JCO precision oncology最新文献

{"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":"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":5.6,"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":"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}

{"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":"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":5.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12313172/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acknowledgment of Reviewers, 2025.","authors":"","doi":"10.1200/PO-25-00728","DOIUrl":"https://doi.org/10.1200/PO-25-00728","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500728"},"PeriodicalIF":5.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145053330","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":"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":"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":"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":"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":5.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12303246/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}