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Clinical Utility of Molecular Tumor Board Review for Identification of Possible Germline Pathogenic Variants on Tumor Next-Generation Sequencing Reports. 分子肿瘤委员会审查对识别肿瘤下一代测序报告中可能的种系致病变异的临床实用性。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-09-01 DOI: 10.1200/PO.24.00301
Taylor A Rives, James Collard, Ning Li, Donglin Yan, Charles S Dietrich, Rachel W Miller, Frederick R Ueland, Justine Pickarski, Jill M Kolesar

Purpose: Tumor next-generation sequencing (NGS) testing identifies possible germline pathogenic variants (PGPVs), creating a dilemma for appropriate recognition, triage, and management. The objective of this study was to determine the clinical utility of an institutional molecular tumor board (MTB) in assessing tumor NGS reports for PGPVs.

Methods: Our institutional MTB reviews all NGS reports to provide treatment and further testing recommendations, including genetic counseling referral and consideration of genetic testing (GC/GT). We studied the patients reviewed by the MTB who were recommended for GC/GT to determine the frequency of referral to a GC, germline test completion, rate of pathogenic germline variants (PGVs), factors related to PGVs, and germline conversion rate (GCR).

Results: Of the 2,355 patients reviewed by the MTB during the study period, 609 (25.9%) had a recommendation for GC/GT. Of the 609 with a GC/GT recommendation, only 181 (29.7%) were referred for GC/GT by their treating physicians, and only 107 (17.6%) completed GT. Of the 107 patients completing GT, 29 (26%) had a confirmed PGV. The only factors significantly associated with PGVs were testing due to a PGPV and higher mean variant allele fraction on the tumor NGS. Only 40 patients with a GC/GT recommendation (14.3%) due to a PGPV completed GT; however, the GCR was 42.5% (n = 17/40).

Conclusion: The MTB review of PGPV is clinically valuable, identifying PGPV in 12% of patients undergoing tumor NGS and a GCR of 42.5%. Rates of GC/GT completion were relatively low due to under-referral by treating physicians. Given the high GCR, the authors encourage institutional algorithms to help increase GC/GT rates for patients found to have PGPV following tumor NGS testing.

目的:肿瘤下一代测序(NGS)检测发现了可能的种系致病变异(PGPVs),为适当的识别、分诊和管理带来了难题。本研究旨在确定机构分子肿瘤委员会(MTB)在评估肿瘤 NGS 报告中 PGPVs 的临床实用性:我们机构的 MTB 审查所有 NGS 报告,提供治疗和进一步检测建议,包括遗传咨询转诊和考虑进行基因检测 (GC/GT)。我们对经 MTB 审查并建议进行 GC/GT 的患者进行了研究,以确定转诊至 GC 的频率、种系检测完成率、致病性种系变异(PGV)率、与 PGV 相关的因素以及种系转换率(GCR):在研究期间,MTB 对 2355 名患者进行了复查,其中 609 人(25.9%)被建议进行 GC/GT。在这 609 名有 GC/GT 建议的患者中,只有 181 人(29.7%)被主治医生转诊为 GC/GT,只有 107 人(17.6%)完成了 GT。在完成 GT 的 107 名患者中,有 29 人(26%)确诊为 PGV。与 PGV 明显相关的唯一因素是 PGPV 导致的检测和肿瘤 NGS 平均变异等位基因比例较高。只有 40 名因 PGPV 而被建议进行 GC/GT 的患者(14.3%)完成了 GT;但 GCR 为 42.5%(n = 17/40):结论:MTB 对 PGPV 的审查具有临床价值,在接受肿瘤 NGS 的患者中有 12% 发现了 PGPV,GCR 为 42.5%。由于主治医生转诊不足,GC/GT 完成率相对较低。鉴于 GCR 较高,作者鼓励采用机构算法,帮助提高肿瘤 NGS 检测后发现 PGPV 患者的 GC/GT 率。
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引用次数: 0
A Decreased Appetite for Prophylactic Total Gastrectomy. 对预防性全胃切除术的胃口下降。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-09-01 Epub Date: 2024-09-30 DOI: 10.1200/PO-24-00434
Jeremy L Davis, Amber F Gallanis

Total gastrectomy should be performed less often in germline CDH1 variant carriers based on mounting clinical evidence.

根据越来越多的临床证据,应减少对 CDH1 基因变异携带者实施全胃切除术。
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引用次数: 0
Detection of Maternal Malignancy After Abnormal Noninvasive Prenatal Testing: A Single-Center Case Series. 无创产前检测异常后母体恶性肿瘤的检测:单中心病例系列。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-09-01 DOI: 10.1200/PO.24.00058
Mwanasha H Merrill, Sophie R Cahill, Hannah W Pepprock, Robert Redd, Huma Q Rana, Katherine E Economy, Judy E Garber, Ann S LaCasce
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引用次数: 0
Progress and Promise for Multicancer Early Detection Testing in Prostate Cancer. 前列腺癌多癌早期检测的进展与前景。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-09-01 DOI: 10.1200/PO-24-00565
Ann Ayzman, Russell K Pachynski, Melissa A Reimers
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引用次数: 0
Accounting for Socioeconomic Factors and Selection Bias That Affect Survival for Patients With Early-Stage Melanoma. 考虑影响早期黑色素瘤患者生存的社会经济因素和选择偏差。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-09-01 Epub Date: 2024-09-30 DOI: 10.1200/PO.24.00280
Hailey Seibert, Hanna Kakish, Jeremy S Bordeaux, Luke D Rothermel, Richard S Hoehn

Socioeconomic factors influence the survival of patients with early stage melanoma and thus should be accounted for in prognostication tools.

社会经济因素会影响早期黑色素瘤患者的存活率,因此应在预后工具中加以考虑。
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引用次数: 0
Early Circulating Tumor DNA Shedding Kinetics for Prediction of Platinum Sensitivity in Patients With Small Cell Lung Cancer. 用于预测小细胞肺癌患者铂敏感性的早期循环肿瘤 DNA 脱落动力学
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-09-01 DOI: 10.1200/PO.24.00216
Yonina R Murciano-Goroff, Angela B-Y Hui, Jose A Araujo Filho, Emily G Hamilton, Jacob J Chabon, Everett J Moding, Rene F Bonilla, Emily S Lebow, Daniel Gomez, Andreas Rimner, Michelle S Ginsberg, Michael Offin, Ritika Kundra, Viola Allaj, Larry Norton, Jorge S Reis-Filho, Pedram Razavi, Alexander Drilon, David R Jones, James M Isbell, W Victoria Lai, Charles M Rudin, Ash A Alizadeh, Bob T Li, Maximilian Diehn

Purpose: Small cell lung cancer (SCLC) is characterized by rapid progression after platinum resistance. Circulating tumor (ctDNA) dynamics early in treatment may help determine platinum sensitivity.

Materials and methods: Serial plasma samples were collected from patients receiving platinum-based chemotherapy for SCLC on the first 3 days of cycle one and on the first days of subsequent cycles with paired samples collected both before and again after infusions. Tumor-informed plasma analysis was carried out using CAncer Personalized Profiling by deep Sequencing (CAPP-Seq). The mean variant allele frequency (VAF) of all pretreatment mutations was tracked in subsequent blood draws and correlated with radiologic response.

Results: ctDNA kinetics were assessed in 122 samples from 21 patients. Pretreatment VAF did not differ significantly between patients who did and did not respond to chemotherapy (mean 22.5% v 4.6%, P = .17). A slight increase in ctDNA on cycle 1, day 1 immediately post-treatment was seen in six of the seven patients with available draws (fold change from baseline: 1.01-1.44), half of whom achieved a response. All patients who responded had a >2-fold decrease in mean VAF on cycle 2 day 1 (C2D1). Progression-free survival (PFS) and overall survival (OS) were significantly longer in patients with a >2-fold decrease in mean VAF after one treatment cycle (6.8 v 2.6 months, log-rank P = .0004 and 21.7 v 6.4 months, log rank P = .04, respectively).

Conclusion: A >2-fold decrease in ctDNA concentration was observed by C2D1 in all patients who were sensitive to platinum-based therapy and was associated with longer PFS and OS.

目的:小细胞肺癌(SCLC)的特点是铂类耐药后进展迅速。治疗早期的循环肿瘤(ctDNA)动态有助于确定铂类药物的敏感性:在接受以铂类为基础的化疗的 SCLC 患者中,在第一周期的前 3 天和后续周期的第一天收集连续血浆样本,并在输液前和输液后再次收集配对样本。利用深度测序肿瘤个体化分析(CAPP-Seq)对血浆进行了肿瘤信息分析。在随后的抽血中跟踪所有治疗前突变的平均变异等位基因频率(VAF),并将其与放射学反应相关联。治疗前 VAF 在对化疗有反应和无反应的患者之间无明显差异(平均 22.5% 对 4.6%,P = .17)。在有抽样结果的七名患者中,有六名患者的ctDNA在治疗后第1周期第1天出现轻微增加(与基线相比的折叠变化:1.01-1.44),其中半数患者出现了反应。所有有应答的患者在第 2 周期第 1 天(C2D1)的平均 VAF 均下降了 2 倍以上。一个治疗周期后平均VAF下降>2倍的患者的无进展生存期(PFS)和总生存期(OS)明显更长(分别为6.8个月对2.6个月,对数秩P = .0004和21.7个月对6.4个月,对数秩P = .04):结论:在所有对铂类疗法敏感的患者中,C2D1可观察到ctDNA浓度下降2倍以上,并与更长的PFS和OS相关。
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引用次数: 0
Comparing the Diagnostic Yield of Germline Exome Versus Panel Sequencing in the Diverse Population of the Texas KidsCanSeq Pediatric Cancer Study. 在德克萨斯州 KidsCanSeq 儿童癌症研究的不同人群中比较种系外显子组测序与基因组测序的诊断率。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-09-01 DOI: 10.1200/PO.24.00187
Lauren R Desrosiers-Battu, Tao Wang, Jacquelyn Reuther, George Miles, Hongzheng Dai, Eunji Jo, Heidi Russell, Robin Raesz-Martinez, Alva Recinos, Stephanie Gutierrez, Amy Thomas, Emily Berenson, Jessica Corredor, Kimberly Nugent, Rachel Wyatt Castillo, Rebecca Althaus, Rebecca Littlejohn, Shawn Gessay, Gail Tomlinson, Jonathan Gill, Juan Carlos Bernini, Kelly Vallance, Timothy Griffin, Sarah Scollon, Frank Y Lin, Christine Eng, Shashikant Kulkarni, Susan G Hilsenbeck, Angshumoy Roy, Amy L McGuire, D Williams Parsons, Sharon E Plon

Purpose: To evaluate the relative diagnostic yield of clinical germline genomic tests in a diverse pediatric cancer population.

Patients and methods: The KidsCanSeq study enrolled pediatric cancer patients across six sites in Texas. Germline analysis included both exome sequencing and a therapy-focused pediatric cancer gene panel. The results were categorized by participants demographics, the presence of pathogenic or likely pathogenic (P/LP) variants, and variants of uncertain significance (VUS) in cancer predisposition genes (CPGs). Pediatric actionable CPGs were defined as those with cancer surveillance recommendations during childhood.

Results: Cancer P/LP variants were reported by at least one platform in 103 of 578 (17.8%) participants of which 76 were dominant cancer genes (13.1%) with no significant differences by self-described race or Hispanic ethnicity. However, the proportion of participants with VUS was greater in Asian and African American participants (P = .0029). Diagnostic yield was 16.6% for exome versus 8.5% for panel (P < .0001) with 42 participants with concordant germline results. Exome-only results included P/LP variants in 30 different CPGs in 54 participants, whereas panel-only results included seven participants with a copy number or structural P/LP variants in CPGs. There was no significant difference in diagnostic yield limited to pediatric actionable CPGs (P = .6171).

Conclusion: Approximately 18% of a diverse pediatric cancer population had germline diagnostic findings with 50% of P/LP variants reported by only one platform because of CPGs not on the targeted panel and copy number variants (CNVs)/rearrangements not reported by exome. Although diagnostic yields were similar in this diverse population, increases in VUS results were observed in Asian and African American populations. Given the clinical significance of CNVs/rearrangements in this cohort, detection is critical to optimize germline analysis of pediatric cancer populations.

目的:评估临床种系基因组检测在不同儿科癌症人群中的相对诊断率:KidsCanSeq研究在得克萨斯州的六个地点招募了儿科癌症患者。种系分析包括外显子组测序和以治疗为重点的儿科癌症基因面板。研究结果按参与者的人口统计学特征、致病或可能致病变异(P/LP)的存在以及癌症易感基因(CPGs)中意义不确定的变异(VUS)进行分类。儿科可采取行动的 CPGs 被定义为在儿童期有癌症监测建议的 CPGs:578名参与者中有103人(17.8%)的至少一个平台报告了癌症P/LP变异,其中76人是显性癌症基因(13.1%),自我描述的种族或西班牙裔没有明显差异。不过,亚裔和非裔美国人的 VUS 比例更高(P = .0029)。外显子组的诊断率为 16.6%,面板组为 8.5%(P < .0001),42 名参与者的种系结果一致。纯外显子组结果包括 54 名参与者 30 个不同 CPG 中的 P/LP 变异,而纯面板结果包括 7 名参与者 CPG 中的拷贝数或结构性 P/LP 变异。仅限于儿科可操作 CPG 的诊断率没有明显差异(P = .6171):结论:在不同的儿科癌症人群中,约有18%的人有种系诊断结果,其中50%的P/LP变异仅由一个平台报告,原因是CPG不在靶向面板上,拷贝数变异(CNV)/重排不在外显子组报告中。尽管在这一多样化人群中诊断率相似,但在亚裔和非裔美国人中观察到 VUS 结果增加。鉴于 CNVs/重排在该人群中的临床意义,检测对于优化儿科癌症人群的种系分析至关重要。
{"title":"Comparing the Diagnostic Yield of Germline Exome Versus Panel Sequencing in the Diverse Population of the Texas KidsCanSeq Pediatric Cancer Study.","authors":"Lauren R Desrosiers-Battu, Tao Wang, Jacquelyn Reuther, George Miles, Hongzheng Dai, Eunji Jo, Heidi Russell, Robin Raesz-Martinez, Alva Recinos, Stephanie Gutierrez, Amy Thomas, Emily Berenson, Jessica Corredor, Kimberly Nugent, Rachel Wyatt Castillo, Rebecca Althaus, Rebecca Littlejohn, Shawn Gessay, Gail Tomlinson, Jonathan Gill, Juan Carlos Bernini, Kelly Vallance, Timothy Griffin, Sarah Scollon, Frank Y Lin, Christine Eng, Shashikant Kulkarni, Susan G Hilsenbeck, Angshumoy Roy, Amy L McGuire, D Williams Parsons, Sharon E Plon","doi":"10.1200/PO.24.00187","DOIUrl":"https://doi.org/10.1200/PO.24.00187","url":null,"abstract":"<p><strong>Purpose: </strong>To evaluate the relative diagnostic yield of clinical germline genomic tests in a diverse pediatric cancer population.</p><p><strong>Patients and methods: </strong>The KidsCanSeq study enrolled pediatric cancer patients across six sites in Texas. Germline analysis included both exome sequencing and a therapy-focused pediatric cancer gene panel. The results were categorized by participants demographics, the presence of pathogenic or likely pathogenic (P/LP) variants, and variants of uncertain significance (VUS) in cancer predisposition genes (CPGs). Pediatric actionable CPGs were defined as those with cancer surveillance recommendations during childhood.</p><p><strong>Results: </strong>Cancer P/LP variants were reported by at least one platform in 103 of 578 (17.8%) participants of which 76 were dominant cancer genes (13.1%) with no significant differences by self-described race or Hispanic ethnicity. However, the proportion of participants with VUS was greater in Asian and African American participants (<i>P</i> = .0029). Diagnostic yield was 16.6% for exome versus 8.5% for panel (<i>P</i> < .0001) with 42 participants with concordant germline results. Exome-only results included P/LP variants in 30 different CPGs in 54 participants, whereas panel-only results included seven participants with a copy number or structural P/LP variants in CPGs. There was no significant difference in diagnostic yield limited to pediatric actionable CPGs (<i>P</i> = .6171).</p><p><strong>Conclusion: </strong>Approximately 18% of a diverse pediatric cancer population had germline diagnostic findings with 50% of P/LP variants reported by only one platform because of CPGs not on the targeted panel and copy number variants (CNVs)/rearrangements not reported by exome. Although diagnostic yields were similar in this diverse population, increases in VUS results were observed in Asian and African American populations. Given the clinical significance of CNVs/rearrangements in this cohort, detection is critical to optimize germline analysis of pediatric cancer populations.</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/PMC11392521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142287719","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
Reply to H. Seibert et al. 对 H. Seibert 等人的答复
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-09-01 Epub Date: 2024-09-30 DOI: 10.1200/PO-24-00405
Christine N Bailey, Brian J Martin, Valentina I Petkov
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引用次数: 0
Phase II Study of Samotolisib in Children and Young Adults With Tumors Harboring Phosphoinositide 3-Kinase/Mammalian Target of Rapamycin Pathway Alterations: Pediatric MATCH APEC1621D. 萨莫替尼对携带磷酸肌酸 3-激酶/哺乳动物雷帕霉素靶点通路改变的儿童和青少年肿瘤的 II 期研究:儿科 MATCH APEC1621D。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-09-01 DOI: 10.1200/PO.24.00258
Theodore W Laetsch, Kathleen Ludwig, P Mickey Williams, Sinchita Roy-Chowdhuri, David R Patton, Brent Coffey, Joel M Reid, Jin Piao, Lauren Saguilig, Todd A Alonzo, Stacey L Berg, Joyce Mhlanga, Elizabeth Fox, Brenda J Weigel, Douglas S Hawkins, Margaret M Mooney, Naoko Takebe, James V Tricoli, Katherine A Janeway, Nita L Seibel, Donald Williams Parsons

Purpose: Patients age 1-21 years with relapsed or refractory solid and CNS tumors were assigned to phase II studies of molecularly targeted therapies on the National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial. Patients whose tumors harbored predefined genetic alterations in the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway and lacked mitogen-activated protein kinase pathway activating alterations were treated with the PI3K/mTOR inhibitor samotolisib.

Methods: Patients received samotolisib twice daily in 28-day cycles until disease progression or unacceptable toxicity. A rolling 6 limited dose escalation was performed as, to our knowledge, this was the first pediatric study of samotolisib. The primary end point was the objective response rate; secondary end points included progression-free survival (PFS) and the recommended phase II dose and toxicity of samotolisib in children.

Results: A total of 3.4% (41/1,206) of centrally tested patients were matched to this arm. Seventeen patients were treated. Among treated patients, the most common diagnoses included osteosarcoma (n = 6) and high-grade glioma (n = 5) harboring alterations in phosphatase and tensin homolog (n = 6), PIK3CA (n = 5), and tuberous sclerosis complex 2 (n = 3). No objective responses or prolonged stable disease were observed. Three-month PFS was 12% (95% CI, 2 to 31). Two patients experienced dose-limiting toxicities (mucositis and pneumonitis). Dose level 2 (115 mg/m2/dose twice daily) was determined to be the recommended phase II dose of samotolisib in children.

Conclusion: This nationwide study was successful at identifying patients and evaluating the efficacy of molecularly targeted therapy for rare molecular subgroups of patients in a histology-agnostic fashion. Unfortunately, there was no activity of samotolisib against tumors with PI3K/mTOR pathway alterations. Prospective trials such as the NCI-COG Pediatric MATCH are necessary to evaluate the efficacy of molecularly targeted therapies given their increasing use in clinical practice.

目的:1-21岁的复发性或难治性实体瘤和中枢神经系统肿瘤患者被分配到美国国立癌症研究所-儿童肿瘤学组(NCI-COG)儿科分子分析治疗选择(MATCH)试验的分子靶向疗法II期研究中。患者的肿瘤在磷酸肌酸3-激酶(PI3K)/哺乳动物雷帕霉素靶蛋白(mTOR)通路中存在预定义的基因改变,但缺乏丝裂原活化蛋白激酶通路激活性改变,他们将接受PI3K/mTOR抑制剂samotolisib的治疗:患者每天接受两次samotolisib治疗,周期为28天,直到疾病进展或出现不可接受的毒性。据我们所知,这是第一项关于samotolisib的儿科研究,因此进行了6次有限剂量的滚动升级。研究的主要终点是客观反应率;次要终点包括无进展生存期(PFS)以及儿童服用萨莫替利的II期推荐剂量和毒性:共有3.4%(41/1,206)的集中检测患者与该治疗组匹配。17名患者接受了治疗。在接受治疗的患者中,最常见的诊断包括骨肉瘤(n = 6)和高级别胶质瘤(n = 5),这些肿瘤携带磷酸酶和天丝同源物(n = 6)、PIK3CA(n = 5)和结节性硬化症复合体2(n = 3)的改变。未观察到客观反应或疾病长期稳定。三个月的 PFS 为 12%(95% CI,2 至 31)。两名患者出现了剂量限制性毒性反应(粘膜炎和肺炎)。2级剂量(115毫克/平方米/剂量,每日两次)被确定为儿童萨莫替利希的II期推荐剂量:这项全国性研究成功地识别了患者,并以组织学诊断的方式评估了分子靶向治疗对罕见分子亚组患者的疗效。遗憾的是,萨莫替尼对PI3K/mTOR通路改变的肿瘤没有活性。鉴于分子靶向疗法在临床实践中的应用越来越广泛,NCI-COG 儿科 MATCH 等前瞻性试验对评估分子靶向疗法的疗效非常必要。
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引用次数: 0
Acknowledgment of Reviewers, 2024. 致谢审稿人,2024 年。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-09-01 DOI: 10.1200/PO-24-00581
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引用次数: 0
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