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Erratum: Tumor Characteristics Associated With Preoperatively Detectable Tumor-Informed Circulating Tumor DNA in Patients With Renal Masses Suspicious for Renal Cell Carcinoma. 更正:怀疑为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 : 2024-11-01 Epub Date: 2024-11-05 DOI: 10.1200/PO-24-00733
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引用次数: 0
DNA Damage Response Alterations Predict for Neoadjuvant Chemotherapy Sensitivity in Muscle-Invasive Bladder Cancer: A Correlative Analysis of the SWOG S1314 Trial. DNA损伤反应改变预测肌浸润性膀胱癌新辅助化疗的敏感性:SWOG S1314 试验的相关分析。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-11-01 Epub Date: 2024-11-05 DOI: 10.1200/PO.24.00287
Gopa Iyer, Catherine M Tangen, Michal Sarfaty, Ashley M Regazzi, I-Ling Lee, Megan Fong, Woonyoung Choi, Colin P N Dinney, Thomas W Flaig, Ian M Thompson, Seth P Lerner, David J McConkey, Jonathan E Rosenberg

Purpose: Alterations in DNA damage response (DDR) genes, including ERCC2, have been correlated with response to neoadjuvant cisplatin-based chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC). The SWOG 1314 (S1314) trial enrolled patients with MIBC who received one of two NAC regimens followed by radical cystectomy. We examined the prevalence of DDR alterations in NAC responders versus nonresponders and correlated DDR alteration status with response.

Methods: Pretreatment tumor specimens from 179 evaluable patients underwent next-generation sequencing (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets assay). Associations were determined between any or only deleterious alterations within nine predefined DDR genes, or any alterations in ERCC2, and progression-free survival (PFS) and overall survival using Cox regression, and, in a subset of evaluable patients, pathologic response (complete response, pT0, or downstaging to

Results: Deleterious DDR alterations were detected in 41 (23%) of 179 patients. Of the 151 patients evaluable for pathologic response, patients with deleterious DDR alterations (n = 39) demonstrated a higher pathologic response rate than those without (odds ratio [OR], 3.24 [95% CI, 1.51 to 6.94]; P = .003). In 24 ERCC2-mutant patients, the OR for pT0 was 3.33 (95% CI, 1.35 to 8.22; P = .009) and for P = .073). The association between deleterious DDR alterations and PFS provided an estimate of hazard ratio, 0.54 (95% CI, 0.29 to 1.01; P = .053).

Conclusion: Deleterious DDR alterations were associated with pathologic response following NAC in S1314. Functional validation of ERCC2 and other DDR alterations is underway to help refine such alterations as biomarkers of NAC in patients with bladder cancer.

目的:包括ERCC2在内的DNA损伤应答(DDR)基因的改变与肌浸润性膀胱癌(MIBC)患者对顺铂新辅助化疗(NAC)的反应有关。SWOG 1314(S1314)试验招募了肌肉浸润性膀胱癌患者,他们接受了两种 NAC 方案中的一种,随后进行了根治性膀胱切除术。我们研究了NAC应答者与非应答者中DDR改变的发生率,并将DDR改变状态与应答相关联:179例可评估患者的治疗前肿瘤标本接受了新一代测序(纪念斯隆-凯特琳癌症靶点可操作突变综合分析)。采用Cox回归法测定了9个预定义DDR基因中的任何或仅有的有害改变或ERCC2中的任何改变与无进展生存期(PFS)和总生存期之间的关系,并在可评估患者的子集中测定了病理反应(完全反应、pT0或降期至结果):在179例患者中,有41例(23%)检测到有害的DDR改变。在可评估病理反应的 151 例患者中,有致畸性 DDR 改变的患者(n = 39)的病理反应率高于无致畸性 DDR 改变的患者(几率比 [OR],3.24 [95% CI,1.51 至 6.94];P = .003)。在24例ERCC2突变患者中,pT0的OR为3.33(95% CI,1.35至8.22;P = .009),P = .073)。有害DDR改变与PFS之间的关联提供了一个估计的危险比,即0.54(95% CI,0.29至1.01;P = .053):结论:畸变的DDR改变与S1314患者NAC治疗后的病理反应有关。目前正在对ERCC2和其他DDR改变进行功能验证,以帮助完善这些改变作为膀胱癌患者NAC生物标志物的功能。
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引用次数: 0
Fully Automated Artificial Intelligence Solution for Human Epidermal Growth Factor Receptor 2 Immunohistochemistry Scoring in Breast Cancer: A Multireader Study. 乳腺癌中人类表皮生长因子受体 2 免疫组化评分的全自动人工智能解决方案:多阅读器研究。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-10-11 DOI: 10.1200/PO.24.00353
Savitri Krishnamurthy, Stuart J Schnitt, Anne Vincent-Salomon, Rita Canas-Marques, Eugenia Colon, Kanchan Kantekure, Marina Maklakovski, Wilfrid Finck, Jeanne Thomassin, Yuval Globerson, Lilach Bien, Giuseppe Mallel, Maya Grinwald, Chaim Linhart, Judith Sandbank, Manuela Vecsler

Purpose: The proven efficacy of human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate therapy for treating HER2-low breast cancers necessitates more accurate and reproducible HER2 immunohistochemistry (IHC) scoring. We aimed to validate performance and utility of a fully automated artificial intelligence (AI) solution for interpreting HER2 IHC in breast carcinoma.

Materials and methods: A two-arm multireader study of 120 HER2 IHC whole-slide images from four sites assessed HER2 scoring by four surgical pathologists without and with the aid of an AI HER2 solution. Both arms were compared with high-confidence ground truth (GT) established by agreement of at least four of five breast pathology subspecialists according to ASCO/College of American Pathologists (CAP) 2018/2023 guidelines.

Results: The mean interobserver agreement among GT pathologists across all HER2 scores was 72.4% (N = 120). The AI solution demonstrated high accuracy for HER2 scoring, with 92.1% agreement on slides with high confidence GT (n = 92). The use of the AI tool led to improved performance by readers, interobserver agreement increased from 75.0% for digital manual read to 83.7% for AI-assisted review, and scoring accuracy improved from 85.3% to 88.0%. For the distinction of HER2 0 from 1+ cases (n = 58), pathologists supported by AI showed significantly higher interobserver agreement (69.8% without AI v 87.4% with AI) and accuracy (81.9% without AI v 88.8% with AI).

Conclusion: This study demonstrated utility of a fully automated AI solution to aid in scoring HER2 IHC accurately according to ASCO/CAP 2018/2023 guidelines. Pathologists supported by AI showed improvements in HER2 IHC scoring consistency and accuracy, especially for distinguishing HER2 0 from 1+ cases. This AI solution could be used by pathologists as a decision support tool for enhancing reproducibility and consistency of HER2 scoring and particularly for identifying HER2-low breast cancers.

目的:人类表皮生长因子受体 2 (HER2) 抗体-药物共轭疗法治疗 HER2 低水平乳腺癌的疗效已得到证实,因此有必要提高 HER2 免疫组织化学 (IHC) 评分的准确性和可重复性。我们的目的是验证全自动人工智能(AI)解决方案在解释乳腺癌HER2 IHC方面的性能和实用性:一项双臂多载体研究对来自四个地点的 120 张 HER2 IHC 全切片图像进行了评估,由四位外科病理学家在没有人工智能 HER2 解决方案的情况下和在该解决方案的帮助下进行 HER2 评分。根据 ASCO/College of American Pathologists (CAP) 2018/2023 指南,两组数据均与五位乳腺病理亚专科医生中至少四位达成一致所建立的高置信度地面实况(GT)进行了比较:在所有 HER2 评分中,GT 病理学家之间的平均观察者间一致性为 72.4%(N = 120)。人工智能解决方案显示出较高的HER2评分准确性,在高置信度GT(n = 92)切片上的一致性为92.1%。人工智能工具的使用提高了阅读者的工作效率,观察者之间的一致性从数字人工阅读的 75.0% 提高到人工智能辅助审查的 83.7%,评分准确性从 85.3% 提高到 88.0%。在区分 HER2 0 和 1+ 病例(n = 58)时,人工智能支持下的病理学家的观察者间一致性(无人工智能时为 69.8% ,有人工智能时为 87.4%)和准确性(无人工智能时为 81.9% ,有人工智能时为 88.8%)均显著提高:这项研究表明,全自动人工智能解决方案有助于根据 ASCO/CAP 2018/2023 指南对 HER2 IHC 进行准确评分。病理学家在人工智能的支持下提高了 HER2 IHC 评分的一致性和准确性,尤其是在区分 HER2 0 和 1+ 病例方面。病理学家可将该人工智能解决方案用作决策支持工具,以提高HER2评分的可重复性和一致性,尤其是在识别HER2低的乳腺癌方面。
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引用次数: 0
Characterization and Clinical Outcome of Philadelphia Chromosome-Positive AML in Thrombocytopenia-Absent Radius Syndrome. 血小板减少-缺失半径综合征中费城染色体阳性急性髓细胞白血病的特征和临床结果
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-10-11 DOI: 10.1200/PO-24-00411
Alejandro Villar-Prados, Arman Odabas, Joshua R Menke, Kerry Kingham, Gabriel N Mannis
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引用次数: 0
Amplification of MYC and Its Enhancer Correlates With Genetic Ancestry in Lung Squamous Cell Carcinoma. 肺鳞状细胞癌中 MYC 及其增强子的扩增与遗传血统有关。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-10-24 DOI: 10.1200/PO.24.00223
Sejal Jain, Xuechun Bai, Samyukta Mallick, Branden Kinghorn, Benjamin May, Alexandria G Yao, Diane Allen-Gipson, Xiaoyang Zhang, Brian S Henick, Fatemeh Momen-Heravi, Jian Carrot-Zhang, Alison M Taylor

Purpose: In lung squamous cell carcinoma (LUSC), Black patients show significantly higher incidence and lower overall survival than White patients. Although socioeconomic factors likely contribute to this survival disparity, genomic factors have yet to be elucidated in LUSC.

Methods: Using 416 LUSC tumor samples in the Cancer Genome Atlas (TCGA), we assessed genomic and transcriptomic profiles by ancestry. We replicated our analyses in pan-cancer data from TCGA, the American Association of Cancer Research (AACR) Genomics Evidence Neoplasia Information Exchange (GENIE), and Columbia University Medical Center.

Results: We found increased MYC amplification, LUSC-specific MYC enhancer amplification, and chromosome arm 8q (chr8q) gain to be significantly associated with genetic AFR (African) ancestry in LUSC in TCGA. Furthermore, expression of MYC target genes was significantly enriched in AFR samples. Local ancestry analysis identified correlation of chr8q gain with AFR ancestry at the MYC locus in TCGA. We also found a significant correlation between chr8q and AFR ancestry in multiple cancer types and pan-cancer in TCGA. Similarly, in a pan-cancer subset of AACR GENIE data, we found a significant correlation between chr8q gain and race.

Conclusion: Together, our data suggest that ancestry may influence amplification of not only MYC but also its enhancer in LUSC. They also suggest a role for genetic ancestry in chr8q aneuploidy in cancer. These studies further define and expand patients who may benefit from future anti-MYC therapeutic approaches.

目的:在肺鳞状细胞癌(LUSC)中,黑人患者的发病率明显高于白人患者,但总体生存率却低于白人患者。虽然社会经济因素可能是造成这种生存差异的原因之一,但肺鳞状细胞癌的基因组因素尚未得到阐明:我们利用癌症基因组图谱(TCGA)中的416个LUSC肿瘤样本,评估了不同血统的基因组和转录组特征。我们在TCGA、美国癌症研究协会(AACR)基因组学证据肿瘤信息交换中心(GENIE)和哥伦比亚大学医学中心的泛癌症数据中重复了我们的分析:结果:我们发现,在TCGA中,MYC扩增增加、LUSC特异性MYC增强子扩增和染色体臂8q(chr8q)增益与LUSC的遗传AFR(非洲)血统显著相关。此外,MYC靶基因的表达在非洲裔样本中明显富集。本地祖先分析发现,在 TCGA 的 MYC 基因座上,chr8q 增益与非洲裔祖先相关。我们还发现,在 TCGA 的多种癌症类型和泛癌症中,chr8q 与 AFR 祖先之间存在明显的相关性。同样,在 AACR GENIE 数据的泛癌症子集中,我们也发现了 chr8q 增益与种族之间的显著相关性:总之,我们的数据表明,祖先不仅可能影响 MYC 的扩增,还可能影响其在 LUSC 中的增强子。这些数据还表明,遗传血统在癌症的 chr8q 非整倍体中起着一定的作用。这些研究进一步确定并扩大了未来抗 MYC 治疗方法的受益患者范围。
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引用次数: 0
5-Hydroxymethylated Biomarkers in Cell-Free DNA Predict Occult Colorectal Cancer up to 36 Months Before Diagnosis in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. 前列腺癌、肺癌、结直肠癌和卵巢癌筛查试验中细胞游离 DNA 中的 5-羟甲基化生物标志物可预测诊断前 36 个月的隐匿性结直肠癌。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-10-11 DOI: 10.1200/PO.24.00277
Diana C West-Szymanski, Zhou Zhang, Xiao-Long Cui, Krissana Kowitwanich, Lu Gao, Zifeng Deng, Urszula Dougherty, Craig Williams, Shannon Merkle, Chuan He, Wei Zhang, Marc Bissonnette

Purpose: Using the prostate, lung, colorectal, and ovarian (PLCO) Cancer Screening Trial samples, we identified cell-free DNA (cfDNA) candidate biomarkers bearing the epigenetic mark 5-hydroxymethylcytosine (5hmC) that detected occult colorectal cancer (CRC) up to 36 months before clinical diagnosis.

Materials and methods: We performed the 5hmC-seal assay and sequencing on ≤8 ng cfDNA extracted from PLCO study participant plasma samples, including n = 201 cases (diagnosed with CRC within 36 months of blood collection) and n = 401 controls (no cancer diagnosis on follow-up). We conducted association studies and machine learning modeling to analyze the genome-wide 5hmC profiles within training and validation groups that were randomly selected at a 2:1 ratio.

Results: We successfully obtained 5hmC profiles from these decades-old samples. A weighted Cox model of 32 5hmC-modified gene bodies showed a predictive detection value for CRC as early as 36 months before overt tumor diagnosis (training set AUC, 77.1% [95% CI, 72.2 to 81.9] and validation set AUC, 72.8% [95% CI, 65.8 to 79.7]). Notably, the 5hmC-based predictive model showed comparable performance regardless of sex and race/ethnicity, and significantly outperformed risk factors such as age and obesity (assessed as BMI). Finally, when splitting cases at median weighted prediction scores, Kaplan-Meier analyses showed significant risk stratification for CRC occurrence in both the training set (hazard ratio, [HR], 3.3 [95% CI, 2.6 to 5.8]) and validation set (HR, 3.1 [95% CI, 1.8 to 5.8]).

Conclusion: Candidate 5hmC biomarkers and a scoring algorithm have the potential to predict CRC occurrence despite the absence of clinical symptoms and effective predictors. Developing a minimally invasive clinical assay that detects 5hmC-modified biomarkers holds promise for improving early CRC detection and ultimately patient outcomes.

目的:利用前列腺癌、肺癌、结直肠癌和卵巢癌(PLCO)筛查试验样本,我们确定了带有表观遗传标记5-羟甲基胞嘧啶(5hmC)的无细胞DNA(cfDNA)候选生物标记物,这些标记物可在临床诊断前36个月检测出隐匿性结直肠癌(CRC):我们对从PLCO研究参与者血浆样本中提取的≤8 ng cfDNA进行了5hmC-seal检测和测序,其中包括n = 201例病例(采血后36个月内诊断为CRC)和n = 401例对照(随访期间未诊断为癌症)。我们进行了关联研究和机器学习建模,以分析按 2:1 比例随机抽取的训练组和验证组的全基因组 5hmC 图谱:我们成功地从这些几十年前的样本中获得了5hmC图谱。32 个 5hmC 修饰基因体的加权 Cox 模型显示,早在肿瘤确诊前 36 个月,CRC 就具有预测检测价值(训练集 AUC,77.1% [95% CI,72.2-81.9];验证集 AUC,72.8% [95% CI,65.8-79.7])。值得注意的是,无论性别和种族/族裔如何,基于 5hmC 的预测模型都显示出相当的性能,并且明显优于年龄和肥胖(以体重指数评估)等风险因素。最后,当按加权预测得分中位数分割病例时,Kaplan-Meier 分析显示,在训练集(危险比,[HR],3.3 [95% CI,2.6 至 5.8])和验证集(HR,3.1 [95% CI,1.8 至 5.8])中,CRC 发生率的风险分层都很显著:尽管没有临床症状和有效的预测指标,候选的 5hmC 生物标志物和评分算法仍有可能预测 CRC 的发生。开发一种可检测 5hmC 修饰生物标志物的微创临床检测方法有望改善早期 CRC 检测并最终改善患者预后。
{"title":"5-Hydroxymethylated Biomarkers in Cell-Free DNA Predict Occult Colorectal Cancer up to 36 Months Before Diagnosis in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.","authors":"Diana C West-Szymanski, Zhou Zhang, Xiao-Long Cui, Krissana Kowitwanich, Lu Gao, Zifeng Deng, Urszula Dougherty, Craig Williams, Shannon Merkle, Chuan He, Wei Zhang, Marc Bissonnette","doi":"10.1200/PO.24.00277","DOIUrl":"https://doi.org/10.1200/PO.24.00277","url":null,"abstract":"<p><strong>Purpose: </strong>Using the prostate, lung, colorectal, and ovarian (PLCO) Cancer Screening Trial samples, we identified cell-free DNA (cfDNA) candidate biomarkers bearing the epigenetic mark 5-hydroxymethylcytosine (5hmC) that detected occult colorectal cancer (CRC) up to 36 months before clinical diagnosis.</p><p><strong>Materials and methods: </strong>We performed the 5hmC-seal assay and sequencing on ≤8 ng cfDNA extracted from PLCO study participant plasma samples, including n = 201 cases (diagnosed with CRC within 36 months of blood collection) and n = 401 controls (no cancer diagnosis on follow-up). We conducted association studies and machine learning modeling to analyze the genome-wide 5hmC profiles within training and validation groups that were randomly selected at a 2:1 ratio.</p><p><strong>Results: </strong>We successfully obtained 5hmC profiles from these decades-old samples. A weighted Cox model of 32 5hmC-modified gene bodies showed a predictive detection value for CRC as early as 36 months before overt tumor diagnosis (training set AUC, 77.1% [95% CI, 72.2 to 81.9] and validation set AUC, 72.8% [95% CI, 65.8 to 79.7]). Notably, the 5hmC-based predictive model showed comparable performance regardless of sex and race/ethnicity, and significantly outperformed risk factors such as age and obesity (assessed as BMI). Finally, when splitting cases at median weighted prediction scores, Kaplan-Meier analyses showed significant risk stratification for CRC occurrence in both the training set (hazard ratio, [HR], 3.3 [95% CI, 2.6 to 5.8]) and validation set (HR, 3.1 [95% CI, 1.8 to 5.8]).</p><p><strong>Conclusion: </strong>Candidate 5hmC biomarkers and a scoring algorithm have the potential to predict CRC occurrence despite the absence of clinical symptoms and effective predictors. Developing a minimally invasive clinical assay that detects 5hmC-modified biomarkers holds promise for improving early CRC detection and ultimately patient outcomes.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406406","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
Multiomic Characterization and Molecular Profiling of Nuclear Protein in Testis Carcinoma. 睾丸癌核蛋白的多组学特征和分子谱分析
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-10-24 DOI: 10.1200/PO.24.00334
Gianna Kroening, Jia Luo, Mark G Evans, Tolulope Adeyelu, Sai-Hong Ignatius Ou, Zhaohui L Arter, Trisha M Wise-Draper, Ammar Sukari, Asfar S Azmi, David R Braxton, Andrew Elliott, David A Bryant, Matthew J Oberley, Chul Kim, Geoffrey I Shapiro, Christopher A French, Misako Nagasaka

Purpose: Nuclear protein in testis carcinoma (NC) is an underdiagnosed and aggressive squamous/poorly differentiated cancer characterized by rearrangement of the gene NUTM1 on chromosome 15q14. Co-occurring alternations have not been fully characterized.

Methods: We analyzed the genomic and immune landscape of 54 cases of NC that underwent DNA- and RNA-based NGS sequencing (Caris).

Results: While NC is driven by NUTM1 fusion oncoproteins, co-occurring DNA mutations in epigenetic or cell cycle pathways were observed in 26% of cases. There was no significant difference between the fusion partner of NUTM1 and co-occurring gene mutations. RNA sequencing analysis showed increased MYC pathway activity in NC compared with head and neck squamous cell carcinoma (HNSCC) and lung squamous cell carcinoma (LUSC), which is consistent with the known pathophysiology of NC. Characterization of the NC tumor microenvironment using RNA sequencing revealed significantly lower immune cell infiltration compared with HNSCC and LUSC. NC was 10× higher in patients with HNSCC and LUSC younger than 50 years than in those older than 70 years.

Conclusion: To our knowledge, this is the first series of NC profiled broadly at the DNA and RNA level. We observed fewer intratumoral immune cells by RNA sequencing, which may be associated with anecdotal data of lack of immunotherapy benefit in NC. High MYC pathway activity in NC supports ongoing trials targeting MYC suppression. The incidence of NC among patients younger than 50 years with LUSC/HNSCC supports testing for NC in these patients. The prognosis of NCs remains dismal, and future studies should focus on improving the response to immunotherapy and targeting MYC.

目的:睾丸癌核蛋白(NC)是一种诊断率低、侵袭性强的鳞状癌/分化差的癌症,其特征是染色体 15q14 上的 NUTM1 基因发生重排。方法:我们分析了基因组和免疫系统:我们分析了 54 例接受 DNA 和 RNA NGS 测序(Caris)的 NC 的基因组和免疫图谱:结果:虽然NC是由NUTM1融合肿瘤蛋白驱动的,但在26%的病例中观察到表观遗传或细胞周期通路中同时存在DNA突变。NUTM1的融合伙伴与共存基因突变之间没有明显差异。RNA测序分析表明,与头颈部鳞状细胞癌(HNSCC)和肺鳞状细胞癌(LUSC)相比,NC的MYC通路活性增加,这与已知的NC病理生理学相一致。利用 RNA 测序分析 NC 肿瘤微环境的特征发现,与 HNSCC 和 LUSC 相比,免疫细胞浸润明显较低。在50岁以下的HNSCC和LUSC患者中,NC的发病率是70岁以上患者的10倍:据我们所知,这是第一例在DNA和RNA水平上对NC进行广泛分析的系列研究。通过RNA测序,我们观察到瘤内免疫细胞较少,这可能与NC缺乏免疫疗法获益的传闻有关。NC中MYC通路的高活性为正在进行的以抑制MYC为目标的试验提供了支持。在 50 岁以下的 LUSC/HNSCC 患者中,NC 的发病率较高,这支持对这些患者进行 NC 检测。NC的预后仍然不容乐观,未来的研究应侧重于改善对免疫疗法和靶向MYC的反应。
{"title":"Multiomic Characterization and Molecular Profiling of Nuclear Protein in Testis Carcinoma.","authors":"Gianna Kroening, Jia Luo, Mark G Evans, Tolulope Adeyelu, Sai-Hong Ignatius Ou, Zhaohui L Arter, Trisha M Wise-Draper, Ammar Sukari, Asfar S Azmi, David R Braxton, Andrew Elliott, David A Bryant, Matthew J Oberley, Chul Kim, Geoffrey I Shapiro, Christopher A French, Misako Nagasaka","doi":"10.1200/PO.24.00334","DOIUrl":"10.1200/PO.24.00334","url":null,"abstract":"<p><strong>Purpose: </strong>Nuclear protein in testis carcinoma (NC) is an underdiagnosed and aggressive squamous/poorly differentiated cancer characterized by rearrangement of the gene <i>NUTM1</i> on chromosome 15q14. Co-occurring alternations have not been fully characterized.</p><p><strong>Methods: </strong>We analyzed the genomic and immune landscape of 54 cases of NC that underwent DNA- and RNA-based NGS sequencing (Caris).</p><p><strong>Results: </strong>While NC is driven by <i>NUTM1</i> fusion oncoproteins, co-occurring DNA mutations in epigenetic or cell cycle pathways were observed in 26% of cases. There was no significant difference between the fusion partner of <i>NUTM1</i> and co-occurring gene mutations. RNA sequencing analysis showed increased <i>MYC</i> pathway activity in NC compared with head and neck squamous cell carcinoma (HNSCC) and lung squamous cell carcinoma (LUSC), which is consistent with the known pathophysiology of NC. Characterization of the NC tumor microenvironment using RNA sequencing revealed significantly lower immune cell infiltration compared with HNSCC and LUSC. NC was 10× higher in patients with HNSCC and LUSC younger than 50 years than in those older than 70 years.</p><p><strong>Conclusion: </strong>To our knowledge, this is the first series of NC profiled broadly at the DNA and RNA level. We observed fewer intratumoral immune cells by RNA sequencing, which may be associated with anecdotal data of lack of immunotherapy benefit in NC. High <i>MYC</i> pathway activity in NC supports ongoing trials targeting <i>MYC</i> suppression. The incidence of NC among patients younger than 50 years with LUSC/HNSCC supports testing for NC in these patients. The prognosis of NCs remains dismal, and future studies should focus on improving the response to immunotherapy and targeting MYC.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11520346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142500782","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
Using Artificial Intelligence to Support Informed Decision-Making on BRAF Mutation Testing. 利用人工智能支持 BRAF 基因突变检测的知情决策。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-10-30 DOI: 10.1200/PO.23.00685
Jennifer Webster, Jennifer Ghith, Orion Penner, Christopher H Lieu, Bob J A Schijvenaars

Purpose: Precision oncology relies on accurate and interpretable reporting of testing and mutation rates. Focusing on the BRAFV600 mutations in advanced colorectal carcinoma, non-small-cell lung carcinoma, and cutaneous melanoma, we developed a platform displaying testing and mutation rates reported in the literature, which we annotated using an artificial intelligence (AI) and natural language processing (NLP) pipeline.

Methods: Using AI, we identified publications that likely reported a testing or mutation rate, filtered publications for cancer type, and identified sentences that likely reported rates. Rates and covariates were subsequently manually curated by three experts. The AI performance was evaluated using precision and recall metrics. We used an interactive platform to explore and present the annotated testing and mutation rates by certain study characteristics.

Results: The interactive dashboard, accessible at the BRAF dimensions website, enables users to filter mutation and testing rates with relevant options (eg, country of study, study type, mutation type) and to visualize annotated rates. The AI pipeline demonstrated excellent filtering performance (>90% precision and recall for all target cancer types) and moderate performance for sentence classification (53%-99% precision; ≥75% recall). The manual annotation of testing and mutation rates revealed inter-rater disagreement (testing rate, 19%; mutation rate, 70%), indicating unclear or nonstandard reporting of rates in some publications.

Conclusion: Our AI-driven NLP pipeline demonstrated the potential for annotating biomarker testing and mutation rates. The difficulties we encountered highlight the need for more advanced AI-powered literature searching and data extraction, and more consistent reporting of testing rates. These improvements would reduce the risk of misinterpretation or misunderstanding of testing and mutation rates by AI-based technologies and the health care community, with beneficial impacts on clinical decision-making, research, and trial design.

目的:精准肿瘤学依赖于准确且可解释的检测和突变率报告。我们以晚期结直肠癌、非小细胞肺癌和皮肤黑色素瘤中的 BRAFV600 突变为重点,开发了一个显示文献中报告的检测率和突变率的平台,并使用人工智能(AI)和自然语言处理(NLP)管道对其进行了注释:利用人工智能,我们确定了可能报告了检测率或突变率的出版物,根据癌症类型过滤了出版物,并确定了可能报告了检测率或突变率的句子。随后,由三位专家对比率和协变量进行人工筛选。人工智能的性能使用精确度和召回率指标进行评估。我们使用了一个交互式平台,按照某些研究特征来探索和展示注释的检测率和突变率:用户可以在 BRAF dimensions 网站上访问交互式仪表板,通过相关选项(如研究国家、研究类型、突变类型)筛选突变率和检测率,并直观显示注释率。人工智能管道显示出卓越的过滤性能(所有目标癌症类型的精确度和召回率均大于 90%)和中等的句子分类性能(精确度为 53%-99%;召回率≥75%)。对测试率和突变率的人工标注显示出评分者之间的意见分歧(测试率为19%;突变率为70%),这表明某些出版物中对比率的报告不明确或不标准:我们的人工智能驱动 NLP 管道展示了注释生物标记物检测率和突变率的潜力。我们遇到的困难突出表明,需要更先进的人工智能驱动的文献搜索和数据提取,以及更一致的检测率报告。这些改进将降低人工智能技术和医疗界对检测和突变率的误读或误解的风险,从而对临床决策、研究和试验设计产生有益的影响。
{"title":"Using Artificial Intelligence to Support Informed Decision-Making on <i>BRAF</i> Mutation Testing.","authors":"Jennifer Webster, Jennifer Ghith, Orion Penner, Christopher H Lieu, Bob J A Schijvenaars","doi":"10.1200/PO.23.00685","DOIUrl":"10.1200/PO.23.00685","url":null,"abstract":"<p><strong>Purpose: </strong>Precision oncology relies on accurate and interpretable reporting of testing and mutation rates. Focusing on the <i>BRAFV600</i> mutations in advanced colorectal carcinoma, non-small-cell lung carcinoma, and cutaneous melanoma, we developed a platform displaying testing and mutation rates reported in the literature, which we annotated using an artificial intelligence (AI) and natural language processing (NLP) pipeline.</p><p><strong>Methods: </strong>Using AI, we identified publications that likely reported a testing or mutation rate, filtered publications for cancer type, and identified sentences that likely reported rates. Rates and covariates were subsequently manually curated by three experts. The AI performance was evaluated using precision and recall metrics. We used an interactive platform to explore and present the annotated testing and mutation rates by certain study characteristics.</p><p><strong>Results: </strong>The interactive dashboard, accessible at the BRAF dimensions website, enables users to filter mutation and testing rates with relevant options (eg, country of study, study type, mutation type) and to visualize annotated rates. The AI pipeline demonstrated excellent filtering performance (>90% precision and recall for all target cancer types) and moderate performance for sentence classification (53%-99% precision; ≥75% recall). The manual annotation of testing and mutation rates revealed inter-rater disagreement (testing rate, 19%; mutation rate, 70%), indicating unclear or nonstandard reporting of rates in some publications.</p><p><strong>Conclusion: </strong>Our AI-driven NLP pipeline demonstrated the potential for annotating biomarker testing and mutation rates. The difficulties we encountered highlight the need for more advanced AI-powered literature searching and data extraction, and more consistent reporting of testing rates. These improvements would reduce the risk of misinterpretation or misunderstanding of testing and mutation rates by AI-based technologies and the health care community, with beneficial impacts on clinical decision-making, research, and trial design.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545622","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
Palbociclib in Patients With Head and Neck Cancer and Other Tumors With CDKN2A Alterations: Results From the Targeted Agent and Profiling Utilization Registry Study. 帕博西尼(Palbociclib)治疗头颈癌及其他CDKN2A基因改变的肿瘤患者:靶向药物和剖析利用登记研究的结果。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-10-16 DOI: 10.1200/PO-24-00477
Francis P Worden, Evan Pisick, Michael Rothe, Pam K Mangat, Elizabeth Garrett-Mayer, Maged F Khalil, Daniel R Carrizosa, Jessica R Bauman, Rom S Leidner, Herbert L Duvivier, Siqing Fu, Min S Park, Kathleen J Yost, Carmen J Calfa, Alissa S Marr, Ani S Balmanoukian, Deepti Behl, Timothy L Cannon, Lisle Nabell, Steven Francis Powell, Ramya Thota, Dominique C Hinshaw, Abigail Gregory, Gina N Grantham, Susan Halabi, Richard L Schilsky

Purpose: Targeted Agent and Profiling Utilization Registry is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and targetable genomic alterations. Two cohorts of patients with cyclin-dependent kinase inhibitor 2A (CDKN2A)-mutated tumors treated with palbociclib are reported: one with head and neck cancer (HNC) with both squamous and nonsquamous cell histologies, and one with histology-pooled (HP) cancers.

Methods: Eligible patients had measurable disease, Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. The primary end point was disease control (DC), defined as objective response (OR) or stable disease (SD) of at least 16+ weeks duration. For the HNC cohort, Simon's two-stage design with a null DC rate of 15% versus 35% (power = 0.85; α = .10) was used. For the HP cohort, the null hypothesis of a DC rate of 15% was rejected if the lower limit of a one-sided 90% CI was >15%. Secondary end points included OR, safety, progression-free survival, overall survival, duration of response, and duration of SD.

Results: Seventy patients with HNC (N = 28) or HP cancers (N = 42) were treated with palbociclib. For the HNC cohort, DC and OR rates were 40% (one-sided 90% CI, 27 to 100) and 4% (95% CI, <1 to 18), respectively. The null hypothesis was rejected (P = .002). For the HP cohort, DC and OR rates were 13% (one-sided 90% CI, 6 to 100) and 5% (95% CI, <1 to 17), respectively. The null hypothesis was not rejected. Thirty-one of 70 patients experienced treatment-related grade 3 to 4 adverse events (AEs) or serious AEs, the most common including neutropenia, thrombocytopenia, and leukopenia.

Conclusion: Palbociclib met prespecified criteria to declare a signal of activity in patients with HNC with CDKN2A alterations, but not in the HP cohort.

目的:靶向药物和剖析利用注册是一项II期篮子试验,评估市售靶向药物在晚期癌症和可靶向基因组改变患者中的抗肿瘤活性。本文报告了两组接受帕博西尼(palbociclib)治疗的细胞周期蛋白依赖性激酶抑制剂2A(CDKN2A)突变肿瘤患者:一组是鳞状细胞和非鳞状细胞组织学的头颈癌(HNC)患者,另一组是组织学汇集(HP)癌症患者:符合条件的患者均患有可测量的疾病、东部合作肿瘤学组(Eastern Cooperative Oncology Group)表现为 0-2 级、器官功能正常且无标准治疗方案。主要终点是疾病控制(DC),即至少持续 16 周以上的客观反应(OR)或疾病稳定(SD)。对于HNC队列,采用西蒙两阶段设计,疾病控制率为15%对35%(功率=0.85;α=0.10)。对于HP队列,如果单侧90% CI的下限>15%,则拒绝直流电率为15%的零假设。次要终点包括OR、安全性、无进展生存期、总生存期、反应持续时间和SD持续时间:70例HNC(28例)或HP癌(42例)患者接受了palbociclib治疗。在HNC队列中,DC和OR率分别为40%(单侧90% CI,27至100)和4%(95% CI,P = .002)。HP队列中,DC和OR率分别为13%(单侧90% CI,6至100)和5%(95% CI,P = .002):Palbociclib在CDKN2A改变的HNC患者中符合宣布活性信号的预设标准,但在HP队列中不符合标准。
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引用次数: 0
Response to Crizotinib After Entrectinib Resistance in ROS1-Rearranged, MET-Amplified Lung Adenocarcinoma. ROS1重排、MET扩增的肺腺癌在恩替雷尼耐药后对克唑替尼的反应
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-10-07 DOI: 10.1200/PO-24-00394
Victor R Vaz, Malini M Gandhi, Biagio Ricciuti, Joao V Alessi, Arielle Elkrief, Marc Ladanyi, Chad Vanderbilt, Federica Pecci, Mihaela Aldea, Adriana Barrichello, Arushi Saini, Lynette Sholl, Jacob M Sands, Mark M Awad

Crizotinib successfully overcomes MET amplification in ROS1-rearranged NSCLC after entrectinib failure.

克唑替尼成功克服了恩替利尼失败后ROS1重排NSCLC中的MET扩增。
{"title":"Response to Crizotinib After Entrectinib Resistance in <i>ROS1</i>-Rearranged, <i>MET</i>-Amplified Lung Adenocarcinoma.","authors":"Victor R Vaz, Malini M Gandhi, Biagio Ricciuti, Joao V Alessi, Arielle Elkrief, Marc Ladanyi, Chad Vanderbilt, Federica Pecci, Mihaela Aldea, Adriana Barrichello, Arushi Saini, Lynette Sholl, Jacob M Sands, Mark M Awad","doi":"10.1200/PO-24-00394","DOIUrl":"https://doi.org/10.1200/PO-24-00394","url":null,"abstract":"<p><p>Crizotinib successfully overcomes MET amplification in ROS1-rearranged NSCLC after entrectinib failure.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390684","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
期刊
JCO precision oncology
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