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Molecular Differences With Therapeutic Implications in Early-Onset Compared With Average-Onset Biliary Tract Cancers. 早发胆道癌与一般发病胆道癌的分子差异及其治疗意义
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-01 DOI: 10.1200/PO.24.00138
Thejus Jayakrishnan, Yasmine Baca, Joanne Xiu, Mehrie Patel, Benjamin A Weinberg, Emil Lou, Jashodeep Datta, Moh'd Khushman, Pat Gulhati, Sanjay Goel, Tiago Biachi de Castria, Vaia Florou, Kanika G Nair, Suneel D Kamath, Alok A Khorana

Purpose: Early-onset biliary tract cancer (eoBTC) is among the fast-growing subset of early-onset cancers, yet little is known about its biology. We sought to identify novel molecular characteristics of eoBTC in relation to average-onset BTC (aoBTC) using a real-world multiomics data set.

Methods: The study comprised patients with BTC whose tumors underwent molecular analyses at Caris Life Sciences and were categorized by age (<50 years for eoBTC, ≥50 years for aoBTC). P values were adjusted for multiple testing and considered significant at Q < 0.05 (molecular comparisons) or Q < 0.25 (Gene Set Enrichment Analysis [GSEA]). Insurance claims data were used for survival analysis.

Results: The study included 5,587 patients with BTC (453 eoBTC, median age = 44 years and 5,134 aoBTC, median age = 68 years). FGFR2 fusion (15.7% in eoBTC v 5.9% in aoBTC) and NIPBL fusion (1.1% v 0%) were significantly more prevalent in eoBTC (both Q < 0.001). The interferon gamma-IFG score (fold change [FC], 1.1; Q = 0.01) and T-cell inflammation score (FC, 17.3; Q = 0.03) were significantly higher in aoBTC. On GSEA, angiogenesis was enriched in eoBTC (normalized enrichment score [NES] = 1.51; Q = 0.16), whereas IFG (NES = -1.58; Q = 0.06) and inflammatory response (NES = -1.46; Q = 0.18) were enriched in aoBTC. The median overall survival (OS) was 16.5 (eoBTC) versus 13.3 months (aoBTC), hazard ratio = 0.86, P = .004. The median OS by FGFR2 fusion (with fusion v without) was 21.7 versus 15.0 months (P = .47) for eoBTC and 18.6 versus 12.2 months (P < .001) for aoBTC.

Conclusion: We identified crucial differences including higher prevalence of FGFR2 fusions in eoBTC and variations in immunotherapy-related markers. Better outcomes in eoBTC were affected by the FGFR2 fusion status. Our findings underscore the need for ensuring access to next-generation sequencing testing, including prompt identification of actionable targets.

目的:早发胆道癌(eoBTC)是快速增长的早发癌亚群之一,但人们对其生物学特性知之甚少。我们试图利用真实世界的多组学数据集确定 eoBTC 与平均发病胆道癌(aoBTC)的新分子特征:研究对象包括BTC患者,他们的肿瘤在Caris生命科学公司进行了分子分析,并按年龄进行了分类(P值经多重检验调整,在Q<0.05(分子比较)或Q<0.25(基因组富集分析[GSEA])时具有显著性)。保险理赔数据用于生存分析:研究共纳入 5587 例 BTC 患者(453 例 eoBTC,中位年龄 = 44 岁;5134 例 aoBTC,中位年龄 = 68 岁)。表皮生长因子受体 2 融合(eoBTC 为 15.7%,aoBTC 为 5.9%)和 NIPBL 融合(eoBTC 为 1.1%,aoBTC 为 0%)在 eoBTC 中的发生率明显更高(两者的 Q 值均小于 0.001)。干扰素γ-IFG评分(折叠变化[FC],1.1;Q = 0.01)和T细胞炎症评分(FC,17.3;Q = 0.03)在aoBTC中明显更高。在 GSEA 中,血管生成在 eoBTC 中富集(归一化富集得分 [NES] = 1.51;Q = 0.16),而 IFG(NES = -1.58; Q = 0.06)和炎症反应(NES = -1.46; Q = 0.18)在 aoBTC 中富集。中位总生存期(OS)为16.5个月(eoBTC)对13.3个月(aoBTC),危险比=0.86,P=0.004。FGFR2融合(融合与未融合)的中位OS:eoBTC为21.7个月对15.0个月(P = .47),aoBTC为18.6个月对12.2个月(P < .001):我们发现了一些关键的差异,包括 eoBTC 中 FGFR2 融合的发生率更高,以及免疫疗法相关标志物的变化。FGFR2融合状态会影响eoBTC更好的预后。我们的研究结果强调了确保获得新一代测序检测的必要性,包括及时发现可采取行动的靶点。
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引用次数: 0
Efficacy of Trametinib in Neurofibromatosis Type 1-Associated Gastrointestinal Stromal Tumors: A Case Report. 特瑞米尼对神经纤维瘤病 1 型相关胃肠道间质瘤的疗效:病例报告。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-01 DOI: 10.1200/PO.23.00649
Misao Fukuda, Toru Mukohara, Takeshi Kuwata, Kuniko Sunami, Yoichi Naito

Trametinib, an MEK inhibitor, may offer a new therapeutic option for patients with NF1-related GIST.

MEK抑制剂Trametinib可为NF1相关GIST患者提供一种新的治疗选择。
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引用次数: 0
Lymphocyte Infiltration Score and Spatial Characteristics Refined the Prognosis and Denosumab Treatment Responsiveness Indicators for Giant Cell Tumor of Bone. 淋巴细胞浸润评分和空间特征完善了骨巨细胞瘤的预后和地诺单抗治疗反应性指标
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-01 DOI: 10.1200/PO.24.00135
Hai-Lin Wu, Chao Xia, Fu-Sheng Liu, Bo-Yv Zheng, Hua-Qing Niu, Guo-Qiang Zhu, Ming-Xiang Zou, Bo-Wen Zheng

Purpose: The prognostic value of lymphocyte infiltration score (LIS) and its nearest neighbor distance to tumor cells (NNDTC) in giant cell tumor of bone (GCTB) is currently not well established. This study aims to characterize LIS and NNDTC and examine their correlation with denosumab treatment responsiveness, clinicopathologic features, and patient prognosis.

Methods: Using multiplexed quantitative immunofluorescence, LIS was evaluated in 253 tumor specimens, whereas NNDTC was computed using HALO software. Subsequently, we analyzed the association of these parameters with patient outcomes (progression-free survival [PFS] and overall survival [OS]), clinicopathologic features, and denosumab treatment responsiveness.

Results: Low LIS was indicative of both poor PFS and OS (both P < .001). In addition, LIS was significantly associated with sex (P = .046), Enneking staging (P < .001), Ki-67 expression (P = .007), and denosumab treatment responsiveness (P = .005). Lower CD8+ (tumor interior [TI]) NNDTC, and CD3+ (TI) NNDTC were associated with worse PFS (P = .003 and .038, respectively), whereas lower CD8+ (TI) NNDTC was associated with worse OS (P = .001), but CD8+ (tumor infiltrating margin) NNDTC had the opposite effect (P = .002). Moreover, NNDTC showed a correlation with several clinicopathologic features. Importantly, LIS outperformed Enneking and Campanacci staging systems in predicting the clinical outcomes of GCTB.

Conclusion: These findings suggest that LIS is a reliable predictive tool for clinically relevant outcomes and response to denosumab therapy in patients with GCTB. These parameters may prove to be useful in guiding prognostic risk stratification and therapeutic optimization for patients.

目的:淋巴细胞浸润评分(LIS)及其与肿瘤细胞的近邻距离(NNDTC)在骨巨细胞瘤(GCTB)中的预后价值目前尚未明确。本研究旨在描述 LIS 和 NNDTC 的特征,并研究它们与地诺单抗治疗反应性、临床病理特征和患者预后的相关性:方法: 我们使用多重定量免疫荧光技术评估了 253 例肿瘤标本中的 LIS,并使用 HALO 软件计算了 NNDTC。随后,我们分析了这些参数与患者预后(无进展生存期[PFS]和总生存期[OS])、临床病理特征和地诺单抗治疗反应性之间的关系:结果:低LIS表明患者的PFS和OS均较差(P均<0.001)。此外,LIS与性别(P = .046)、Enneking分期(P < .001)、Ki-67表达(P = .007)和denosumab治疗反应性(P = .005)有明显相关性。CD8+(肿瘤内部 [TI])较低的 NNDTC 和 CD3+(TI)较低的 NNDTC 与较差的 PFS 相关(分别为 P = .003 和 .038),而 CD8+(TI)较低的 NNDTC 与较差的 OS 相关(P = .001),但 CD8+(肿瘤浸润边缘)较低的 NNDTC 具有相反的影响(P = .002)。此外,NNDTC 还与多种临床病理特征相关。重要的是,LIS在预测GCTB的临床结果方面优于Enneking和Campanacci分期系统:这些研究结果表明,LIS 是预测 GCTB 患者临床相关预后和对地诺单抗治疗反应的可靠工具。这些参数可能有助于指导患者进行预后风险分层和优化治疗。
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引用次数: 0
A Targeted Methylation-Based Multicancer Early Detection Blood Test Preferentially Detects High-Grade Prostate Cancer While Minimizing Overdiagnosis of Indolent Disease. 一种基于目标甲基化的多癌症早期检测血液检验能优先检测高级别前列腺癌,同时最大限度地减少对隐匿性疾病的过度诊断。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-01 DOI: 10.1200/PO.24.00269
Brandon A Mahal, Matthew Margolis, Earl Hubbell, Cheng Chen, Jeffrey M Venstrom, John Abran, Jordan J Kartlitz, Alexander W Wyatt, Eric A Klein

Purpose: Indolent prostate cancer (PCa) is prevalent in the intended use population (adults age 50-79 years) for blood-based multicancer early detection (MCED) tests. We examined the detectability of PCa by a clinically validated, targeted methylation-based MCED test.

Methods: Detectability by Gleason grade group (GG), clinical stage, association of detection status with tumor methylated fraction (TMeF), and overall survival (OS) were assessed in substudy 3 of Circulating Cell-Free Genome Atlas (CCGA; ClinicalTrials.gov identifier: NCT02889978) and PATHFINDER (ClinicalTrials.gov identifier: NCT04241796) studies.

Results: Test sensitivity for PCa in substudy 3 of CCGA was 11.2% (47/420). The test detected 0 (0%) of 58 low-grade (GG1), 3 (1.9%) of 157 favorable intermediate-grade (GG2), 4 (5.1%) of 78 unfavorable intermediate-grade (GG3), and 36 (31.9%) of 113 high-grade (GG4 and 5) cancers and 3 (3.2%) of 95 stage I, 11 (4.7%) of 235 stage II, 7 (14.9%) of 47 stage III, and 22 (81.5%) of 27 stage IV cases. The median TMeF was higher for detected than nondetected cases (2,106.0 parts per million [PPM]; IQR, 349.8-24,376.3 v 24.4 PPM; IQR, 17.8-38.5; P < .05). Nondetected cases had better OS (P < .05; hazard ratio [HR], 0.263 [95% CI, 0.104 to 0.533]) and detected cases had similar survival (P = .2; HR, 0.672 [95% CI, 0.323 to 1.21]) compared with SEER adjusted for age, GG, and stage. Performance was similar in PATHFINDER, with no detected GG1/2 (0/13) or stage I/II (0/16) cases.

Conclusion: This MCED test preferentially detects high-grade, clinically significant PCa. Use in population-based screening programs in addition to standard-of-care screening is unlikely to exacerbate overdiagnosis of indolent PCa.

目的:在基于血液的多癌症早期检测(MCED)试验的预期使用人群(50-79 岁的成年人)中,多见偶发性前列腺癌(PCa)。我们研究了一种经过临床验证的、基于甲基化靶向的 MCED 检验对 PCa 的检测能力:方法:在循环无细胞基因组图谱(CCGA;ClinicalTrials.gov identifier:NCT02889978)和PATHFINDER(ClinicalTrials.gov identifier:NCT04241796)研究的子研究3中,按格里森分级组(GG)、临床分期、检测状态与肿瘤甲基化率(TMeF)的关系以及总生存率(OS)评估了检测能力:CCGA子研究3的PCa检测灵敏度为11.2%(47/420)。该检测发现了 58 例低度癌(GG1)中的 0 例(0%)、157 例中度癌(GG2)中的 3 例(1.9%)、78 例中度癌(GG3)中的 4 例(5.1%)和 113 例高级别癌(GG4 和 5)中的 36 例(31.9%),以及 95 例 I 期癌中的 3 例(3.2%)、235 例 II 期癌中的 11 例(4.7%)、47 例 III 期癌中的 7 例(14.9%)和 27 例 IV 期癌中的 22 例(81.5%)。检测到的病例的 TMeF 中值高于未检测到的病例(百万分之 2,106.0 [PPM];IQR,349.8-24,376.3 v 24.4 PPM;IQR,17.8-38.5;P < .05)。与根据年龄、GG 和分期调整的 SEER 相比,未检出病例的 OS 更好(P < .05;危险比 [HR],0.263 [95% CI,0.104 至 0.533]),检出病例的生存率相似(P = .2;HR,0.672 [95% CI,0.323 至 1.21])。在PATHFINDER中的表现类似,没有发现GG1/2(0/13)或I/II期(0/16)病例:结论:这种 MCED 检验能优先检测出高级别、有临床意义的 PCa。结论:该MCED检验能优先检测出高级别、有临床意义的PCa。在人群筛查项目中,除了标准治疗筛查外,使用该检验不太可能加剧对不太严重的PCa的过度诊断。
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引用次数: 0
False-Positive Circulating Tumor DNA Results Do Not Explain Lack of Efficacy for PARP Inhibitors in Patients With Castration-Resistant Prostate Cancer Harboring ATM and CHEK2 Mutations. 循环肿瘤DNA假阳性结果不能解释PARP抑制剂对携带ATM和CHEK2突变的阉割耐药前列腺癌患者缺乏疗效。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-01 DOI: 10.1200/PO.24.00354
Jaleh Fallah, Jianjin Xu, Hee-Koung Joeng, Chana Weinstock, Brian L Heiss, William F Maguire, Xin Gao, Joyce Cheng, Elaine Chang, Sundeep Agrawal, Mallorie H Fiero, Richard Pazdur, Paul G Kluetz, Laleh Amiri-Kordestani, Daniel L Suzman

False-positive ctDNA results do not explain lack of efficacy for PARPi in patients with ATMm and CHEK2m CRPC.

ctDNA假阳性结果并不能解释PARPi对ATMm和CHEK2m CRPC患者缺乏疗效。
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引用次数: 0
Landscape of Concomitant Driver Alterations in Classical EGFR-Mutated Non-Small Cell Lung Cancer. 典型表皮生长因子受体突变非小细胞肺癌中并发驱动基因改变的情况
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-01 DOI: 10.1200/PO.23.00520
Huaying Wang, Lie Lin, Chuqiao Liang, Jiaohui Pang, Jiani C Yin, Junli Zhang, Yang Shao, Chengming Sun, Renhua Guo

Purpose: Next-generation sequencing (NGS) has enabled the detection of concomitant driver alterations in non-small cell lung cancer (NSCLC). However, the magnitude and clinical relevance of concomitant drivers remain to be explored.

Methods: We profiled concomitant driver alterations of EGFR+ NSCLC by using targeted NGS. The associated genomic and clinical features were analyzed and validated in an independent The Cancer Genome Atlas cohort of patients with EGFR+ NSCLC.

Results: Out of the total patient population, 334 patients had EGFR mutations along with concomitant driver mutations, comprising 3.09% of the entire cohort. The most frequent co-occurring mutations with sensitizing EGFR mutations include KRAS at 53.9%, followed by ERBB2 at 24.3%, MET at 16.5%, and BRAF at 3.3%. KRAS mutations in concomitant drivers were frequently hyperexchange mutations (25.6% v 8.2%, P < .001), compared with KRAS single drivers. EGFR/ERBB2 drivers exhibited a higher incidence of ERBB2 amplification (40.7% v 16.5%, P < .001) and p.S310F/Y mutations (44.4% v 4.3%, P < .001) compared with ERBB2 alone. EGFR/MET drivers had a higher frequency of MET amplification (71.4% v 43.3%) than MET single drivers. At the genomic level, the median number of additional concurrent mutations was four, with TSC2 (4%), CD274 (1%), and TP53 (63%) being the most frequently coaltered genes in concomitant driver tumors. Interestingly, clonality analysis indicated that EGFR mutations were more likely to occur as clonal events, whereas the codrivers were more often subclonal. Patients with concomitant drivers or with concomitant MET amplification exhibited worse prognosis.

Conclusion: These findings might aid in the selection of effective therapeutic regimens and facilitate the development of combination therapies.

目的:下一代测序(NGS)能够检测非小细胞肺癌(NSCLC)中的并发驱动基因改变。然而,并发驱动基因的程度和临床相关性仍有待探索:方法:我们利用靶向 NGS 分析了表皮生长因子受体(EGFR)+ NSCLC 的伴随驱动基因改变。我们在癌症基因组图谱(The Cancer Genome Atlas)的一个独立的表皮生长因子受体(EGFR)+ NSCLC 患者队列中分析并验证了相关的基因组和临床特征:结果:在所有患者中,有334名患者的表皮生长因子受体突变同时伴有驱动基因突变,占整个队列的3.09%。最常与致敏表皮生长因子受体突变同时发生的突变包括KRAS突变(53.9%)、ERBB2突变(24.3%)、MET突变(16.5%)和BRAF突变(3.3%)。与 KRAS 单个驱动因子相比,并发驱动因子中的 KRAS 基因突变经常是低变异突变(25.6% 对 8.2%,P < .001)。与ERBB2单独驱动相比,EGFR/ERBB2驱动表现出更高的ERBB2扩增发生率(40.7% v 16.5%,P < .001)和p.S310F/Y突变发生率(44.4% v 4.3%,P < .001)。表皮生长因子受体/MET驱动者的MET扩增频率(71.4% v 43.3%)高于MET单一驱动者。在基因组水平上,额外并发突变的中位数为 4 个,TSC2(4%)、CD274(1%)和 TP53(63%)是并发驱动肿瘤中最常见的变异基因。有趣的是,克隆性分析表明,表皮生长因子受体突变更有可能作为克隆事件发生,而同源基因突变则更常见于亚克隆。伴有驱动基因或伴有MET扩增的患者预后较差:这些发现可能有助于选择有效的治疗方案,并促进联合疗法的开发。
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引用次数: 0
Current Landscape of Antibody-Drug Conjugate Development in Head and Neck Cancer. 头颈癌抗体药物共轭物开发的现状。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-01 DOI: 10.1200/PO.24.00179
Jong Chul Park, Donghoon Shin

Antibody-drug conjugates (ADCs) are fusions of therapeutic drugs and antibodies conjugated by a linker, designed to deliver a therapeutic payload to cells expressing the target antigen. By delivering the highly cytotoxic agent directly to cancer cells, ADCs are designed to enhance safety and broaden the therapeutic window. Recently, ADCs have demonstrated promising efficacy in various solid tumors and are rapidly expanding their indications. The prognosis of patients with advanced head and neck squamous cell carcinoma (HNSCC) remains poor, with no new therapeutics since the advent of anti-PD-1 antibodies in 2016, highlighting a critical need for innovative therapies. Recent preliminary results suggest that ADCs could be promising treatment options for HNSCC as they explore a variety of target antigens, payloads, and linkers. However, for successful adaptation of ADCs in the treatment of HNSCC, addressing key challenges such as payload toxicities, antigen heterogeneity, and adaptive resistance will be essential. Current research focused on new ADC structures, including multispecific antibodies and noncytotoxic payloads, and diverse combination approaches, show promise for future advancements.

抗体药物共轭物(ADCs)是治疗药物和抗体通过连接体共轭的融合体,旨在向表达靶抗原的细胞输送治疗载荷。通过直接向癌细胞输送高细胞毒性药物,ADCs 可提高安全性并扩大治疗窗口期。最近,ADC 在各种实体瘤中显示出良好的疗效,并迅速扩大了其适应症。晚期头颈部鳞状细胞癌(HNSCC)患者的预后仍然很差,自2016年抗PD-1抗体问世以来一直没有新的疗法,这凸显了对创新疗法的迫切需求。最近的初步研究结果表明,ADCs可能是治疗HNSCC的有前途的选择,因为它们探索了多种靶抗原、有效载荷和连接体。然而,要成功将 ADCs 用于治疗 HNSCC,解决有效载荷毒性、抗原异质性和适应性抗药性等关键挑战至关重要。目前的研究重点是新型 ADC 结构,包括多特异性抗体和非细胞毒性有效载荷,以及多样化的组合方法,这些都为未来的进步带来了希望。
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引用次数: 0
Identification and Validation of Prognostic Model for Tumor Microenvironment-Associated Genes in Bladder Cancer Based on Single-Cell RNA Sequencing Data Sets. 基于单细胞RNA测序数据集的膀胱癌肿瘤微环境相关基因预后模型的鉴定与验证
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-01 DOI: 10.1200/PO.23.00661
Imran Safder, Henkel Valentine, Nicole Uzzo, John Sfakianos, Robert Uzzo, Shilpa Gupta, Jason Brown, Daniel Ranti, Elizabeth Plimack, George Haber, Christopher Weight, Alexander Kutikov, Philip Abbosh, Laura Bukavina

Purpose: The purpose of this study was to elucidate the relationship between the tumor microenvironment (TME) and cellular diversity in bladder cancer (BLCA) progression, leveraging single-cell RNA sequencing (scRNA-seq) data to identify potential prognostic biomarkers and construct a prognostic model for BLCA.

Methods: We analyzed scRNA-seq data of normal and tumor bladder cells from the Gene Expression Omnibus (GEO) database to uncover crucial markers within the bladder TME. The study compared gene expression in normal versus tumor bladder cells, identifying differentially expressed genes. These genes were subsequently assessed for their prognostic significance using patient follow-up data from The Cancer Genome Atlas. Prognostic models were constructed using Least Absolute Shrinkage and Selection Operator and multivariate Cox regression analyses, focusing on eight genes of interest. The predictive performance of the model was also tested against additional GEO data sets (GSE31684, GSE13507, and GSE32894).

Results: The prognostic model demonstrated reliable prediction of patient outcomes. Validation through gene set enrichment analysis and immune cell infiltration assessment supported the model's efficacy. The results from both the univariate and multivariate analyses suggest that the risk score is an independent prognostic factor with a hazard ratio of 2.97 (95% CI, 2.28 to 3.9, P < .001). In the validation cohort, the AUC at 1, 2, and 3 years is 0.74, 0.74, and 0.72, respectively.

Conclusion: Our findings proposed biomarkers with prognostic potential, laying the groundwork for future in vitro validation and therapeutic exploration. This contributes to a deeper understanding of the genes associated with bladder TME and may improve prognostic precision in BLCA management.

目的:本研究旨在阐明肿瘤微环境(TME)与膀胱癌(BLCA)进展过程中细胞多样性之间的关系,利用单细胞RNA测序(scRNA-seq)数据确定潜在的预后生物标志物,并构建BLCA的预后模型:我们分析了基因表达总库(GEO)数据库中正常和肿瘤膀胱细胞的scRNA-seq数据,以发现膀胱TME中的关键标记物。研究比较了正常膀胱细胞和肿瘤膀胱细胞的基因表达,确定了不同表达的基因。随后,利用癌症基因组图谱(The Cancer Genome Atlas)中的患者随访数据对这些基因的预后意义进行了评估。利用最小绝对缩减和选择操作器以及多变量考克斯回归分析构建了预后模型,重点分析了八个相关基因。该模型的预测性能还通过其他 GEO 数据集(GSE31684、GSE13507 和 GSE32894)进行了测试:结果:预后模型对患者的预后进行了可靠的预测。通过基因组富集分析和免疫细胞浸润评估验证了该模型的有效性。单变量和多变量分析结果表明,风险评分是一个独立的预后因素,其危险比为 2.97(95% CI,2.28 至 3.9,P < .001)。在验证队列中,1年、2年和3年的AUC分别为0.74、0.74和0.72:我们的研究结果提出了具有预后潜力的生物标志物,为未来的体外验证和治疗探索奠定了基础。这有助于加深对膀胱TME相关基因的理解,并可提高BLCA管理的预后精确度。
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引用次数: 0
Kinetic Profiling of RAS Mutations With Circulating Tumor DNA in the Canadian Cancer Trials Group CO.26 Trial Suggests the Loss of RAS Mutations in Neo-RAS-Wildtype Metastatic Colorectal Cancer Is Transient. 加拿大癌症试验小组 CO.26 试验中利用循环肿瘤 DNA 对 RAS 基因突变进行的动力学分析表明,新 RAS 野生型转移性结直肠癌中 RAS 基因突变的缺失是短暂的。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-01 DOI: 10.1200/PO.24.00031
Florence T H Wu, James T Topham, Chris J O'Callaghan, Harriet Feilotter, Hagen F Kennecke, Leylah Drusbosky, Daniel J Renouf, Derek J Jonker, Dongsheng Tu, Eric X Chen, Jonathan M Loree

Purpose: In metastatic colorectal cancer (mCRC), RAS mutations drive resistance to anti-epidermal growth factor receptor antibodies. It is unclear whether RAS mutations ever become clonally undetectable.

Methods: CO.26 was a phase II clinical trial that assessed durvalumab + tremelimumab in heavily pretreated mCRC. RAS mutation status was tracked over time using circulating tumor DNA (ctDNA) sequencing at baseline, week 8, and on progression.

Results: Among the 95 patients with KRAS/NRAS mutations in their archival tumor tissue, 6.3% (6/95) had undetectable RAS mutations in ctDNA collected at baseline or week 8 of the CO.26 study. Of these, 67% (4/6) of disappearances were transient, with the same mutation reappearing with progressive disease. In three cases, the simultaneous persistence of other preexisting CRC-associated truncal mutations could not be demonstrated, suggestive of low tumor shedding of ctDNA, leaving the incidence of true clonal reversion to RAS-wildtype (WT) possibly as low as 3.2% (3/95). Fewer patients in the neo-RAS-WT group (33%) had greater than four lesions at trial baseline compared with patients with persistent RAS mutations (75%), P = .046. The likelihood of synchronous metastases at cancer diagnosis (33% v 63%; P = .15) or liver metastases at trial baseline (50% v 68.5%; P = .17) was not significantly different between patients with disappearing versus persistent RAS mutations. Overall survival from stage IV diagnosis (hazard ratio, 0.77 [95% CI, 0.35 to 1.72]; P = .52) was not significantly different between those with disappearing versus persistent RAS mutations. The disappearance of RAS mutations was not associated with primary tumor sidedness (P = .41), archival BRAF/MEK/ERK-mutant status (P = .16/1.00/.09), nor baseline ctDNA HER2 amplifications (P = 1.00).

Conclusion: We identified a 3.2%-6.3% prevalence of the neo-RAS-WT phenomenon in the CO.26 trial. However, 67% of apparent cases were transient with subsequent re-emergence.

目的:在转移性结直肠癌(mCRC)中,RAS突变会导致患者对抗表皮生长因子受体抗体产生耐药性。目前还不清楚RAS突变是否会导致克隆检测不到:CO.26是一项II期临床试验,评估了杜伐单抗+曲妥珠单抗在重度预处理mCRC中的疗效。在基线、第8周和进展期使用循环肿瘤DNA(ctDNA)测序对RAS突变状态进行长期追踪:在存档肿瘤组织中存在 KRAS/NRAS 突变的 95 例患者中,6.3%(6/95)在 CO.26 研究的基线或第 8 周采集的 ctDNA 中检测不到 RAS 突变。其中,67%(4/6)的突变消失是短暂的,随着疾病的进展,同一突变会再次出现。在三个病例中,无法证明同时存在其他先前存在的与 CRC 相关的截断突变,这表明肿瘤脱落的 ctDNA 很低,因此真正克隆还原为 RAS-野生型(WT)的发生率可能低至 3.2%(3/95)。与RAS突变持续存在的患者(75%)相比,新RAS-WT组在试验基线时病变超过4个的患者较少(33%),P = .046。癌症诊断时同步转移的可能性(33% 对 63%;P = .15)或试验基线时肝脏转移的可能性(50% 对 68.5%;P = .17)在RAS突变消失和持续存在的患者之间没有显著差异。从 IV 期诊断开始的总生存期(危险比为 0.77 [95% CI, 0.35 至 1.72];P = .52)在 RAS 突变消失与持续存在的患者之间没有明显差异。RAS突变的消失与原发肿瘤的偏侧(P = .41)、存档的BRAF/MEK/ERK突变状态(P = .16/1.00/.09)以及基线ctDNA HER2扩增(P = 1.00)无关:我们在CO.26试验中发现新RAS-WT现象的发生率为3.2%-6.3%。结论:我们在 CO.26 试验中发现了 3.2%-6.3% 的新 RAS-WT 现象,但 67% 的明显病例是一过性的,随后又重新出现。
{"title":"Kinetic Profiling of <i>RAS</i> Mutations With Circulating Tumor DNA in the Canadian Cancer Trials Group CO.26 Trial Suggests the Loss of <i>RAS</i> Mutations in Neo-<i>RAS</i>-Wildtype Metastatic Colorectal Cancer Is Transient.","authors":"Florence T H Wu, James T Topham, Chris J O'Callaghan, Harriet Feilotter, Hagen F Kennecke, Leylah Drusbosky, Daniel J Renouf, Derek J Jonker, Dongsheng Tu, Eric X Chen, Jonathan M Loree","doi":"10.1200/PO.24.00031","DOIUrl":"10.1200/PO.24.00031","url":null,"abstract":"<p><strong>Purpose: </strong>In metastatic colorectal cancer (mCRC), <i>RAS</i> mutations drive resistance to anti-epidermal growth factor receptor antibodies. It is unclear whether <i>RAS</i> mutations ever become clonally undetectable.</p><p><strong>Methods: </strong>CO.26 was a phase II clinical trial that assessed durvalumab + tremelimumab in heavily pretreated mCRC. <i>RAS</i> mutation status was tracked over time using circulating tumor DNA (ctDNA) sequencing at baseline, week 8, and on progression.</p><p><strong>Results: </strong>Among the 95 patients with <i>KRAS/NRAS</i> mutations in their archival tumor tissue, 6.3% (6/95) had undetectable <i>RAS</i> mutations in ctDNA collected at baseline or week 8 of the CO.26 study. Of these, 67% (4/6) of disappearances were transient, with the same mutation reappearing with progressive disease. In three cases, the simultaneous persistence of other preexisting CRC-associated truncal mutations could not be demonstrated, suggestive of low tumor shedding of ctDNA, leaving the incidence of true clonal reversion to <i>RAS</i>-wildtype (WT) possibly as low as 3.2% (3/95). Fewer patients in the neo-<i>RAS</i>-WT group (33%) had greater than four lesions at trial baseline compared with patients with persistent <i>RAS</i> mutations (75%), <i>P</i> = .046. The likelihood of synchronous metastases at cancer diagnosis (33% <i>v</i> 63%; <i>P</i> = .15) or liver metastases at trial baseline (50% <i>v</i> 68.5%; <i>P</i> = .17) was not significantly different between patients with disappearing versus persistent <i>RAS</i> mutations. Overall survival from stage IV diagnosis (hazard ratio, 0.77 [95% CI, 0.35 to 1.72]; <i>P</i> = .52) was not significantly different between those with disappearing versus persistent <i>RAS</i> mutations. The disappearance of <i>RAS</i> mutations was not associated with primary tumor sidedness (<i>P</i> = .41), archival <i>BRAF/MEK/ERK</i>-mutant status (<i>P</i> = .16/1.00/.09), nor baseline ctDNA <i>HER2</i> amplifications (<i>P</i> = 1.00).</p><p><strong>Conclusion: </strong>We identified a 3.2%-6.3% prevalence of the neo-<i>RAS</i>-WT phenomenon in the CO.26 trial. However, 67% of apparent cases were transient with subsequent re-emergence.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400031"},"PeriodicalIF":5.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11371075/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142043914","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}
引用次数: 0
Urachal and Nonurachal Adenocarcinomas of the Urinary Bladder: A Comprehensive Genomic Profiling Study. 膀胱尿道腺癌和非尿道腺癌:综合基因组剖析研究
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-01 DOI: 10.1200/PO.24.00200
Antonio Cigliola, Alina Basnet, Joseph M Jacob, Chiara Mercinelli, Valentina Tateo, Damiano Alfio Patanè, Gennady Bratslavsky, Liang Cheng, Petros Grivas, Ashish M Kamat, Philippe E Spiess, Dean C Pavlick, Douglas I Lin, Jeffrey S Ross, Andrea Necchi

Purpose: Although both urachal (U) and nonurachal (NU) bladder adenocarcinomas (adenoCas) share several histologic similarities, they differ in location and sometimes in therapeutic options. We analyzed the differences in genomic alterations (GAs) between these tumor entities, with the aim of identifying potential therapeutic targets for clinical trials.

Materials and methods: Overall, 133 U and 328 NU adenoCas were analyzed. Hybrid capture-based comprehensive genomic profiling (CGP) was performed to evaluate all classes of GA. Germline status of GA was predicted using a validated somatic-germline computational method. CGP was performed using the FoundationOne and FoundationOne CDx assays (Foundation Medicine, Inc).

Results: The most frequent GA in both U and NU cohorts included TP53 (86.5% v 81.1%) and KRAS (34.6% v 27.7%). GAs characteristic of colorectal adenoCa, such as SMAD4 (P = .069) and GNAS (P = .071), were more common in U versus NU. Conversely, TERT (P < .01) and RB1 (P = .071) were more prevalent in NU adenoCa. Notably, both U and NU adenoCas exhibited possibly targetable GA in PIK3CA (7.5% v 7.9%) and ERBB2 (6.8% v 7.6%). Biomarkers associated with potential benefit from anti-PD-1/L1 were infrequent. Median tumor mutational burden was 2.6 and 3.5 mutations per megabase for U and NU, respectively, and PD-L1 expression >1% was rare. Genomic ancestry and genomic signature distribution were similar in both tumor types. GAs were most commonly of somatic nature. Limitations include lack of clinical data, tumor heterogeneity, and retrospective nature.

Conclusion: U and NU adenoCAs revealed differences in GA, with PIK3CA and ERBB2 being identified as putative therapeutic targets. Biomarkers of response to anti-PD-(L)1 were uncommon. Results highlight the potential of CGP to personalize treatment options of bladder adenoCa and inform clinical trial designs.

目的:虽然尿道(U)膀胱腺癌(adenoCas)和非尿道(NU)膀胱腺癌(adenoCas)在组织学上有一些相似之处,但它们的位置不同,有时治疗方案也不同。我们分析了这些肿瘤实体之间基因组改变(GAs)的差异,目的是为临床试验确定潜在的治疗靶点:总共分析了 133 例 U 型腺癌和 328 例 NU 型腺癌。进行了基于混合捕获的综合基因组图谱分析(CGP),以评估所有类别的GA。使用经过验证的体细胞-种系计算方法预测 GA 的种系状态。CGP使用FoundationOne和FoundationOne CDx测定(Foundation Medicine, Inc)进行:结果:在 U 和 NU 队列中,最常见的 GA 包括 TP53(86.5% 对 81.1%)和 KRAS(34.6% 对 27.7%)。具有结直肠腺癌特征的GA,如SMAD4(P = .069)和GNAS(P = .071),在U组和NU组中更为常见。相反,TERT(P < .01)和 RB1(P = .071)在 NU 腺癌中更为常见。值得注意的是,U腺癌和NU腺癌中的PIK3CA(7.5% v 7.9%)和ERBB2(6.8% v 7.6%)都表现出可能的靶向性GA。与抗 PD-1/L1 潜在获益相关的生物标志物并不常见。U和NU的中位肿瘤突变负荷分别为2.6和3.5个突变/兆碱基,PD-L1表达>1%的情况很少见。两种肿瘤类型的基因组祖先和基因组特征分布相似。体细胞基因组特征最常见。不足之处包括缺乏临床数据、肿瘤异质性和回顾性:结论:U腺癌和NU腺癌显示出GA的差异,PIK3CA和ERBB2被确定为潜在的治疗靶点。对抗PD-(L)1反应的生物标志物并不常见。研究结果凸显了CGP在个性化膀胱腺癌治疗方案和临床试验设计方面的潜力。
{"title":"Urachal and Nonurachal Adenocarcinomas of the Urinary Bladder: A Comprehensive Genomic Profiling Study.","authors":"Antonio Cigliola, Alina Basnet, Joseph M Jacob, Chiara Mercinelli, Valentina Tateo, Damiano Alfio Patanè, Gennady Bratslavsky, Liang Cheng, Petros Grivas, Ashish M Kamat, Philippe E Spiess, Dean C Pavlick, Douglas I Lin, Jeffrey S Ross, Andrea Necchi","doi":"10.1200/PO.24.00200","DOIUrl":"https://doi.org/10.1200/PO.24.00200","url":null,"abstract":"<p><strong>Purpose: </strong>Although both urachal (U) and nonurachal (NU) bladder adenocarcinomas (adenoCas) share several histologic similarities, they differ in location and sometimes in therapeutic options. We analyzed the differences in genomic alterations (GAs) between these tumor entities, with the aim of identifying potential therapeutic targets for clinical trials.</p><p><strong>Materials and methods: </strong>Overall, 133 U and 328 NU adenoCas were analyzed. Hybrid capture-based comprehensive genomic profiling (CGP) was performed to evaluate all classes of GA. Germline status of GA was predicted using a validated somatic-germline computational method. CGP was performed using the FoundationOne and FoundationOne CDx assays (Foundation Medicine, Inc).</p><p><strong>Results: </strong>The most frequent GA in both U and NU cohorts included <i>TP53</i> (86.5% <i>v</i> 81.1%) and <i>KRAS</i> (34.6% <i>v</i> 27.7%). GAs characteristic of colorectal adenoCa, such as <i>SMAD4</i> (<i>P</i> = .069) and <i>GNAS</i> (<i>P</i> = .071), were more common in U versus NU. Conversely, <i>TERT</i> (<i>P</i> < .01) and <i>RB1</i> (<i>P</i> = .071) were more prevalent in NU adenoCa. Notably, both U and NU adenoCas exhibited possibly targetable GA in <i>PIK3CA</i> (7.5% <i>v</i> 7.9%) and <i>ERBB2</i> (6.8% <i>v</i> 7.6%). Biomarkers associated with potential benefit from anti-PD-1/L1 were infrequent. Median tumor mutational burden was 2.6 and 3.5 mutations per megabase for U and NU, respectively, and PD-L1 expression >1% was rare. Genomic ancestry and genomic signature distribution were similar in both tumor types. GAs were most commonly of somatic nature. Limitations include lack of clinical data, tumor heterogeneity, and retrospective nature.</p><p><strong>Conclusion: </strong>U and NU adenoCAs revealed differences in GA, with <i>PIK3CA</i> and <i>ERBB2</i> being identified as putative therapeutic targets. Biomarkers of response to anti-PD-(L)1 were uncommon. Results highlight the potential of CGP to personalize treatment options of bladder adenoCa and inform clinical trial designs.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"8 ","pages":"e2400200"},"PeriodicalIF":5.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141992322","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}
引用次数: 0
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JCO precision oncology
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