JCO precision oncology最新文献

{"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":"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":"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":"https://doi.org/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":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"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":"https://doi.org/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":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/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":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"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-25-00010","DOIUrl":"https://doi.org/10.1200/PO-25-00010","url":null,"abstract":"<p><strong>Purpose: </strong>Microsatellite instability (MSI) is a vital biomarker for cancer immunotherapy and prognosis, necessitating precise detection. However, data on MSI status changes following neoadjuvant therapy (NT) and standardized testing in biopsy samples are limited. The study aimed to investigate the concordance of MSI status between paired biopsy and surgical samples, as well as the impact of NT on MSI status using a novel MSI next-generation sequencing (MSI-NGS) detection panel.</p><p><strong>Methods: </strong>Involving 137 patients with colorectal cancer (CRC), 116 with matched biopsies and surgical samples were analyzed. A custom MSI-NGS panel was used and its performance was compared with MSI polymerase chain reaction (MSI-PCR), which served as the gold standard.</p><p><strong>Results: </strong>The MSI-NGS panel showed 97% accuracy, with 112 patients exhibiting consistent MSI status between samples. In both surgical and biopsy samples, 3% of patients had MSI-high by MSI-NGS but microsatellite stable by MSI-PCR, whereas 1% had the opposite results. Both the surgical and biopsy samples demonstrated an overall discrepancy of 4% for both methodologies. Neoadjuvant chemotherapy in eight patients did not alter MSI status. Compared with F1CDx, MSK-IMPACT, and a 556-gene panel including146 MSI loci, the NGS panel exhibits higher accuracy, as well as excellent specificity.</p><p><strong>Conclusion: </strong>There is a high consistency in the detection of MSI status between surgical and biopsy samples. Moreover, the study confirms the reliability of the MSI-NGS panel for MSI detection in limited biopsy specimens.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500010"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600458","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":"Prostate-Related Germline Variant Frequencies Detected in a Cohort of Men With Metastatic Prostate Cancer in Northern India.","authors":"Atul Batra, Jessica G Cockburn, Abhenil Mittal, Rui M Bernardino, Tiiu Sildva, Marian Severin Wettstein, Amlesh Seth, Brusabhanu Nayak, Sameer Bakhshi, Ranjit K Sahoo, Akash Kumar, Rishabh Jain, Seema Kaushal, Mayank Singh, Sneha Gund, Sunakshi Chowdhary, Karina Lakhani, Krishna Patel, Raymond H Kim, Mohammad R Akbari, Neil Eric Fleshner","doi":"10.1200/PO-25-00130","DOIUrl":"10.1200/PO-25-00130","url":null,"abstract":"<p><strong>Purpose: </strong>Although prostate cancer is generally associated with favorable outcomes, metastatic disease remains incurable. Additionally, a subset of individuals with high-risk or metastatic disease are likely to harbor at least one germline variant in known prostate cancer association genes. Because of differences in cohort selection and sequencing strategies, the prevalence of germline variants in global populations is unclear.</p><p><strong>Methods: </strong>A whole-exome sequencing (WES) approach was used to explore germline variants in a cohort of patients with metastatic prostate cancer from India. In total, 276 individuals treated at the All India Institute of Medical Sciences in New Delhi, India, were prospectively and consecutively recruited. Blood specimens underwent standard WES and bioinformatic analysis to determine the prevalence of pathogenic and likely pathogenic (PV/LPV) prostate cancer variants, which were then assessed for associations with clinical features.</p><p><strong>Results: </strong>In total, PV/LPVs were detected in 11% of individuals across eight genes linked to prostate cancer, most frequently in BRCA2 (3.98%). The distribution reflects previously published findings from other global cohorts, although frequencies in the prevalence of specific variants differ slightly. No relationship between variant status and clinical features were detected, although analysis of a larger cohort may show otherwise.</p><p><strong>Conclusion: </strong>These results indicate that germline screening for prostate cancer following existing guidelines yield similar variant detection frequencies when focusing on individuals with metastatic disease in the Indian context. In summary, some men are more likely to develop an advanced form of metastatic prostate cancer than others because of differences in their genes, known as variants. This study looked at the how many of these variants are in a group of patients from India. We found that the number of variants in this group was similar to those from other parts of the world, including more found in a gene called <i>BRCA2</i>.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500130"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12262130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608399","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":"Personalized <i>N</i>-of-1 Combination Therapies for Advanced Gastrointestinal Stromal Tumors.","authors":"Sangkyu Noh, Ashwyn K Sharma, Paul T Fanta, Shumei Kato, Razelle Kurzrock, Jason K Sicklick","doi":"10.1200/PO-25-00066","DOIUrl":"https://doi.org/10.1200/PO-25-00066","url":null,"abstract":"<p><strong>Purpose: </strong>Gastrointestinal stromal tumor (GIST) resistance to imatinib and other tyrosine kinase inhibitors poses an ongoing clinical challenge. We investigated molecularly matched combination therapies for treatment-refractory GIST, including drugs not previously combined in human studies.</p><p><strong>Methods: </strong>Patients of all ages with unresectable and/or metastatic GIST treated with combination therapies were included (February 13, 2015-December 31, 2022). These patients were discussed at molecular tumor board and enrolled in the prospective Investigation of Profile-Related Evidence Determining Individualized Cancer Therapy (I-PREDICT) study (ClinicalTrials.gov identifier: NCT02534675). Patient demographics, tumor next-generation sequencing (NGS), treatment responses, and survival outcomes were retrospectively analyzed.</p><p><strong>Results: </strong>Six (1.6%) patients met the inclusion criteria. The median age at diagnosis was 59.5 years with the majority (4/6) of patients being male. NGS revealed median of six deleterious genomic alterations per patient excluding variants of unknown significance. Five (5/6) patients had <i>KIT</i>-mutant GIST, and one patient had <i>BRAF</i>^V600E-mutant GIST. Two thirds of tumors had <i>CDKN2A/B</i> loss. Patients received median of 1 (range, 1-3) customized combination therapy consisting of median of 2 (range, 2-3) drugs targeting median of 2 (range, 2-4) genomic alterations. One patient experienced a treatment-related grade ≥3 adverse event (hypertension). For all patients, the best response by RECIST v1.1 was stable disease (SD). Combination therapies led to SD ≥6 months (range, 6.2-11.3 months) in four (4/6) patients compared with none in the immediate previous single-agent targeted therapies (SD range, 1.5-5.4 months). Most (5/6) patients had at least 60% prolongation of their progression-free survival compared with their immediate previous single-agent targeted therapy.</p><p><strong>Conclusion: </strong>Our results demonstrate that a multitargeted, biomarker-matched combination approach can be safely administered to obtain disease control. Tailored combination therapies for advanced GIST with multiple genomic alterations warrant further investigation.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500066"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144698547","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":"Prospective Clinical Validation of a Combinatorial Functional Precision Medicine Platform in Relapsed/Refractory Non-Hodgkin's Lymphoma.","authors":"Rui Xue Lee, Masturah Bte Mohd Abdul Rashid, Noor Rashidha Binte Meera Sahib, Jasmine Goh, Sanjay De Mel, Yogeshini Batumalai, Jayalakshmi, Reiya Chua, Limei Poon, Esther Chan, Joanne Lee, Yen Lin Chee, Siok-Bian Ng, Wee Lee Chan, Daryl Tan, Cheong May Anne, Chandramouli Nagarajan, Jason Yongsheng Chan, Lay Poh Khoo, Nagavalli Somasundaram, Choon Kiat Ong, Huang Dachuan, Nur Ayuni Binte Muhammad Taib, Kelila Xin Ye Chai, Phang Beng Hooi, Soon Thye Lim, Edward Kai-Hua Chow, Anand D Jeyasekharan","doi":"10.1200/PO-24-00780","DOIUrl":"https://doi.org/10.1200/PO-24-00780","url":null,"abstract":"<p><strong>Purpose: </strong>Despite initially responding to first-line treatment, many patients with non-Hodgkin's lymphoma (NHL) eventually relapse or are refractory. These patients are empirically subjected to salvage therapies that may not be efficacious. We had previously presented feasibility evidence of an ex vivo functional precision medicine (FPM) platform, quadratic phenotypic optimization platform (QPOP), being potentially useful in identifying alternative therapeutic options for patients with relapsed/refractory (R/R)-NHL. We now present an analysis of the completed prospective study, with clinical concordance and benefit of QPOP in predicting treatment responses of patients with R/R-NHL.</p><p><strong>Materials and methods: </strong>One hundred seventeen patients with R/R B-cell NHL (B-NHL) or natural killer or T-cell NHL (NK/T-NHL) were recruited for QPOP testing. Isolated tumor cells were incubated for 48 hours with drug combinations determined by an orthogonal array composite design. QPOP reports with patient-specific optimal drug therapies were generated. Patients were given off-label treatments according to the clinician's decision. Patient characteristics and responses to treatments after QPOP testing were recorded.</p><p><strong>Results: </strong>Within 126 QPOP cases, 105 (52 B-NHL and 53 NK/T-NHL) were evaluable. QPOP-suggested drug responses were concordant with actual patient outcome, with an overall test accuracy of 74.5%. An overall response rate of 59% was achieved in those prescribed off-label QPOP-guided combinations. In all, 59.3% of QPOP-guided patients had improved response durations compared with their previous treatment. Compared with those who received salvage therapy, QPOP-guided patients also had longer progression-free survival 2 years after treatment.</p><p><strong>Conclusion: </strong>There is increasing evidence that genetic factors are not sole determinants of patient drug response and FPM approaches may improve cancer treatment guidance. This study further confirms that advancements in ex vivo combinatorial drug screening platforms like QPOP could complement existing genomic methods in identifying effective treatment options for patients with cancer, especially in R/R cases.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2400780"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144698548","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}