TP53和PI-3激酶/AKT通路中的致癌突变是晚期甲状腺癌生存的独立预测因素：来自分子筛查与治疗（MoST）项目的分析。

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.

作者信息

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

机构信息

St Vincent's Hospital, Sydney, NSW, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia.

St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia; The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.

出版信息

Surgery. 2025 Jan;177:108858. doi: 10.1016/j.surg.2024.05.058. Epub 2024 Oct 18.

DOI:10.1016/j.surg.2024.05.058

PMID:39424488

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.

摘要

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，关于组织学、突变谱与预后之间关系的认识仍在不断发展。本研究评估了基因组图谱对常规治疗后病情进展的晚期甲状腺癌患者的预后价值。

方法

对纳入一项全国临床肿瘤项目以治疗难治性局部晚期、复发性或转移性癌症的患者进行分析。对患者的存档肿瘤样本进行全面的基因组分析。特定的致癌突变和癌症相关通路的存在与总生存期相关。

结果

2018年至2021年，共招募了4955例患者，其中44例（0.9%）被诊断为甲状腺癌，包括4例髓样癌，其余为滤泡性来源：17例分化型、13例低分化型和10例未分化型甲状腺癌。在40例滤泡性来源的甲状腺癌样本中，17例（42.5%）携带TP53突变，其次是11例携带BRAF V600E突变（27.5%）、9例携带NRAS突变（22.5%）、9例磷脂酰肌醇-3激酶/AKT通路突变（22.5%）以及7例TERT启动子突变（17.5%）。TP53和磷脂酰肌醇-3激酶/AKT通路改变均与总生存期缩短相关（风险比，5.19；95%置信区间，1.59 - 16.70，P = 0.02；风险比，10.12；95%置信区间，1.61 - 63.76，P = 0.01）。Cox回归显示，组织学类型为未分化型甲状腺癌（风险比，12.93，P = 0.004）、低分化型甲状腺癌（风险比，5.19，P = 0.039）以及TP53和/或磷脂酰肌醇-激酶/AKT通路突变（风险比，4.73，P = 0.017）与总生存期独立相关。