Systemic Treatment of Advanced Thymic Malignancies

Abstract

The rarity of thymic malignancies prevents us from performing large randomized clinical trials. As a result, systemic treatment decisions are often guided by a small amount of prospective trial data, retrospective series, and individual case reports. In recent years, we have begun to unravel the molecular biology of thymic tumors. It is becoming more apparent as a result of gene expression profiling and genomic clustering studies that the subclassifications of type A, AB, B1, B2, B3, and thymic carcinoma have different molecular features that may be clinically relevant. Genomic profiling distinguishes type B3 thymoma and thymic carcinoma as distinct entities from type A and type B2 thymoma. Furthermore, type B2 thymomas can be separated from other subgroups in that it has a more distinct lymphocytic component than the other groups where epithelial cells predominate. Next generation RNA sequencing has recently identified a large microRNA cluster on chromosome 19q13.42 in types A and AB thymomas, which is absent in type B thymomas and thymic carcinomas. This cluster has been shown to result in activation of the phosphoinositide 3-kinase (PI3K)/AKT pathway, which suggests a possible role for PI3K inhibitors in these subtypes. The presence of KIT mutations in thymic carcinomas is also well described. Herein we discuss the chemotherapeutic and targeted treatment options for advanced thymic malignancies and highlight important advances in our understanding of the molecular biology of these rare tumors.KEY POINTSA collaborative effort by the International Thymic Malignancies Interest Group (ITMIG) and the International Association for the Study of Lung Cancer (IASLC) is now underway to develop a tumor, node, metastasis staging system for thymic tumors.Although surgery remains the treatment of choice in thymic tumors, chemotherapy is recommended in the locally advanced, unresectable or metastatic setting.A better understanding of the biology of both thymomas and thymic carcinomas has occurred in recent years thanks to advanced technologies such as comparative genomic hybridization, expression array analysis, and next generation sequencing.Prognostic and predictive gene signatures for thymic tumors are in development.Targeted agents have been investigated in small phase II clinical trials. Results to date have shown modest responses, but biomarker-driven patient selection via molecular profiling studies may improve efficacy.