety and maximum tolerated dose; secondary objectives included plasma pharmacokinetics and antitumor activity.</p><p><strong>Results: </strong>The most common (≥30%) adverse events were diarrhea (59.0%), nausea (55.1%), and vomiting (47.4%). Four deaths occurred because of adverse events: cardiac arrest, sepsis, tumor lysis syndrome, and acute respiratory failure; only tumor lysis syndrome was related to AZD5991. Dose-limiting toxicities occurred in five patients. Three patients with myelodysplastic syndrome achieved an objective response: one marrow complete remission without hematologic improvement, one partial remission with AZD5991 monotherapy, and one marrow complete remission with AZD5991 + venetoclax. Asymptomatic elevations of troponin I or T were observed in eight (10.3%) patients. Post hoc retrospective analysis revealed elevated troponin T in 14/31 patients before any AZD5991 dose and in 54/65 patients after any AZD5991 dose at or after Cycle 1. No associations were found between elevated troponin and cardiovascular risk factors.</p><p><strong>Conclusions: </strong>Treatment with AZD5991 was associated with high incidence of laboratory troponin elevation and a low overall response rate.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"4844-4855"},"PeriodicalIF":10.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528199/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016551","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":"The Infiltrative Margins in Glioblastoma: Important Is What Has Been Left behind.","authors":"Philipp Karschnia, Joerg-Christian Tonn, Daniel P Cahill","doi":"10.1158/1078-0432.CCR-24-1819","DOIUrl":"10.1158/1078-0432.CCR-24-1819","url":null,"abstract":"<p><p>Supramaximal resection beyond the contrast-enhancing tumor borders represents an emerging surgical strategy for patients with newly diagnosed glioblastoma. A recent study provides evidence detailing the interactive effects of more aggressive surgery on other clinical predictors of outcome, supporting guidance for surgical decision-making and informing clinical trialists about the need to stratify for extent of resection. See related article by Park et al., p. 4866.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"4811-4812"},"PeriodicalIF":10.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003746","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":"Translational Imaging in Cerebral Tumors.","authors":"Alexey Surov, Jan Borggrefe","doi":"10.1158/1078-0432.CCR-24-2013","DOIUrl":"10.1158/1078-0432.CCR-24-2013","url":null,"abstract":"<p><p>Despite emerging possibilities of molecular histopathologic characterization, multiparametric MRI plays a key role in the diagnosis and classification of cerebral tumors. Imaging may also provide additional information about relevant histopathologic features of these tumors. See related article by Gao et al., p. 4876.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"4813-4814"},"PeriodicalIF":10.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035363","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":"Targeted Therapies, Novel Antibodies, and Immunotherapies in Advanced Non-Small Cell Lung Cancer: Clinical Evidence and Drug Approval Patterns.","authors":"Marén U Koban, Markus Hartmann, Georgios Amexis, Pedro Franco, Laura Huggins, Imran Shah, Niki Karachaliou","doi":"10.1158/1078-0432.CCR-24-0741","DOIUrl":"10.1158/1078-0432.CCR-24-0741","url":null,"abstract":"<p><p>Since 2011, the US FDA has approved 30 new drugs for use in advanced non-small cell lung cancer (NSCLC), mainly comprising tyrosine kinase inhibitors and immune checkpoint inhibitors. NSCLC with oncogene driver alterations is amenable to treatment with targeted drugs, usually small-molecule inhibitors. In these cases, the demonstration of high overall response rates, coupled with a lasting duration of response, has allowed for accelerated approval in the United States, based on single-cohort or multicohort trials. Confirmatory clinical evidence was subsequently provided through postmarketing trials. In NSCLC without such driver alterations, regulatory agencies in both the United States and the European Union set clinical evidence expectations that foster the conduct of studies primarily focused on determining survival or event-free survival, based on randomized controlled trial designs. This review analyzes the approval patterns of novel therapeutics for NSCLC with a focus on small-molecule inhibitors that target driver alterations, as well as biologics. The latter include mAbs inhibiting immune checkpoints like PD-(L)1 or cell surface receptors and antibody-drug conjugates, highly potent biologics linked to a cytotoxic compound. The differentiation of NSCLC into oncogene- and non-oncogene-addicted subtypes determines drug development strategies, the extent of the clinical development program, access to orphan drug development incentives, and regulatory approval strategies.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"4822-4833"},"PeriodicalIF":10.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035362","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":"Association of Tumor Mutational Burden and PD-L1 with the Efficacy of Pembrolizumab with or without Chemotherapy versus Chemotherapy in Advanced Urothelial Carcinoma.","authors":"Aude Fléchon, Rafael Morales-Barrera, Thomas Powles, Ajjai Alva, Mustafa Özgüroğlu, Tibor Csöszi, Yohann Loriot, Alejo Rodriguez-Vida, Lajos Géczi, Susanna Y Cheng, Yves Fradet, Stéphane Oudard, Christof Vulsteke, Seyda Gunduz, Ronac Mamtani, Evan Y Yu, Alvaro Montesa Pino, Urbano Anido, Mehmet A N Sendur, Gwenaelle Gravis, János Révész, Vladimir Kostorov, Olivier Huillard, Junshui Ma, Mohini Rajasagi, Amir Vajdi, Jared Lunceford, Razvan Cristescu, Kentaro Imai, Blanca Homet Moreno, Nobuaki Matsubara","doi":"10.1158/1078-0432.CCR-23-3518","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-23-3518","url":null,"abstract":"<p><strong>Purpose: </strong>The three-arm, phase III KEYNOTE-361 study did not meet its dual primary endpoints of progression-free survival (PFS) or overall survival (OS) with first-line pembrolizumab plus chemotherapy versus chemotherapy in advanced urothelial carcinoma. This prespecified exploratory analysis assessed the association of tumor mutational burden (TMB) and PD-L1 combined positive score (CPS) with clinical outcomes.</p><p><strong>Patients and methods: </strong>TMB and PD-L1 CPS were determined via whole-exome sequencing and PD-L1 IHC 22C3 pharmDx, respectively. The association was evaluated in each treatment arm using logistic regression [objective response rate (ORR)] and Cox proportional hazards regression models (PFS and OS); one-sided (pembrolizumab monotherapy; pembrolizumab plus chemotherapy) and two-sided (chemotherapy) nominal P values were calculated. Significance was prespecified at α = 0.05 without multiplicity adjustment. Efficacy was evaluated by prespecified cutoffs of 175 mutations/exome (TMB) and CPS 10 (PD-L1).</p><p><strong>Results: </strong>Of the 993 treated patients, 820 (82.6%) and 993 (100%) had evaluable TMB and CPS data, respectively. Continuous TMB was positively associated with ORR, PFS, and OS for pembrolizumab monotherapy (one-sided P < 0.001, P < 0.001, and P = 0.007, respectively); PFS and OS for pembrolizumab plus chemotherapy (one-sided P = 0.007 and P = 0.010, respectively); and OS for chemotherapy alone (two-sided P = 0.040). Continuous PD-L1 CPS showed evidence of anticipated association with ORR and PFS for pembrolizumab monotherapy. The subgroup with TMB ≥175 mutations/exome and PD-L1 CPS ≥10 had the highest PFS and OS improvements with pembrolizumab alone or with chemotherapy versus chemotherapy alone.</p><p><strong>Conclusions: </strong>These data suggest that TMB may be predictive of the response to pembrolizumab alone or with chemotherapy in advanced urothelial carcinoma.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"OF1-OF12"},"PeriodicalIF":10.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544088","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: Olutasidenib for Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia with an Isocitrate Dehydrogenase-1 Mutation.","authors":"Ashley C Woods, Kelly J Norsworthy, Moran Choe, Brenda J Gehrke, Haiyan Chen, Jonathon Vallejo, Lili Pan, Xiling Jiang, Hongshan Li, Jeffrey Kraft, Jiang Liu, Rosane Charlab, Olanrewaju O Okusanya, Brian Booth, Richard Pazdur, Marc R Theoret, R Angelo de Claro","doi":"10.1158/1078-0432.CCR-24-2196","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2196","url":null,"abstract":"<p><p>On December 1st, 2022, the FDA approved the new molecular entity olutasidenib (Rezlidhia: Rigel Pharmaceuticals), a small-molecule inhibitor of isocitrate dehydrogenase-1 (IDH1), for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (R/R AML) with a susceptible IDH1 mutation as detected by an FDA-approved test. The efficacy of olutasidenib was established based on complete remission (CR) + CR with partial hematological recovery (CRh) rate, duration of CR + CRh, and conversion of transfusion dependence (TD) to transfusion independence (TI) in Study 2102-HEM-101. In the pivotal trial, 147 adult patients treated with 150mg twice daily (BID) of olutasidenib were evaluable for efficacy. With a median follow-up of 10.2 months, the CR/CRh rate was 35% (95% CI: 27-43%), with a median duration of response of 25.9 months (95% CI: 13.5 months, not reached [NR]). Of the 86 patients that were TD at baseline, 29 became TI (34%). The most common (≥20%) adverse reactions were nausea, fatigue, arthralgia, leukocytosis, dyspnea, pyrexia, rash, mucositis, diarrhea, and transaminitis. An assessment of long-term safety of olutasidenib is a condition of this approval.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544089","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":"Phase I/II Investigator-Initiated Study of Olaparib and Temozolomide in SCLC: Final Analysis and CNS Outcomes.","authors":"Catherine B Meador, Subba R Digumarthy, Beow Y Yeap, Yin P Hung, Mari Mino-Kenudson, Anna F Farago, Rebecca S Heist, J Paul Marcoux, Deepa Rangachari, David A Barbie, Zofia Piotrowska","doi":"10.1158/1078-0432.CCR-24-2350","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2350","url":null,"abstract":"<p><strong>Purpose: </strong>Temozolomide plus PARP inhibition has shown promise in small cell lung cancer (SCLC). We previously reported outcomes from the first 50 patients (cohort 1) of a phase I/II trial of olaparib/temozolomide in recurrent SCLC. Here, we report a final analysis of this trial, including a second cohort with an alternate dosing strategy and an exploratory analysis of CNS-specific outcomes.</p><p><strong>Methods: </strong>This was an open-label phase I/II trial testing the combination of olaparib and temozolomide in relapsed SCLC. The primary endpoint was ORR. Secondary endpoints were safety, PFS, and OS. We tested escalating doses of olaparib/temozolomide across two cohorts, both of which had temozolomide dosed on D1-7 of each 21-days cycle. In previously published cohort 1, olaparib was dosed on D1-7; in cohort 2 olaparib was dosed continuously.</p><p><strong>Results: </strong>Sixty-six patients were enrolled across the two cohorts, 50 in cohort 1 and 16 in cohort 2. The confirmed ORR of cohort 1 was 41.7% (20/48 evaluable), and the confirmed ORR of cohort 2 was 7% (1/14 evaluable; closed after dose escalation to enrollment for lack of observed efficacy). Among 15/66 patients (22.7%) with untreated brain metastases at enrollment, best overall intracranial response was CR in 6/15 patients, PR in 4/15 patients, and SD in 3/15 patients for a CNS disease control rate of 87% (95% CI: 59.5-98.3%).</p><p><strong>Conclusions: </strong>Olaparib/temozolomide may be effective in relapsed SCLC, especially for patients with CNS disease. Ongoing analyses regarding optimal dosing schedule will inform potential for future use of this combination in SCLC.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521167","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":"Integrating molecular imaging and transcriptomic profiling in advanced HER2-positive breast cancer receiving trastuzumab emtansine (T-DM1): an analysis of the ZEPHIR clinical trial.","authors":"Mattia Rediti, Danai Fimereli, Magdalena Mileva, Zéna Wimana, David Venet, Patrick Flamen, Thomas Guiot, Elisabeth G E de Vries, Carolina P Schröder, C Willemien Menke-van der Houven van Oordt, Marion Maetens, Samira Majjaj, Denis Larsimont, Françoise Rothé, Christos Sotiriou, Géraldine Gebhart","doi":"10.1158/1078-0432.CCR-24-1007","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-1007","url":null,"abstract":"<p><strong>Purpose: </strong>The ZEPHIR clinical trial evaluated the role of [89Zr]trastuzumab-PET/CT (HER2-PET/CT) and 2-[18F]fluoro-2-deoxy-D-glucose PET/CT ([18F]FDG-PET/CT) in predicting outcomes in patients with advanced HER2-positive breast cancer treated with trastuzumab emtansine (T-DM1). Here, we combined molecular/metabolic imaging and transcriptomic data to investigate the biological processes associated with [89Zr]trastuzumab and [18F]FDG uptake, and to dissect the mechanisms involved in T-DM1 resistance.</p><p><strong>Experimental design: </strong>RNA was extracted from metastasis biopsies obtained in the ZEPHIR trial. HER2-PET/CT and [18F]FDG-PET/CT imaging data of biopsied lesions were integrated with transcriptomic data. Lesions were compared based on the level of [89Zr]trastuzumab uptake as well as on the presence/absence of metabolic response, defined comparing baseline and on-treatment [18F]FDG-PET/CT.</p><p><strong>Results: </strong>We analyzed matched transcriptomic and molecular/metabolic imaging data for 24 metastases. Genes and pathways involved in extracellular matrix (ECM) organization and glycosylphosphatidylinositol synthesis were enriched in lesions presenting low [89Zr]trastuzumab uptake. [18F]FDG uptake at baseline correlated with proliferation and immune-related processes. Hypoxia and ECM-related processes were enriched in lesions showing no metabolic response to T-DM1, while immune-related processes were associated with high [89Zr]trastuzumab uptake and metabolic response. Gene signatures including differentially expressed genes according to [89Zr]trastuzumab uptake and metabolic response showed predictive value in an external cohort.</p><p><strong>Conclusions: </strong>To our knowledge, this study represents the first correlative analysis between [89Zr]trastuzumab tumor uptake and gene expression profiling in humans. Our findings suggest a role of ECM in impairing [89Zr]trastuzumab tumor uptake and T-DM1 metabolic response in advanced HER2-positive breast cancer, highlighting the potential of molecular imaging to depict tumor microenvironment features.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521166","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}