Clinical Cancer Research最新文献

{"title":"Unravelling relatlimab-specific biology using biomarker analyses in patients with advanced melanoma in RELATIVITY-047","authors":"Evan J. Lipson, Sonia Dolfi, Hao Tang, Hussein A. Tawbi, Francisco Medina-Soto, Erika Castillo Gutiérrez, Piotr Rutkowski, Helen Gogas, Emilio Murillo, Paolo A. Ascierto, Keyur Desai, Michele Maio, Korey Demers, Antonella Mazzei, Sarah Keidel, Karen Miller-Moslin, Jia Xin Yu, F. Stephen Hodi, Dirk Schadendorf, Georgina V. Long, Charlie Garnett-Benson","doi":"10.1158/1078-0432.ccr-24-2499","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2499","url":null,"abstract":"Purpose: Administration of the lymphocyte-activation gene-3 (LAG-3) inhibitor relatlimab (RELA) and programmed death-1 (PD-1) inhibitor nivolumab (NIVO) significantly prolonged progression-free survival (PFS) versus NIVO alone in patients with advanced melanoma treated in RELATIVITY-047. This report describes correlative analyses of biospecimens collected within that trial to better understand mechanisms of action and identify patients who could benefit from treatment with NIVO + RELA. Patients and Methods: Pre- and on-treatment peripheral blood samples from 563 patients were analyzed by flow cytometry for changes in 77 pre-specified immune cell populations, and by immunoassay for peripheral interferon gamma (IFNγ). Pre-treatment tumor biopsies were evaluated using immunohistochemistry and RNA sequencing. Results: On-treatment expansion of 25 peripheral immune cell populations was significantly greater with NIVO + RELA versus NIVO alone. Responders to NIVO + RELA had greater on-treatment increases in LAG-3+CD4+ T cells than non‑responders. Significantly greater increases in peripheral IFNγ occurred after treatment with NIVO + RELA versus NIVO alone. A longer PFS was observed in patients treated with NIVO + RELA whose tumors had low CD8 expression compared with the NIVO arm. When evaluating co-expression of CD8 and LAG-3, patients whose tumors had high CD8+LAG-3+ also showed a PFS benefit with NIVO + RELA versus NIVO. RNA sequencing revealed several distinct gene signatures associated with response to NIVO + RELA. Conclusions: These results highlight the unique biological effects of RELA in combination with NIVO and provide further understanding of the patient characteristics associated with increased benefit from NIVO + RELA.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"69 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547622","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":"Characterization of Plasma Cell-Free DNA Variants as of Tumor or Clonal Hematopoiesis Origin in 16,812 Advanced Cancer Patients.","authors":"Daniel Magee, Valeriy Domenyuk, Jim Abraham, Nieves Perdigones Borderias, Jeff Swensen, Praveena Solipuram, Adanma Ayanambakkam, Raja Mehdi, Jagathi Challagalla, Elisabeth Heath, Megan Landsverk, Magdalena Jurkiewicz, Brian Shimkus, Ian Pinto, Daniel Patterson, David Hsiehchen, Supriya Koya, Bradley Somer, Michel Velez, Anthony F Shields, Jennifer Cultrera, Jennifer R Ribeiro, Robert Hahn-Lowry, George W Sledge, Matthew Oberley, Milan Radovich, David Spetzler","doi":"10.1158/1078-0432.CCR-24-3335","DOIUrl":"10.1158/1078-0432.CCR-24-3335","url":null,"abstract":"<p><strong>Purpose: </strong>Plasma-based liquid biopsy tests can detect tumor-specific genetic alterations and offer many advantages that complement tissue-based comprehensive genomic profiling. However, age-related clonal hematopoiesis (CH) mutations can confound liquid biopsy results and potentially lead to incorrect therapy choice.</p><p><strong>Experimental design: </strong>We assessed the landscape of 16,812 liquid profiles across 49 cancer types using the Caris Assure assay, a whole-exome and whole-transcriptome next-generation sequencing workflow that independently sequences both plasma-derived cell-free total nucleic acids and the white blood cell DNA and RNA from the buffy coat. The variant source was identified algorithmically by comparing plasma and buffy coat variant frequency and read quality metrics.</p><p><strong>Results: </strong>Of 16,812 patients, 42.3% presented at least one CH variant among reportable clinical genes. We found 39% of BRCA2 variants to be of CH origin, as well as 37.9% of CHEK2, 27.4% of BRCA1, 20.1% of ATM, 7.3% of NRAS, 5.8% of BRAF, 2.1% of EGFR, 2.1% of KRAS, and 18.5% of TP53. For patients aged 65 to 69 years, the median proportion of CH variant classification was 20%, whereas it was 33% for patients aged 70 to 74 years, 33% for ages 75 to 79 years, and 50% for ages 80+ years. We found high rates of CH detected in what would be otherwise druggable targets in many cancer types typically treated with PARP inhibitors, including breast, female genital tract, ovarian, pancreatic, prostate, and endometrial cancers.</p><p><strong>Conclusions: </strong>This large study highlights the need for thorough CH classification during liquid biopsy to appropriately recommend therapies, especially PARP inhibitors. See related commentary by Bernard and Micol, p. 2545.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"2710-2718"},"PeriodicalIF":10.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390445","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":"p-AKT Protein Expression Predicts Response to AKT Inhibitor Combined with Docetaxel Therapy in Adenocarcinoma and Neuroendocrine Prostate Cancer.","authors":"Hipacia Werneck Gomes, Natalie L Lister, Shivakumar Keerthikumar, Birunthi Niranjan, Michelle G Richards, Andrew Ryan, Edmond M Kwan, Gail P Risbridger, Renea A Taylor","doi":"10.1158/1078-0432.CCR-24-3848","DOIUrl":"10.1158/1078-0432.CCR-24-3848","url":null,"abstract":"<p><strong>Purpose: </strong>AKT inhibitors, such as capivasertib, have shown activity in specific patients with metastatic castration-resistant prostate cancer when combined with docetaxel although none have been approved. Although PTEN loss is often linked to AKT pathway activation and response to AKT inhibitors, clinical trials show no consistent association. This study uses patient-derived tumor models to identify biomarkers associated with an effective response to AKT inhibitor plus docetaxel.</p><p><strong>Experimental design: </strong>Targeted DNA sequencing and immunostaining for PTEN and phosphorylated AKT (p-AKT; Ser473) were assessed in 39 patient-derived xenografts (PDX) from patients with prostate cancer, including adenocarcinoma and neuroendocrine (NE) phenotypes. Matching PDX-derived organoids were used to evaluate the functional effects of capivasertib and docetaxel on in vitro tumor growth.</p><p><strong>Results: </strong>p-AKT protein expression varied widely across PDX models and showed no correlation with PTEN/PI3K/AKT mutations or PTEN protein levels. NE tumors displayed higher p-AKT expression than adenocarcinomas. Knockdown of AKT1 in NE organoids increased sensitivity to docetaxel, whereas AKT1 overexpression decreased it. In three of seven organoids tested, the combination of capivasertib and docetaxel produced a synergistic effect, resulting in greater growth inhibition than either agent alone. These responsive organoids exhibited an NE phenotype and high p-AKT expression, consistent with a predictive response.</p><p><strong>Conclusions: </strong>Our preclinical findings indicate that p-AKT protein expression, rather than PTEN, may be a more reliable predictor of response to AKT inhibition combined with docetaxel. Using p-AKT as a parameter, we uncovered the efficacy of this combination in NE prostate cancer, highlighting the potential to refine patient selection criteria for future clinical trials.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"2727-2740"},"PeriodicalIF":10.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143986153","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":"Multimetric MRI Captures Early Response and Acquired Resistance of Pancreatic Cancer to KRAS Inhibitor Therapy.","authors":"Mamta Gupta, Hoon Choi, Samantha B Kemp, Emma E Furth, Stephen Pickup, Cynthia Clendenin, Margo Orlen, Mark Rosen, Fang Liu, Quy Cao, Ben Z Stanger, Rong Zhou","doi":"10.1158/1078-0432.CCR-24-4049","DOIUrl":"10.1158/1078-0432.CCR-24-4049","url":null,"abstract":"<p><strong>Purpose: </strong>In pancreatic ductal adenocarcinoma (PDAC), Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations drive both cancer cell growth and formation of a dense stroma. Small-molecule KRAS inhibitors (KRASi) represent a promising new class of therapy for PDAC; hence, clinical tools that can assess early response, detect resistance, and/or predict prolonged survival are desirable to understand clinical biology of KRASi. We hypothesized that diffusion-weighted MRI can detect cell death, whereas dynamic contrast-enhanced MRI and magnetization transfer ratio imaging are sensitive to tumor microenvironment changes, and these metrics shed insights into tumor size change induced by KRASi treatment.</p><p><strong>Experimental design: </strong>Multiple preclinical PDAC models, including a genetically engineered mouse model (KPC), received MRTX1133, a KRASi specific for KRASG12D mutation. Quantitative imaging markers were corroborated with IHC analyses.</p><p><strong>Results: </strong>A significant increase in tumor apparent diffusion coefficient (a diffusion-weighted MRI metric) was detected as early as 48 hours and persisted to day 7 after the initiation of KRASi treatment and was strongly correlated with cell death and reduced cellularity, resulting in greatly prolonged median survival in treated mice. Capillary perfusion/permeability (a dynamic contrast-enhanced MRI metric) exhibited an inverse relationship with microvascular density. Distinct responses of KRASG12C versus KRASG12D tumors to MRTX1133 were captured by the MRI metrics corroborated with IHC. When tumors developed resistance to MRTX1133, the imaging marker values exhibited a reversal from those of responding tumors.</p><p><strong>Conclusions: </strong>Multiparametric MRI provides early biological insights of cancer and stromal responses to KRASi treatment and sets the stage for testing the utility of these clinically ready MRI methods in patients receiving KRASi therapy.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"2663-2674"},"PeriodicalIF":10.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143985824","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: Ivosidenib for Treatment of Adult Patients with Relapsed/Refractory Myelodysplastic Syndrome with an IDH1 Mutation","authors":"Ashley C. Woods, E. Dianne Pulte, Xin Wang, Jonathon Vallejo, Ritu Chadda, Nan Zheng, Javier G. Blanco, Sarah E. Dorff, Hongshan Li, Jiang Liu, Olanrewaju O. Okusanya, Richard Pazdur, Marc R. Theoret, R. Angelo de Claro, Kelly J. Norsworthy","doi":"10.1158/1078-0432.ccr-25-1005","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1005","url":null,"abstract":"On October 24th, 2023, the FDA approved a supplemental application for ivosidenib (Tibsovo; Servier) for the treatment of adult patients with relapsed/refractory (R/R) IDH1-mutated myelodysplastic syndrome (MDS). The efficacy of ivosidenib in patients with R/R MDS was established in study AG120-C-001, an open-label, single-arm trial, based on complete remission (CR) + partial remission (PR) rate, duration of CR + PR, and conversion of transfusion dependence (TD) to transfusion independence (TI). With a median follow-up of 27.1 months in 18 patients with IDH1-mutated R/R MDS treated with ivosidenib 500mg once daily, the CR + PR rate was 39% (95% CI: 17.3-64.3) (all CR responses), with a median duration of response not estimable (range 1.9, 80.8+ months). Of the 9 patients that were TD at baseline, 6 achieved TI (67%). Serious adverse reactions in ≥5% included differentiation syndrome, fatigue, and rash. The most common (≥20%) adverse reactions were arthralgia, fatigue, cough, diarrhea, decreased appetite, mucositis, myalgia, and pruritis.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"18 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533084","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":"Pre-clinical Modeling of Navtemadlin Pharmacokinetics, Pharmacodynamics, and Efficacy in IDH-wildtype Glioblastoma","authors":"Rachael A. Vaubel, Wenjuan Zhang, Ju-Hee Oh, Ann C. Mladek, Tugce I. Pasa, Jennifer K. Gantchev, Katie L. Waller, Gerard Baquer, Sylwia A. Stopka, Michael S. Regan, Md Amin Hossain, Paul A. Decker, Matthew L. Kosel, Shiv K. Gupta, Sonia Jain, Paige P. Sarkaria, Zeng Hu, Lauren L. Ott, Brett L. Carlson, Katrina K. Bakken, Surabhi Talele, Wenqiu Zhang, Keith L. Ligon, Eudocia Q. Lee, Jeanette E. Eckel Passow, Danielle M. Burgenske, Nathalie Y.R. Agar, William F. Elmquist, Jann N. Sarkaria","doi":"10.1158/1078-0432.ccr-25-0244","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0244","url":null,"abstract":"Background: Navtemadlin is a potent small molecule inhibitor of MDM2, which has completed a Phase 0 window of opportunity study in glioblastoma (GBM). To optimally interpret the clinical data, a detailed analysis of navtemadlin pharmacokinetics (PK), pharmacodynamics, and efficacy was performed in GBM patient derived xenografts (PDXs). Methods: Response to navtemadlin was characterized in vitro and in vivo in GBM PDXs with and without MDM2 amplification. Efficacy in vivo was integrated with measured plasma and intra-tumoral drug levels to develop a translational PK/efficacy model comparing exposure effective in PDX to exposure achieved in phase 0 patient samples. Results: In vitro, navtemadlin showed robust on-target activity in TP53 wild-typeGBM. In vivo efficacy strongly correlated with MDM2 amplification status. In subcutaneous PDXs, navtemadlin significantly extended survival when dosed at 25 mg/kg in an MDM2-amplified PDX, compared to 100 mg/kg in a non-amplified PDX. CNS distribution was limited by blood-brain barrier efflux (Kp_brain=0.009). In an MDM2-amplified orthotopic PDX model, navtemadlin was ineffective at 100 mg/kg; when established in mice with deficient blood-brain barrier efflux (Rag-/-Abcb1a-/- Abcg2-/-), 25 mg/kg doubled survival. A tumor PK/efficacy model was built to define target exposure for efficacy in GBM, using the effective 25 mg/kg dose. Modeled exposures exceeded this threshold in 3 (of 16) tumor samples from phase 0 study patients at the 240 mg dose level. Conclusion: Navtemadlin efficacy was highly dependent on adequate brain penetration. Our translational PK/efficacy model suggests that the minimum effective tumor exposures were achieved only in a minority of GBM patients.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"2 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Tamoxifen Response at Single Cell Resolution in Estrogen Receptor-Positive Primary Human Breast Tumors.","authors":"Hyunsoo Kim, Austin A Whitman, Kamila Wisniewska, Rasha T Kakati, Susana Garcia-Recio, Benjamin C Calhoun, Hector L Franco, Lisa A Carey, Charles M Perou, Philip M Spanheimer","doi":"10.1158/1078-0432.CCR-25-1944","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-25-1944","url":null,"abstract":"","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"31 13","pages":"2839"},"PeriodicalIF":10.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526573","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":"Application of Neoadjuvant Docetaxel plus Cisplatin in Early-Stage Triple-Negative Breast Cancer (HELEN-001): Results from a Phase II Trial.","authors":"Dechuang Jiao, Jianghua Qiao, Xianfu Sun, Chengzheng Wang, Zhenduo Lu, Chongjian Zhang, Lianfang Li, Min Yan, Yueqing Feng, Yong Zhou, Miao Deng, Xinlan Liu, Mingde Ma, Haiquan Jia, Qingxin Xia, Geok Hoon Lim, Naohiro Ishii, Armando Orlandi, Fernando Hernanz, Xiuchun Chen, Zhenzhen Liu","doi":"10.1158/1078-0432.CCR-25-0289","DOIUrl":"10.1158/1078-0432.CCR-25-0289","url":null,"abstract":"<p><strong>Purpose: </strong>This study investigated the effects of taxane-cisplatin combinations on pathologic complete response (pCR) rates and survival outcomes in triple-negative breast cancer (TNBC).</p><p><strong>Patients and methods: </strong>The HELEN-001 trial enrolled patients ages 18 to 70 years with stage II-III TNBC, randomly assigning them to receive either docetaxel (75 mg/m2) plus cisplatin (75 mg/m2; TP) or docetaxel (75 mg/m2), doxorubicin (50 mg/m2), and cyclophosphamide (500 mg/m2; TAC). Treatments were administered every 3 weeks for six cycles, with the primary endpoint being pCR (ypT0/isN0) and secondary endpoints being event-free survival (EFS), overall response rate, breast-conserving surgery rate, and toxicity.</p><p><strong>Results: </strong>From November 2018 to June 2022, 212 Asian female patients were enrolled across six hospitals in China, with 106 patients in each group. The pCR rate was significantly higher for TP (51.9%) than for TAC (35.8%; P = 0.028). After a median follow-up of 40 months, EFS was 86.1% in the TP group and 80.0% in the TAC group (HR, 0.639; P = 0.196). In germline BRCA1/2 mutation carriers, EFS was significantly higher with TP than with TAC (100% vs. 53.8%; P = 0.008). Grade 3 or higher adverse events occurred in 54% of patients in the TP group and 48% in the TAC group.</p><p><strong>Conclusions: </strong>The TP regimen demonstrated significantly improved pCR rates with a manageable toxicity profile, suggesting the potential benefit of taxane plus platinum regimens in patients with TNBC.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"2589-2598"},"PeriodicalIF":10.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143980720","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":"Low Allele Frequency Variants Identified on Germline Multi-Gene Panel Testing for Cancer Predisposition Can Suggest the Presence of Constitutional Mosaicism.","authors":"Adela Rodriguez-Hernandez, Linda M Polfus, Brittany L Bychkovsky, Beth Souders, Aleix Prat, Barbara Adamo, Judy E Garber, Carolyn Horton, Huma Q Rana","doi":"10.1158/1078-0432.CCR-24-4105","DOIUrl":"10.1158/1078-0432.CCR-24-4105","url":null,"abstract":"<p><strong>Purpose: </strong>Enabled by advancements in next-generation sequencing for hereditary cancer conditions, low allele frequency variants (LAFV) are detected by testing laboratories. This study describes the frequency and clinical factors associated with LAFVs and reports results of follow-up testing when available.</p><p><strong>Experimental design: </strong>This retrospective study analyzed LAFV cases identified through multi-gene panel testing (MGPT) at a single high-volume germline genetic testing laboratory. LAFVs were defined as variant allele frequencies (VAF) between 10% and 30% as confirmed by Sanger sequencing. Comparative analyses were conducted between pathogenic variants with a VAF of 30% to 60% (inferred heterozygous) and LAFV cohorts. Clinical characteristics were analyzed using descriptive statistics and logistic regression models. Ancillary testing was performed on alternative specimens or family members to determine whether LAFVs were due to constitutional mosaicism.</p><p><strong>Results: </strong>Among 363,405 individuals undergoing MGPT, 965 (1.8%) had variants with a VAF between 10% and 30%. Sanger sequencing confirmed 463 (0.1%) as LAFVs. Among the confirmed LAFVs, 262 (57.6%) were classified as pathogenic variants. The LAFV cohort compared with the control heterozygous cohort was significantly older, with a higher proportion of individuals >50 years (84.1% vs. 54.9%; P < 0.001). LAFVs were present in the following genes: TP53 (110; 64.7%), NF1 (23; 13.5%), CHEK2 (13; 7.6%), ATM (12; 7.1%), and BRCA1 (4; 2.4%). Ancillary testing performed on 62 cases with LAFVs confirmed 17.7% (11/62) as constitutional mosaicism.</p><p><strong>Conclusions: </strong>LAFVs were infrequently detected in MGPT, representing 0.8% of the total variants and 0.1% of total tested. Ancillary testing is needed to understand the origins and clinical implications of LAFVs in patients and families.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"2814-2823"},"PeriodicalIF":10.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143976724","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":"Quantitative Protein Expression of Antibody-Drug Conjugate Targets in EGFR Mutated and Wild-type Non-Small Cell Lung Cancer.","authors":"Ioannis P Trontzas, Mengni He, Anna Wurtz, Charles J Robbins, Nathaniel Robinson, Katherine Bates, Matthew Liu, Thazin N Aung, Liam Scott, Nay Chan, Sneha Burela, Jacob Schillo, Daniel C Liebler, Salisha Hill, Ryan D Morrison, Ioannis Vathiotis, Konstantinos N Syrigos, Sarah B Goldberg, Katerina Politi, David L Rimm","doi":"10.1158/1078-0432.CCR-24-3347","DOIUrl":"10.1158/1078-0432.CCR-24-3347","url":null,"abstract":"<p><strong>Purpose: </strong>Antibody-drug conjugates (ADC) are a promising approach for the management of patients with non-small cell lung cancer (NSCLC). However, only a small subset of patients derive benefit from these therapies.</p><p><strong>Experimental design: </strong>We used quantitative immunofluorescence assays to measure the levels of four ADC target proteins (HER2, TROP2, HER3, and EGFR) in three NSCLC tissue microarray cohorts stratified according to EGFR mutation [EGFR mutated (n = 83), EGFR wild-type (n = 128), and EGFR unknown (n = 232)]. Assay limits were established by mass spectrometry on standard cell lines.</p><p><strong>Results: </strong>All four targets demonstrated a broad and comparable dynamic range of expression in all three cohorts. High proportions of cases were above the assay limits for all targets. A comparison of target expression showed a significant association of HER2 with EGFR expression and a nonsignificant association with EGFR mutation (P = 0.0005 and 0.14, respectively). TROP2 expression was not associated with EGFR expression or mutation. HER3 demonstrated a significant negative correlation with EGFR mutation but no significant association with EGFR expression (P < 0.0001 and 0.9869, respectively). EGFR expression was significantly associated with EGFR mutation (P = 0.047).</p><p><strong>Conclusions: </strong>ADC targets are highly expressed in NSCLC, implying that the benefit from these agents may be broad. Benefit from these therapies may go beyond mutation status, and fully quantitative approaches may help select patients for ADC targeting. Intertarget correlation may provide an insight on the underlying signaling pathways and/or treatment-related resistant mechanisms. In the future, quantitative immunofluorescence may be a valuable tool to select ADC treatment sequence. See related commentary by Hirsch, p. 2550.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"2767-2776"},"PeriodicalIF":10.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566198","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}