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Combination of MDM2 and Targeted Kinase Inhibitors Results in Prolonged Tumor Control in Lung Adenocarcinomas With Oncogenic Tyrosine Kinase Drivers and MDM2 Amplification. 在具有致癌酪氨酸激酶驱动因子和 MDM2 扩增的肺腺癌中联合使用 MDM2 和靶向激酶抑制剂可延长肿瘤控制时间
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-09-01 DOI: 10.1200/PO.24.00241
Arielle Elkrief, Igor Odintsov, Roger S Smith, Morana Vojnic, Takuo Hayashi, Inna Khodos, Vladimir Markov, Zebing Liu, Allan J W Lui, Jamie L Bloom, Michael D Offin, Charles M Rudin, Elisa de Stanchina, Gregory J Riely, Romel Somwar, Marc Ladanyi

Purpose: MDM2, a negative regulator of the TP53 tumor suppressor, is oncogenic when amplified. MDM2 amplification (MDM2amp) is mutually exclusive with TP53 mutation and is seen in 6% of patients with lung adenocarcinoma (LUAD), with significant enrichment in subsets with receptor tyrosine kinase (RTK) driver alterations. Recent studies have shown synergistic activity of MDM2 and MEK inhibition in patient-derived LUAD models with MDM2amp and RTK driver alterations. However, the combination of MDM2 and RTK inhibitors in LUAD has not been studied.

Methods: We evaluated the combination of MDM2 and RTK inhibition in patient-derived models of LUAD.

Results: In a RET-fusion LUAD patient-derived model with MDM2amp, MDM2 inhibition with either milademetan or AMG232 combined with selpercatinib resulted in long-term in vivo tumor control markedly superior to either agent alone. Similarly, in an EGFR-mutated model with MDM2amp, combining either milademetan or AMG232 with osimertinib resulted in long-term in vivo tumor control, which was strikingly superior to either agent alone.

Conclusion: These preclinical in vivo data provide a rationale for further clinical development of this combinatorial targeted therapy approach.

目的:MDM2 是 TP53 肿瘤抑制因子的负调控因子,一旦扩增就会致癌。MDM2扩增(MDM2amp)与TP53突变互斥,见于6%的肺腺癌(LUAD)患者,在受体酪氨酸激酶(RTK)驱动基因改变的亚群中有显著的富集。最近的研究表明,在具有 MDM2amp 和 RTK 驱动基因改变的患者衍生 LUAD 模型中,MDM2 和 MEK 抑制具有协同活性。然而,在LUAD中联合使用MDM2和RTK抑制剂的研究尚未开展:我们评估了在 LUAD 患者衍生模型中联合使用 MDM2 和 RTK 抑制剂的效果:结果:在具有MDM2amp的RET融合LUAD患者衍生模型中,使用米拉德米坦或AMG232联合赛帕替尼抑制MDM2,其体内肿瘤的长期控制效果明显优于单独使用其中一种药物。同样,在具有MDM2amp的表皮生长因子受体突变模型中,将米拉德米坦或AMG232与奥希替尼联合使用可获得长期的体内肿瘤控制效果,其效果明显优于单独使用其中一种药物:这些临床前体内数据为这种组合靶向治疗方法的进一步临床开发提供了依据。
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引用次数: 0
Palbociclib in Solid Tumor Patients With Genomic Alterations in the cyclinD-cdk4/6-INK4a-Rb Pathway: Results From National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice Trial Arm I (APEC1621I). 帕博西尼(Palbociclib)用于 cyclinD-cdk4/6-INK4a-Rb 通路基因组改变的实体瘤患者:美国国立癌症研究所-儿童肿瘤学组儿科分子分析治疗选择试验I臂(APEC1621I)的结果。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-09-01 DOI: 10.1200/PO-24-00418
Margaret E Macy, Rajen Mody, Joel M Reid, Jin Piao, Lauren Saguilig, Todd A Alonzo, Stacey L Berg, Elizabeth Fox, Brenda J Weigel, Douglas S Hawkins, Margaret M Mooney, P Mickey Williams, David R Patton, Brent D Coffey, Sinchita Roy-Chowdhuri, Naoko Takebe, James V Tricoli, Katherine A Janeway, Nita L Seibel, D Williams Parsons

Purpose: The National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice trial assigned patients age 1-21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with tumors that harbored prespecified genomic alterations in the cyclinD-CDK4/6-INK4a-Rb pathway with intact Rb expression were assigned and treated with the cdk4/6 inhibitor palbociclib.

Methods: Patients received palbociclib orally once daily for 21 days of 28-day cycles until disease progression, intolerable toxicity, or up to 2 years. The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival.

Results: Twenty-three patients (median age, 15 years; range, 8-21) were enrolled; 20 received protocol therapy and were evaluable for toxicity and response. Of the evaluable patients, the most common diagnoses were osteosarcoma (n = 9) and rhabdomyosarcoma (n = 6). A single actionable gene amplification was found in 19 tumors (CDK4, n = 11, CDK6, n = 2, CCND3, n = 6), with one tumor harboring two amplifications (CDK4 and CCND2). Hematologic toxicities were the most common treatment-related events. No objective responses were seen. Two patients with tumors harboring CDK4 amplifications (neuroblastoma and sarcoma) had best response of stable disease for six and three cycles. Six-month progression was 10% (95% CI, 1.7 to 27.2).

Conclusion: The CDK4/6 inhibitor palbociclib at 75 mg/m2 orally daily was tolerable in this heavily pretreated cohort. No objective responses were observed in this histology-agnostic biomarker-selected population with treatment-refractory solid tumors, demonstrating that pathway alteration alone is insufficient in pediatric cancers to generate a response to palbociclib monotherapy.

目的:美国国立癌症研究所-儿童肿瘤学组儿科分子分析治疗选择试验根据肿瘤中检测到的基因改变,将1-21岁复发或难治性实体瘤、淋巴瘤和组织细胞疾病患者分配到分子靶向疗法的II期治疗组。在cyclinD-CDK4/6-KINK4a-Rb通路中存在预设基因组改变且Rb表达完好的肿瘤患者被分配并接受cdk4/6抑制剂palbociclib的治疗:患者每天口服一次palbociclib,21天为一个周期,28天为一个周期,直到疾病进展、出现不可耐受的毒性或最长2年。主要终点是客观反应率;次要终点包括安全性/耐受性和无进展生存期:23名患者(中位年龄为15岁;年龄范围为8-21岁)入组;20名患者接受了方案治疗,并进行了毒性和反应评估。在可评估的患者中,最常见的诊断是骨肉瘤(9 例)和横纹肌肉瘤(6 例)。在19个肿瘤中发现了单个可操作基因扩增(CDK4,n = 11;CDK6,n = 2;CCND3,n = 6),其中一个肿瘤有两个扩增(CDK4和CCND2)。血液学毒性是最常见的治疗相关事件。未出现客观反应。两名携带 CDK4 扩增的肿瘤(神经母细胞瘤和肉瘤)患者的最佳反应是病情在六个和三个周期内保持稳定。6个月进展率为10%(95% CI,1.7至27.2):CDK4/6抑制剂帕博西尼(palbociclib)每天口服75毫克/平方米的剂量在这个重度预处理队列中是可耐受的。在这组经过组织学诊断生物标志物筛选的难治性实体瘤患者中,没有观察到客观反应,这表明在儿童癌症中,单靠通路改变不足以产生对palbociclib单药治疗的反应。
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引用次数: 0
Tumor Characteristics Associated With Preoperatively Detectable Tumor-Informed Circulating Tumor DNA in Patients With Renal Masses Suspicious for Renal Cell Carcinoma. 疑似肾细胞癌的肾肿块患者术前可检测到的肿瘤信息循环肿瘤 DNA 的相关肿瘤特征
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-09-01 Epub Date: 2024-09-30 DOI: 10.1200/PO.24.00281
Reuben Ben-David, Parissa Alerasool, Hitasha Kalola, Neeraja Tillu, Mohammed Almoflihi, Che-Kai Tsao, Matthew D Galsky, John P Sfakianos, Peter Wiklund, Nikhil Waingankar, Reza Mehrazin

Purpose: Understanding the specific tumor characteristics associated with detectable circulating tumor DNA (ctDNA) in patients with renal cell carcinoma (RCC) is critical for informing future studies aiming to establish the clinical utility of such testing. We characterized the pathologic and clinical features associated with preoperatively detectable ctDNA in patients with renal masses suspicious for RCC.

Methods: Consecutive patients who underwent partial or radical nephrectomy for nonmetastatic suspected RCC (cT1b-T3) during 2022-2023 had prospectively collected tumor-informed ctDNA analyses conducted preoperatively and postoperatively. Descriptive statistics and univariate analyses were used to describe the study findings.

Results: Sixty-nine patients with a median age of 62 years (IQR, 51-70) and a median follow-up time of 7 months (IQR, 3-11) had 205 ctDNA samples collected for analysis. Thirty-nine (61%) had preoperative detectable ctDNA of 64 patients. Postoperative ctDNA status was available for 47 patients, and three (6%) had detectable ctDNA. Two had inferior vena cava (IVC) involvement, and one developed metastatic disease. Subgroup analysis of solely malignant RCC (n = 65) revealed that patients with preoperative detectable ctDNA had a higher pathologic stage (P = .001), larger tumors (7 v 4.5 cm; P = .001), higher tumor complexity (P = .022), and increased rates of tumor grades 3-4 (P = .038). All patients with gross renal vein or IVC involvement (n = 9) and those with lymphovascular invasion (n = 6) on pathology had detectable preoperative ctDNA. On univariate analysis, high tumor complexity, larger tumors, and tumor grades 3-4 were found to be predictors of preoperatively detectable ctDNA status.

Conclusion: Preoperative ctDNA was detectable in 61% of patients with nonmetastatic RCC, and it correlated with clinically relevant features. Clinical trials should consider incorporating both preoperative and postoperative ctDNA analyses to augment prediction of disease recurrence and to refine treatment decision making.

目的:了解与肾细胞癌(RCC)患者体内可检测到的循环肿瘤 DNA(ctDNA)相关的特定肿瘤特征对于今后旨在确定此类检测的临床实用性的研究至关重要。我们对怀疑为RCC的肾肿块患者术前检测到的ctDNA的相关病理和临床特征进行了描述:2022-2023年期间,因非转移性疑似RCC(cT1b-T3)而接受肾部分或根治性切除术的连续患者在术前和术后进行了前瞻性肿瘤信息ctDNA分析。研究采用描述性统计和单变量分析来描述研究结果:69名患者的中位年龄为62岁(IQR,51-70),中位随访时间为7个月(IQR,3-11),共收集了205份ctDNA样本进行分析。在 64 名患者中,39 人(61%)术前可检测到 ctDNA。有 47 名患者的术后 ctDNA 状态可用,其中 3 人(6%)可检测到 ctDNA。其中两人受累于下腔静脉(IVC),一人出现转移性疾病。对单纯恶性RCC(n = 65)进行的亚组分析显示,术前检测到ctDNA的患者病理分期更高(P = .001),肿瘤更大(7 v 4.5 cm; P = .001),肿瘤复杂程度更高(P = .022),肿瘤3-4级的比例更高(P = .038)。病理结果显示,所有肾静脉或 IVC 严重受累(9 例)和淋巴管受侵(6 例)的患者术前都能检测到 ctDNA。单变量分析发现,肿瘤复杂程度高、肿瘤较大和肿瘤分级3-4级是术前检测到ctDNA的预测因素:结论:61%的非转移性RCC患者术前可检测到ctDNA,且ctDNA与临床相关特征相关。临床试验应考虑结合术前和术后的ctDNA分析,以增强对疾病复发的预测并完善治疗决策。
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引用次数: 0
Genomic Landscape of Pancreatic Neuroendocrine Tumors and Implications for Clinical Practice. 胰腺神经内分泌肿瘤的基因组图谱及其对临床实践的影响
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-09-01 DOI: 10.1200/PO.24.00221
Ana De Jesus-Acosta, Chirayu Mohindroo

Pancreatic neuroendocrine tumors (pNETs) are the second most prevalent neoplasms of the pancreas with variable prognosis and clinical course. Our knowledge of the genetic alterations in patients with pNETs has expanded in the past decade with the availability of whole-genome sequencing and germline testing. This review will focus on potential clinical applications of the genetic testing in patients with pNETs. For somatic testing, we discuss the commonly prevalent somatic mutations and their impact on prognosis and treatment of patients with pNET. We also highlight the relevant genomic biomarkers that predict response to specific treatments. Previously, germline testing was only recommended for high-risk patients with syndromic features (MEN1, VHL, TSC, and NF1), we review the evolving paradigm of germline testing in pNETs as recent studies have now shown that sporadic-appearing pNETs can also harbor germline variants.

胰腺神经内分泌肿瘤(pNETs)是胰腺中发病率第二高的肿瘤,其预后和临床过程各不相同。在过去十年中,随着全基因组测序和种系检测技术的普及,我们对 pNET 患者基因改变的了解不断加深。本综述将重点讨论基因检测在 pNET 患者中的潜在临床应用。在体细胞检测方面,我们将讨论常见的体细胞突变及其对 pNET 患者预后和治疗的影响。我们还强调了可预测对特定治疗反应的相关基因组生物标志物。以前,种系检测仅被推荐用于具有综合征特征(MEN1、VHL、TSC 和 NF1)的高风险患者,最近的研究表明,散发性出现的 pNET 也可能携带种系变异,因此我们回顾了 pNET 种系检测范式的演变。
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引用次数: 0
Mutational Features and Tumor Microenvironment Alterations in High-Grade Appendiceal Cancers Treated With Iterative Hyperthermic Intraperitoneal Chemotherapy. 采用迭代腹腔热化疗治疗的高级别阑尾癌的突变特征和肿瘤微环境变化
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-09-01 DOI: 10.1200/PO.24.00149
David G Su, Ankit Dhiman, Varun V Bansal, Yuanyuan Zha, Ardaman Shergill, Blasé Polite, Lindsay Alpert, Kiran K Turaga, Oliver S Eng

Purpose: High-grade appendiceal adenocarcinomas (HGAA) with peritoneal metastases (PMs) are associated with poor survival. Hyperthermic intraperitoneal chemotherapy (HIPEC) is a novel treatment approach for unresectable HGAA-PM. However, its influence on immunogenomic profiles has not yet been fully explored.

Materials and methods: We obtained 79 samples of metastatic peritoneal tumor deposits from patients diagnosed with HGAA and performed whole-exome sequencing, RNA sequencing, and immunoprofiling before and after HIPEC. Tumor biopsies were subjected to immunogenomic profiling to detect mutational signatures and immune populations associated with oncologic outcomes.

Results: Fifteen patients with HGAA-PMs were included in the study. The median progression-free survival (PFS) was 6.7 months (2.7-25.3) and the median overall survival was 11.4 months (4.7-42). Mucin-associated genes (MUC16, MUC3A, and MUC5AC) and titin (TTN) had the highest mutation frequencies. Mutational signatures such as single-base substitution 29 and doublet-base substitution 11 were present in >50% of single-base and double-base mutations. Higher PD-L1 coexpression on CD8+ T cells demonstrated a higher PFS both intratumorally (P = .019) and at the margin (P = .025).

Conclusion: HIPEC-associated mutational signatures were identified in HGAA-PMs. Elevated PD-L1+ cytotoxic T-cell populations after HIPEC had better PFS, offering valuable insights for prognostication in the context of HIPEC treatment.

目的:伴有腹膜转移(PM)的高级别阑尾腺癌(HGAA)生存率很低。腹腔内热化疗(HIPEC)是一种治疗无法切除的 HGAA-PM 的新方法。然而,其对免疫基因组图谱的影响尚未得到充分探讨:我们从确诊为HGAA的患者身上获取了79份转移性腹膜肿瘤沉积物样本,并在HIPEC前后进行了全外显子组测序、RNA测序和免疫谱分析。对肿瘤活检组织进行了免疫基因组学分析,以检测与肿瘤结果相关的突变特征和免疫群体:研究共纳入了15名HGAA-PMs患者。中位无进展生存期(PFS)为6.7个月(2.7-25.3),中位总生存期为11.4个月(4.7-42)。粘蛋白相关基因(MUC16、MUC3A和MUC5AC)和钛蛋白(TTN)的突变频率最高。在超过50%的单碱基和双碱基突变中存在单碱基替换29和双碱基替换11等突变特征。CD8+ T细胞上较高的PD-L1共表达表明,肿瘤内(P = .019)和肿瘤边缘(P = .025)的PFS均较高:结论:在HGAA-PMs中发现了与HIPEC相关的突变特征。结论:在HGAA-PMs中发现了HIPEC相关突变特征,HIPEC治疗后PD-L1+细胞毒性T细胞群升高,PFS较好,为HIPEC治疗的预后提供了有价值的见解。
{"title":"Mutational Features and Tumor Microenvironment Alterations in High-Grade Appendiceal Cancers Treated With Iterative Hyperthermic Intraperitoneal Chemotherapy.","authors":"David G Su, Ankit Dhiman, Varun V Bansal, Yuanyuan Zha, Ardaman Shergill, Blasé Polite, Lindsay Alpert, Kiran K Turaga, Oliver S Eng","doi":"10.1200/PO.24.00149","DOIUrl":"10.1200/PO.24.00149","url":null,"abstract":"<p><strong>Purpose: </strong>High-grade appendiceal adenocarcinomas (HGAA) with peritoneal metastases (PMs) are associated with poor survival. Hyperthermic intraperitoneal chemotherapy (HIPEC) is a novel treatment approach for unresectable HGAA-PM. However, its influence on immunogenomic profiles has not yet been fully explored.</p><p><strong>Materials and methods: </strong>We obtained 79 samples of metastatic peritoneal tumor deposits from patients diagnosed with HGAA and performed whole-exome sequencing, RNA sequencing, and immunoprofiling before and after HIPEC. Tumor biopsies were subjected to immunogenomic profiling to detect mutational signatures and immune populations associated with oncologic outcomes.</p><p><strong>Results: </strong>Fifteen patients with HGAA-PMs were included in the study. The median progression-free survival (PFS) was 6.7 months (2.7-25.3) and the median overall survival was 11.4 months (4.7-42). Mucin-associated genes (<i>MUC16</i>, <i>MUC3A</i>, and <i>MUC5AC</i>) and titin (<i>TTN</i>) had the highest mutation frequencies. Mutational signatures such as single-base substitution 29 and doublet-base substitution 11 were present in >50% of single-base and double-base mutations. Higher PD-L1 coexpression on CD8<sup>+</sup> T cells demonstrated a higher PFS both intratumorally (<i>P</i> = .019) and at the margin (<i>P</i> = .025).</p><p><strong>Conclusion: </strong>HIPEC-associated mutational signatures were identified in HGAA-PMs. Elevated PD-L1+ cytotoxic T-cell populations after HIPEC had better PFS, offering valuable insights for prognostication in the context of HIPEC treatment.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11432692/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142287721","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
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。
{"title":"Molecular Differences With Therapeutic Implications in Early-Onset Compared With Average-Onset Biliary Tract Cancers.","authors":"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","doi":"10.1200/PO.24.00138","DOIUrl":"https://doi.org/10.1200/PO.24.00138","url":null,"abstract":"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>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). <i>P</i> values were adjusted for multiple testing and considered significant at <i>Q</i> < 0.05 (molecular comparisons) or <i>Q</i> < 0.25 (Gene Set Enrichment Analysis [GSEA]). Insurance claims data were used for survival analysis.</p><p><strong>Results: </strong>The study included 5,587 patients with BTC (453 eoBTC, median age = 44 years and 5,134 aoBTC, median age = 68 years). <i>FGFR2</i> fusion (15.7% in eoBTC <i>v</i> 5.9% in aoBTC) and <i>NIPBL</i> fusion (1.1% <i>v</i> 0%) were significantly more prevalent in eoBTC (both <i>Q</i> < 0.001). The interferon gamma-IFG score (fold change [FC], 1.1; <i>Q</i> = 0.01) and T-cell inflammation score (FC, 17.3; <i>Q</i> = 0.03) were significantly higher in aoBTC. On GSEA, angiogenesis was enriched in eoBTC (normalized enrichment score [NES] = 1.51; <i>Q</i> = 0.16), whereas IFG (NES = -1.58; <i>Q</i> = 0.06) and inflammatory response (NES = -1.46; <i>Q</i> = 0.18) were enriched in aoBTC. The median overall survival (OS) was 16.5 (eoBTC) versus 13.3 months (aoBTC), hazard ratio = 0.86, <i>P</i> = .004. The median OS by FGFR2 fusion (with fusion <i>v</i> without) was 21.7 versus 15.0 months (<i>P</i> = .47) for eoBTC and 18.6 versus 12.2 months (<i>P</i> < .001) for aoBTC.</p><p><strong>Conclusion: </strong>We identified crucial differences including higher prevalence of <i>FGFR2</i> fusions in eoBTC and variations in immunotherapy-related markers. Better outcomes in eoBTC were affected by the <i>FGFR2</i> fusion status. Our findings underscore the need for ensuring access to next-generation sequencing testing, including prompt identification of actionable targets.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893483","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
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
Improving Access to Hereditary Testing in Pancreatic Ductal Carcinoma. 提高胰腺导管癌遗传检测的可及性。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-01 DOI: 10.1200/PO.24.00167
Carol Cremin, Angela C Bedard, Quan Hong, Sze Wing Mung, Jennifer Nuk, Andrew Wong, Husain Akbar, Eugene Cheung, Daniel Renouf, David Schaeffer, Sophie Sun, Kasmintan A Schrader

Purpose: Approximately 5%-10% of patients with pancreatic ductal adenocarcinoma (PDAC) have an inherited basis, yet uptake of genetic testing remains low and subject to disparities. This study compared two genetic testing pathways available to patients referred to a provincial cancer center, BC Cancer: a traditional hereditary cancer clinic-initiated testing (HCT) pathway and a new oncology clinic-initiated testing (OCT) pathway.

Methods: Study subjects were patients with confirmed PDAC referred for genetic testing through the HCT or OCT pathway between June 1, 2020, and February 1, 2022. Charts were retrospectively reviewed for patient characteristics and testing outcomes.

Results: The study population was 397 patients (HCT, n = 279 and OCT, n = 118). OCT patients were more likely to have non-European ethnicity compared with HCT patients (41.9% v 25.6%, P = .004), to have earlier-stage disease (P = .012), and to have better Eastern Cooperative Oncology Group performance status than the HCT group (P = .001). A total of 306 patients completed testing (77%). OCT patients had higher test completion rates than HCT patients (odds ratio, 3.74 [95% CI, 1.66 to 9.62]). Median time for results was shorter in OCT than in HCT (53 days [IQR, 44-76] v 107 days [IQR, 63.8-158.3]). Pancreatic cancer susceptibility pathogenic gene variants were identified in 8.5% (26/306).

Conclusion: The real-world observations in our study show that oncology clinic-initiated hereditary testing is more effective and faster than testing through hereditary cancer clinic referrals and reaches a more ethnically diverse population. This has important implications for publicly funded environments with limited resources for genetic counseling.

目的:约5%-10%的胰腺导管腺癌(PDAC)患者有遗传基础,但基因检测的接受率仍然很低,而且存在差异。本研究比较了转诊至省级癌症中心(不列颠哥伦比亚省癌症中心)的患者可接受的两种基因检测途径:一种是传统的遗传性癌症诊所主动检测(HCT)途径,另一种是新的肿瘤诊所主动检测(OCT)途径:研究对象为 2020 年 6 月 1 日至 2022 年 2 月 1 日期间通过 HCT 或 OCT 途径转诊进行基因检测的确诊 PDAC 患者。对病历进行回顾性审查,以了解患者特征和检测结果:研究对象为397名患者(HCT,n = 279;OCT,n = 118)。与 HCT 患者相比,OCT 患者更有可能是非欧洲人种(41.9% 对 25.6%,P = .004),更有可能罹患早期疾病(P = .012),而且与 HCT 组相比,OCT 患者的东部合作肿瘤学组表现状态更好(P = .001)。共有 306 名患者完成了检测(77%)。OCT 患者的检测完成率高于 HCT 患者(几率比为 3.74 [95% CI,1.66 至 9.62])。OCT 患者获得结果的中位时间比 HCT 患者短(53 天 [IQR, 44-76] 对 107 天 [IQR, 63.8-158.3])。8.5%的患者(26/306)发现了胰腺癌易感致病基因变异:我们研究中的实际观察结果表明,肿瘤诊所发起的遗传检测比通过遗传性癌症诊所转诊进行的检测更有效、更快捷,而且能覆盖更多不同种族的人群。这对遗传咨询资源有限的公共资助环境具有重要意义。
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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。
{"title":"Lymphocyte Infiltration Score and Spatial Characteristics Refined the Prognosis and Denosumab Treatment Responsiveness Indicators for Giant Cell Tumor of Bone.","authors":"Hai-Lin Wu, Chao Xia, Fu-Sheng Liu, Bo-Yv Zheng, Hua-Qing Niu, Guo-Qiang Zhu, Ming-Xiang Zou, Bo-Wen Zheng","doi":"10.1200/PO.24.00135","DOIUrl":"https://doi.org/10.1200/PO.24.00135","url":null,"abstract":"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>Low LIS was indicative of both poor PFS and OS (both <i>P</i> < .001). In addition, LIS was significantly associated with sex (<i>P</i> = .046), Enneking staging (<i>P</i> < .001), <i>Ki-67</i> expression (<i>P</i> = .007), and denosumab treatment responsiveness (<i>P</i> = .005). Lower CD8<sup>+</sup> (tumor interior [TI]) NNDTC, and CD3<sup>+</sup> (TI) NNDTC were associated with worse PFS (<i>P</i> = .003 and .038, respectively), whereas lower CD8<sup>+</sup> (TI) NNDTC was associated with worse OS (<i>P</i> = .001), but CD8<sup>+</sup> (tumor infiltrating margin) NNDTC had the opposite effect (<i>P</i> = .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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142043915","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
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。
{"title":"Landscape of Concomitant Driver Alterations in Classical <i>EGFR</i>-Mutated Non-Small Cell Lung Cancer.","authors":"Huaying Wang, Lie Lin, Chuqiao Liang, Jiaohui Pang, Jiani C Yin, Junli Zhang, Yang Shao, Chengming Sun, Renhua Guo","doi":"10.1200/PO.23.00520","DOIUrl":"https://doi.org/10.1200/PO.23.00520","url":null,"abstract":"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>We profiled concomitant driver alterations of <i>EGFR</i>+ 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 <i>EGFR</i>+ NSCLC.</p><p><strong>Results: </strong>Out of the total patient population, 334 patients had <i>EGFR</i> mutations along with concomitant driver mutations, comprising 3.09% of the entire cohort. The most frequent co-occurring mutations with sensitizing <i>EGFR</i> mutations include <i>KRAS</i> at 53.9%, followed by <i>ERBB2</i> at 24.3%, <i>MET</i> at 16.5%, and <i>BRAF</i> at 3.3%. <i>KRAS</i> mutations in concomitant drivers were frequently hyperexchange mutations (25.6% <i>v</i> 8.2%, <i>P</i> < .001), compared with <i>KRAS</i> single drivers. <i>EGFR</i>/<i>ERBB2</i> drivers exhibited a higher incidence of <i>ERBB2</i> amplification (40.7% <i>v</i> 16.5%, <i>P</i> < .001) and p.S310F/Y mutations (44.4% <i>v</i> 4.3%, <i>P</i> < .001) compared with <i>ERBB2</i> alone. <i>EGFR</i>/<i>MET</i> drivers had a higher frequency of <i>MET</i> amplification (71.4% <i>v</i> 43.3%) than <i>MET</i> single drivers. At the genomic level, the median number of additional concurrent mutations was four, with <i>TSC2</i> (4%), <i>CD274</i> (1%), and <i>TP53</i> (63%) being the most frequently coaltered genes in concomitant driver tumors. Interestingly, clonality analysis indicated that <i>EGFR</i> mutations were more likely to occur as clonal events, whereas the codrivers were more often subclonal. Patients with concomitant drivers or with concomitant <i>MET</i> amplification exhibited worse prognosis.</p><p><strong>Conclusion: </strong>These findings might aid in the selection of effective therapeutic regimens and facilitate the development of combination therapies.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893482","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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