JCO precision oncology最新文献

{"title":"Erratum: Consistency and Heterogeneity of Microsatellite Instability (MSI) Status in Paired Biopsy and Surgical Specimens of Colorectal Cancer: A Necessity for MSI Reassessment After Treatment?","authors":"Yuan Tang, Wei Cui, Shanshan Shi, Linyong Sun, Linghua Yan, Baoye Wei, Fei Liu, Yanfeng Xi, Bin Xie, Zhihong Zhang","doi":"10.1200/PO-25-00651","DOIUrl":"https://doi.org/10.1200/PO-25-00651","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500651"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Implementation of <i>DPYD</i> and <i>UGT1A1</i> Testing in Patients With GI Cancer: A Prospective, Nonrandomized Clinical Trial.","authors":"Sony Tuteja, Mari Angelica S Cayabyab, Glenda Hoffecker, Lisa A Varughese, Jean de Dieu Ndayishimiye, Victoria A Wittner, Xingmei Wang, Rachel Hatch, Donna Capozzi, Margaret Harr, Avni Santani, Hakon Hakonarson, Deborah Watson, Peter Gabriel, Abigail Doucette, Ryan Massa, Nevena Damjanov, Nandi Reddy, Randall Oyer, Ursina R Teitelbaum","doi":"10.1200/PO-25-00086","DOIUrl":"10.1200/PO-25-00086","url":null,"abstract":"<p><strong>Purpose: </strong>To determine the feasibility and effectiveness of implementing pretreatment <i>DPYD/UGT1A1</i> testing in patients with gastrointestinal cancer and its impact compared with a biobank population.</p><p><strong>Materials and methods: </strong>A prospective, nonrandomized implementation trial of pretreatment <i>DPYD/UGT1A1</i> testing with preemptive dose reduction was conducted in patients initiating treatment with a fluoropyrimidine (FP, [fluorouracil or capecitabine]) or irinotecan. The primary end point was feasibility, defined as proportion of results available prior to cycle 1 of treatment. Secondarily, occurrence of severe treatment-related adverse events (TRAEs), defined as toxicity resulting in hospitalization or emergency department visit, was compared with a biobank population receiving standard dose chemotherapy.</p><p><strong>Results: </strong>Of the 288 patients prospectively tested, 225 (median age 60.7 years, 54% male, 18% Black, 47% colorectal cancer) received a qualifying chemotherapy. Eight of 11 DPYD variant carriers received an FP and eight of 39 UGT1A1 poor metabolizers received irinotecan. The median test turnaround time was 10 days (IQR, 9-13) with 57.4% of results available before cycle 1. Eleven of 16 (69%) participants with a drug-gene interaction (DGI) had results available before chemotherapy initiation and received pharmacogenetic-recommended dose reductions. Compared with the biobank cohort (n = 229), the prospective DGI group experienced fewer severe TRAEs (38% <i>v</i> 65%, <i>P</i> = .123), treatment discontinuations (31% <i>v</i> 47%, <i>P</i> = .356), and treatment modifications (38% <i>v</i> 76%, <i>P</i> = .028).</p><p><strong>Conclusion: </strong>Pretreatment <i>DPYD/UGT1A1</i> testing and dose reduction was feasible, enabling clinicians to make the appropriate chemotherapy dose reductions, reducing occurrence of adverse outcomes. <i>DPYD/UGT1A1</i> testing is an important precision oncology approach to optimize patient safety.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500086"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12352563/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pan-Cancer Landscape of B- and T-Lymphocyte Attenuator: Implications for Potential Immunotherapy Combinations.","authors":"Daisuke Nishizaki, Sharon Choi, Chinmayi Pandya, Suzanna Lee, Sarabjot Pabla, Paul DePietro, Taylor J Jensen, Razelle Kurzrock, Shumei Kato","doi":"10.1200/PO-25-00304","DOIUrl":"10.1200/PO-25-00304","url":null,"abstract":"<p><strong>Purpose: </strong>Cotargetable immune pathways for available immune checkpoint inhibitors (ICIs) may mediate response and mitigate resistance. Immune profiling may provide insights into potential immunotherapy combinations and guide ongoing clinical trials. This study investigated the transcriptomic expression and clinical implications of B- and T-lymphocyte attenuator (BTLA), a promising immune target.</p><p><strong>Methods: </strong>Altogether, 514 advanced/metastatic samples (pan-solid cancers) were analyzed using RNA sequencing. Transcriptomic expression was normalized to a reference population of 735 tumors and expressed as percentiles. BTLA, BTLA-related markers (herpes virus entry mediator [HVEM], CD160, LIGHT), and currently targetable immune pathway checkpoints (PD-1, PD-L1, PD-L2, cytotoxic T-cell lymphocyte-4 [CTLA-4], lymphocyte-activation gene 3) as well as clinical outcomes were evaluated.</p><p><strong>Results: </strong>High BTLA RNA expression (≥75th percentile) was observed in 19% of tumors (96 of 514). Approximately half of these patients (44 of 96) exhibited higher coexpression (RNA) of targetable checkpoints (cluster analysis). High BTLA expression was independently associated with elevated PD-1, CTLA-4, HVEM, and CD160 RNA levels and with a breast cancer diagnosis. Outcome analysis (Kaplan-Meier) indicated that high BTLA expression correlated with significantly longer survival among ICI recipients in univariable analysis, with a trend in multivariable Cox regression (adjusted hazard ratio, 0.43 [95% CI, 0.17 to 1.08], <i>P</i> = .07). Notably, expression patterns of BTLA, other immune checkpoints, and BTLA-interacting molecules (HVEM, CD160, LIGHT) varied from patient to patient.</p><p><strong>Conclusion: </strong>High BTLA transcript expression correlates with high transcript levels of PD-1 and CTLA-4 and with high levels of its ligand HVEM. These findings might support combining anti-PD-1 or anti-CTLA-4 therapy with anti-BTLA. BTLA expression varied across cancers and showed diverse coexpression patterns with other immune markers, suggesting that individual immunomic analysis is needed as part of a precision immunotherapy approach to understanding response and resistance.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500304"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12331147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Use of Protein Arginine Methyltransferase Inhibitors in Gliomas.","authors":"Emirhan Harbi, Christopher E Mason","doi":"10.1200/PO-25-00518","DOIUrl":"https://doi.org/10.1200/PO-25-00518","url":null,"abstract":"<p><p>Gliomas are a type of CNS tumors. Protein arginine methyltransferases (PRMTs) play important epigenetic regulatory roles in various cancers, including gliomas, by regulating DNA repair and cellular signaling pathways. Recent studies have also identified overexpression of PRMTs in gliomas and have shown that it is associated with tumor progression and resistance to conventional therapies. Targeting PRMTs has shown promising preclinical results demonstrating the potential to disrupt tumor growth, enhance DNA damage responses, and improve the sensitivity of gliomas to radiotherapy and temozolomide. In this review, we focus on the translational and clinical relevance of PRMT inhibitors in glioma subtypes, highlighting their latest clinical developments and ongoing clinical trials. Unlike previous reviews, our article provides an updated synthesis of clinical data, discusses challenges and opportunities in clinical translation, and suggests future directions for integrating PRMT inhibitors into glioma therapy.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500518"},"PeriodicalIF":5.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and Tolerability of Berzosertib, an Ataxia-Telangiectasia-Related Inhibitor, and Veliparib, an Oral Poly (ADP-ribose) Polymerase Inhibitor, in Combination With Cisplatin in Patients With Refractory Solid Tumors.","authors":"Geraldine O'Sullivan Coyne, Khanh T Do, Shivaani Kummar, Sarina Piha-Paul, Lawrence Rubinstein, Robert Kinders, Ralph E Parchment, Deborah Wilsker, Katherine Ferry-Galow, Brandon Miller, Naoko Takebe, Lamin Juwara, Mary Jane Ong, Ashley Bruns, Murielle Hogu, Abdul Rafeh Naqash, Arjun Mittra, Andrea Regier Voth, James H Doroshow, Alice P Chen","doi":"10.1200/PO-25-00055","DOIUrl":"10.1200/PO-25-00055","url":null,"abstract":"<p><strong>Purpose: </strong>We conducted a phase I trial of the combination of cisplatin with the ataxia-telangiectasia-related protein kinase inhibitor berzosertib and the poly (ADP-ribose) polymerase inhibitor (PARPi) veliparib, with the objective of creating a DNA damage response (DDR)-impaired, BRCA null-like phenotype to potentiate the antitumor activity of cisplatin.</p><p><strong>Patients and methods: </strong>In this open label, 3 + 3 trial design, cisplatin and berzosertib were administered intravenously on day 1 (D1) and D8, and D2 and D9, respectively, together with twice-daily oral veliparib on D1-D3 and D8-D10 in 21-day cycles. Previous platinum and PARPi therapy were permitted. A pharmacodynamic study compared tumor nuclear DDR biomarker response on C1D1 and C1D9 at the combination maximum tolerated dose (MTD).</p><p><strong>Results: </strong>Fifty-three patients enrolled with 46 evaluable for response (41 with measurable disease). The MTD and recommended phase II dose (RP2D) were determined to be cisplatin 40 mg/m² once daily on D1/D8, berzosertib 210 mg/m² once daily on D2/D9, and veliparib 200 mg twice a day on D1-D3 and D8-D10. Three patients achieved confirmed partial responses (PRs; 3/41, 7.3%); two patients experienced unconfirmed PRs. Median time on study was four cycles (range, 1-25), and 35 patients (66.0%) required at least one dose reduction. The most common grade 3/4 adverse events were myelosuppressive (anemia [37.7%], thrombocytopenia [32.1%], leukopenia [24.5%], neutropenia [22.6%], lymphopenia [20.8%]); no new safety signals were observed. Adding berzosertib to veliparib/cisplatin increased the frequency of RAD51-positive tumor cells in <i>BRCA</i>-wildtype biopsy specimens.</p><p><strong>Conclusion: </strong>This combination shows antitumor activity, including in patients with and without homologous recombination-compromised tumors and those previously treated with platinum. Adding berzosertib further increases the DDR response elicited by combination cisplatin/veliparib treatment in <i>BRCA</i>-wildtype patients, indicating increased replication stress at the RP2D/MTD.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500055"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12278758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reducing Fluorouracil Doses in Patients With Partial Dihydropyrimidine Dehydrogenase Deficiency Is a Treatment Safety Strategy, Not a Panacea of Precision Dosing.","authors":"Daniel L Hertz, Alan P Venook","doi":"10.1200/PO-25-00440","DOIUrl":"https://doi.org/10.1200/PO-25-00440","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500440"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep-Learning Model for Real-Time Prediction of Recurrence in Early-Stage Non-Small Cell Lung Cancer: A Multimodal Approach (RADAR CARE Study).","authors":"Hyun Ae Jung, Daehwan Lee, Boram Park, Kiwon Lee, Ho Yun Lee, Tae Jung Kim, Yeong Jeong Jeon, Junghee Lee, Seong Yong Park, Jong Ho Cho, Yong Soo Choi, Sehhoon Park, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Myung-Ju Ahn, Hong Kwan Kim","doi":"10.1200/PO-25-00172","DOIUrl":"10.1200/PO-25-00172","url":null,"abstract":"<p><strong>Purpose: </strong>The surveillance protocol for early-stage non-small cell lung cancer (NSCLC) is not contingent upon individualized risk factors for recurrence. This study aimed to use comprehensive data from clinical practice to develop a deep-learning model for practical longitudinal monitoring.</p><p><strong>Methods: </strong>A multimodal deep-learning model with transformers was developed for real-time recurrence prediction using baseline clinical, pathological, and molecular data with longitudinal laboratory and radiologic data collected during surveillance. Patients with NSCLC (stage I to III) who underwent surgery with curative intent between January 2008 and September 2022 were included. The primary outcome was predicting recurrence within 1 year after the monitoring point. This study demonstrates the timely provision of risk scores (RADAR score) and determined thresholds and the corresponding AUC.</p><p><strong>Results: </strong>A total of 14,177 patients were enrolled (10,262 with stage I, 2,380 with stage II, and 1,703 with stage III). The model incorporated 64 clinical-pathological-molecular factors at baseline, along with longitudinal laboratory and computed tomography imaging interpretation data. The mean baseline RADAR score was 0.324 (standard deviation [SD], 0.256) in stage I, 0.660 (SD, 0.210) in stage II, and 0.824 (SD, 0.140) in stage III. The AUC for predicting relapse within 1 year of the monitoring point was 0.854 across all stages, with a sensitivity of 86.0% and a specificity of 71.3% (AUC = 0.872 in stage I, AUC = 0.737 in stage II, and AUC = 0.724 in stage III).</p><p><strong>Conclusion: </strong>This pilot study introduces a deep-learning model that uses multimodal data from routine clinical practice to predict relapses in early-stage NSCLC. It demonstrates the timely provision of RADAR risk scores to clinicians for recurrence prediction, potentially guiding risk-adapted surveillance strategies and aggressive adjuvant systemic treatment.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500172"},"PeriodicalIF":5.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12309513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144698603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fidelity of Next-Generation Sequencing to Predict Human Epidermal Growth Factor 2 Overexpression Across Solid Tumors.","authors":"Mya Tran, Christopher A Fausel, Steven Bray, Guanglong Jiang, Erica Cantor, Santosh Philips, Fei Shen, Bryan P Schneider","doi":"10.1200/PO-24-00935","DOIUrl":"https://doi.org/10.1200/PO-24-00935","url":null,"abstract":"<p><strong>Purpose: </strong>Human epidermal growth factor 2 (HER2/ERBB2) has recently become a pan-tumor-agnostic target after the approval of trastuzumab deruxtecan for solid tumors with HER2 overexpression (3+). HER2 positivity is currently assessed by immunohistochemistry (IHC) and/or <i>HER2</i> amplification through in situ hybridization (ISH), owing to the fact that HER2 overexpression is secondary to HER2 gene amplification in many cases. Outside of breast/gastroesophageal cancer, the optimal IHC scoring method to assess overexpression across solid tumors remains undefined. Next-generation sequencing (NGS) is frequently used in practice and could be leveraged to predict HER2 positivity. However, less is known regarding the correlation between these methodologies. We sought to evaluate the ability of NGS to predict HER2 overexpression.</p><p><strong>Methods: </strong>We compared the concordance of HER2 IHC and/or ISH results with <i>HER2</i> amplification status detected by NGS in 1,009 patients with solid tumors who were referred to the Indiana University Precision Genomics program between September 2021 and October 2024.</p><p><strong>Results: </strong>HER2 3+ by IHC was identified in 4.3% (43 of 1,009) of cases. When including HER2 2+/ISH-positive (ISH+), the overall incidence of HER2 positivity was 5.1% (51 of 1,009). <i>HER2</i> amplification was not detected by NGS in 20.9% (9 of 43) of HER2 3+ and 75.0% (6 of 8) of HER2 2+/ISH+ cases. The rate of discordance varies across the type of NGS testing platform and sample status, with the highest incidence seen in liquid NGS (80.3%) and the lowest incidence observed when the same sample was used for testing (26.7%).</p><p><strong>Conclusion: </strong>Relying solely on NGS-based <i>HER2</i> amplification could result in missing cases of HER2 positivity and thus deprive patients of anti-HER2 therapy options. NGS, IHC, and/or ISH should be used as complementary tools for optimal detection of HER2 positivity.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2400935"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CNS Involvement by North American-Adult T-cell Leukemia/Lymphoma Is Associated With Discrete Dissemination Patterns and Molecular Profiles, Involving XPO1 E571 and KLF2/PI3KCD in Selected Cases.","authors":"Nishi Shah, Melissa Suchanek, Astha Thakkar, Riya Jayesh Patel, Shafia Rahman, Ana Acuna-Villaorduna, Urvi Shah, Diego Adrianzen Herrera, Shira Slasky, Kira Gritsman, Mendel Goldfinger, Aditi Shastri, Ioannis Mantzaris, Noah Kornblum, Lizamarie Bachier-Rodriguez, Eric Feldman, Dennis Cooper, Katharine Anne McNeill, Yanhua Wang, Yang Shi, Amit Verma, B Hilda Ye, Murali Janakiram, R Alejandro Sica","doi":"10.1200/PO.23.00526","DOIUrl":"10.1200/PO.23.00526","url":null,"abstract":"<p><strong>Purpose: </strong>CNS involvement in North American adult T-cell leukemia/lymphoma (NA-ATLL) remains poorly understood. This study examined the CNS involvement in patients with ATLL treated at a tertiary hospital in New York City.</p><p><strong>Methods: </strong>CNS involvement was defined by positive cerebrospinal fluid (CSF) cytology, flow cytometry, positive CNS imaging, or neurological examination findings.</p><p><strong>Results: </strong>Among 94 patients with NA-ATLL, 21 (22.3%) had CNS involvement. CSF was involved in 13 patients at diagnosis and five at relapse. Magnetic resonance imaging detected brain and spinal involvement in 24% and 14% of the patients, respectively. Results of neurological examinations were abnormal in 33% and 14% of the patients at diagnosis and relapse, respectively. The <i>XPO1</i> <i>E571K</i> mutation was found in two patients with extensive, treatment-refractory CNS disease, with a median overall survival (OS) of 2 months. Other mutations, including <i>KLF2</i> and <i>PI3KCD</i>, were noted in two patients. The median OS was 8.5 months, and the median relapse-free survival (RFS) was 6.5 months in our series. In most cases (5/21), the lymphomatous phenotype appeared to have a direct mass-like extension, whereas in patients with predominant blood involvement tended to spread to the CSF by traversing the blood-brain barrier.</p><p><strong>Conclusion: </strong>In this report, we describe the patterns of CNS involvement in ATLL and their association with mutations. We also describe two rapidly fatal cases with the <i>XPO1 E571K</i> mutation, which may represent a novel therapeutic target for T-cell lymphomas.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2300526"},"PeriodicalIF":5.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12309975/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144715076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative Multiplex Immunofluorescence Assay for Trophoblast Cell-Surface Antigen 2 and Human Epidermal Growth Factor Receptor 2 Expression in Breast Cancer: Toward Guiding Patient Selection for Antibody-Drug Conjugate Therapies.","authors":"Charles J Robbins, Mengni He, Nay Chan, Revekka Khaimova, Katherine Bates, Ioannis P Trontzas, Liam Scott, Myrto Moutafi, Chandra B Coleman, Salisha Hill, Daniel C Liebler, Regan Fulton, David L Rimm","doi":"10.1200/PO-25-00128","DOIUrl":"10.1200/PO-25-00128","url":null,"abstract":"<p><strong>Purpose: </strong>Accurate quantification of human epidermal growth factor receptor 2 (HER2) and trophoblast cell-surface antigen 2 (TROP2) expression could aid in identifying patients with cancer likely to benefit from emerging HER2 and TROP2 antibody-drug conjugate (ADC) therapies or potentially help oncologists choose which drug to use first, on the basis of the level of the ADC target in the tumor. We developed a standardized multiplex quantitative immunofluorescence (QIF) assay to simultaneously measure HER2 and TROP2 protein levels in cancer tissue.</p><p><strong>Materials and methods: </strong>A multiplex QIF assay was optimized on tissue microarrays (TMAs) by selecting optimal antibody clones and concentrations to achieve maximal signal-to-noise ratios. We create and release Qymia, a QuPath extension to enable simultaneous molecular compartmentalization and fluorescence quantification in TMAs and whole-slide images. Calibration curves, generated from cell line microarrays with HER2/TROP2 measured by mass spectrometry, were used to convert QIF signal into protein concentrations (attomoles/mm²). The validated assay was applied to a serial collection of 323 breast cancer specimens in TMA format to characterize HER2 and TROP2 expression distributions.</p><p><strong>Results: </strong>The assay demonstrated linearity across a wide dynamic range of biomarker expression with strong interassay and interoperator reproducibility. Application to 323 breast cancer TMA specimens revealed a weak inverse correlation between HER2 and TROP2 (<i>r</i> = -0.17; <i>P</i> = .001). HER2 was detectable in approximately 85% of TMA cores, including 51% of triple-negative breast cancer TMA cores. TROP2 was detectable in over 96% of specimens across all subtypes.</p><p><strong>Conclusion: </strong>This multiplex immunofluorescence assay provides an approach to accurately and precisely measure HER2/TROP2 levels within breast cancer tissue and compare relative levels of target expression in a breast cancer tissue population. This assay is now ready for studies to assess clinical validity and utility.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500128"},"PeriodicalIF":5.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}