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Long Lasting Response to the Multikinase Inhibitor Bay 43-9006 (Sorafenib) in a Heavily Pretreated Metastatic Thymic Carcinoma
CASE REPORT
Long Lasting Response to the Multikinase Inhibitor Bay 43-9006 (Sorafenib) in a Heavily Pretreated Metastatic Thymic Carcinoma Giancarlo Bisagni, MD,* Giulio Rossi, MD, PhD,† Alberto Cavazza, MD,‡ Giuliana Sartori, PhD,† Giorgio Gardini, MD,‡ and Corrado Boni, MD*
Abstract: Metastatic thymic carcinoma is an aggressive neoplasm for which multimodal therapies are often ineffective. We describe here a heavily pretreated patient with advanced thymic carcinoma responsive to multikinases inhibitor BAY 43-9006 (Sorafenib). Of note, a hitherto unreported c-kit missense mutation on exon 17 (D820E) identified in tumor cells seems to explain the clinical response and highlight the key role of molecular analysis in predicting efficacy of targeted therapies even in thymic neoplasms. Key Words: Thymoma, Thymic carcinoma, c-kit, CD117, Tyrosine kinase. (J Thorac Oncol. 2009;4: 773–775)
CASE REPORT A 46-year-old man was referred to our institution in August 2001 after the assessment of a 9 cm mass in the upper anterior mediastinum extending to the sternum for which he underwent surgical resection. Surgery was not radical because of pericardial involvement and the presence of liver metastasis in the left lobe. The tumor consisted of a proliferation of relatively monomorphic, rounded-to-spindled cells with prominent eosinophilic nucleoli (Figure 1A), showing necrotic foci and high mitotic rate (35 ⫻ 10 high-powerfields). Tumor cells immunostained with cytokeratins, CD5, c-kit/CD117 (Figure 1B), but not for chromogranin, synaptophysin, and CD56. A diagnosis of undifferentiated thymic carcinoma with extensive capsular invasion (pT3, N2, M1) was made. The patient then was treated with one course of PE (Cisplatin 70 mg/m2, day 1 and Etoposide 120 mg/m2, q3w) and five courses of PEI (Cisplatin 20 mg/m2, Etoposide 75 *Operative Units of Oncology, Azienda Ospedaliera S. Maria Nuova, Reggio Emilia; †Section of Pathologic Anatomy, Azienda Ospedaliero-Universitaria Policlinico, Modena; and ‡Pathologic Anatomy, Azienda Ospedaliera S. Maria Nuova, Reggio Emilia, Italy. Disclosure: The authors declare no potential conflicts of interest. Address for correspondence: Giulio Rossi, MD, Sezione di Anatomia Patologica, Azienda Ospedaliero-Universitaria Policlinico, Via del Pozzo, 71, 41100 Modena, Italy. E-mail: [email protected] Copyright © 2009 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/09/0406-0773
Journal of Thoracic Oncology • Volume 4, Number 6, June 2009
mg/m2, and Ifosfamide 1200 mg/m2, days 1– 4, q3w) with partial response in liver metastases and subsequent total excision of left hepatic lobe. He was disease-free for 1 year when pulmonary and hepatic metastases were detected. Radiofrequency ablation of the hepatic lesion followed by three additional PEI courses were performed with partial remission and subsequent complete excision of pulmonary metastases. In April 2004, computed tomography (CT) detected multiple lung and liver nodules and four cycles of chemotherapy with doxorubicin and ifosfamide (Doxorubicin 35 mg/m2 and Ifosfamide 3000 mg/m2, days 1–3, q3w) were given achieving clinical partial response. In January 2005, the patient had disease progression with increase of liver and lungs metastases. In the absence of any standardized subsequent-line chemotherapy, an empiric treatment with longacting release octreotide (20 mg per month, subcutaneously) was performed. Intracranial tumor progression occurred and a cerebral necrotic lesion was surgically removed. Liver and lung metastases were stable and octreotide treatment was stopped. Further restaging showed multiple bilateral lung and liver metastases, and a parietal intracranial metastasis. In the meantime, tumor cells were investigated by immunohistochemical expression of epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), c-met, and platelet-derived growth factor receptor (PDGFR)alpha and -beta without evidence of immunoreactivity. Most important, molecular analysis by polymerase chain reactionbased direct sequencing showed a missense mutation in c-kit exon 17 (D820E) (Figure 1C). No alterations were observed in the other tested genes: c-kit exons 9, 11, 13, and 14, PDGFR-alpha exons 12, 14, 17, PDGFR-beta exons 12, 14, 18, 19, 20, c-met exons 14, 17, 18, 19, EGFR exons 18, 19, 20, 21, and BRAF exon 15. The finding of this mutational event lead us to start a targeted therapy with BAY 43-9006 (sorafenib, Nexavar, Bayer Pharmaceutical), an oral inhibitor acting against several tyrosine (VEGFR, PDGFR, c-kit), and serine/threonine (B-RAF, p38) kinases. The institutional Ethical Committee of our Hospital approved the treatment and the patient gave written informed consent. Treatment with two 100 mg capsules of sorafenib twice daily was started in October 2007.
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Journal of Thoracic Oncology • Volume 4, Number 6, June 2009
Bisagni et al.
FIGURE 1. Undifferentiated thymic carcinoma consisting of a monomorphic proliferation of rounded-tospindled shaped cells with prominent nucleoli and mitotic rate (A) strongly expressing c-kit/CD117 (B) and harboring a missense mutation at c-kit exon 17 (D820E) (electropherogram, see arrows C).
After 8 weeks of this treatment, a partial response was detected by CT scan according to World Health Organization criteria. Before sorafenib therapy, multiple metastases were present in liver, lungs (Figures 2A, B), and brain. After treatment with sorafenib, a clinical response was confirmed in all metastatic sites (Figures 2C, D). Sorafenib was well tolerated and improvement in both symptoms control and performance status was registered. Adverse events consisted of a grade 2 of skin desquamation and pruritus, grade 1 diarrhea, and grade 1 fatigue. Skin toxicity was resolved discontinuing sorafenib for 1 week every 4 weeks of treatment. No other toxicities were noted. After 15 months, this heavily pretreated patient (followed-up with CT scans every 3 months) is still in partial response continuously receiving sorafenib.
DISCUSSION When metastatic spread from thymic carcinomas occurs, multimodal treatment basically represents the only effective therapy.1 Most regimens include cisplatin and the best results have been reported with the PE, cyclophosphamide, doxorubicin, cisplatin (PAC) and cisplatin doxorubicin, vincristine, cyclophosphamide (ADOC) regimens.1 The overall response rate has ranged from 30 to 90% and the median duration of response has ranged from 12 to 36 months.1 To date, there are no established therapeutic protocols for advanced, metastatic thymomas or thymic carcinomas,
774
mainly due to the rarity of the disease. Among anecdotic experiences with targeted therapy, somatostatin analogues (namely octreotide) in advanced thymomas have reported a response rate of 32% and 2-year survival of 76%.1 Interestingly, previous studies demonstrated that thymic carcinomas, but not thymomas, strongly stain with c-kit,2 a type III receptor tyrosine kinase (RTK) consistently overexpressed by gastrointestinal stromal tumors (GIST) in which the relevant c-kit gene is mutated in up to 90% of cases. By contrast, thymomas, but not thymic carcinomas, significantly express the EGFR,2 another RTK widely expressed in carcinomas from different sites and mutated in 10 to 30% of pulmonary adenocarcinomas. Based on these preliminary observations, partial responses has been reported in single case reports using imatinib mesylate, a type III RTK small molecule inhibitor, in a thymic carcinoma showing a c-kit in-frame deletion in exon 11 (V560del),3 and cetuximab, a monoclonal humanized antibody against EGFR, in an advanced B2-type thymoma strongly expressing EGFR.4 More recently, a partial tumor size resolution was observed in a metastatic B2-type thymoma using dasatinib, a multitargeted small molecule inhibitor of several RTK, as Bcr-Abl, kinases along Src family, PDGFRs, and c-kit.5 Preclinical and clinical activity with sorafenib, an oral multikinase inhibitor with effects on tumor cell proliferation
Copyright © 2009 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 4, Number 6, June 2009
Long Lasting Response to Sorafenib
FIGURE 2. Computed tomography (CT) scan studies of the lungs (A, B) before sorafenib therapy (October 2007) showing multiple pulmonary metastases. Absence of contrast enhancement or disappearance of pulmonary lesions (C, D) confirmed partial response to sorafenib therapy (December 2007).
and tumor angiogenesis, was well-demonstrated mainly in a small subset of renal cell and hepatocellular carcinomas, although no clear-cut molecular explanations on the exact mechanisms of antitumor activity have been so far reported. So far, only a recent case report by Li et al.6 evidenced a clinical response with sorafenib in a 46-year-old man with a thymic carcinoma expressing c-kit (CD117) and VEGF, but without clear-cut molecular explanation for such a clinical result. In the current case, we demonstrated the presence of a hitherto unreported gain-of-function constitutive somatic mutation involving the proto-oncogene c-kit in tumor cells of a metastatic, chemoresistant thymic carcinoma. The patient had a prompt and prolonged partial response using sorafenib, in absence of significant toxicity. Of note, an identical somatic missense mutation (D820E) involving the activation loop of the c-kit tyrosine kinase (TK) was previously identified only in a small subset of GIST resistant to imatinib mesylate.7 Exactly in GIST harboring imatinib-resistant c-kit mutations involving gatekeeper and kinase catalytic domains, sorafenib seems particularly effective, these molecular findings convincingly explaining the clinical response obtained in our patient. Unfortunately, we did not observe mutations in c-kit, PDGFR (-alpha and -beta), and EGFR in a series of primary thymic neoplasms including 10 thymic carcinomas and 20 thymomas (5 type A, 4 type AB, 2 type B1, 4 type B2, and 5 type B3) (Rossi G., personal not published observations June 2008). Our results are in agreement with recent studies, confirming that c-kit, PDGFRs, and EGFR mutations in
thymic tumors are extremely rare.8,9 Although sporadic, these genetic alterations represent critical molecular events in tumor growth of thymic epithelial neoplasms and can predict responsiveness with TK inhibitors, as well-exemplified in GIST. Given the lack of effective therapy for unresectable or metastatic chemoresistant thymic tumors and the dismalrelated prognosis, knowledge of the role of “drugable” receptor kinases possibly through molecular screening for activating mutations may be helpful in identifying patients that could benefit from sorafenib or other targeted therapies. REFERENCES 1. Srirajaskanthan R, Toubanakis C, Dusmet M, Caplin ME. A review of thymic tumours. Lung Cancer 2008;60:4 –13. 2. Henley JD, Cummings OW, Loehrer PJ Sr. Tyrosine kinase receptor expression in thymomas. J Cancer Res Clin Oncol 2004;130:222–224. 3. Strobel P, Hartmann M, Jakob A, et al. Thymic carcinoma with overexpression of mutated KIT and the response to imatinib. N Engl J Med 2004;350:2625–2626. 4. Farina G, Garassino MC, Gambacorta M, La Verde N, Gherardi G, Scanni A. Response of thymoma to cetuximab. Lancet Oncol 2007;8: 449 – 450. 5. Chuah C, Lim TH, Tiong Lim AS, et al. Dasatinib induces a response in malignant thymoma. J Clin Oncol 2006;24:56 –58. 6. Li X, Chen Q, Huang WX, Ye YB. Response to sorafenib in cisplatin-resistant thymic carcinoma: a case report. Med Oncol In press. doi: 10.1007/s12032-008-9100-0. 7. Guo T, Agaram NP, Wong GC, et al. Sorafenib inhibits the imatinibresistant KITT670I gatekeeper mutation in gastrointestinal stromal tumor. Clin Cancer Res 2007;13:4874 – 4881. 8. Yoh K, Nishiwaki Y, Ishii G, et al. Mutational status of EGFR and KIT in thymoma and thymic carcinoma. Lung Cancer 2008;62:316 –320. 9. Tsuchida M, Umezu H, Takehisa H, et al. Absence of gene mutations in KIT-positive thymic epithelial tumors. Lung Cancer 2008;62:321–325.
Copyright © 2009 by the International Association for the Study of Lung Cancer
775
Long Lasting Response to the Multikinase Inhibitor Bay 43-9006 (Sorafenib) in a Heavily Pretreated Metastatic Thymic Carcinoma Giancarlo Bisagni, MD,* Giulio Rossi, MD, PhD,† Alberto Cavazza, MD,‡ Giuliana Sartori, PhD,† Giorgio Gardini, MD,‡ and Corrado Boni, MD*
Abstract: Metastatic thymic carcinoma is an aggressive neoplasm for which multimodal therapies are often ineffective. We describe here a heavily pretreated patient with advanced thymic carcinoma responsive to multikinases inhibitor BAY 43-9006 (Sorafenib). Of note, a hitherto unreported c-kit missense mutation on exon 17 (D820E) identified in tumor cells seems to explain the clinical response and highlight the key role of molecular analysis in predicting efficacy of targeted therapies even in thymic neoplasms. Key Words: Thymoma, Thymic carcinoma, c-kit, CD117, Tyrosine kinase. (J Thorac Oncol. 2009;4: 773–775)
CASE REPORT A 46-year-old man was referred to our institution in August 2001 after the assessment of a 9 cm mass in the upper anterior mediastinum extending to the sternum for which he underwent surgical resection. Surgery was not radical because of pericardial involvement and the presence of liver metastasis in the left lobe. The tumor consisted of a proliferation of relatively monomorphic, rounded-to-spindled cells with prominent eosinophilic nucleoli (Figure 1A), showing necrotic foci and high mitotic rate (35 ⫻ 10 high-powerfields). Tumor cells immunostained with cytokeratins, CD5, c-kit/CD117 (Figure 1B), but not for chromogranin, synaptophysin, and CD56. A diagnosis of undifferentiated thymic carcinoma with extensive capsular invasion (pT3, N2, M1) was made. The patient then was treated with one course of PE (Cisplatin 70 mg/m2, day 1 and Etoposide 120 mg/m2, q3w) and five courses of PEI (Cisplatin 20 mg/m2, Etoposide 75 *Operative Units of Oncology, Azienda Ospedaliera S. Maria Nuova, Reggio Emilia; †Section of Pathologic Anatomy, Azienda Ospedaliero-Universitaria Policlinico, Modena; and ‡Pathologic Anatomy, Azienda Ospedaliera S. Maria Nuova, Reggio Emilia, Italy. Disclosure: The authors declare no potential conflicts of interest. Address for correspondence: Giulio Rossi, MD, Sezione di Anatomia Patologica, Azienda Ospedaliero-Universitaria Policlinico, Via del Pozzo, 71, 41100 Modena, Italy. E-mail: [email protected] Copyright © 2009 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/09/0406-0773
Journal of Thoracic Oncology • Volume 4, Number 6, June 2009
mg/m2, and Ifosfamide 1200 mg/m2, days 1– 4, q3w) with partial response in liver metastases and subsequent total excision of left hepatic lobe. He was disease-free for 1 year when pulmonary and hepatic metastases were detected. Radiofrequency ablation of the hepatic lesion followed by three additional PEI courses were performed with partial remission and subsequent complete excision of pulmonary metastases. In April 2004, computed tomography (CT) detected multiple lung and liver nodules and four cycles of chemotherapy with doxorubicin and ifosfamide (Doxorubicin 35 mg/m2 and Ifosfamide 3000 mg/m2, days 1–3, q3w) were given achieving clinical partial response. In January 2005, the patient had disease progression with increase of liver and lungs metastases. In the absence of any standardized subsequent-line chemotherapy, an empiric treatment with longacting release octreotide (20 mg per month, subcutaneously) was performed. Intracranial tumor progression occurred and a cerebral necrotic lesion was surgically removed. Liver and lung metastases were stable and octreotide treatment was stopped. Further restaging showed multiple bilateral lung and liver metastases, and a parietal intracranial metastasis. In the meantime, tumor cells were investigated by immunohistochemical expression of epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), c-met, and platelet-derived growth factor receptor (PDGFR)alpha and -beta without evidence of immunoreactivity. Most important, molecular analysis by polymerase chain reactionbased direct sequencing showed a missense mutation in c-kit exon 17 (D820E) (Figure 1C). No alterations were observed in the other tested genes: c-kit exons 9, 11, 13, and 14, PDGFR-alpha exons 12, 14, 17, PDGFR-beta exons 12, 14, 18, 19, 20, c-met exons 14, 17, 18, 19, EGFR exons 18, 19, 20, 21, and BRAF exon 15. The finding of this mutational event lead us to start a targeted therapy with BAY 43-9006 (sorafenib, Nexavar, Bayer Pharmaceutical), an oral inhibitor acting against several tyrosine (VEGFR, PDGFR, c-kit), and serine/threonine (B-RAF, p38) kinases. The institutional Ethical Committee of our Hospital approved the treatment and the patient gave written informed consent. Treatment with two 100 mg capsules of sorafenib twice daily was started in October 2007.
773
Journal of Thoracic Oncology • Volume 4, Number 6, June 2009
Bisagni et al.
FIGURE 1. Undifferentiated thymic carcinoma consisting of a monomorphic proliferation of rounded-tospindled shaped cells with prominent nucleoli and mitotic rate (A) strongly expressing c-kit/CD117 (B) and harboring a missense mutation at c-kit exon 17 (D820E) (electropherogram, see arrows C).
After 8 weeks of this treatment, a partial response was detected by CT scan according to World Health Organization criteria. Before sorafenib therapy, multiple metastases were present in liver, lungs (Figures 2A, B), and brain. After treatment with sorafenib, a clinical response was confirmed in all metastatic sites (Figures 2C, D). Sorafenib was well tolerated and improvement in both symptoms control and performance status was registered. Adverse events consisted of a grade 2 of skin desquamation and pruritus, grade 1 diarrhea, and grade 1 fatigue. Skin toxicity was resolved discontinuing sorafenib for 1 week every 4 weeks of treatment. No other toxicities were noted. After 15 months, this heavily pretreated patient (followed-up with CT scans every 3 months) is still in partial response continuously receiving sorafenib.
DISCUSSION When metastatic spread from thymic carcinomas occurs, multimodal treatment basically represents the only effective therapy.1 Most regimens include cisplatin and the best results have been reported with the PE, cyclophosphamide, doxorubicin, cisplatin (PAC) and cisplatin doxorubicin, vincristine, cyclophosphamide (ADOC) regimens.1 The overall response rate has ranged from 30 to 90% and the median duration of response has ranged from 12 to 36 months.1 To date, there are no established therapeutic protocols for advanced, metastatic thymomas or thymic carcinomas,
774
mainly due to the rarity of the disease. Among anecdotic experiences with targeted therapy, somatostatin analogues (namely octreotide) in advanced thymomas have reported a response rate of 32% and 2-year survival of 76%.1 Interestingly, previous studies demonstrated that thymic carcinomas, but not thymomas, strongly stain with c-kit,2 a type III receptor tyrosine kinase (RTK) consistently overexpressed by gastrointestinal stromal tumors (GIST) in which the relevant c-kit gene is mutated in up to 90% of cases. By contrast, thymomas, but not thymic carcinomas, significantly express the EGFR,2 another RTK widely expressed in carcinomas from different sites and mutated in 10 to 30% of pulmonary adenocarcinomas. Based on these preliminary observations, partial responses has been reported in single case reports using imatinib mesylate, a type III RTK small molecule inhibitor, in a thymic carcinoma showing a c-kit in-frame deletion in exon 11 (V560del),3 and cetuximab, a monoclonal humanized antibody against EGFR, in an advanced B2-type thymoma strongly expressing EGFR.4 More recently, a partial tumor size resolution was observed in a metastatic B2-type thymoma using dasatinib, a multitargeted small molecule inhibitor of several RTK, as Bcr-Abl, kinases along Src family, PDGFRs, and c-kit.5 Preclinical and clinical activity with sorafenib, an oral multikinase inhibitor with effects on tumor cell proliferation
Copyright © 2009 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 4, Number 6, June 2009
Long Lasting Response to Sorafenib
FIGURE 2. Computed tomography (CT) scan studies of the lungs (A, B) before sorafenib therapy (October 2007) showing multiple pulmonary metastases. Absence of contrast enhancement or disappearance of pulmonary lesions (C, D) confirmed partial response to sorafenib therapy (December 2007).
and tumor angiogenesis, was well-demonstrated mainly in a small subset of renal cell and hepatocellular carcinomas, although no clear-cut molecular explanations on the exact mechanisms of antitumor activity have been so far reported. So far, only a recent case report by Li et al.6 evidenced a clinical response with sorafenib in a 46-year-old man with a thymic carcinoma expressing c-kit (CD117) and VEGF, but without clear-cut molecular explanation for such a clinical result. In the current case, we demonstrated the presence of a hitherto unreported gain-of-function constitutive somatic mutation involving the proto-oncogene c-kit in tumor cells of a metastatic, chemoresistant thymic carcinoma. The patient had a prompt and prolonged partial response using sorafenib, in absence of significant toxicity. Of note, an identical somatic missense mutation (D820E) involving the activation loop of the c-kit tyrosine kinase (TK) was previously identified only in a small subset of GIST resistant to imatinib mesylate.7 Exactly in GIST harboring imatinib-resistant c-kit mutations involving gatekeeper and kinase catalytic domains, sorafenib seems particularly effective, these molecular findings convincingly explaining the clinical response obtained in our patient. Unfortunately, we did not observe mutations in c-kit, PDGFR (-alpha and -beta), and EGFR in a series of primary thymic neoplasms including 10 thymic carcinomas and 20 thymomas (5 type A, 4 type AB, 2 type B1, 4 type B2, and 5 type B3) (Rossi G., personal not published observations June 2008). Our results are in agreement with recent studies, confirming that c-kit, PDGFRs, and EGFR mutations in
thymic tumors are extremely rare.8,9 Although sporadic, these genetic alterations represent critical molecular events in tumor growth of thymic epithelial neoplasms and can predict responsiveness with TK inhibitors, as well-exemplified in GIST. Given the lack of effective therapy for unresectable or metastatic chemoresistant thymic tumors and the dismalrelated prognosis, knowledge of the role of “drugable” receptor kinases possibly through molecular screening for activating mutations may be helpful in identifying patients that could benefit from sorafenib or other targeted therapies. REFERENCES 1. Srirajaskanthan R, Toubanakis C, Dusmet M, Caplin ME. A review of thymic tumours. Lung Cancer 2008;60:4 –13. 2. Henley JD, Cummings OW, Loehrer PJ Sr. Tyrosine kinase receptor expression in thymomas. J Cancer Res Clin Oncol 2004;130:222–224. 3. Strobel P, Hartmann M, Jakob A, et al. Thymic carcinoma with overexpression of mutated KIT and the response to imatinib. N Engl J Med 2004;350:2625–2626. 4. Farina G, Garassino MC, Gambacorta M, La Verde N, Gherardi G, Scanni A. Response of thymoma to cetuximab. Lancet Oncol 2007;8: 449 – 450. 5. Chuah C, Lim TH, Tiong Lim AS, et al. Dasatinib induces a response in malignant thymoma. J Clin Oncol 2006;24:56 –58. 6. Li X, Chen Q, Huang WX, Ye YB. Response to sorafenib in cisplatin-resistant thymic carcinoma: a case report. Med Oncol In press. doi: 10.1007/s12032-008-9100-0. 7. Guo T, Agaram NP, Wong GC, et al. Sorafenib inhibits the imatinibresistant KITT670I gatekeeper mutation in gastrointestinal stromal tumor. Clin Cancer Res 2007;13:4874 – 4881. 8. Yoh K, Nishiwaki Y, Ishii G, et al. Mutational status of EGFR and KIT in thymoma and thymic carcinoma. Lung Cancer 2008;62:316 –320. 9. Tsuchida M, Umezu H, Takehisa H, et al. Absence of gene mutations in KIT-positive thymic epithelial tumors. Lung Cancer 2008;62:321–325.
Copyright © 2009 by the International Association for the Study of Lung Cancer
775