摘要：

Thymic malignancies are rare epithelial tumors that may be aggressive and difficult totreat. Thymomas are usually localized to the anterior mediastinum and are frequentlyeligible for upfront surgical resection. However, nearly 30% of patients present withlocally advanced tumor at time of diagnosis, and chemotherapy is then used to reducethe tumor burden, possibly allowing subsequent surgery and/or radiotherapy. Thymiccarcinomas have a tendency towards metastatic spread, and systemic treatment isa major component in the multimodal strategy. Metastatic and recurrent thymicmalignancies may similarly be treated with chemotherapy, with limited long-termefficacy, especially beyond first-line treatment. The molecular characterization ofthymoma and thymic carcinoma recently led to identify potentially druggable targets;significant preclinical and clinical data are available for the EGF receptor (EGFR), theKIT/mast/stem-cell growth factor receptor, and the IGF-1 receptor (IGF-1R) pathways.While there is currently no rationale to recommend the use of EGFR tyrosine kinaseinhibitors in thymoma or thymic carcinoma, the frequent overexpression of EGFRby epithelial tumor cells is a strong rationale for further evaluation of anti-EGFRmonoclonal antibodies, such as cetuximab. A phase II trial is ongoing in unresectablelocally advanced thymomas. KIT-mutant thymic carcinomas represent a small molecular subset of thymic tumors. The clinical relevance of KIT mutations is more limited thanin other cancers such as gastro-intestinal stromal tumors, as KIT mutations are far lessfrequently observed, KIT expression does not correlate with the presence of mutations,and nonpretreated KIT mutants are not uniformly sensitive to imatinib. The use ofsecond-generation multikinase inhibitors is then mandatory to inhibit the KIT signaling pathway. IGF-1R is overexpressed in 30% of thymomas and 80% of thymic carcinomas;results from a phase II with cixutumumab have recently been reported, showingpromising response and survival rates. Another target of interest in thymic malignancies is neoangiogenesis, as activation of the Vascular Endothelial Growth Factor/VEGF-Receptor signaling pathway has been correlated with tumor invasion, aggressivehistology, and higher clinical stage. Only sparse data are available regarding the use ofspecific anti-angiogenic drugs. Besides bevacizumab and vascular disrupting agents,the reported effect of multikinase inhibitors, such as sunitinib or sorafenib, especiallyin KIT-wild-type thymic carcinomas, may be partially related to their antiangiogeniceffect. Other molecular targets include histone deacetylase, with promising resultsreported with belinostat, and cyclin-dependant kinases, with specific inhibitorscurrently under investigation. Besides these predictive biomarkers, the identificationof prognostic markers would help to better select patients with thymic malignanciesfor aggressive treatment, including postoperative radiotherapy and chemotherapy.However, the favorable outcome of thymoma after surgery and the highly significantprognostic value of complete resection make the identification of prognostic factorschallenging. Integrated genomic analyses, including standard genomic, expression,and mutational profiling, but also next-generation sequencing, represent a new avenuefor the identification of predictive and prognostic biomarkers. One example is theestablishment of RNA-based and/or micro-RNA-based prognostic signatures, whichwill be evaluated in prospective studies, to assess their value as surrogate markers topredict the aggressiveness of a tumor. Taken together, these data show that the conceptof personalized molecular medicine, which consists of establishing a therapeuticstrategy based on the individual assessment of predictive and prognostic biomarkers, is applicable to rare tumors such as thymomas and thymic carcinomas. This paradigm shift will represent a major area of investigation in the next future.Keywords: molecular biology, biomarker, thymoma, thymic carcinoma

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