In this article, we summarize the progress made in lung cancer, mesothelioma, and thymic epithelial malignancy during the period 2005–2025. We enlisted multidisciplinary thoracic oncologic experts to tackle this task. The main focus of the article concerns how basic science with translational impact has improved the diagnosis, prognosis, and therapy of these cancers. During the past 20 years, we have come to the realization that “lung cancer” is a name that encompasses tumors with vast histologic, immune, and genomic differences that in turn influence prognosis and response to therapy. For example, programmed death-ligand 1 levels are being used as an immune signature which guides the use of immunotherapy. There is an 85% higher risk for developing lung cancer among first-degree relatives of patients with lung cancer. Accordingly, an increasing number of lung cancers are being identified in carriers of predisposing germline pathogenic inactivating mutations, suggesting that screening programs for early lung cancer detection may benefit family members. Underscoring the role of genetics, and the importance of germline testing, a different variant of mesothelioma has been identified developing in carriers of inactivating heterozygous germline mutations of BAP1 and of other tumor suppressor genes, including a new variant of mesothelioma caused by fusion genes. These variants of mesothelioma are characterized by specific histologic and molecular genetic alterations. These patients benefit from screening programs as they are at risk of multiple malignancies, their tumors are usually much less aggressive, and they are more responsive to therapy compared with sporadic, asbestos-induced mesotheliomas. Thus, the tailored therapeutic approach that is described here for lung cancer may extend to patients with mesothelioma, rather than the previous “one therapy fits all” approach. Progress in the rare thymic epithelial tumors has been less marked; however, recent insights into the biology of thymic tumors have resulted in the development of clinically relevant interventions.
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