JCO precision oncology最新文献

{"title":"Immunotherapy Response and Survival Outcome by Immunophenotypic Signature in Non-Small Cell Lung Cancer.","authors":"Dhruv Bansal, Ben Ponvilawan, Dmitrii Grachev, Vladimir Kushnarev, Artem Tarasov, Ivan Valiev, Konstantin Danilov, Anna Butusova, Polina Turova, Alexander Bagaev, Nikita Kotlov, Ammar Al-Obaidi, Christopher Ward, Janakiraman Subramanian","doi":"10.1200/PO-25-00837","DOIUrl":"https://doi.org/10.1200/PO-25-00837","url":null,"abstract":"<p><strong>Purpose: </strong>Current predictive biomarkers for immune checkpoint inhibitor (ICI)-based therapy in patients with lung adenocarcinoma (LUAD) or lung squamous cell carcinoma (LUSC), such as PD-L1 protein expression or tumor mutation burden, are still suboptimal. We aim to explore immunophenotypic factors as potential biomarkers in this patient population.</p><p><strong>Methods: </strong>Clinical, genomic, and transcriptomic data from five patient cohorts, consisting of three publicly available data and two retrospective cohorts, were included. Immune tumor microenvironment (TME) subtype and tertiary lymphoid structure (TLS) signature were evaluated using RNA expression data, and deconvolutional cellular decomposition of tumor samples was performed using the Kassandra algorithm. Survival analysis was performed using a log-rank test and multivariate Cox regression. All statistical analyses were performed using Python version 3.10.</p><p><strong>Results: </strong>In total, 514 patients were included in this analysis. A minority of LUAD (40.8%) had an immune-hot phenotype, which corresponded to better overall survival (OS) and progression-free survival (PFS) than the immune-cold phenotype. TLS-high signature was also associated with a superior ICI response rate and improved PFS, even with multivariate adjustments. Increased T-cell and macrophage infiltration and trafficking were predictive of ICI response. PD-L1 status and <i>KEAP1</i> or <i>STK11</i> mutations did not affect the response rates but were associated with poorer OS and PFS.</p><p><strong>Conclusion: </strong>Dynamic and active immune recruitment, indicated by immune-hot TME and high TLS score, was predictive of ICI benefit in patients with LUAD. Further prospective studies are warranted to expand to other treatment combinations with PD-(L)1 inhibitors.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 5","pages":"e2500837"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147838052","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":"Targeting KRAS G12C in Rare Mesonephric Carcinoma of the Cervix: A Promising Response to Sotorasib.","authors":"Bryan Cho Wing Li, Joshua Jing Xi Li, Ka Yu Tse, Haonan Lu, Karen Kar Loen Chan","doi":"10.1200/PO-25-01077","DOIUrl":"https://doi.org/10.1200/PO-25-01077","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 5","pages":"e2501077"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837882","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":"Potential of Minimal Residual Disease in Guiding Adjuvant Therapy Decisions in Non-Small Cell Lung Cancer.","authors":"Siyu Lei, Yaning Yang, Wenxin Jiang, Haiyan Xu, Yousheng Mao, Yan Wang","doi":"10.1200/PO-25-00977","DOIUrl":"https://doi.org/10.1200/PO-25-00977","url":null,"abstract":"<p><strong>Purpose: </strong>Circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) detection has become a strong prognostic stratification factor in postoperation non-small cell lung cancer (NSCLC). Here, we sought to investigate the guiding potential of MRD in informing adjuvant therapy (AT) decisions.</p><p><strong>Materials and methods: </strong>Patients with stage IA to IIIB NSCLC who had undergone confirmed R0 resection were enrolled. Blood samples were collected 1 month after surgery before initiation of AT (landmark) and longitudinally every 3-6 months since surgery. Postoperative AT was conducted according to the guideline recommendations, and regular radiographical examinations were recommended for relapse surveillance. MRD detection was conducted using the MinerVa platform (Genecast Precision Diagnostic Co., Ltd. Wuhan, China) using a tumor-informed strategy based on a fixed next-generation sequencing panel spanning 769 cancer-related genes.</p><p><strong>Results: </strong>One hundred sixty-five patients were included in this study, with 35 (21.2%) relapses. At landmark, positive MRD was associated with shorter disease-free survival (DFS) than negative MRD (<i>P</i> < .001, hazard ratio, 12.0). MRD was an independent risk factor for shorter DFS, irrespective of the disease stage and high-risk factors. In the case of negative landmark MRD, there was no significant difference between the DFS of (1) those who received AT and those who did not in stage IB patients with high-risk factors (<i>P</i> = .974), (2) epidermal growth factor receptor (<i>EGFR</i>)-mutant patients with or without adjuvant chemotherapy before adjuvant targeted therapy (<i>P</i> = .502), and (3) <i>EGFR</i>/<i>ALK</i> wild-type with or without adjuvant immunotherapy (<i>P</i> = .534). Clearance of ctDNA during AT was associated with a better prognosis than persistently detected ctDNA (<i>P</i> < .001).</p><p><strong>Conclusion: </strong>ctDNA-based MRD stratifies prognosis after curative resection in NSCLC, with MRD negativity indicating limited benefit from treatment in selected patients and ctDNA clearance reflecting improved outcomes. These findings support the clinical utility of MRD-guided adjuvant treatment strategies.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 5","pages":"e2500977"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837916","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":"<i>NTRK</i> Gene Fusions: A Compendium of Fusion Partners and Tumor Types.","authors":"Soo-Ryum Yang, Matteo Repetto, Erin R Rudzinski, Marilyn M Li, Angshumoy Roy, Lauren Gutstein, Karen Huang, Jinhua Wu, Julia Glade Bender, Nicoletta Brega, Arthur M Buchberg, Vadim Bernard-Gauthier, David S Hong, Alexander Drilon, Theodore W Laetsch","doi":"10.1200/PO-25-01150","DOIUrl":"https://doi.org/10.1200/PO-25-01150","url":null,"abstract":"<p><strong>Purpose: </strong><i>NTRK</i> gene fusions are oncogenic drivers for a variety of adult and pediatric tumors, making them a target for tumor-agnostic precision medicine. Tropomyosin receptor kinase (TRK) inhibitors are approved by the US Food and Drug Administration for cancers driven by TRK fusions. However, <i>NTRK</i> genes can fuse with many different partner genes, leading to diverse TRK fusion proteins, highlighting the importance of identifying the specific fusion partner with optimal pan-cancer diagnostics. This analysis aims to provide an updated descriptive compendium of <i>NTRK</i> gene fusions.</p><p><strong>Methods: </strong><i>NTRK</i> gene fusions were identified via literature searches (PubMed), a search of a clinical trials database (larotrectinib), and searches of two genomic databases (Memorial Sloan Kettering and Children's Hospital of Philadelphia).</p><p><strong>Results: </strong>In total, 358 distinct <i>NTRK</i> gene fusion-tumor pairings were identified across 25 tumor types. Primary CNS tumors were observed to harbor 86 distinct <i>NTRK</i> gene fusions, followed by sarcomas (n = 73). Overall, 229 different fusion partners were identified across tumor types (regardless of <i>NTRK</i> gene). Twenty-three fusion partners were found to fuse with >1 <i>NTRK</i> gene across tumor types, while 183 fusion partners were associated with only a single <i>NTRK</i> gene in one tumor type. <i>ETV6</i>::<i>NTRK3</i> was found in the highest number of different tumor types.</p><p><strong>Conclusion: </strong>This analysis illustrates the diversity of <i>NTRK</i> gene fusion partners across various tumor types and highlights the importance of selecting a pan-tumor fusion-partner agnostic test that can identify both known and novel fusion partners to identify patients who may benefit from treatment with TRK inhibitors.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 5","pages":"e2501150"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147838136","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":"Integrating Somatic and Germline Pharmacogenomics for Therapeutic Decisions in Precision Oncology.","authors":"Vai S Pathak, Courtney E Hershberger, Suneel Kamath, Porscha Johnson Williams, Terence D Rhodes, Howard L McLeod, Daniel M Rotroff","doi":"10.1200/PO-25-01238","DOIUrl":"https://doi.org/10.1200/PO-25-01238","url":null,"abstract":"<p><strong>Purpose: </strong>Clinical genomic profiling of tumors identifies therapeutic targets, while germline pharmacogenomics (PGx) guides drug dosing and toxicity avoidance. However, the combined clinical landscape of both somatic and germline actionable variants across cancers has not been comprehensively defined.</p><p><strong>Methods: </strong>Tumor and matched germline whole-exome sequencing data were analyzed for 10,302 patients in The Cancer Genome Atlas. Somatic mutations with therapeutic relevance were mapped to US Food and Drug Administration (FDA)-approved targeted drugs using the Oncology Knowledge Base database (levels 1-4). Germline PGx variants were identified using PyPGx and cross-referenced with drug-gene interactions in PharmGKB (levels of clinical annotation 1-2). This enabled construction of an integrated germline-somatic PGx profile per patient.</p><p><strong>Results: </strong>All 10,302 patients (100%) harbored at least one actionable germline PGx variant (median = 3; range = 1-9), including 7,520 (73%) with variants relevant to chemotherapy toxicity or supportive care medications (<i>DPYD, UGT1A1, CYP2C9,</i> and <i>CYP2C19</i>). Somatic profiling revealed 4,312 patients (42%) with at least one actionable mutation matched to an FDA-approved targeted therapy (eg, <i>PIK3CA</i>, <i>KRAS</i>). Across the cohort, 5,275 (51%) patients had more actionable germline variants than somatic mutations, whereas 1,988 (19%) had more actionable somatic mutations.</p><p><strong>Conclusion: </strong>Integrating germline PGx with somatic profiling reveals that actionable germline variants are nearly universal among patients with cancer in our cohort, extending beyond tumor-specific therapy to encompass toxicity and supportive care management. Routine implementation of combined germline and somatic sequencing in oncology could enhance therapeutic precision, minimize adverse effects, and inform individualized treatment decisions.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 5","pages":"e2501238"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837832","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":"Clinical Response to Poly(ADP-ribose) Polymerase Inhibitor in Metastatic Breast Cancer With a Germline Reduced-Penetrance BRCA2 Pathogenic Variant: A Molecular Tumor Board Discussion.","authors":"Diocésio Alves Pinto de Andrade, Carlos Alberto Fruet Filho, Cristiane Alves Mendes, Eduardo Miguel Febrônio, Viviane Fernandes Schiavon, Carolina de Bustamante Fernandes, Fernanda Christtanini Koyama, Patrícia Ashton-Prolla, Rodrigo Dienstmann, Leandro Jonata de Carvalho Oliveira","doi":"10.1200/PO-25-01274","DOIUrl":"https://doi.org/10.1200/PO-25-01274","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 4","pages":"e2501274"},"PeriodicalIF":5.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147616139","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":"<i>BRCA1</i> Methylation in Circulating Free DNA: A Constitutional Matter?","authors":"Per Eystein Lønning, Stian Knappskog","doi":"10.1200/PO-26-00197","DOIUrl":"https://doi.org/10.1200/PO-26-00197","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 4","pages":"e2600197"},"PeriodicalIF":5.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147698421","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":"Biomarker Testing Rates and Patterns in Patients With Metastatic Non-Small Cell Lung Cancer: A Prospective, Observational Study in Community Practices.","authors":"Makenzi Evangelist, Bo Wang, James E Butrynski, John Paschold, Patrick J Ward, David M Waterhouse, Robert M Jotte, Kashif Ali, Donald A Richards, Kartik Konduri, Anton Melnyk, Rami S Owera, David Hakimian, Habib Ghaddar, Eric M Lander, Nicholas J Robert, Jennifer L Yori, Vikalp Upadhyay, David R Spigel, Melissa L Johnson","doi":"10.1200/PO-25-00832","DOIUrl":"https://doi.org/10.1200/PO-25-00832","url":null,"abstract":"<p><strong>Purpose: </strong>As targeted therapies are associated with improved outcomes in patients with non-small cell lung cancer (NSCLC) with genetic alterations, biomarker testing is recommended to identify actionable alterations (AAs). Here, we report findings on biomarker testing in the subset of patients with metastatic (m)NSCLC from the Molecularly Informed Lung Cancer Treatment in a Community Cancer Network: A Pragmatic Consortium Protocol 2 study.</p><p><strong>Methods: </strong>In this prospective, noninterventional, observational study, patients 18 years and older with NSCLC (excluding stage IA) were enrolled from 18 community practices in the United States from 2020 to 2022 (ClinicalTrials.gov identifier: NCT05644808). Biomarker testing rates relative to timing of first-line (1L) therapy initiation, testing modalities, AAs, 1L therapies, next-generation sequencing (NGS) characteristics, and survival outcomes were examined. In addition, testing rates were compared with our previous retrospective analysis (Protocol 1).</p><p><strong>Results: </strong>Among 556 patients with mNSCLC, 98.8% received testing for ≥1 biomarker at any time and 79.0% received ≥1 test result before initiating 1L therapy (versus 89.9% and 79.2%, respectively, in Protocol 1 [2018-2020]); 72.8% and 55.6% of patients received NGS testing and NGS results before 1L therapy, respectively (versus 37.0% and 5.0%, respectively, in Protocol 1); 63.5% and 44.1% of patients received guideline-compliant (8-gene) testing and 8-gene test results, respectively, before 1L therapy. Among patients who received biomarker test results before 1L therapy and had an AA (n = 94), 77.7% (n = 73) received 1L-targeted therapy. Survival outcomes trended favorably in these patients.</p><p><strong>Conclusion: </strong>Although guideline-compliant (8-gene) and NGS testing rates fall short of recommended guidelines, several improvements in testing rates from Protocol 1 were observed. In addition, almost 80% of patients, who received test results before 1L therapy and had an AA, received 1L targeted therapy. Improved survival outcomes in these patients highlight the importance of effective follow-through from testing to treatment.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 4","pages":"e2500832"},"PeriodicalIF":5.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13105603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771992","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":"Evaluating Tumor Burden as a Predictive Biomarker for Epidermal Growth Factor Receptor Targeted Kinase Inhibitor Therapy in Advanced Non-Small Cell Lung Cancer.","authors":"Rika Terashima, Judy Fan, Fatma Gunturkun, Grant Nieda, Xiaomei Fan, Emily M Rodriguez, Annabel X Tan, Stefan Thottunkal, Maggie Shaw, Chloe C Su, Aparajita Khan, Victoria Y Ding, Ingrid Luo, Mina Satoyoshi, Archana Bhat, Bo Gu, Solomon M Henry, Timothy J Ellis-Caleo, Michelle Odden, Allison W Kurian, Joel W Neal, Heather A Wakelee, Julie T Wu, Summer S Han","doi":"10.1200/PO-25-00884","DOIUrl":"10.1200/PO-25-00884","url":null,"abstract":"<p><strong>Purpose: </strong>As treatment options for advanced non-small cell lung cancer (NSCLC) evolve, biomarkers are needed to guide therapy selection while balancing efficacy and toxicity. Although tumor burden is a promising candidate, its prognostic role in guiding epidermal growth factor receptor (EGFR)-targeted kinase inhibitor (TKI) therapies remains understudied in real-world settings.</p><p><strong>Methods: </strong>We identified patients with de novo stage IV <i>EGFR</i>-mutant NSCLC treated with first-line EGFR-TKI at Stanford Health Care (2000-2021). Tumor burden metrics were manually annotated from 592 baseline radiology reports, encompassing size, number, and location (1,807 lesions). Multivariable Cox regression evaluated associations between tumor burden metric and overall survival (OS), adjusting for confounders, in the overall cohort and an osimertinib subgroup. A weighted composite tumor burden score was constructed using statistically significant metrics to stratify risk.</p><p><strong>Results: </strong>Of 312 patients, bone metastasis (hazard ratio (HR)_adjusted, 1.64 [95% CI, 1.23 to 2.19]) and the number of metastatic organs (HR_adjusted, 1.21 [95% CI, 1.10 to 1.32]) were independently associated with worse OS and used to construct the composite score. Patients with low tumor burden (composite-score ≤ median 1.06) experienced better OS than those with high tumor burden, with a 3-year OS of 59.8% versus 41.5% (<i>P</i> = .001). Consistent findings were observed in the osimertinib subgroup, with a 3-year OS of 62.2% versus 44.6% (<i>P</i> = .03) for low versus high tumor burden.</p><p><strong>Conclusion: </strong>Tumor burden may serve as a prognostic biomarker in advanced NSCLC receiving EGFR-TKIs. These findings raise the hypothesis that durable survival in low-burden patients may be achievable with monotherapy, potentially sparing unnecessary toxicity from combination regimens. This warrants prospective validation comparing monotherapy versus combination strategies.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 4","pages":"e2500884"},"PeriodicalIF":5.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13086115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147645300","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":"Clinicogenomic Landscape and Function of <i>PIK3CA</i>, <i>AKT1</i>, and <i>PTEN</i> Mutations in Breast Cancer.","authors":"Jacqueline J Tao, Saumya D Sisoudiya, Hanna Tukachinsky, Alexa B Schrock, Ericka M Ebot, Smruthy Sivakumar, Ethan S Sokol, Neil Vasan","doi":"10.1200/PO-25-00609","DOIUrl":"10.1200/PO-25-00609","url":null,"abstract":"<p><strong>Purpose: </strong>To comprehensively characterize the clinical and genomic landscapes of <i>PIK3CA</i>, <i>AKT1</i>, and <i>PTEN</i> alterations and examine their functional and therapeutic implications in AKT-driven breast cancer.</p><p><strong>Methods: </strong>Comprehensive genomic profiling of 51,767 breast tumors was performed using FoundationOne CDx or FoundationOne. We examined the genomic landscape of <i>PIK3CA</i>, <i>AKT1</i>, and <i>PTEN</i> alterations and their distribution across clinical variables of interest. Prior deep mutational scanning (DMS) data were used to functionally characterize clinical <i>PTEN</i> variants. Real-world clinical outcomes were assessed in patients treated with capivasertib plus fulvestrant.</p><p><strong>Results: </strong>A total of 29,157 variants were identified across the three genes, including pathogenic variants and variants of uncertain significance. The most frequently altered gene was <i>PIK3CA</i> (37.4% of cases), followed by <i>PTEN</i> (13.5%) and <i>AKT1</i> (5.4%). The most common alterations in each gene were <i>PIK3CA</i> H1047R (35.6% of <i>PIK3CA</i>-altered cases), E545K (19.7%), and E542K (11.7%); <i>AKT1</i> E17K (69.7%); and <i>PTEN</i> homozygous copy number deletion (37.3%). <i>PIK3CA</i> alterations were less prevalent in patients of African genetic ancestry (27.1% vs 38.6% in European genetic ancestry), whereas <i>AKT1</i> and <i>PTEN</i> alterations were balanced across ancestries. DMS data on missense <i>PTEN</i> mutations revealed that 32.5% showed discordant effects on protein stability and phosphatase activity. A subset of patients with rare AKT pathway variants derived meaningful progression-free survival and overall survival benefit from capivasertib.</p><p><strong>Conclusion: </strong>Here, we present the landscape of <i>PIK3CA</i>, <i>AKT1</i>, and <i>PTEN</i> alterations in, to our knowledge, the largest clinical cohort examined to date. The functional complexity of rare <i>PTEN</i> variants underscores the need for functional validation by tools such as DMS. Rare AKT pathway variants may predict clinical benefit from AKT inhibitors and warrant further clinical investigation.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 4","pages":"e2500609"},"PeriodicalIF":5.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13086116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147645292","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}