Clinical Cancer Research最新文献

{"title":"Nivolumab with or without Ipilimumab Combined with Stereotactic Body Radiotherapy in Patients with Metastatic Biliary Tract Cancer: A Randomized Phase 2 Study.","authors":"Alice Markussen, Julia S Johansen, Finn O Larsen, Susann Theile, Jane P Hasselby, Gro L Willemoe, Torben Lorentzen, Kasper Madsen, Estrid Høgdall, Tim S Poulsen, Eva E Wilken, Poul Geertsen, Claus P Behrens, Inge M Svane, Dorte Nielsen, Inna M Chen","doi":"10.1158/1078-0432.CCR-24-0286","DOIUrl":"10.1158/1078-0432.CCR-24-0286","url":null,"abstract":"<p><strong>Purpose: </strong>The purpose of this study was to evaluate the clinical benefits of nivolumab with/without ipilimumab combined with stereotactic body radiotherapy (SBRT) in patients with pretreated metastatic biliary tract cancer (mBTC).</p><p><strong>Patients and methods: </strong>The study was a phase 2 randomized trial with Simon's optimal two-stage design requiring 36 evaluable patients per group after second stage. Sixty-one patients were included from September 2018 to January 2022 and randomized (1:1) to receive SBRT (15 Gy × 1 on day 1 to a primary or metastatic lesion) and nivolumab (3 mg/kg intravenously on day 1 and every 2 weeks) with/without ipilimumab (1 mg/kg intravenously on day 1 and every 6 weeks). Primary endpoint was clinical benefit rate (CBR), defined as the percentage of patients with complete response, partial response, or stable disease. Decision to continue accrual into the second stage depended on the CBR from the first stage.</p><p><strong>Results: </strong>Forty-two patients received SBRT/nivolumab/ipilimumab with a CBR of 31.0% [95% confidence interval (CI), 17.6-47.1]. Five patients (11.9%) achieved partial response with median duration of 4.4 months (range, 1.1-21.5). Nineteen patients received SBRT/nivolumab. This group was closed after the initial stage based on a CBR of 10.5% (95% CI, 1.3-33.1). Adverse events were graded with National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Grade ≥3 treatment-related adverse events occurred in 13 (31%) and 3 (16%) patients in the SBRT/nivolumab/ipilimumab and SBRT/nivolumab groups, respectively. One patient died from immune-related hepatitis in the SBRT/nivolumab/ipilimumab group.</p><p><strong>Conclusions: </strong>Combining SBRT, nivolumab, and ipilimumab is well tolerated, feasible, and shows response in a subgroup of patients with mBTC.</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":"141316825","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":"Oral Estrogen Receptor PROTAC Vepdegestrant (ARV-471) Is Highly Efficacious as Monotherapy and in Combination with CDK4/6 or PI3K/mTOR Pathway Inhibitors in Preclinical ER+ Breast Cancer Models.","authors":"Sheryl M Gough, John J Flanagan, Jessica Teh, Monica Andreoli, Emma Rousseau, Melissa Pannone, Mark Bookbinder, Ryan Willard, Kim Davenport, Elizabeth Bortolon, Gregory Cadelina, Debbie Gordon, Jennifer Pizzano, Jennifer Macaluso, Leofal Soto, John Corradi, Katherine Digianantonio, Ieva Drulyte, Alicia Morgan, Connor Quinn, Miklós Békés, Caterina Ferraro, Xin Chen, Gan Wang, Hanqing Dong, Jing Wang, David R Langley, John Houston, Richard Gedrich, Ian C Taylor","doi":"10.1158/1078-0432.CCR-23-3465","DOIUrl":"10.1158/1078-0432.CCR-23-3465","url":null,"abstract":"<p><strong>Purpose: </strong>Estrogen receptor (ER) alpha signaling is a known driver of ER-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Combining endocrine therapy (ET) such as fulvestrant with CDK4/6, mTOR, or PI3K inhibitors has become a central strategy in the treatment of ER+ advanced breast cancer. However, suboptimal ER inhibition and resistance resulting from the ESR1 mutation dictates that new therapies are needed.</p><p><strong>Experimental design: </strong>A medicinal chemistry campaign identified vepdegestrant (ARV-471), a selective, orally bioavailable, and potent small molecule PROteolysis-TArgeting Chimera (PROTAC) degrader of ER. We used biochemical and intracellular target engagement assays to demonstrate the mechanism of action of vepdegestrant, and ESR1 wild-type (WT) and mutant ER+ preclinical breast cancer models to demonstrate ER degradation-mediated tumor growth inhibition (TGI).</p><p><strong>Results: </strong>Vepdegestrant induced ≥90% degradation of wild-type and mutant ER, inhibited ER-dependent breast cancer cell line proliferation in vitro, and achieved substantial TGI (87%-123%) in MCF7 orthotopic xenograft models, better than those of the ET agent fulvestrant (31%-80% TGI). In the hormone independent (HI) mutant ER Y537S patient-derived xenograft (PDX) breast cancer model ST941/HI, vepdegestrant achieved tumor regression and was similarly efficacious in the ST941/HI/PBR palbociclib-resistant model (102% TGI). Vepdegestrant-induced robust tumor regressions in combination with each of the CDK4/6 inhibitors palbociclib, abemaciclib, and ribociclib; the mTOR inhibitor everolimus; and the PI3K inhibitors alpelisib and inavolisib.</p><p><strong>Conclusions: </strong>Vepdegestrant achieved greater ER degradation in vivo compared with fulvestrant, which correlated with improved TGI, suggesting vepdegestrant could be a more effective backbone ET for patients with ER+/HER2- breast cancer.</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/PMC11325148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141179221","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":"Targeting GPC2 on Intraocular and CNS Metastatic Retinoblastomas with Local and Systemic Delivery of CAR T Cells.","authors":"Guillem Pascual-Pasto, Brendan McIntyre, Anna M Giudice, Fatemeh Alikarami, Amanda Morrissey, Stephanie Matlaga, Ted J Hofmann, Victor Burgueño, Kyra Harvey, Daniel Martinez, Amish C Shah, Jessica B Foster, Jennifer Pogoriler, Ralph C Eagle, Angel M Carcaboso, Carol L Shields, Ann-Marie Leahey, Kristopher R Bosse","doi":"10.1158/1078-0432.CCR-24-0221","DOIUrl":"10.1158/1078-0432.CCR-24-0221","url":null,"abstract":"<p><strong>Purpose: </strong>Retinoblastoma is the most common intraocular malignancy in children. Although new chemotherapeutic approaches have improved ocular salvage rates, novel therapies are required for patients with refractory intraocular and metastatic disease. Chimeric antigen receptor (CAR) T cells targeting glypican-2 (GPC2) are a potential new therapeutic strategy.</p><p><strong>Experimental design: </strong>GPC2 expression and its regulation by the E2F1 transcription factor were studied in retinoblastoma patient samples and cellular models. In vitro, we performed functional studies comparing GPC2 CAR T cells with different costimulatory domains (4-1BB and CD28). In vivo, the efficacy of local and systemic administration of GPC2 CAR T cells was evaluated in intraocular and leptomeningeal human retinoblastoma xenograft models.</p><p><strong>Results: </strong>Retinoblastoma tumors, but not healthy retinal tissues, expressed cell surface GPC2, and this tumor-specific expression was driven by E2F1. GPC2-directed CARs with 4-1BB costimulation (GPC2.BBz) were superior to CARs with CD28 stimulatory domains (GPC2.28z), efficiently inducing retinoblastoma cell cytotoxicity and enhancing T-cell proliferation and polyfunctionality. In vivo, GPC2.BBz CARs had enhanced persistence, which led to significant tumor regression compared with either control CD19 or GPC2.28z CARs. In intraocular models, GPC2.BBz CAR T cells efficiently trafficked to tumor-bearing eyes after intravitreal or systemic infusions, significantly prolonging ocular survival. In central nervous system (CNS) retinoblastoma models, intraventricular or systemically administered GPC2.BBz CAR T cells were activated in retinoblastoma-involved CNS tissues, resulting in robust tumor regression with substantially extended overall mouse survival.</p><p><strong>Conclusions: </strong>GPC2-directed CAR T cells are effective against intraocular and CNS metastatic retinoblastomas.</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/PMC11326963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141305579","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":"Correction: Ovarian Cancers Harbor Defects in Nonhomologous End Joining Resulting in Resistance to Rucaparib.","authors":"Aiste McCormick, Peter Donoghue, Michelle Dixon, Richard O'Sullivan, Rachel L O'Donnell, James Murray, Angelika Kaufmann, Nicola J Curtin, Richard J Edmondson","doi":"10.1158/1078-0432.CCR-24-2051","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2051","url":null,"abstract":"","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":"141981854","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":"Editor's Note: 4E-Binding Protein 1, a Cell Signaling Hallmark in Breast Cancer That Correlates with Pathologic Grade and Prognosis.","authors":"Federico Rojo, Laura Najera, José Lirola, José Jiménez, Marta Guzmán, M Dolors Sabadell, Jose Baselga, Santiago Ramon Y Cajal","doi":"10.1158/1078-0432.CCR-24-2176","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2176","url":null,"abstract":"","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":"141981855","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":"Urinary Metabolite Diagnostic and Prognostic Liquid Biopsy Biomarkers of Lung Cancer in Nonsmokers and Tobacco Smokers.","authors":"Bhavik Dalal, Takeshi Tada, Daxesh P Patel, Sharon R Pine, Mohammed Khan, Takahiro Oike, Yasuyuki Kanke, Amelia L Parker, Majda Haznadar, Leila Toulabi, Kristopher W Krausz, Ana I Robles, Elise D Bowman, Frank J Gonzalez, Curtis C Harris","doi":"10.1158/1078-0432.CCR-24-0637","DOIUrl":"10.1158/1078-0432.CCR-24-0637","url":null,"abstract":"<p><strong>Purpose: </strong>Nonsmokers account for 10% to 13% of all lung cancer cases in the United States. Etiology is attributed to multiple risk factors including exposure to secondhand smoking, asbestos, environmental pollution, and radon, but these exposures are not within the current eligibility criteria for early lung cancer screening by low-dose CT (LDCT).</p><p><strong>Experimental design: </strong>Urine samples were collected from two independent cohorts comprising 846 participants (exploratory cohort) and 505 participants (validation cohort). The cancer urinary biomarkers, creatine riboside (CR) and N-acetylneuraminic acid (NANA), were analyzed and quantified using liquid chromatography-mass spectrometry to determine if nonsmoker cases can be distinguished from sex and age-matched controls in comparison with tobacco smoker cases and controls, potentially leading to more precise eligibility criteria for LDCT screening.</p><p><strong>Results: </strong>Urinary levels of CR and NANA were significantly higher and comparable in nonsmokers and tobacco smoker cases than population controls in both cohorts. Receiver operating characteristic analysis for combined CR and NANA levels in nonsmokers of the exploratory cohort resulted in better predictive performance with the AUC of 0.94, whereas the validation cohort nonsmokers had an AUC of 0.80. Kaplan-Meier survival curves showed that high levels of CR and NANA were associated with increased cancer-specific death in nonsmokers as well as tobacco smoker cases in both cohorts.</p><p><strong>Conclusions: </strong>Measuring CR and NANA in urine liquid biopsies could identify nonsmokers at high risk for lung cancer as candidates for LDCT screening and warrant prospective studies of these biomarkers.</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/PMC11325153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141260838","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":"Clinical Updates and Surveillance Recommendations for DNA Replication Repair Deficiency Syndromes in Children and Young Adults.","authors":"Anirban Das, Suzanne P MacFarland, Julia Meade, Jordan R Hansford, Kami W Schneider, Roland P Kuiper, Marjolijn C J Jongmans, Harry Lesmana, Kris Ann P Schultz, Kim E Nichols, Carol Durno, Kristin Zelley, Christopher C Porter, Lisa J States, Shay Ben-Shachar, Sharon A Savage, Jennifer M Kalish, Michael F Walsh, Hamish S Scott, Sharon E Plon, Uri Tabori","doi":"10.1158/1078-0432.CCR-23-3994","DOIUrl":"10.1158/1078-0432.CCR-23-3994","url":null,"abstract":"<p><p>Replication repair deficiency (RRD) is a pan-cancer mechanism characterized by abnormalities in the DNA mismatch repair (MMR) system due to pathogenic variants in the PMS2, MSH6, MSH2, or MLH1 genes, and/or in the polymerase-proofreading genes POLE and POLD1. RRD predisposition syndromes (constitutional MMR deficiency, Lynch, and polymerase proofreading-associated polyposis) share overlapping phenotypic and biological characteristics. Moreover, cancers stemming from germline defects of one mechanism can acquire somatic defects in another, leading to complete RRD. Here we describe the recent advances in the diagnostics, surveillance, and clinical management for children with RRD syndromes. For patients with constitutional MMR deficiency, new data combining clinical insights and cancer genomics have revealed genotype-phenotype associations and helped in the development of novel functional assays, diagnostic guidelines, and surveillance recommendations. Recognition of non-gastrointestinal/genitourinary malignancies, particularly aggressive brain tumors, in select children with Lynch and polymerase proofreading-associated polyposis syndromes harboring an RRD biology have led to new management considerations. Additionally, universal hypermutation and microsatellite instability have allowed immunotherapy to be a paradigm shift in the treatment of RRD cancers independent of their germline etiology. These advances have also stimulated a need for expert recommendations about genetic counseling for these patients and their families. Future collaborative work will focus on newer technologies such as quantitative measurement of circulating tumor DNA and functional genomics to tailor surveillance and clinical care, improving immune surveillance; develop prevention strategies; and deliver these novel discoveries to resource-limited settings to maximize benefits for patients globally.</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":"141300173","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":"GD2 Target Antigen and CAR T Cells: Does It Take More Than Two to Tango?","authors":"Franco Locatelli, Concetta Quintarelli","doi":"10.1158/1078-0432.CCR-24-0486","DOIUrl":"10.1158/1078-0432.CCR-24-0486","url":null,"abstract":"<p><p>Over the past decade, chimeric antigen receptor T cells have emerged as a breakthrough cancer therapy in selected hematologic malignancies. Translating the success of this therapy to solid tumors is challenging. In this issue, we discuss strategies potentially useful to increase the chimeric antigen receptor T-cell efficacy in this clinical indication. See related article by Fischer-Riepe et al., p. 3564.</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":"141310209","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":"Tissue-Free Liquid Biopsies Combining Genomic and Methylation Signals for Minimal Residual Disease Detection in Patients with Early Colorectal Cancer from the UK TRACC Part B Study.","authors":"Susanna Slater, Annette Bryant, Maria Aresu, Ruwaida Begum, Hsiang-Chi Chen, Clare Peckitt, Retchel Lazaro-Alcausi, Paul Carter, Gayathri Anandappa, Shelize Khakoo, Lucinda Melcher, Vanessa Potter, Francisca M Marti, Joesph Huang, Graham Branagan, Nicol George, Muti Abulafi, Sarah Duff, Ashraf Raja, Ashish Gupta, Nicholas West, Leslie Bucheit, Thereasa Rich, Ian Chau, David Cunningham, Naureen Starling","doi":"10.1158/1078-0432.CCR-24-0226","DOIUrl":"10.1158/1078-0432.CCR-24-0226","url":null,"abstract":"<p><strong>Purpose: </strong>The absence of postoperative circulating tumor DNA (ctDNA) identifies patients with resected colorectal cancer (CRC) with low recurrence risk for adjuvant chemotherapy (ACT) de-escalation. Our study presents the largest resected CRC cohort to date with tissue-free minimal residual disease (MRD) detection.</p><p><strong>Experimental design: </strong>TRACC (tracking mutations in cell-free tumor DNA to predict relapse in early colorectal cancer) included patients with stage I to III resectable CRC. Prospective longitudinal plasma collection for ctDNA occurred pre- and postsurgery, post-ACT, every 3 months for year 1 and every 6 months in years 2 and 3 with imaging annually. The Guardant Reveal assay evaluated genomic and methylation signals. The primary endpoint was 2-year recurrence-free survival (RFS) by postoperative ctDNA detection (NCT04050345).</p><p><strong>Results: </strong>Between December 2016 and August 2022, 1,203 were patients enrolled. Plasma samples (n = 997) from 214 patients were analyzed. One hundred forty-three patients were evaluable for the primary endpoint; 92 (64.3%) colon, 51 (35.7%) rectal; two (1.4%) stage I, 64 (44.8%) stage II, and 77 (53.8%) stage III. Median follow-up was 30.3 months (95% CI, 29.5-31.3). Two-year RFS was 91.1% in patients with ctDNA not detected postoperatively and 50.4% in those with ctDNA detected [HR, 6.5 (2.96-14.5); P < 0.0001]. Landmark negative predictive value (NPV) was 91.2% (95% CI, 83.9-95.9). Longitudinal sensitivity and specificity were 62.1% (95% CI, 42.2-79.3) and 85.9% (95% CI, 78.9-91.3), respectively. The median lead time from ctDNA detection to radiological recurrence was 7.3 months (IQR, 3.3-12.5; n = 9).</p><p><strong>Conclusions: </strong>Tissue-free MRD detection with longitudinal sampling predicts recurrence in patients with stage I to III CRC without the need for tissue sequencing. The UK TRACC Part C study is currently investigating the potential for ACT de-escalation in patients with undetectable postoperative ctDNA, given the high NPV indicating a low likelihood of residual disease.</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/PMC11325146/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141305580","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 Novel Approach to Quantify Heterogeneity of Intrahepatic Cholangiocarcinoma: The Hidden-Genome Classifier.","authors":"Yi Song, Thomas Boerner, Esther Drill, Paul Shin, Sandeep Kumar, Carlie Sigel, Andrea Cercek, Nancy Kemeny, Ghassan Abou-Alfa, Christine Iacobuzio-Donahue, Darren Cowzer, Nikolaus Schultz, Henry Walch, Vinod Balachandran, Bas Groot Koerkamp, Peter Kingham, Kevin Soares, Alice Wei, Michael D'Angelica, Jeffrey Drebin, Rohit Chandwani, James J Harding, William Jarnagin","doi":"10.1158/1078-0432.CCR-24-0657","DOIUrl":"10.1158/1078-0432.CCR-24-0657","url":null,"abstract":"<p><strong>Purpose: </strong>Intrahepatic cholangiocarcinoma (IHC) is a heterogeneous tumor. The hidden-genome classifier, a supervised machine learning-based algorithm, was used to quantify tumor heterogeneity and improve classification.</p><p><strong>Experimental design: </strong>A retrospective review of 1,370 patients with IHC, extrahepatic cholangiocarcinoma (EHC), gallbladder cancer (GBC), hepatocellular carcinoma (HCC), or biphenotypic tumors was conducted. A hidden-genome model classified 527 IHC based on genetic similarity to EHC/GBC or HCC. Genetic, histologic, and clinical data were correlated.</p><p><strong>Results: </strong>In this study, 410 IHC (78%) had >50% genetic homology with EHC/GBC; 122 (23%) had >90% homology (\"biliary class\"), characterized by alterations of KRAS, SMAD4, and CDKN2A loss; 117 IHC (22%) had >50% genetic homology with HCC; and 30 (5.7%) had >90% homology (\"HCC class\"), characterized by TERT alterations. Patients with biliary- versus non-biliary-class IHC had median overall survival (OS) of 1 year (95% CI, 0.77, 1.5) versus 1.8 years (95% CI, 1.6, 2.0) for unresectable disease and 2.4 years (95% CI, 2.1, NR) versus 5.1 years (95% CI, 4.8, 6.9) for resectable disease. Large-duct IHC (n = 28) was more common in the biliary class (n = 27); the HCC class was composed mostly of small-duct IHC (64%, P = 0.02). The hidden genomic classifier predicted OS independent of FGFR2 and IDH1 alterations. By contrast, the histology subtype did not predict OS.</p><p><strong>Conclusions: </strong>IHC genetics form a spectrum with worse OS for tumors genetically aligned with EHC/GBC. The classifier proved superior to histologic subtypes for predicting OS independent of FGFR2 and IDH1 alterations. These results may explain the differential treatment responses seen in IHC and may direct therapy by helping stratify patients in future clinical trials.</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/PMC11326964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141305577","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}