The Multidisciplinary Approach to Thymoma: Combining Molecular and Clinical Approaches

MALIGNANCIES

OF THE

THYMUS

The Multidisciplinary Approach to Thymoma Combining Molecular and Clinical Approaches Nicole G. Chau, MD,* Edward S. Kim, MD,† and Ignacio Wistuba, MD‡

Abstract: Thymomas are rare epithelial tumors that display significant heterogeneity. Thymomas are usually indolent; however, thymic carcinomas are typically invasive with a high risk of relapse and death. Current treatment approaches are primarily based on clinical stage. Surgery is the mainstay for treatment of early stage disease, whereas multimodality therapy is required for advanced disease. The most important prognostic factors are stage and histology; however, increasing recognition of disease heterogeneity has led to recent exploration of underlying molecular mechanisms. Molecular characterization of thymic tumors may offer strategies to improve diagnosis, therapy, and prognosis. This article describes recently identified molecular characteristics of thymoma and thymic carcinoma that may potentially impact disease classification, targeted therapeutic decision making, and design of future clinical trials. Key Words: Thymoma, Thymic carcinoma, Classification, Targeted therapy, KIT inhibitors, HDAC inhibitors, VEGF inhibitors, IGF-1R inhibitors, DNA methyltransferase inhibitors, CDK/TRKA inhibitors. (J Thorac Oncol. 2010;5: S313–S317)

T

hymoma is a rare epithelial tumor, with an incidence of 0.15 per 100,000 person-years.1 Thymic tumors are classified into types A, AB, B1, B2, B3, and C (thymic carcinoma) according to the World Health Organization (WHO) criteria based on morphology of epithelial cells with increasing degree of atypia from type A to thymic carcinoma.2 Clinically, the most important prognostic indicator is thought to be tumor stage (invasion of the capsule and tumor resectibility).3 Recent molecular characterization of thymic tumors includes identification of important oncogenes (EGFR, HER2, KIT, KRAS, and BCL2), tumor suppressor genes (TP53, p16INK4A), chromosomal aberrations (LOH 3p, 6p, 6q, 7p, 8p), angiogenic factors (vascular endothelial growth *Division of Medical Oncology and Hematology; University of Toronto, Toronto, Canada; †Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, and ‡Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. Disclosure: The authors declare no conflicts of interest. Address correspondence to: Edward S. Kim, MD, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit Number 432, Houston, TX 77030. E-mail: [email protected] Copyright © 2010 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/10/0510-0313

factor [VEGF]), and tumor invasion factors (matrix metalloproteinases and tissue inhibitor of metalloproteinases); however, these findings have yet to affect clinical practice.4 Molecular profiling analyses at the DNA level using comparative genomic hybridization have confirmed a distinction between WHO types A to B2 versus type B3 and thymic carcinomas.5–7 Furthermore, mRNA expression analysis using reverse-transcriptase polymerase chain reaction has identified two genes (c-JUN and AL050002 [an unknown gene]) at higher levels in advanced-stage thymomas.8 The biologic significance of these findings remains to be determined. Current treatment strategies are based on stage. Evidence from prospective randomized trials is lacking. Controversy exists in early and advanced disease and provides impetus for a greater understanding of disease heterogeneity through molecular characterization. Patients with stage I and II disease are usually treated with surgery alone. Identification of patients at high risk of local recurrence who require postoperative radiation is controversial and only about 4% of patients with stage II disease will recur postoperatively within 5 years.9 Patients with stage III and IV disease are offered multimodality therapy with chemotherapy, surgery, and radiation. The choice, timing, and sequencing of combined therapy in stage III disease are unclear. Recurrent disease is treated with surgery and radiation wherever possible; however, the optimal use of systemic therapy is controversial and molecularly targeted agents remain experimental.

CHEMOTHERAPY AGENTS Chemotherapy is offered to patients with advanced thymoma (stage III/IV) based on evidence from small phase II studies in the context of upfront multimodality therapy and in the setting of refractory or recurrent disease. The highest response rates (70 – 81%) have been achieved with neoadjuvant cisplatin and doxorubicin combination chemotherapy (Table 1).10 –12 Nonanthracycline platinum-based combinations have demonstrated inferior response rates (32–56%).13–15 Single-agent chemotherapy is inferior to combined chemotherapy. Pemetrexed, in a phase II study of patients with refractory thymoma, demonstrated two complete responses (CRs) and two partial responses (PRs) of 23 evaluable patients (all four responders had stage IVA thymoma).16 Predictors of response to chemotherapy are unclear. The largest phase II trial to date of 44 patients treated with carboplatin and paclitaxel confirmed different outcomes for thymoma (n ⫽ 23, median overall survival 60 months, 13%

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TABLE 1. Major Prospective Chemotherapy Trials in Stage III, IV Invasive Thymoma Author

No. of Patients

Platinum-based chemotherapy with anthracycline Berruti et al.10

Response Rate, %

Median Survival (mo)

Cisplatin, doxorubicin, vincristine, cyclophosphamide (ADOC)a Cyclophosphamide, doxorubicin, cisplatin, predinisone (CAP⫹P)a Cyclophosphamide, doxorubicin, cisplatin, (CAP)a

81

48

77

95% at 5 yr (median not reached)

70

93

16 28 (8 TC) 24

Cisplatin, etoposide Cisplatin, ifosfamide, etoposide (VIP) Carboplatin, paclitaxel

56 35 33

51.6 31.6 ⬎60

27 (11 TC)

Pemetrexed alone

17

NR

16

Kim et al.11

22

Loehrer et al.12

23

Platinum-based chemotherapy without anthracycline Giaccone et al.13 Loehrer et al.14 Lemma et al.15 Nonplatinum chemotherapy Loehrer et al.16

Chemotherapy Regimen

a

Chemotherapy administered as part of multimodality treatment with surgery and radiation. TC, thymic carcinoma; NR, not reported.

CR rate) and thymic carcinoma (n ⫽ 21, overall survival ⫽ 15 months, CR ⫽ 0%).15 No validated biomarkers exist to predict response to chemotherapy or radiation. Topoisomerase 2-alpha protein overexpression, detected in four of 14 cases of thymic carcinoma and of one of 15 type B3 thymoma, was reported to predict response to cyclophosphamide, adriamycin, cisplatin (CAP) chemotherapy (cyclophosphamide, adriamycin, cisplatin), whereas HER2/neu or topoisomerase 2-alpha gene amplification and expression of ERCC1 or thymidylate synthase did not.17 Thymoma tumor specimens compared with normal thymus tissue have higher mRNA levels of thymidylate synthase (which correlates with resistance to 5-fluorouracil) and elevated dihydropyrimidine dehydrogenase (which degrades 5-flurouracil), but this did not correlate with clinicopathologic factors.18

MOLECULARLY TARGETED AGENTS Epidermal Growth Factor Receptor Inhibitors Epidermal growth factor receptor (EGFR) is overexpressed in thymomas and thymic carcinomas. EGFR gene amplification by fluorescence in situ hybridization (FISH) was detected by Ionescu et al.19 in 30% of 32 cases of thymoma, particularly in type B3 and thymic carcinomas. EGFR amplification and polysomy were associated with more advanced stage and capsule invasion.19 EGFR protein overexpression by immunohistochemistry is present in 46 to 85% of thymomas.19 –22 In a Japanese series of 38 thymoma cases, EGFR protein overexpression was associated with more advanced invasive thymomas.20 However, Ionescu et al.19 detected EGFR protein overexpression in 69% of cases and did not find an association with clinicopathologic features. Somatic activating EGFR mutations have not been detected in a total of 129 thymomas collectively analyzed.6,20,22–24 Interestingly, EGFR mutations have been observed in a Japanese series in two of 29 thymomas (both L858R and G863D missense mutations in exons 21) and zero of nine thymic carcinomas.25 The only report of an EGFR mutation in thymic

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carcinoma is a single case report of a 29-year-old Japanese woman with thymic carcinoma harboring a G719A in exon 18 and L858R in exon 21 detected by polymerase chain reaction-restriction fragment length polymorphism method who was treated with gefitinib (Table 2).26 The EGFR-tyrosine kinase inhibitors, gefitinib and erlotinib, have produced minimal objective responses in thymoma. A phase II study of gefitinib 250 mg daily in 26 patients with previously treated, advanced thymoma or thymic carcinoma revealed only one PR, 15 patients with stable disease (SD), and no CR.23 DNA sequencing from five patients (including 1 PR) revealed no mutations in EGFR exons 18 to 21 or KRAS exon 2.23 Erlotinib produced a clinical response in a female patient with myasthenia gravis and recurrent stage IV, malignant mixed thymoma with tumor biopsies confirming EGFR overexpression by immunohistochemistry (IHC) but no EGFR amplification or mutations.24 Cetuximab, a monoclonal antibody to EGFR, produced a prolonged PR (⬎12 months) and symptom benefit in a single patient with advanced B2-type thymoma strongly expressing EGFR (IHC), who had previously received CAP (cisplatin, doxorubicin, and cyclophosphamide) chemotherapy and octreotide and prednisone.27 No EGFR amplification or mutation was detected.27 Another case report of two heavily pretreated patients with metastatic thymoma expressing EGFR by IHC reported PR after 3 months of therapy.28 Further evaluation of EGFR inhibition strategies, particularly in tumors with EGFR overexpression by IHC, is of great interest. A phase II trial of neoadjuvant cisplatin, doxorubicin, cyclophosphamide chemotherapy, and cetuximab in locally advanced thymoma is underway (NCT01025089). It is unclear whether KRAS mutations affect response to cetuximab in thymoma. The lack of activating EGFR mutations in thymoma supports the minimal benefit demonstrated from current EGFR tyrosine kinase inhibitors.

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TABLE 2. Molecularly Targeted Agents Class EGFR inhibitors

Agent Cetuximab

Gefitinib, Erlotinib

KIT inhibitor

HDAC inhibitor

Imatinib Dasatinib Sorafenib Belinostat

VEGF inhibitor

Bevacizumab

IGF-1R inhibitor

Cixutumumab (IMC-A12)

DNMTis

Decitabine

CDK/TRKA inhibitor

PHA-848125AC

Mechanism Recombinant, chimeric monoclonal antibody directed against the EGFR. Binds to the extracellular domain of the EGFR, thereby preventing receptor activation and signal transduction. Small-molecule tyrosine kinase inhibitor of the EGFR. Competes with the binding of ATP to the tyrosine kinase domain of EGFR, thereby inhibiting receptor autophosphorylation and resulting in inhibition of signal transduction. Small-molecule multi-kinase inhibitor of KIT, Bcr-Abl, and PDGFR. Small-molecule multi-kinase inhibitor of KIT, Bcr-Abl, PDGFR, and Src family kinases. Small-molecule multi-kinase inhibitor of Raf kinases, KIT, VEGFR, and PDGFR. Inhibitor of HDAC class I and II enzymes, thereby inhibiting tumor cell proliferation, inducing apoptosis, promoting cellular differentiation, and inhibiting angiogenesis. Recombinant humanized monoclonal antibody directed against the VEGF, a proangiogenic cytokine. Inhibits VEGF receptor binding, thereby preventing growth and maintenance of tumor blood vessels. Fully human IgG1 monoclonal antibody directed against IGF-1R. Prevents binding of the natural ligand IGF-1 and subsequent activation of PI3K/AKT signaling pathway. Cytidine antimetabolite analogue, which incorporates into DNA and inhibits DNA methyltransferase, resulting in hypomethylation of DNA and intra-S-phase arrest of DNA replication. Inhibits CDK2, CDK1, CDK4, and TRKA, and thus may result in cell cycle arrest and apoptosis.

EGFR, epidermal growth factor receptor; HDAC, hydroxamic acid-type histone deacetylase; VEGF, vascular endothelial growth factor; IGF-1R, insulin-like growth factor-1 receptor; DNMTis, DNA methyltransferase inhibitors; CDK, cyclin-dependent kinase; TRKA, thropomyosin receptor kinase A.

HER2 HER2/neu immunohistochemical protein overexpression is infrequent in thymoma.29 In thymic carcinoma, HER2/ neu immunohistochemical overexpression is present in 53% of cases (9/17); however, no cases of HER2 gene amplification by FISH were detected.29 Hence, therapies targeting HER2 have remained unexplored to date.

RAS Ras mutations have been detected in three of 62 thymic tumors collectively analyzed6,23,24,30: one thymic carcinoma and one B2-type thymoma harbored KRAS mutations (G12V and G12A respectively),6 and one A-type thymoma harbored an HRAS mutation (G13V).6 EGFR expression was high in the KRAS-mutant tumors and moderate in the HRAS-mutant tumor.6 KRAS mutations may predict for primary resistance to EGFR tyrosine kinase inhibitors in lung cancer and resistance to cetuximab in colorectal cancer. Therefore, clinical trials with EGFR inhibitors in thymoma should evaluate Ras mutation status.

KIT Inhibitors KIT immunostaining is rare in thymomas (0 –5%). In contrast, KIT immunostaining is present in about 80% of thymic carcinomas and represents a potential target for KIT tyrosine kinase receptor inhibitors.21,31,32 KIT mutations were present in five of 151 thymic tumors collectively analyzed, all of which occurred only in thymic carcinomas.6,25,32–37 Girard et al.6 reported a KIT mutation frequency of 4.4% (2 of 45 tumors) and found a mutant form harboring V560 deletion in exon 14, which is associated with sensitivity to imatinib, and another KIT mutant with a novel KIT H697Y mutation in

exon 14, which is associated in vitro with greater sensitivity to sunitinib versus imatinib. Imatinib is an oral multikinase inhibitor of KIT, BcrAbl, and PDGFR. An objective response to imatinib was first reported in a patient with metastatic thymic carcinoma overexpressing KIT and harboring an activating V560del KIT mutation.33 A pilot study of second-line imatinib 600 mg daily in 11 patients with advanced thymic carcinoma and KIT positive (n ⫽ 9) or PDGFR positive (n ⫽ 2) by IHC reported no objective responses, three patients achieved SD for a median duration of 6 weeks.38 A phase II study of seven patients with unresectable WHO B3 or C thymoma also reported no responses (two patients had SD and five patients had progression); however, there were no activating KIT mutations or PDGFR mutations detected in five patients with available mutational analysis.36 Dasatinib is an oral multikinase inhibitor of KIT, BcrAbl, PDGFR, and Src family kinases and has demonstrated responses in imatinib-resistant BCR-ABL positive leukemias. A PR to dasatainib 140 mg/d, has been documented in a patient with a Masaoka stage I, B2-type thymoma that was EGFR positive (IHC and FISH) and KIT negative (IHC), suggesting that non-KIT-targeted inhibition of Src kinases by dasatinib may be important.35 Sorafenib, an oral multikinase inhibitor of KIT, VEGFR, PDGFR, and BRAF, resulted in a PR in a heavily pretreated patient with metastatic thymic carcinoma harboring a KIT missense mutation on exon 17 (D820E).37 Another recent case report of response to sorafenib exists in a 46-yearold man with metastatic platinum resistant thymic carcinoma expressing KIT (CD 117) and VEGF.39

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KIT remains an interesting therapeutic target in thymic carcinomas and activating mutations although rare, warrant further prospective evaluation in trials with KIT inhibitors as they seem to be associated with response to imatinib. KIT protein expression does not seem to be associated with response to KIT inhibitors. Further evaluation of combined inhibition of KIT and Src family kinases may be warranted.

Histone Deacetylase Inhibitor Histone deacetylase (HDAC) enzymes catalyze the removal of an acetyl group from the terminal lysine residues of histone proteins, leading to more compact chromatin and repression of associated genes. Belinostat, an inhibitor of HDAC class I and II enzymes, demonstrated tumor shrinkage and SD for 17 months in a patient with thymoma in the first in human trial.40 Belinostat has demonstrated some activity in a phase II study of 32 patients with recurrent or metastatic thymoma and thymic carcinoma.41 Of 27 evaluable patients, two patients had a PR, 15 had SD, and 10 had progression, but no responses were seen in patients with thymic carcinomas.41 An increase in protein acetylation in PBMCs was observed in all patients analyzed. A phase I/II study of first-line belinostat in combination with cisplatin, doxorubicin, and cyclophosphamide in advanced or recurrent thymoma is underway (NCT01100944). The first in human study of another HDAC inhibitor, 4SC-201, also demonstrated activity in a patient with thymoma with marginal response beyond 6 months.42

VEGF Inhibitor VEGF-A and VEGFR-1 and -2 are expressed in both normal and malignant thymic tissue.43 Bevazicumab (15 mg/kg q3 weeks) combined with erlotinib (150 mg/d) has demonstrated limited activity in a phase II trial of 18 patients with refractory thymoma (n ⫽ 11) and thymic carcinoma (n ⫽ 7).44 Although well tolerated, there were no CR, 11 patients achieved SD (60%) and seven had PD.44 A phase I study of aflibercept, a soluble decoy receptor that binds VEGF-A, and docetaxel 75 mg/m2, demonstrated a PR in a patient with thymoma.45 In a phase IB study of motesanib, an oral VEGFR-1, -2, -3, KIT, and PDGFR inhibitor, a patient with chemotherapy-refractory thymoma achieved tumor shrinkage after 39 weeks on therapy.46

Insulin-Like Growth Factor-1 Receptor Inhibitor The insulin-like growth factor-1 receptor (IGF-1R) is found in thymic tumors and thought to play an important role in tumorigenicity. A multicenter phase II study of IMC-A12, an IGF-1R inhibitor, in advanced platinum-refractory thymoma and thymic carcinoma is underway (NCT00965250).

DNA Methyltransferase Inhibitors Decitabine was developed as a cytotoxic agent to treat leukemia at high doses, but at lower doses over longer duration, DNA methyltransferase inhibitors are predominantly epigenetic modulating. Decitabine inhibits DNMT, induces global DNA hypomethylation and increases expression of specific genes. In a phase I study of decitabine in 31 patients with refractory solid tumors, one of four patients with thymoma had a PR.47

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Cyclin-Dependent Kinases/Thropomyosin Receptor Kinase A Inhibitor Cyclin-dependent kinases (CDK) are serine/threonine kinases involved in regulation of the cell cycle. Thropomyosin receptor kinase A (TRKA) is a neurotrophin receptor that is mutated in several cancer types. Inhibition of CDKs and TRKA may result in cell cycle arrest and apoptosis of tumor cells that express these kinases. A phase II study in advanced thymic carcinoma of PHA-848125AC, an oral CDK inhibitor and TRKA inhibitor, is underway (NCT01011439).

SUMMARY Improved understanding of molecular characteristics of thymoma may facilitate greater accuracy in disease classification and application of novel targeted therapies. Advances in molecular understanding and clinical research in thymoma have been limited due to the rarity and heterogeneity of this disease and evolving multidisciplinary treatment approaches. Discovery of clinically important biomarkers is difficult due to the limited statistical power of small case series in the literature. A desperate need exists for prospective collaborative research efforts to obtain statistically significant findings. Future research questions remain as to whether we can use biomarkers to identify patients with stage II or III disease who do not require adjuvant therapy and to determine the optimal strategy for testing single or combined targeted therapies alone or with chemotherapy in the advanced or locally advanced disease. Chemotherapeutic agents with the most activity include cisplatin and doxorubicin. Targeted agents offer less toxicity, but several phase II trials have failed to demonstrate responses in advanced disease; EGFR inhibition with gefitinib in unselected patients, KIT inhibition with imatinib in patients without KIT mutations, VEGF inhibition with bevacizumab in unselected patients, and HDAC inhibition with belinostat in unselected patients. This suggests that the success of clinical trials using targeted therapies requires greater attention to tumor specimen collection and extensive molecular profiling to facilitate patient enrichment strategies to improve response rates, confirm proof of principle, and identify potential mechanisms of sensitivity and resistance. In thymoma, cetuximab may have efficacy particularly in thymomas with EGFR overexpression; while in thymic carcinoma, KIT inhibitors remain promising agents in those with KIT mutations. In such a rare tumor, creative models to guide targeted therapies based on molecular signatures in tumor biopsies48 may help to maximize efficacy of future clinical trials. REFERENCES 1. Engels EA, Pfeiffer RM. Malignant thymoma in the United States: demographic patterns in incidence and associations with subsequent malignancies. Int J Cancer 2003;105:546 –551. 2. Travis WB, Brambilla E, Muller-Hermelinck HK, et al., editors. World Health Organization classification of tumours. Pathology and genetics of tumours of the lung, pleura, thymus and heart. Lyon: IARC Press, 2004. 3. Suster S, Moran CA. Thymoma classification: current status and future trends. Am J Clin Pathol 2006;125:542–554. 4. Kuhn E, Wistuba II. Molecular pathology of thymic epithelial neoplasms. Hematol Oncol Clin North Am 2008;22:443– 455. 5. Inoue M, Starostik P, Zettl A, et al. Correlating genetic aberrations with World Health Organization-defined histology and stage across the spectrum of thymomas. Cancer Res 2003;63:3708 –3715.

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