Longitudinal Molecular Analysis of Tumor Exome and Transcriptome to Evaluate Clonal Evolution and Identify Novel Therapeutic Targets in Thymoma
Year: 2023
Type: article
Study design: Case Report
Abstract: The rarity of thymic epithelial tumors and limited preclinical modeling constrain our understanding of disease biology and the advancement of rational treatment strategies.Tumor mutational profiling has demonstrated sporadic activating mutations in targetable tyrosine kinases that have not been successfully targeted outside of individual case reports. 1 Additionally, most molecular studies to date have focused on profiling treatment-na ïve tumors, failing to capture potential changes that accompany recurrence and resistance to therapy. 2 To profile evolutionary changes through recurrence and identify novel treatment options in advanced thymoma, we present the molecular analysis of exome and bulk RNA sequences from a primary thymic tumor and multiple resected metachronous tumors from a single patient.The patient initially presented because of bulbar symptoms of myasthenia gravis at age 25 years.Computed tomography imaging at that time demonstrated an anterior mediastinal mass without any pleural deposits, pulmonary nodules, or other findings concerning for distant metastatic disease.Median sternotomy, radical thymectomy, and partial pericardiectomy were performed.Pathologic analysis demonstrated a mixed B1/B2/B3 thymoma with two margins that were microscopically positive for disease.After R1 resection, the patient received adjuvant mediastinal radiation to reduce the risk of disease recurrence.Five years later, the patient underwent left-sided thoracotomy, total parietal pleurectomy, and diaphragmatic tumor resection with diaphragm reconstruction for recurrence in the pleural space, persistently progressive over 2 years.WHO subtype B3 histology was predominant, with B2 foci present.Six years later, the patient had another recurrence in the pleural space observed over 18 months, managed with redo thoracotomy, lysis of adhesions, and resection of implants on parietal pleura, pericardium, and diaphragm, with left lower lobe lung wedge resection for visceral implants.Histologic subtype was unchanged.One year later, the patient experienced another left-sided recurrence in the pleural space along with lateral diaphragm lesion with symptomatic chest wall involvement necessitating palliative intervention.Debulking was attempted with two cycles of CAP (cisplatin 50 mg/m 2 , doxorubicin 50 mg/m 2 , cyclophosphamide 500 mg/m 2 once every 3 weeks), but restaging scans demonstrated no radiographic response and the patient was taken for a repeat thoracotomy with pleural metastasis resection, parietal diaphragm resection, and primary diaphragm repair, along with retroperitoneal implant resection, again with unchanged tumor subtype.In total, the patient underwent a total of four surgeries for tumor debulking yielding the primary tumor and metastases from three metachronous recurrences, all outside the adjuvant radiation field (Fig 1A).For all recurrences, surgical exploration demonstrated additional subcentimeter deposits on visceral and parietal pleura below the detection limits of computed tomography imaging.This study was performed in accordance with the precepts of the Helsinki Declaration.The patient provided informed consent to a research protocol (13-416) previously approved by the Dana-Farber/Harvard Cancer Center Institutional Review Board, with Massachusetts General Hospital as the study site.The study was specifically performed after the patient provided informed consent.All protected health information has been removed to protect the patient's identity.The patient also provided informed consent for publication of information resulting from this study.
Source: JCO Precision Oncology
DOI: 10.1200/po.23.00107
Authors: Christopher S. Nabel, Yin P. Hung, Anna Kurilovich, Aleksandra Lopareva, Dora Dias-Santagata, Nikita Batashkov, Dmitry Tabakov, Maria Sorokina, Aleksey Makarov, Georgy Sagaradze, Anna Butusova, Olga Kudryashova, Lev Bedniagin, Cameron D. Wright, Nara Shin, Alexander Bagaev, Ekaterina Postovalova, Abner Louissaint
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W4384024056