Oncogenic mutations in the TP53 and PI-3 kinase/AKT pathway are independent predictors of survival for advanced thyroid cancer: Analysis from the Molecular Screening and Therapeutics (MoST) program.

IF 3.2 2区医学 Q1 SURGERY

Surgery Pub Date : 2024-10-17 DOI:10.1016/j.surg.2024.05.058

Elan Novis, Anthony Glover, John P Grady, Audrey Silvestri, Subotheni Thavaneswaran, Frank Lin, Mandy L Ballinger, David M Thomas

{"title":"Oncogenic mutations in the TP53 and PI-3 kinase/AKT pathway are independent predictors of survival for advanced thyroid cancer: Analysis from the Molecular Screening and Therapeutics (MoST) program.","authors":"Elan Novis, Anthony Glover, John P Grady, Audrey Silvestri, Subotheni Thavaneswaran, Frank Lin, Mandy L Ballinger, David M Thomas","doi":"10.1016/j.surg.2024.05.058","DOIUrl":null,"url":null,"abstract":"Background: Thyroid cancers with mutations in the phosphatidylinositol-3 kinase/AKT pathway have a poorer prognosis. However, knowledge about the relationship between histology, mutation profile, and outcomes is still developing. This study assessed the prognostic value of genomic profiles for patients with advanced thyroid cancer who experienced progression on conventional treatment.Methods: Patients recruited to a national clinical oncology program for treatment-refractory locally advanced, recurrent or metastatic cancers were analyzed. Patients' archival tumor samples underwent comprehensive genomic profiling. Specific oncogenic mutations and the presence of cancer related pathways were correlated with overall survival.Results: From 2018 to 2021, 4,955 patients were recruited, with 44 (0.9%) having a diagnosis of thyroid cancer with 4 medullary and the remaining follicular derived: 17 differentiated, 13 poorly differentiated, and 10 anaplastic thyroid cancers. Of the 40 follicular-derived thyroid cancer samples, 17 (42.5%) carried TP53 mutations, followed by 11 with BRAF V600E (27.5%), 9 with NRAS (22.5%), 9 with mutations in the phosphatidylinositol-3 kinase/AKT pathway (22.5%), and 7 with TERT promoter mutations (17.5%). Both TP53 and phosphatidylinositol-3 kinase/AKT pathway alterations were associated with reduced overall survival (hazard ratio, 5.19; 95% confidence interval, 1.59-16.70, P = .02 and hazard ratio, 10.12; 95% confidence interval, 1.61-63.76, P = .01). Cox regression showed histologic type anaplastic thyroid cancer (hazard ratio, 12.93, P = .004), poorly differentiated thyroid cancer (hazard ratio, 5.19, P = .039), and TP53 and/or phosphatidylinositol-3 kinase/AKT pathway mutations (hazard ratio, 4.73, P = .017) were independently associated with overall survival.Conclusion: TP53 and/or phosphatidylinositol-3 kinase/AKT pathway mutations correlated with overall survival independently of histotype in patients with advanced thyroid cancer. Comprehensive genomic profiling has potential to inform prognosis, as well as identifying treatment targets for patients with advanced thyroid cancer.","PeriodicalId":22152,"journal":{"name":"Surgery","volume":" ","pages":""},"PeriodicalIF":3.2000,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Surgery","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.surg.2024.05.058","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"SURGERY","Score":null,"Total":0}

引用次数: 0

Abstract

Background: Thyroid cancers with mutations in the phosphatidylinositol-3 kinase/AKT pathway have a poorer prognosis. However, knowledge about the relationship between histology, mutation profile, and outcomes is still developing. This study assessed the prognostic value of genomic profiles for patients with advanced thyroid cancer who experienced progression on conventional treatment.

Methods: Patients recruited to a national clinical oncology program for treatment-refractory locally advanced, recurrent or metastatic cancers were analyzed. Patients' archival tumor samples underwent comprehensive genomic profiling. Specific oncogenic mutations and the presence of cancer related pathways were correlated with overall survival.

Results: From 2018 to 2021, 4,955 patients were recruited, with 44 (0.9%) having a diagnosis of thyroid cancer with 4 medullary and the remaining follicular derived: 17 differentiated, 13 poorly differentiated, and 10 anaplastic thyroid cancers. Of the 40 follicular-derived thyroid cancer samples, 17 (42.5%) carried TP53 mutations, followed by 11 with BRAF V600E (27.5%), 9 with NRAS (22.5%), 9 with mutations in the phosphatidylinositol-3 kinase/AKT pathway (22.5%), and 7 with TERT promoter mutations (17.5%). Both TP53 and phosphatidylinositol-3 kinase/AKT pathway alterations were associated with reduced overall survival (hazard ratio, 5.19; 95% confidence interval, 1.59-16.70, P = .02 and hazard ratio, 10.12; 95% confidence interval, 1.61-63.76, P = .01). Cox regression showed histologic type anaplastic thyroid cancer (hazard ratio, 12.93, P = .004), poorly differentiated thyroid cancer (hazard ratio, 5.19, P = .039), and TP53 and/or phosphatidylinositol-3 kinase/AKT pathway mutations (hazard ratio, 4.73, P = .017) were independently associated with overall survival.

Conclusion: TP53 and/or phosphatidylinositol-3 kinase/AKT pathway mutations correlated with overall survival independently of histotype in patients with advanced thyroid cancer. Comprehensive genomic profiling has potential to inform prognosis, as well as identifying treatment targets for patients with advanced thyroid cancer.

查看原文本刊更多论文

TP53和PI-3激酶/AKT通路中的致癌突变是晚期甲状腺癌生存率的独立预测因素：分子筛选与治疗（MoST）项目分析。

背景：磷脂酰肌醇-3 激酶/AKT 通路发生突变的甲状腺癌预后较差。然而，有关组织学、突变特征和预后之间关系的知识仍在发展中。本研究评估了常规治疗进展的晚期甲状腺癌患者基因组图谱的预后价值：方法：对国家临床肿瘤学计划招募的治疗难治性局部晚期、复发性或转移性癌症患者进行分析。对患者的存档肿瘤样本进行了全面的基因组分析。特定的致癌突变和癌症相关通路的存在与总生存率相关：从2018年到2021年，共招募了4955名患者，其中44人（0.9%）确诊为甲状腺癌，4人髓质型，其余为滤泡型：17例分化型甲状腺癌、13例分化不良型甲状腺癌和10例无细胞型甲状腺癌。在40例滤泡源性甲状腺癌样本中，17例（42.5%）携带TP53突变，11例携带BRAF V600E突变（27.5%），9例携带NRAS突变（22.5%），9例携带磷脂酰肌醇-3激酶/AKT通路突变（22.5%），7例携带TERT启动子突变（17.5%）。TP53和磷脂酰肌醇-3激酶/AKT通路的改变均与总生存率降低有关（危险比为5.19；95%置信区间为1.59-16.70，P = .02；危险比为10.12；95%置信区间为1.61-63.76，P = .01）。Cox回归显示，组织学类型为无性甲状腺癌（危险比为12.93，P = .004）、分化不良的甲状腺癌（危险比为5.19，P = .039）以及TP53和/或磷脂酰肌醇-3激酶/AKT通路突变（危险比为4.73，P = .017）与总生存期独立相关：结论：TP53和/或磷脂酰肌醇-3激酶/AKT通路突变与晚期甲状腺癌患者的总生存期相关，与组织型无关。全面的基因组分析有望为晚期甲状腺癌患者的预后提供信息，并确定治疗目标。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Surgery 医学-外科

CiteScore

5.40

自引率

5.30%

发文量

687

审稿时长

64 days

期刊介绍： For 66 years, Surgery has published practical, authoritative information about procedures, clinical advances, and major trends shaping general surgery. Each issue features original scientific contributions and clinical reports. Peer-reviewed articles cover topics in oncology, trauma, gastrointestinal, vascular, and transplantation surgery. The journal also publishes papers from the meetings of its sponsoring societies, the Society of University Surgeons, the Central Surgical Association, and the American Association of Endocrine Surgeons.