Skip Navigation LinksHome > October 2010 - Volume 5 - Issue 10 > Thymic Tumors: Relevant Molecular Data in the Clinic
Journal of Thoracic Oncology:
doi: 10.1097/JTO.0b013e3181f209b9
Malignancies of the Thymus Supplement

Thymic Tumors: Relevant Molecular Data in the Clinic

Girard, Nicolas MD

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Author Information

Department of Respiratory Medicine, Reference Center for Rare Pulmonary Diseases, Pilot Unit for the Management of Rare Intra-Thoracic Tumors, Hospices Civils de Lyon, Lyon, France; and Claude-Bernard University, University of Lyon, Lyon, France.

Disclosure: The author has no conflict of interest to declare.

Address for correspondence: Nicolas Girard, MD, Service de Pneumologie, Hopital Louis Pradel, 28, Avenue Doyen Lepine, 69500 Bron, France. E-mail: nicolas.girard@chu-lyon.fr

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Abstract

Introduction: Thymic malignancies are rare intrathoracic tumors that may be aggressive and difficult to treat in advanced stage. Over the past years, significant efforts have been conducted to dissect the molecular pathways involved in the carcinogenesis of these tumors. Insights have been made following anecdotal clinical responses to targeted therapies, and large-scale genomic analyses have been conducted.

Methods: Review of the literature, 1990–2010.

Results: The Epidermal Growth Factor Receptor (EGFR) is frequently overexpressed in thymomas and thymic carcinomas, but EGFR mutations are exceptional, and this does not support the use of EGFR tyrosine kinase inhibitors. On the contrary, single observations of responses create a basis for further evaluation of cetuximab in thymomas. KIT-mutant thymic carcinomas represent a small molecular subset of thymic tumors. The clinical relevance of KIT mutations is more limited in thymic carcinoma than in GIST as KIT mutations are far less frequent (7% of thymic carcinomas) and are not correlated with KIT expression; furthermore, KIT mutants are not uniformly sensitive to imatinib. Beyond EGFR and KIT signaling pathways, other molecular alterations with potential prognostic or predictive relevance are emerging in thymic malignancies.

Conclusions: Given the rarity of these tumors, translation of preclinical findings to the clinic may be quick and represents one of the most promising therapeutic approaches for advanced-stage thymic malignancies.

Thymic malignancies are rare intrathoracic tumors that may be aggressive and difficult to treat in advanced stage.1 The current histopathologic classification distinguishes thymomas (types A, AB, B1, B2, B3) and thymic carcinoma2 based on the morphology of epithelial cells (with an increasing degree of atypia from type A to thymic carcinoma), the relative proportion of the nontumoral lymphocytic component (decreasing from types B1 to B3), and resemblance to normal thymic architecture.2 After surgery, thymomas have a tendency toward local and regional progression, whereas thymic carcinomas are highly aggressive tumors with frequent systemic involvement at time of diagnosis and poor prognosis despite multimodal treatment including surgery, radiotherapy, and chemotherapy.3,4 Beyond histology, tumor invasiveness as evaluated by the Masaoka et al.3 staging system is a major prognostic indicator. However, the most significant prognostic factor in thymic tumors is whether the tumor may undergo complete resection or not.4

Cancers results from the accumulation of multiple molecular alterations including oncogene activation and tumor suppressor gene inactivation.5 Large-scale genomic analyses suggest that, beyond stage or histology, cancers may be subdivided in molecular subsets, based on expression, genomic, mutational, and proteomic profiling data. Among these multiple molecular alterations, only a few are considered to be “driver” of the oncogenesis process, i.e., necessary and sufficient for cancer development and maintenance, a concept also called “oncogene addiction.”6 These driver mutations are as “Achille heels” that can predict response to specific targeted agents. Beyond a predictive value, molecular alterations may have a prognostic significance on time-to-progression and overall survival.

Over the past years, significant efforts have been conducted to dissect the molecular pathways involved in the carcinogenesis of thymic malignancies.7 Research is hampered by the rarity of the tumor, evolution of histopathologic concepts, and a lack of established cell lines and animal models. Insights in the biology of thymic tumors have also been made following anecdotal clinical responses to targeted therapies.8–12 Here, we review current knowledge about the molecular biology of thymic malignancies that define molecular subsets with potential clinical and therapeutic relevance.

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EPIDERMAL GROWTH FACTOR PATHWAY

The epidermal growth factor receptor (EGFR) is one of the most studied biomarkers in epithelial cancers.13 An extensive review of the EGFR signaling pathway is out of the scope of this article, and readers may refer to previously published reviews.13 Overall, EGFR mutations in lung adenocarcinoma are the best illustration of the therapeutic relevance of identifying molecular clusters of cancer based on driver genetic alterations. The presence of EGFR activating mutations in lung tumor cells is a strong predictor of efficacy of specific inhibitors, gefitinib (Iressa, AstraZeneca, Macclefields, UK) and erlotinib (Tarceva, Roche, Basel, Switzerland), with response rates and progression-free survival significantly higher than after standard platinum-based doublet chemotherapy (70 versus 30%, and 9.5 versus 6.3 months, respectively).14 Beyond these mutations, EGFR amplification has also been identified as a predictor of response to these agents, as well as to cetuximab, a humanized monoclonal antibody targeting EGFR (Erbitux, Merk, Darmstadt, Germany).

Downstream EGFR, KRAS is a GTPase transducing signal from the membrane to cytoplasmic proteins.13 In lung cancer, KRAS may present with activating mutations that are mutually exclusive with EGFR mutations.6,13 KRAS-mutant tumors then represent a specific molecular subset of cancers for which EGFR inhibitors are not effective.

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EGFR Signaling Pathway Biomarkers in Thymic Tumors

Several studies investigated EGFR expression levels in thymic tumors using immunohistochemistry (Table 1).7,15–21 EGFR was overexpressed in 70% of thymomas and 53% of thymic carcinomas. Collectively, there was no strong correlation between EGFR staining and thymic tumor type (p = 0.23, χ2 test) (Table 1). Higher EGFR staining was significantly associated with stage III to IV tumors (p = 0.023, χ2 test) in two studies.7,18

Table 1
Table 1
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EGFR copy number status was measured in one study including 32 patients with thymomas or thymic carcinomas.22 In this study, EGFR was significantly amplified in type B3 thymomas. The degree of EGFR amplification as measured by fluorescence in situ hybridization poorly correlated with EGFR overexpression but was higher in stage II to IV versus stage I tumors (p = 0.005).

EGFR mutations are rare in thymic malignancies.7,11,18–20,23,24 Thus far, only three EGFR mutations have been found out of a total of 158 tumors collectively analyzed. The mutations were L858R in two cases and G863D in one case,20,24 which are both associated with response to EGFR inhibitors in lung cancer. There was no correlation between EGFR expression and EGFR mutational status.

Regarding EGFR downstream proteins, no mutation has been identified in the following genes: PIK3CA, AKT1, ERBB2, MEK1, and PTEN.8 RAS mutations were observed in 3 (7%) out of 45 thymic epithelial tumors from Memorial Sloan-Kettering Cancer Center series.8 One mutation was a G12A KRAS mutation, one was a G12V KRAS mutation, and one was an HRAS G13V mutation.8 Of the 17 thymic tumors assessed elsewhere for KRAS status,11,23,25 no mutation had been identified.

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Clinical Significance

Together with the presence of RAS mutations, the low frequency of EGFR activating mutations in thymic tumors may explain why responses to EGFR inhibitors have been rarely observed.23,26 One phase II trial with gefitinib was conducted in patients with chemorefractory thymic tumors. Among 19 thymomas and 7 thymic carcinomas, partial response and stable disease were observed in 1 and 14 patients, respectively.23 Several observations of heavily pretreated recurrent thymoma exhibiting partial response to cetuximab have been reported.12,27 All tumors harbored strong EGFR expression by immunohistochemistry. A phase II trial is ongoing that evaluates the feasibility of delivering cetuximab in combination with the standard cyclophosphamide, adriamycin, and platin regimen in unresectable thymomas (clinicaltrails.gov ID: NCT01025089).

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KIT SIGNALING PATHWAY

KIT is a transmembrane growth factor with tyrosine kinase activity whose ligand is the scatter cell factor. KIT plays a major role in the development and maintenance of gastrointestinal stromal tumors (GISTs), which overexpress KIT in 95% of cases.28 KIT expression has been associated with activating mutations occurring in exons 9 (extracellular domain), 11 (juxta-membrane domain), 13 (first kinase domain), and 17 (activation loop) of the KIT gene.28 These mutations lead to constitutive activation of the KIT kinase. The discovery of KIT mutations revolutionized the treatment of GISTs, which is associated with poor outcome when treated with chemotherapy. On the contrary, the use of Imatinib mesylate (Gleevec, Novartis, Basel), an oral KIT inhibitor leads to rapid, substantial, and durable tumor responses.29 Interestingly, not all KIT mutations are associated with equal sensitivity to imatinib,30 and second-generation KIT inhibitors have been developed.

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KIT Biomarkers in Thymic Tumors

The pooled analysis of data reported in the literature indicates that collectively, KIT is overexpressed in 2% of thymomas and 79% of thymic carcinomas (p < 0.001; χ2 test) (Table 2).31–34 All immunohistochemistry studies used the same anti-KIT rabbit polyclonal antibody from Dako (Carpinteria, CA). Given the significantly highest frequency of KIT expression in thymic carcinoma, some authors proposed KIT as a diagnostic marker of thymic carcinoma versus thymoma in the setting of a mediastinal tumor.32

Table 2
Table 2
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Despite the frequent expression of KIT, KIT mutations are found only in 7% of thymic carcinomas (5/70 collectively analyzed) (Table 3).7–9,20,34–36 The mutation was in two cases a V560 deletion, that was previously observed in imatinib-responsive GISTs.7,8 Another KIT mutation was an L576P substitution,20 which had been identified in GIST and melanoma as an imatinib- and sunitinib-sensitive mutation.30 The third mutation was a D820E mutation, that was found in a patient with thymic carcinoma responding to sorafenib tosylate (BAY43-9006; Nexavar; Bayer, West Haven, CT).35 This residue is known to frequently harbor imatinib-resistant mutations.30 The fourth KIT mutation was an H697Y mutation in exon 14, which was characterized in vitro to be associated with higher sensitivity to sunitinib than to imatinib.7

Table 3
Table 3
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Clinical Significance

KIT-mutant thymic carcinomas represent a small molecular subset of thymic tumors. The clinical relevance of KIT mutations is more limited in thymic carcinoma than in GIST, because (1) KIT mutations are far less frequent; (2) KIT expression does not correlate with the presence of KIT mutation; and (3) nonpretreated KIT mutants are not uniformly sensitive to imatinib (Table 3). These findings may explain why 2 phase II trials with imatinib, where patients were selected based on histologic type (B3 thymomas and thymic carcinomas)36 or KIT staining by immunohistochemistry37 and not on KIT genotyping, were negative.

Given the existence of molecular platforms that routinely genotype KIT in GIST, one option would be to systematically sequence KIT in thymic carcinoma tumors. Ultimately, the use of imatinib should not be recommended in mutant cases, given the higher efficacy of second-generation inhibitors and the results of available clinical trials.38

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IGF-1R PATHWAY

Insuilin-like growth factor-1 receptor (IGF-1R) is a transmembrane receptor that was previously reported to be frequently overexpressed in squamous cell carcinomas.39,40 Although not identified so far as a driver molecular alteration, IGF-1R activation participates in multiple processes involved in oncogenesis. IGF-1R activation has also been linked to resistance to EGFR inhibitors through formation of EGFR/IGF-1R heterodimers, continued activation of the PI3K-AKT pathway and inhibition of the pro-apoptotic protein survivin.39 Interestingly, the growth of cell lines harboring high IGF-1R expression levels was more readily inhibited after exposure to R1507, a monoclonal antibody against IGF-1R.40

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IGF-1R Expression in Thymic Tumors

IGF-1R expression was studied by immunohistochemistry in a cohort of 63 thymic tumors.41 Moderate to high IGF-1R expression was more frequent in thymic carcinomas than in thymomas (86 versus 43% respectively, p = 0.039), and was associated with higher EGFR staining (p = 0.015 in the whole cohort; p = 0.034 in thymomas). IGF-1R expression level was not a significant prognostic variable on time-to-progression at multivariate analysis (OR = 3.07; 95% CI = 0.38–24.59; p = 0.291).

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Clinical Significance

Figitumumab (CP751,871; Pfizer), an anti-IGF1-R antibody,42 recently showed clinical activity in a patient with refractory thymoma.43 A phase II trial is ongoing evaluating IMC-A12 (ImClone Systems Incorporated, Branchburg, NJ), another anti-IGF-1R antibody, in advanced and refractory thymomas and thymic carcinomas (clinicaltrials.gov ID: NCT00965250).

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ANGIOGENESIS INHIBITION

Neovascularization is a crucial process in the development and progression of cancer that is mandatory when tumors grow beyond 1 cm3 in volume.44 Numerous proangiogenesis factors regulating the proliferation of endothelial cells have been identified, which stimulate vasculature formation, growth of the primary tumor, and migration of tumor cells to the systemic circulation. The most potent proangiogenic molecules are those of the vascular endothelial growth factor (VEGF) receptor (VEGFR) signaling pathway. VEGFRs are found on the surface of endothelial cells and vascular pericytes, promote angiogenesis, and stimulate cell migration, proliferation, and survival.

In 2003, VEGF was validated as a clinically relevant target in renal cell carcinoma in a landmark randomized phase II trial comparing the effect of placebo with the anti-VEGF antibody bevacizumab (rhuMAb-VEGF, Avastin, Genentech, San Francisco, CA).45 Bevacizumab significantly prolonged time-to-progression of patients.45 In lung cancer, the addition of bevacizumab to chemotherapy confers a 2-month survival benefit to patients with nonsquamous tumors over those receiving chemotherapy alone.46 VEGF or VEGFR expression levels do not appear to be consistent predictive markers of response to bevacizumab.

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VEGFR Expression in Thymic Tumors

VEGF-A and VEGFR-1 and -2 are overexpressed in thymomas and thymic carcinomas.47 Microvessel density and VEGF expression levels have been shown to correlate with tumor invasion and clinical stage.48 Patients with thymic carcinoma have increased levels of VEGF in the serum, what is not observed in patients with thymoma.49

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Clinical Significance

Only sparse data is available regarding the use of angiogenesis inhibitors in thymic malignancies. In a phase II trial, bevacizumab was tested in combination with erlotinib in 11 thymomas and 7 thymic carcinomas.26 No tumor response was observed. In a phase I study combining docetaxel with aflibercept, a soluble receptor that binds VEGF-A (also called VEGF trap), one patient with thymoma experienced partial response.50 Interestingly, despite the large tumor burden of thymic tumors and the frequent abutment to mediastinal vascular structures, no hemorrhagic side-effect has been reported with the use of these drugs in these studies.

Multikinase inhibitors may also be of interest to target angiogenesis. Beyond the inhibition of KIT, sunitinib and sorafenib also inhibit VEGFR-1, VEGFR-2, VEGFR-3 at the nanomolar range. The effect of these drugs in thymic carcinoma tumors may then be partially related to an antiangiogenic effect.9,10,35 As sunitinib and sorafenib, motesanib diphosphonate (AMG-706; Amgen, Thousand Oaks, CA) is a specific inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, which was reported to control the growth of a thymic carcinoma tumor refractory to chemotherapy for 12 months.51

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OTHER GENETIC ALTERATIONS

The increasing access of clinicians to molecular profiling platforms for cancer research leads to the rapid identification of additional genetic alterations that may be predictive or prognostic in thymic malignancies. Translation to the clinic may be easier with the concurrent development of specific targeted agents. In this setting, several investigators recently showed that cyclin-dependent kinase (CDK) proteins that control the cell cycle G1-S phases transition, may be altered through p16INK4 loss in thymomas.52 A phase II trial with a CDK inhibitor, PHA-848125AC has been launched in advanced thymic tumors (clinicaltrials. gov ID: NCT01011439).

Another avenue of interest is the identification of prognostic markers that may help to select patients with thymic malignancies for aggressive treatment, including postoperative radiotherapy and chemotherapy.2 However, the favorable outcome of thymic tumors after surgery and the highly significant value of R0 resection make the identification of such prognostic factors challenging. A recent report identified high EGFR and low KIT expression as being associated with longer time-to-progression after treatment with octreotide.21 Another study suggested that high P53 with low P21and P27 expression levels might predict overall survival of patients (hazard ratio = 11.6; 95% CI = 1.49–102.63; p = 0.02).53 These findings are preliminary data that need to be validated independently in further studies.

To conclude, the concept of personalized molecular medicine, which consists of selecting patients for available targeted therapies based on predictive biomarkers, is applicable to rare tumors such as thymomas and thymic carcinomas. Research efforts are currently being conducted to dissect the molecular biology of thymic malignancies. Given the rarity of the tumor, translation of preclinical findings to the clinic may be quick and represents one of the most promising therapeutic approaches for advanced-stage thymic malignancies.

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ACKNOWLEDGMENTS

The author thanks Giuseppe Giaccone for critical reading of the manuscript.

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Keywords:

Thymoma; Thymic carcinoma; Epidermal growth factor receptor; Biology; KIT; Chemotherapy

© 2010International Association for the Study of Lung Cancer

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