Thymic malignancies: from clinical management to targeted therapies

Abstract

Purpose: A key challenge in the treatment of thymoma and thymic carcinoma (TC) is in improving our understanding of the molecular biology of these relatively rare tumors. In recent years, significant efforts have been made to dissect the molecular pathways involved in their carcinogenesis. Here we discuss the results of large-scale genomic analyses conducted to date and review the most active chemotherapies and targeted treatments.

Methods: We reviewed the literature for chemotherapeutic trials in the last 20 years and trials involving targeted therapies between 1999 and 2010. The search was supplemented by a review of abstracts presented at the annual meetings of the American Society of Clinical Oncology (from 1999 to 2010), at the first International Conference on Thymic Malignancies in 2009, and at a follow-up meeting of the newly formed International Thymic Malignancies Interest Group in 2010.

Results: Surgery remains the treatment of choice for operable tumors, whereas chemotherapy is standard in locally advanced and metastatic disease. Thus far, targeted therapies have been developed empirically. Histone deacetylase inhibitors have shown some activity in thymoma whereas sunitinib may be active in TC. There are no data to support the use of HER2- or EGFR-targeted therapies in thymic malignancies.

Conclusion: Drug development for the treatment of thymic malignancies is difficult because of the rarity of these tumors. Ethnic differences are becoming apparent, with aggressive subtypes being observed in Asians and African Americans. Incremental improvements in our understanding of tumor biology suggest that molecular profiling-directed therapies may be the preferred route of investigation in the future.

Fig 1.

Summary of array comparative genomic hybridization results for autosomic chromosomes of two patients with thymic epithelial tumors. Regions highlighted in red represent copy number (CN) losses and regions highlighted in green represent CN gains. Blue dots represent the array probes, and their respective positions aligned to the chromosomes are shown on the left. The divergences from the median axis of the blue dots indicate regions of CN aberrations. Tumor DNA was cohybridized with commercially available normal reference DNA on Agilent 180K Sure Print array (Agilent, Palo Alto, CA). Data were collected from the Agilent microarray scanner (Agilent) and analyzed by using Nexus 5.1 software (Biodiscovery, La Jolla, CA). (A) Type A thymoma exhibits a much less aberrant karyotype than (B) thymic carcinoma.

Fig 2.

(A) Thymic epithelial tumors are classified according to their histologic appearance into type A, AB, B1, B2, B3, and TC (thymic carcinoma) groups. (B) Correlation of thymic epithelia histotypes with specific genomic abnormalities. Comparative genomic hybridization diagram is derived from Girard et al, reprinted by permission from Clinical Cancer Research. Red represents the frequency of copy number (CN) gain, and blue represents the frequency of CN loss for eight type A thymomas, 22 type B2 thymomas, eight type B3 thymomas, and seven thymic carcinomas. (C) Modified chromosome ideograms (Reprinted by permission from Macmillan Publishers Ltd: Lee et al: Nature 465:473-477, 2010) depict complete genome sequencing from a lung adenocarcinoma. Next-generation sequencing technology allows genome-wide identification of single nucleotide mutations (d, red dots), CN aberrations (c, red, regions of CN gain; blue, regions of CN loss), loss of heterozygosity and allelic imbalance (b, green), and somatic structural variations (a, red lines, interchromosomal variations; blue lines, intrachromosomal variations).