JCO precision oncology最新文献

{"title":"Comments on the Study of Outcomes After Radiation for Oligoprogressive Disease Sites in Patients With <i>EGFR</i>-Mutant Lung Cancer.","authors":"Shu-Ning Li, Jun-Nv Xu, Nan-Nan Ji, Ming Xue, Yue-Can Zeng","doi":"10.1200/PO-25-00449","DOIUrl":"https://doi.org/10.1200/PO-25-00449","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500449"},"PeriodicalIF":5.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033227","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":"Real-World Validation of the Purity Independent Subtyping of Tumors Classifier for Informing Therapy Selection in Pancreatic Ductal Adenocarcinoma.","authors":"Stephane Wenric, Chithra Sangli, John Guittar, Farahnaz Islam, Alia Zander, Seung Won Hyun, James M Davison, Gregory M Mayhew, Kirk Beebe, Kyle Beauchamp, Miral Patel, Kacie Brown, James Chen, Halla Nimeiri, Michael V Milburn, Charles M Perou, Justin Guinney, Timothy J Taxter, Al Benson","doi":"10.1200/PO-25-00197","DOIUrl":"10.1200/PO-25-00197","url":null,"abstract":"<p><strong>Purpose: </strong>FOLFIRINOX (FFX) and gemcitabine + nab-paclitaxel (GnP) are the most commonly administered first-line (1L) regimens for advanced, nonresectable, pancreatic ductal adenocarcinoma (PDAC). In the absence of biomarkers to predict response, clinical covariates such as age and performance status are often used by clinicians to select optimal treatment regimens. Purity independent subtyping of tumors (PurIST) is a molecular subtyping algorithm that classifies tumors as classical or basal. The current study was designed to validate PurIST as a prognostic biomarker for patients receiving 1L FFX and as a predictive biomarker for patients more likely to benefit from FFX versus GnP.</p><p><strong>Patients and methods: </strong>This is a prospectively designed, retrospective study using a real-world data set of 931 patients with advanced PDAC, treated with either 1L FFX or GnP, and designed to demonstrate associations of PurIST subtypes with clinical outcomes. The primary end point was overall survival (OS) in classical versus basal patients treated with 1L FFX, while the secondary end point was OS in classical patients-with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1-to compare 1L FFX versus GnP.</p><p><strong>Results: </strong>Within the cohort of patients receiving 1L FFX (n = 536), basal subtype patients had a median OS of 7 months compared with classical subtype patients with a median OS of 11.8 months (hazard ratio [HR], 1.86 [95% CI, 1.49 to 2.33]; <i>P</i> < .001). In an analysis restricted to patients with classical subtype and ECOG PS of 0 or 1 (n = 311), there was a 33% relative risk reduction of death in patients treated with FFX compared with GnP, adjusting for age and ECOG PS (HR, 0.67 [95% CI, 0.48 to 0.94]; <i>P</i> < .009), with no comparable risk reduction in basal patients (subtype-treatment interaction, <i>P</i> = .002).</p><p><strong>Conclusion: </strong>Patients with PDAC of the PurIST classical subtype showed a significant OS benefit when treated with FFX as 1L versus GnP.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500197"},"PeriodicalIF":5.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12419025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000661","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":"Open-Label, Phase II Trial of Extracellular Regulated Kinase Inhibition Alone and in Combination With Autophagy Inhibition in Patients With Metastatic Pancreatic Cancer.","authors":"Rishi Surana, Micaela Morgado, Ashwin Somasundaram, Bruno Bockorny, Colin D Weekes, Emma C Coleman, Alexandra Bird, Junning Wang, Hannah L Williams, Hui Zheng, Lauren K Brais, Neetu Saxena, Christopher Graham, Lauren Ritterband, Mark Sawin, Mary Linton Peters, Peter Whooley, Andrea Bullock, Jessica Zerillo, Hanna K Sanoff, Jeffrey W Clark, Aparna R Parikh, Matthew B Yurgelun, Anuj K Patel, Robert J Mayer, James M Cleary, Peter Enzinger, Douglas A Rubinson, Nadine J McCleary, Andrea Enzinger, Sarah Slater, Kimmie Ng, Leah H Biller, Thomas A Abrams, Brandon M Huffman, Harshabad Singh, Srivatsan Raghavan, Joseph D Mancias, Kirsten L Bryant, Jonathan O Nowak, Andrew J Aguirre, Channing J Der, Brian M Wolpin, Kimberly Perez","doi":"10.1200/PO-25-00332","DOIUrl":"10.1200/PO-25-00332","url":null,"abstract":"<p><strong>Purpose: </strong>Oncogenic mutations in Kirsten rat sarcoma virus are present in over 90% of pancreatic ductal adenocarcinomas (PDACs). Preclinical data suggest that PDAC cells treated with inhibitors of the mitogen-activated protein kinase pathway demonstrate elevated autophagic flux. In this study, we evaluate the clinical efficacy of combining LY3214996 (extracellular regulated kinase inhibitor) with hydroxychloroquine (HCQ; autophagy inhibitor) in patients with metastatic PDAC.</p><p><strong>Methods: </strong>Eligible patients had metastatic PDAC and at least one, but no more than two prior lines of systemic therapy. A safety lead-in evaluating the combination was conducted and the maximum tolerated dose level of LY3214996 was identified. Patients were then randomly assigned in a 1:1 fashion to receive either LY3214996 200 mg orally (PO) once daily + HCQ 600 mg PO twice a day (arm 1) or LY3214996 400 mg PO once daily (arm 2). The primary end point for this study was disease control rate (DCR). Secondary end points included overall survival (OS) and progression-free survival (PFS).</p><p><strong>Results: </strong>Thirty-nine patients enrolled (20 in arm 1, 19 in arm 2). The DCR rates were 5% in arm 1 and 5.3% in arm 2. The median OS was 2.4 months in arm 1 (95% CI, 1.3 to 5.8) and 4.6 months in arm 2 (95% CI, 3.1 to 5.7). The median PFS was 1.3 months in arm 1 (95% CI, 0.8 to 1.8) and 1.9 months in arm 2 (95% CI, 1.644 to 2.4). The most frequently observed toxicities in both arms included nausea, diarrhea, elevated creatine phosphokinase, anorexia, and cytopenias. Exploratory analysis using patient-derived PDAC organoids did not show evidence of synergistic antiproliferative activity of LY3214996 in combination with chloroquine.</p><p><strong>Conclusion: </strong>LY3214996 alone or in combination with HCQ did not result in clinical activity in patients with metastatic PDAC.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500332"},"PeriodicalIF":5.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955068","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":"Reply to: Beyond the Score: Integrating Hypoxia Signatures Into Risk-Adapted Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer.","authors":"Nicholas J Eustace, Terence M Williams, Nicholas C Denko","doi":"10.1200/PO-25-00747","DOIUrl":"https://doi.org/10.1200/PO-25-00747","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500747"},"PeriodicalIF":5.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091823","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":"Multihit Somatic Mosaicism of <i>TP53</i> Pathogenic Variants in a Patient Mimicking Li-Fraumeni Syndrome.","authors":"Kazuaki Yokoyama, Nozomi Yokoyama, Aya Shinozaki-Ushiku, Mika Ito, Hiroyuki Takamori, Satoshi Takahashi, Eigo Shimizu, Seiya Imoto, Tomoki Todo, Yasuhito Nannya","doi":"10.1200/PO-25-00392","DOIUrl":"https://doi.org/10.1200/PO-25-00392","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500392"},"PeriodicalIF":5.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955008","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":"Reply to: Comments on the Study of Outcomes After Radiation for Oligoprogressive Disease Sites in Patients With <i>EGFR</i>-Mutant Lung Cancer.","authors":"Monica F Chen, Daniel Gomez, Helena A Yu","doi":"10.1200/PO-25-00631","DOIUrl":"https://doi.org/10.1200/PO-25-00631","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500631"},"PeriodicalIF":5.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033390","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":"Identification of Targetable <i>EGFR</i> Mutations in Ovarian Cancer.","authors":"Arjan Gower, Susan Win, Rituparna Ganguly, Melissa Johnson, Maria A Velez, Amy L Cummings, Aaron Lisberg, Edward B Garon, Brian Di Carlo","doi":"10.1200/PO-25-00390","DOIUrl":"https://doi.org/10.1200/PO-25-00390","url":null,"abstract":"<p><strong>Purpose: </strong><i>EGFR</i> mutations are classically seen in non-small cell lung cancers (NSCLCs), and EGFR-directed inhibitors have changed the therapeutic landscape in patients with <i>EGFR</i>-mutated NSCLC. The real-world prevalence of <i>EGFR</i>-mutated ovarian cancers has not been previously described. We aim to determine the prevalence of pathogenic or likely pathogenic <i>EGFR</i> mutations in ovarian cancer and describe a case of <i>EGFR</i>-mutated metastatic ovarian cancer with a durable response to osimertinib, an EGFR-directed targeted therapy.</p><p><strong>Methods: </strong>Retrospective review of 33,850 molecularly profiled ovarian cancer samples from real-world patients who underwent next-generation sequencing (NGS) of DNA between 2016 and 2025. <i>EGFR</i>-mutated cases were defined as those harboring known pathogenic or likely pathogenic mutations based on the <i>EGFR</i> genomic alteration discovered by Caris.</p><p><strong>Results: </strong>Of 33,850 patients, 27 (0.08%) harbored a genomic alteration in the <i>EGFR</i> gene that was pathogenic or likely pathogenic, including <i>EGFR</i> exon 20 mutation (n = 12, including five patients with <i>EGFR</i> T790M mutation), <i>EGFR</i> L858R (n = 3), and an <i>EGFR</i> exon 19 deletion (n = 2). Only one patient was treated with osimertinib, a third-generation EGFR-inhibitor, and achieved a durable objective response for over 17 months.</p><p><strong>Conclusion: </strong>Ovarian cancer driven by an oncogenic <i>EGFR</i> mutation is a rare occurrence, yet it is an actionable molecular target with EGFR-directed inhibitors. This underlies the potential value of comprehensive NGS in the management of ovarian cancer for discovering actionable genomic alterations.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500390"},"PeriodicalIF":5.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033402","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":"Heterozygous Germline Fanconi Anemia-Related Gene Mutations Increase Susceptibility to Germ Cell Tumors.","authors":"Jing Wang, Ningning Luo, Tiantian Han, Xiangyu Yin, Guangyu Wang","doi":"10.1200/PO-25-00435","DOIUrl":"10.1200/PO-25-00435","url":null,"abstract":"<p><strong>Purpose: </strong>Germ cell tumors (GCTs) are a heterogeneous group of neoplasms that predominantly affect adolescents and young adults. Notably, geographical disparities in GCT incidence exist, with higher rates observed in East Asia. Although numerous studies have established links between heterozygous germline mutations in Fanconi anemia (FA) genes and the development of certain human cancers, the association between germline pathogenic or likely pathogenic (P/LP) variants in FA genes and the relative risk of developing GCTs remains incompletely characterized.</p><p><strong>Methods: </strong>In this study, we used next-generation sequencing (NGS) to investigate the genetic susceptibility patterns of Chinese patients with GCTs for the first time. We investigated the association between germline P/LP variants in FA-related genes and the risk of developing GCTs. Furthermore, we compared clinical characteristics, mutational landscape, and mutational signatures between patients with and without germline P/LP variants in FA-related genes.</p><p><strong>Results: </strong>We identified heterozygous germline P/LP variants in FA-related genes in 12.12% (8/66) of patients with GCTs, involving <i>FANCA</i>, <i>BRCA2</i>, <i>FANCD2</i>, <i>FANCE</i>, and <i>SLX4</i>. Our findings demonstrate a significant association between a subset of FA genes and an increased relative risk of GCTs, indicating a role for these variants in GCT predisposition. Furthermore, patients harboring these FA gene variants exhibited a higher number of mutations, increased propensity for gene fusions, and demonstrated a greater degree of genomic instability.</p><p><strong>Conclusion: </strong>These results elucidate the contribution of FA-related germline variants to GCT pathogenesis and advance our understanding of the genetic determinants influencing GCT relative risk. This research provides a basis for developing more effective screening strategies, personalized treatment approaches, and improved patient management strategies for GCTs.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500435"},"PeriodicalIF":5.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12419011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000669","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":"Case-Control Study for 23 Cancer Types With Functional Analysis of <i>CHEK2</i>: Risk Estimation and Clinical Recommendations in East Asia.","authors":"Yuri Takehara, Yoshiaki Usui, Lenka Stolařová, Petra Kleiblova, Yusuke Iwasaki, Todd A Johnson, Makoto Hirata, Yoichiro Kamatani, Yoshinori Murakami, Mikiko Endo, Kouya Shiraishi, Takashi Kohno, Kokichi Sugano, Koichi Matsuda, Teruhiko Yoshida, Amanda B Spurdle, Hidewaki Nakagawa, Libor Macurek, Zdenek Kleibl, Yukihide Momozawa","doi":"10.1200/PO-24-00945","DOIUrl":"10.1200/PO-24-00945","url":null,"abstract":"<p><strong>Purpose: </strong><i>CHEK2</i> is the frequently detected cancer-predisposing gene in female breast cancer. In addition, the association with the risks of other cancer types has been suggested, and clinical management has also been discussed. Although clinical relevance of germline variants differs across population, there is little evidence of the clinical relevance of <i>CHEK2</i> germline variants in East Asia.</p><p><strong>Methods: </strong>Targeted sequencing and functional analyses of missense variants for the coding region of <i>CHEK2</i> in 111,571 East Asian individuals were performed. Variants classified as pathogenic/likely pathogenic in ClinVar, predicted loss-of-function, or functionally impaired in functional analysis were defined as germline damaging variants (gDVs). We evaluated the association between <i>CHEK2</i> gDVs and the risk of 23 cancer types. We also compared the clinical characteristics of carriers and noncarriers among patients with <i>CHEK2</i>-associated cancers.</p><p><strong>Results: </strong>We identified 77 gDVs including 36 functionally impaired missense variants. <i>CHEK2</i> gDVs were significantly associated exclusively with prostate cancer (odds ratio [OR], 1.8 [95% CI, 1.2 to 2.6]; <i>P =</i> 1.7 × 10^-3), in addition to female breast cancer (OR, 1.8 [95% CI, 1.3 to 2.6]; <i>P =</i> 1.2 × 10^-3), among 23 cancer types. There were no differences in age at diagnosis, pathologic status, and prognosis between carriers and noncarriers. Besides, there was no association with the risk of cancer types with high incidence rates in East Asian countries.</p><p><strong>Conclusion: </strong><i>CHEK2</i> gDVs were associated with female breast and prostate cancer risks in East Asia. The necessity of additional systematic clinical management for all <i>CHEK2</i> gDV carriers should be carefully discussed, and standard cancer screening is recommended unless no other clinical features suggestive of cancer predisposition are noted in East Asia.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2400945"},"PeriodicalIF":5.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12410089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955028","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":"Multicenter Phase II Study of Olaparib and the ATR Inhibitor Ceralasertib in Metastatic Castration-Resistant Prostate Cancer (TRAP).","authors":"Irene Tsung, David C Smith, Elisabeth I Heath, Frank Cackowski, Michael E Devitt, Thomas M Braun, Sarah Yentz, Charles B Nguyen, Arul M Chinnaiyan, Neel Shah, Simon Smith, Emma Dean, Ulka Vaishampayan, Megan E V Caram, Phillip Palmbos, Joshi J Alumkal, Zachery R Reichert","doi":"10.1200/PO-25-00457","DOIUrl":"10.1200/PO-25-00457","url":null,"abstract":"<p><strong>Purpose: </strong>Preclinical studies suggest the combination of the poly(adenosine diphosphate[ADP]-ribose) polymerase (PARP) inhibitor olaparib and the ataxia telangiectasia-mutated and Rad3-related (ATR) inhibitor ceralasertib has synergistic antitumor activity in homologous recombination proficient (HRP) and homologous recombination repair gene mutation (HRRm) patients. This study aims to determine the efficacy of olaparib plus ceralasertib in metastatic castration-resistant prostate cancer (mCRPC) with and without HRRm.</p><p><strong>Patients and methods: </strong>Thirty-five HRP and 12 HRRm PARP inhibitor-naïve patients with mCRPC progressing on ≥1 line of therapy or previous androgen receptor pathway inhibitor were enrolled. Patients received olaparib (300 mg twice daily) and ceralasertib (160 mg once daily, days 1-7) in 28-day cycles. HRRm was defined as biallelic inactivation of <i>BRCA2</i> or <i>BRCA1</i>, monoallelic inactivation of <i>ATM</i>, or germline inactivation of any of these genes. The primary end point was disease response rate (dRR; confirmed prostate-specific antigen decline ≥50% and/or complete/partial radiographic response by RECIST v1.1) in HRP patients. Secondary end points included dRR in HRRm patients, progression-free survival (PFS), and safety/toxicity. Two-stage designs were used.</p><p><strong>Results: </strong>Four of 35 (11%; 95% CI, 3.2 to 26.7) HRP and four of 12 HRRm patients responded. Median PFS was 8.2 months (95% CI, 5.3 to not reached) for HRP patients. Thirty-six percent of patients had ≥grade 3 toxicity, most commonly from anemia. Limitations include small, single-arm, nonrandomized trial design.</p><p><strong>Conclusion: </strong>Combining ceralasertib with olaparib had limited activity in patients with HRP mCRPC. HRRm response rate was not greater than previous single-agent PARP inhibitor clinical trials.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500457"},"PeriodicalIF":5.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075377","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}