Comprehensive Genomic Profiling of 274 Thymic Epithelial Tumors Unveils Oncogenic Pathways and Predictive Biomarkers

BACKGROUND: Thymic malignancies represent a heterogeneous group of rare thoracic cancers, which are classified according to the World Health Organization histopathologic classification, that distinguishes thymomas from thymic carcinomas. Data regarding the biology of those tumors are limited in the literature, and the vast majority have been obtained using surgical specimens from early-stage disease. Meanwhile, treatment of advanced, refractory thymic tumors currently relies on chemotherapy, with limited efficacy. Comprehensive genomic profiling (CGP) of advanced, refractory tumors would open some opportunities for innovative treatments. PATIENTS AND METHODS: A total of 90 and 174 consecutive patients with thymoma or thymic carcinoma, respectively, for whom formalin-fixed, paraffin-embedded specimens from recurrent, refractory tumor were sequenced, were included. Sequencing was performed using hybridization-captured, adaptor ligation-based libraries to a mean coverage depth of >500× for up to 315 cancer-related genes plus 37 introns from 28 genes frequently rearranged in cancer. RESULTS: Thymomas featured a low frequency of genomic alterations (average of 1.8/tumor), and low levels of TMB. The genomic alterations identified in more than 10% of cases were in the CDKN2A/B and TP53 genes. Amplification in the NTRK1 gene was found in an unresectable, stage III, type B3 thymoma. Thymic carcinomas featured a significantly higher frequency of alterations at 4.0/tumor (P < .0001). Clinically relevant genomic alterations were observed in the CDKN2A, KIT, and PTEN/PI3K/MTOR pathways. Elevated TMB in thymic carcinomas was uncommon with only 6% of cases featuring ≥10 mutations/Mb. CONCLUSIONS: Our cohort is the largest available so far, reporting on CGP of thymic epithelial tumors in the setting of advanced disease. The identification of clinically relevant genomic alterations in the KIT, PI3K, CDKN2A/B, or NTRK genes provides a strong rationale for potential precision medicine approaches using targeted agents. A subset of thymic carcinomas show high tumor mutation burden, what may be a predictor of efficacy of immune checkpoint inhibitors.