JCO precision oncology最新文献

{"title":"Clinical Significance of <i>TERT</i> Promoter Mutations in Neuroblastoma.","authors":"Natasha Persaud, Gunes Gundem, Brian H Kushner, Marc Ladanyi, Neerav Shukla, Shakeel Modak","doi":"10.1200/PO-25-00074","DOIUrl":"10.1200/PO-25-00074","url":null,"abstract":"<p><strong>Purpose: </strong>Telomere maintenance mechanisms including <i>MYCN</i> amplification (<i>MYCN-</i>A) (via upregulated telomerase reverse transcriptase [<i>TERT</i>] expression), <i>TERT</i> rearrangements (<i>TERT</i>-RA), and <i>ATRX</i> mutations confer neoplastic immortality in neuroblastoma (NB) cells. Clinical characterization of patients with NB harboring activating somatic <i>TERT</i> promoter point mutations (<i>TERT</i>-PM) in NB may improve stratification.</p><p><strong>Methods: </strong>To identify <i>TERT</i>-PM and <i>TERT</i>-RA, tumors were profiled by the Memorial Sloan Kettering Cancer Center-Integrated Mutation Profiling of Actionable Cancer Targets targeted next-generation sequencing platform and whole-genome sequencing, respectively. Associated clinical outcomes were studied.</p><p><strong>Results: </strong><i>TERT</i>-PM and <i>TERT</i>-RA were detected in 17 of 603 (2.8%) and 31of 168 (18.4%) tumors from individual patients, respectively. The median age at diagnosis was 32 (range, 15-79) and 48 (range, 3-168) months for <i>TERT</i>-PM and <i>TERT</i>-RA, respectively. <i>TERT</i>-PM were located at canonical hotspots (C228T [16/17] and C250T [1/17]) and were concurrent with <i>MYCN-</i>A in 9 of 17 (53%). By contrast, <i>MYCN</i>-A occurred in 1 of 31 <i>TERT</i>-RA tumors. Most patients with <i>TERT</i>-PM had stage M (94%) and high-risk NB (HR-NB) (81%) at diagnosis. Twenty-eight patients with <i>TERT</i>-RA had HR-NB (90%). After risk appropriate therapy, complete response was achieved in 7 of 17 (41%) and 17 of 31 (55%) patients with <i>TERT</i>-PM and <i>TERT</i>-RA, respectively. The median progression-free (PFS) and overall survival (OS) were 9.7 ± 1.2 and 16.5 ± 2 months for patients with <i>TERT</i>-PM. Corresponding PFS/OS for patients with <i>TERT</i>-RA were 20 ± 6.4/56.8 ± 8.6 months (<i>P</i> = .015 for OS). Excluding <i>MYCN</i>-A status produced no significant survival difference (<i>P</i> > .1) between the two groups. CNS relapse occurred in 11 of 31 (35%) patients with <i>TERT</i>-RA versus 1 of 17 (6%) patients with <i>TERT</i>-PM.</p><p><strong>Conclusion: </strong><i>TERT</i>-PM is rarer than <i>TERT</i>-RA but both are associated with HR-NB and poor prognosis. <i>MYCN-</i>A frequently co-occurs with <i>TERT</i>-PM and might represent an ultra-high-risk subset of patients.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500074"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12252578/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608396","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":"Physiologically Based Pharmacokinetic Model to Assess the Drug-Drug-Gene Interaction Potential of Belzutifan in Combination With Cyclin-Dependent Kinase 4/6 Inhibitors.","authors":"Darius Meiman, Todd C Skaar, Tyler Shugg, Sara K Quinney","doi":"10.1200/PO-25-00153","DOIUrl":"10.1200/PO-25-00153","url":null,"abstract":"<p><strong>Purpose: </strong>Belzutifan is a novel treatment for von Hippel-Lindau-associated cancers and is being evaluated in clinical trials for the treatment of renal cell carcinoma in combination with the cyclin-dependent kinase 4/6 inhibitors abemaciclib (ClinicalTrials.gov identifier: NCT04627064) and palbociclib (ClinicalTrials.gov identifier: NCT05468697). Belzutifan is metabolized via CYP2C19 and UGT2B17 and is a weak inducer of CYP3A. Induction of CYP3A is predicted to have a greater effect in dual CYP2C19/UGT2B17 poor metabolizers (PMs) relative to normal metabolizers (referred to as extensive metabolizers [EMs] in Simcyp). Our objective was to assess the drug-drug-gene interaction (DDGI) potential of belzutifan when coadministered with the CYP3A substrates abemaciclib and palbociclib in individuals with varying CYP2C19/UGT2B17 phenotypes.</p><p><strong>Methods: </strong>Physiologically based pharmacokinetic (PBPK) models for belzutifan, abemaciclib, and palbociclib were constructed in Simcyp v.21 and confirmed using data from US Food and Drug Administration reviews and previous publications. Virtual trials evaluating the area under the concentration-time curve from time 0 to infinity (AUC_0-inf) of single-dose palbociclib (125 mg) or abemaciclib (200 mg) alone and after 7 days of belzutifan (120 mg once daily) were simulated in healthy volunteers with differing CYP2C19/UGT2B17 phenotypes.</p><p><strong>Results: </strong>Compared with dual CYP2C19/UGT2B17 EMs, predicted belzutifan exposure increased approximately 4.4-fold in dual PMs. Belzutifan decreased the AUC_0-inf of abemaciclib by 24.3% and 52.2% in dual EMs and dual PMs, respectively, with the relative potency-adjusted unbound AUC_0-inf decreasing by 23.5% and 47.9%. Similarly, belzutifan decreased the AUC_0-inf of palbociclib by 13.2% and 36.8% in dual EMs and dual PMs, respectively.</p><p><strong>Conclusion: </strong>Our simulations predict that belzutifan decreases the exposure of combination therapies metabolized via CYP3A, with the severity of interaction dependent on CYP2C19 and UGT2B17 phenotypes.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500153"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144715078","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":"Immune Checkpoint Inhibitors in Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor-Resistant Chemotherapy-Naïve Advanced Non-Small Cell Lung Cancer: A Meta-Analysis Based on Eight Randomized Trials.","authors":"Letian Huang, Shuling Zhang, Li Sun, Jietao Ma, Chengbo Han","doi":"10.1200/PO-24-00907","DOIUrl":"10.1200/PO-24-00907","url":null,"abstract":"<p><strong>Purpose: </strong>The efficacy and safety of combination strategies involving immune checkpoint inhibitors (ICIs) in patients with advanced epidermal growth factor receptor (<i>EGFR</i>)-mutant non-small cell lung cancer (NSCLC) who have developed resistance to EGFR-tyrosine kinase inhibitors (TKIs) remains uncertain.</p><p><strong>Methods: </strong>We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing ICIs combined with chemotherapy with or without antiangiogenic therapy (C/A) versus C/A alone in the treatment of advanced NSCLC after resistance to EGFR-TKIs. We searched databases, including PubMed, Cochrane Library, Embase, Web of Science, and meeting abstracts. Hazard ratios (HRs) and 95% CI for median overall survival (OS) and median progression-free survival (PFS) were calculated. Risk ratios (RRs) and 95% CI were used as indicators of objective response rate (ORR) and adverse events (AEs).</p><p><strong>Results: </strong>Eight RCTs involving 10 cohorts and 2,269 patients were included. Adding ICIs to C/A significantly improved PFS (HR, 0.67 [95% CI, 0.57 to 0.80]; <i>P</i> < .001), OS (HR, 0.89 [95% CI, 0.79 to 0.99]; <i>P</i> = .031), and ORR (RR, 0.80 [95% CI, 0.74 to 0.88]; <i>P</i> < .001) comparedwith C/A alone. Subgroup analyses showed that the benefits were more pronounced in patients with PD-L1 expression ≥50%, specific <i>EGFR</i> mutations (Leu858Arg), absence of Thr790Met mutation, and treatment with pemetrexed-platinum. No significant increase in grade 3 or higher AEs was observed, but rates of discontinuation and specific AEs (rash, hypothyroidism, and hypertension) were significantly higher in the ICI+C/A group.</p><p><strong>Conclusion: </strong>This meta-analysis suggests that the addition of ICIs to C/A may improve survival outcomes in patients with advanced NSCLC after resistance to EGFR-TKIs, particularly in selected subpopulations such as those with high PD-L1 expression or specific <i>EGFR</i> mutations. However, careful monitoring for specific AEs is warranted.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2400907"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12262128/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608397","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":"Transcriptomic Predictors of Survival for Palbociclib + Endocrine Therapy Versus Capecitabine in Aromatase Inhibitor-Resistant Breast Cancer From the GEICAM/2013-02 PEARL Trial.","authors":"Yash N Agrawal, Aranzazu Fernández-Martínez, Miguel Gil-Gil, Christoph Zielinski, Manuel Ruiz-Borrego, Eva María Ciruelos, Montserrat Muñoz, Mireia Margelí, Begoña Bermejo, Antonio Antón, Zsuzsanna Kahan, Tibor Csöszi, José Luis Alonso-Romero, José Ángel García-Saenz, Pedro Sánchez-Rovira, Elena Álvarez, José Ignacio Chacón, Santiago González-Santiago, César A Rodríguez, Sonia Servitja, Adam D Pfefferle, Jesús Herranz, Yuan Liu, Lisa A Carey, Isabel Romero-Camarero, Rosalía Caballero, Ángel Guerrero-Zotano, Charles M Perou, Miguel Martín","doi":"10.1200/PO-24-00937","DOIUrl":"10.1200/PO-24-00937","url":null,"abstract":"<p><strong>Purpose: </strong>For hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (MBC), first-line cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) + endocrine therapy (ET) is the standard of care. They are also used after progression on first-line aromatase inhibitors (AIs), but some patients may respond better to chemotherapy-based options. We examined tumor features associated with survival from GEICAM/2013-02 PEARL, a phase III trial of palbociclib + ET versus capecitabine in AI-resistant HR+/HER2- MBC.</p><p><strong>Methods: </strong>For 158 and 155 patients from each arm, 878 previously published gene expression signatures were derived using RNA sequencing on pretreatment tumor specimens, both primary and metastatic. Multivariable Cox models for progression-free survival (PFS) and overall survival (OS) were constructed with 16 preselected signatures related to proliferation, loss of retinoblastoma, and immune infiltration, and via Elastic Net using all signatures.</p><p><strong>Results: </strong>Significant PFS difference by PAM50 intrinsic subtype was observed with palbociclib + ET. Comparing treatment arms, luminal A subtype trended toward longer PFS with palbociclib + ET, and luminal B and nonluminal subtypes had significantly longer PFS with capecitabine. Three B-cell (B-lymphocyte)-associated signatures correlated with shorter OS with palbociclib + ET. The immune-activated Immune1 TCGA breast cancer signature had significant treatment arm interaction for OS. Elastic Net iteratively selected B-cell-associated signatures independently associated with shorter OS with palbociclib + ET.</p><p><strong>Conclusion: </strong>PAM50 intrinsic subtype predicted PFS differences between palbociclib + ET and capecitabine. Lower B-cell-associated gene expression predicted longer OS with palbociclib + ET versus capecitabine. These features may help identify HR+/HER2- tumors resistant to further ET-based treatment with CDK4/6i.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2400937"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12261110/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600463","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":"Combination Therapy With Olaparib Plus Lenvatinib in a Patient With <i>BRCA2</i>-Mutated, Radioiodine-Refractory, Metastatic Papillary Thyroid Cancer: A Case Report.","authors":"Zachary Young, Jason Tasoulas, Marco Fajardo, Morgan Gwynn, Jacqueline Morris, Steven M Johnson, Siddharth Sheth","doi":"10.1200/PO-24-00802","DOIUrl":"https://doi.org/10.1200/PO-24-00802","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2400802"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144698602","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":"Genomic Landscape and Clinical Relevance in Chinese Patients With Upper Tract Urothelial Carcinoma.","authors":"Zhi Shang, Jian Pan, Shanshan Wang, Chengyuan Gu, Hailiang Zhang, Guohai Shi, Dalong Cao, Yu Zhu, Yao Zhu, Yijun Shen, Yiping Zhu, Shengming Jin, Junlong Wu, Dingwei Ye","doi":"10.1200/PO-25-00195","DOIUrl":"10.1200/PO-25-00195","url":null,"abstract":"<p><strong>Purpose: </strong>Upper tract urothelial carcinoma (UTUC) is one of the common urothelial cancers. Although large cohorts have illustrated spectrum of germline mutations, landscape of somatic alterations has not been revealed in Chinese patients with UTUC.</p><p><strong>Methods: </strong>This study involved 122 Chinese patients with UTUC. Paired tumor and germline DNA was sequenced to elucidate somatic mutation landscape, using targeted next-generation sequencing panel covering 520 cancer-related genes. We correlated specific gene mutations with clinicopathologic features, compared mutational signatures with previously reported data in other populations, and explored the similarities and differences in mutational signatures of UTUC originated from renal pelvis or ureter.</p><p><strong>Results: </strong>Somatic mutations were detected in 120/122 (98.4%) patients using this 520-gene panel sequencing. The top-ranking altered genes in Chinese patients with UTUC were <i>KMT2D</i> (48.4%), <i>TERT</i> promoter (46.7%), <i>FGFR3</i> (41.0%), and <i>TP53</i> (37.7%). Renal pelvis tumors had significantly higher <i>TERT</i> promoter (60.5% <i>v</i> 30.8%; <i>P</i> < .05) and <i>CDKN2A</i> (29.6% <i>v</i> 7.7%; <i>P</i> < .05) alteration frequency, while <i>TP53</i> (56.4% <i>v</i> 30.9%; <i>P</i> < .05) and <i>KMT2D</i> (76.9% <i>v</i> 35.8%; <i>P</i> < .001) gene mutations were enriched in patients with ureteral tumors. By comparing the mutational spectrum with Japanese and Western populations, we identified the unique genetic characteristics and potential precision treatment targets of the Chinese UTUC population. Finally, we found that patients with <i>TP53/MDM2</i>-mutant subtype or triple-negative subtype had significantly worse progression-free survival than other subtypes.</p><p><strong>Conclusion: </strong>This study elucidated genomic landscape of Chinese patients with UTUC and revealed similarity and disparity of genomic alterations with other populations. Our research lays the foundation for understanding UTUC in China and designing precise diagnosis and treatment.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500195"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144715077","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":"Elusive Promise of Predictive Biomarkers in Metastatic Urothelial Carcinoma.","authors":"Salvador Jaime-Casas, Shilpa Gupta","doi":"10.1200/PO-25-00305","DOIUrl":"https://doi.org/10.1200/PO-25-00305","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500305"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540258","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":"Intrapatient Variation in Response to Systemic Therapy in Advanced Hepatocellular Carcinoma.","authors":"Philip J Johnson, Ellen L Boswell","doi":"10.1200/PO-25-00015","DOIUrl":"https://doi.org/10.1200/PO-25-00015","url":null,"abstract":"<p><strong>Purpose: </strong>Progression-free survival (PFS) has been proposed as a surrogate end point in clinical trials for advanced hepatocellular carcinoma (aHCC). However, there have been concerns about the discrepancy between PFS and overall survival. Here, we aimed to characterize the behavior of individual lesions within the same patient/liver that play a key role in response assessment to a systemic treatment and how this changed temporally.</p><p><strong>Methods: </strong>We obtained serial lesion measurement data from six clinical trials undertaken in the modern era (by which we mean since the first controlled trial in aHCC). In each patient, the percentage change of their lesion size was calculated at each visit compared with the baseline/screening phase. To assess lesion behavior, the patients were classified according to the degree of divergence (DOD) categories that ranged from 0 (all lesions behaved similarly) to 2 (completely discordant behavior). Finally, the results were summarized per treatment arm as the proportion of patients in each divergence category per follow-up visit.</p><p><strong>Results: </strong>Of the 8,260 visits where DOD was assessed in patients, there was a considerable proportion of patients with divergent lesion behavior at the treatment arm level-approximately 58% were DOD 0, 38% were DOD 1, and 4% were DOD 2. Individually, there was evidence of lesions both increasing and decreasing in size within the same liver despite the treatment remaining the same.</p><p><strong>Conclusion: </strong>The evidence presented here suggests that caution should be exercised in the application of progression-based metrics such as PFS as an end point in HCC clinical trials. Ultimately, there was consistently a considerable proportion of patients who were classified as having lesions within their liver which had a divergent response to treatment.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500015"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649493","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":"Phase II Trial of TAS-102 in Colorectal Cancer Patients With Circulating Tumor DNA-Defined Minimal Residual Disease After Adjuvant Therapy: INTERCEPT-TT.","authors":"Andrew J Pellatt, Alisha Bent, Nicholas Hornstein, Christine Parseghian, Ryan Huey, Kanwal Raghav, Van Morris, Michael Overman, Pia Morelli, Jason Willis, Phat Le, John Paul Shen, Bryan Kee, Madhulika Eluri, Victoria Higbie, Kristin Alfaro-Munoz, Kathryn Aziz, Robert Kell, Ryan Sun, Scott Kopetz, Arvind Dasari","doi":"10.1200/PO-25-00142","DOIUrl":"10.1200/PO-25-00142","url":null,"abstract":"<p><strong>Purpose: </strong>To determine whether treatment with TAS-102 can induce circulating tumor DNA (ctDNA) clearance at 6 months and delay/prevent disease recurrence in colorectal cancer (CRC) patients with ctDNA-defined minimal residual disease (MRD) after completion of adjuvant therapy.</p><p><strong>Patients and methods: </strong>This was a single-arm, single-institution, phase II study. Fifteen patients with stage II to IV CRC and ctDNA-defined MRD after curative-intent therapy and adjuvant chemotherapy were enrolled prospectively. Participants received 6 months of therapy with TAS-102 35 mg/m² twice a day on days 1-5 and 8-12 of each 28-day cycle. Disease recurrence was monitored every 3 months with ctDNA and cross-sectional imaging. For comparison, 30 patients matched for key variables who received standard of care were retrospectively identified for a synthetic control (SC) cohort. The primary end point was 6-month ctDNA clearance. Secondary end points included 3-month ctDNA clearance, disease-free survival (DFS), and safety.</p><p><strong>Results: </strong>Among 15 patients enrolled, median age was 60.2 years (range, 37-73) and 80% were stage IV with an average of 2.1 lines of previous therapy (range, 1-3). At 3 and 6 months, respectively, seven (47%) and five (36%) patients had ctDNA clearance. In the SC, two patients (6.7%) had spontaneous ctDNA clearance at 3 months (<i>P</i> = .0034) sustained at 6 months (<i>P</i> = .025). Among patients receiving TAS-102, nine patients had radiographic recurrence with a median DFS of 9.4 months compared with 28 patients in the SC with radiographic recurrence and a median DFS of 5.75 months (<i>P</i> = .03).</p><p><strong>Conclusion: </strong>Additional treatment with TAS-102 after adjuvant chemotherapy in CRC patients with ctDNA-defined MRD can induce ctDNA clearance but this may be transient without long-term cures.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500142"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649494","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":"Relationship Among DNA Damage Response Gene Alterations, Molecular Subtypes, and Survival Outcomes in Patients With Metastatic Bladder Cancer Treated on CALGB 90601.","authors":"Gopa Iyer, Woonyoung Choi, Bin Luo, Filipe Carvalho, Timothy Hanlon, Henning Reis, Brendan J Guercio, Megan Fong, Jack Mountain, Mingxiao Feng, Ashley M Regazzi, Linda McCart, Yujia Wen, Hikmat Al-Ahmadie, Kent W Mouw, Eliezer M Van Allen, Joaquim Bellmunt, Robert Dreicer, Thomas W Flaig, Susan Halabi, David J McConkey, Jonathan E Rosenberg","doi":"10.1200/PO-24-00938","DOIUrl":"10.1200/PO-24-00938","url":null,"abstract":"<p><strong>Purpose: </strong>In urothelial carcinoma, prior studies have indicated that the basal/squamous molecular subtype and the presence of select DNA damage response (DDR) gene alterations are associated with improved benefit from cisplatin-based chemotherapy. We sought to evaluate these biomarkers in specimens from the phase III Cancer and Leukemia Group B (CALGB) 90601 trial.</p><p><strong>Methods: </strong>We performed whole-transcriptome sequencing (n = 188) and exon capture DNA sequencing (n = 208) on pretreatment tumors from the CALGB 90601 randomized trial of gemcitabine/cisplatin plus bevacizumab or placebo in patients with treatment-naïve metastatic bladder cancer. Whole-exome sequencing (WES) was performed on tumors from 22 patients who exhibited rapid progression or durable response. Tumors were assigned to molecular subtypes using three different classifiers. Proportional hazards model was used to correlate molecular subtype with overall survival (OS) and progression-free survival (PFS), adjusting for stratification factors and treatment arm (for PFS).</p><p><strong>Results: </strong>Patients with basal tumors had the shortest PFS and OS in the entire cohort. PFS was numerically longer in patients with basal tumors receiving bevacizumab. DDR gene alterations were not associated with improved outcomes. <i>FRY</i>, a candidate predictive biomarker of chemosensitivity identified by WES, did not confer sensitivity to cisplatin or gemcitabine in functional studies.</p><p><strong>Conclusion: </strong>Molecular subtype and DDR alterations did not correlate with improved outcomes in CALGB 90601. Possible explanations for these results include the small cohort size, lack of strong therapeutic effects of the treatments, genomic heterogeneity between profiled specimens and the metastatic lesions under treatment pressure, and differences in biology associated with different disease states (muscle-invasive <i>v</i> metastatic disease).</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2400938"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540260","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}