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ANTICANCER RESEARCH 34: 5105-5110 (2014)

Sorafenib Efficacy in Thymic Carcinomas Seems Not to Require c-KIT or PDGFR-alpha Mutations

MARIA PAGANO1, NURIA MARIA ASENSIO SIERRA1, MICHELE PANEBIANCO1, GIULIO ROSSI2, ROBERTA GNONI1, GIANCARLO BISAGNI1 and CORRADO BONI1

Department of Oncology and Advanced Technologies, 1Oncology Unit and 2Operative Unit of Pathology, Azienda Ospedaliera S.Maria Nuova/IRCCS of Reggio Emilia, Reggio Emilia, Italy

Abstract. Purpose: To retrospectively evaluate sorafenib in the United States) (1), they are among the most common activity and safety in patients with metastatic thymic mediastinal primary tumours with up to 50% of anterior carcinoma (TC) and to correlate outcome with c-KIT and mediastinal masses proving to be of thymic origin. Males PDGFR-alpha mutational status. Patients and Methods: have a slightly higher risk of developing thymic carcinomas Patients with metastatic thymic carcinoma treated with than females and this risk rises with age, reaching a peak in sorafenib after at least one prior line of were the seventh decade of life. included. Objective response rate (ORR) and toxicity were Thymic carcinomas (TC) are aggressive neoplasms with evaluated. Analysis of c-KIT and PDGFR-alpha mutational poor prognosis and limited effective therapeutic options status was performed retrospectively. Results: From (2-5). October 2007 to August 2011, 5 patients with metastatic In early stages, surgery is the standard treatment, while thymic carcinoma were evaluated. A median of 8 cycles of systemic chemotherapy is mainly reserved for patients with sorafenib (range=3–29) were administered. Two patients an unresectable or recurrent disease (1, 2). (40%) displayed a partial response (PR), two patients Current regimens consist of a combination of drugs almost presented stable disease (SD), while one patient had always including a platinum compound; other effective drugs progression. The median progression-free (PFS) and overall are , etoposide, cyclophosphamide, epirubicin survival were 28 weeks and 92 weeks, respectively. At and vincristine. The response rate with this regime is 50- mutational analysis, only one patient with PR had c-KIT 90%, with a median survival of 12-48 months (6-8). mutation in exon 17 and was successfully treated with Expression of the protein c-KIT, the product of the proto- for 12 months after progression to sorafenib. No oncogene c-KIT immunohistochemically-recognized by the PDGFR-alpha mutations were found. Conclusion: antibody CD117, has been reported in a wide variety of Sorafenib activity seems independent from the c-KIT and human solid tumours, including TC type C, and is thought PDGFR-alpha mutational status. After progression, to play an important role in multiple cellular functions like sequence treatment with a different tyrosine inhibitor survival, adhesion, differentiation, proliferation and can be considered. These results are promising and need functional maturation (9). further confirmation on larger, possibly prospective, series Several studies have analyzed the presence of c-KIT of patients. mutations in TC, evidencing that mutational alterations, although uncommon, are present in about 10% of cases (10- Although thymic malignancies are relatively rare (0.2% to 13). Promising results have been previously published in 1.5% of all malignancies or 0.13 per 100,000 person-years patients with TC harboring c-KIT mutations and treated with selective tyrosine inhibitors (TKI), namely sunitinib (14, 15), (16) and sorafenib (17, 18). Based on the aforementioned data and our own clinical Correspondence to: Dr. Pagano Maria, Department of Oncology experience with one patient treated with sorafenib (17), we and Advanced Technologies, Oncology Unit, Azienda Ospedaliera decided to treat with sorafenib a series of patients with TC S. Maria Nuova/IRCCS , Viale Risorgimento, 80 42123- Reggio type C. Emilia, Italy. Tel: +39 0522296628, Fax: +39 0522296854, e-mail: In this brief manuscript we report the efficacy and toxicity [email protected] results obtained with sorafenib in this oncological setting, Key Words: Thymic carcinoma, c-KIT, , PDGFR also investigating the correlation between clinical response alpha, sorafenib. and mutational status of c-KIT and PDGFR-alpha genes.

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Table I. Patients’ characteristics and outcome.

Patient Gender Age Previous Stage Histology Status PS Response Toxicity TTP Following Survival No. yr therapy c-Kit/PDGFR (weeks) therapy (weeks)

1 M 50 Debulking; PEI; IVB , Νeuro- c-Kit 1 RP Ipertension, 116 Sunitinib; 180 metastasectomy; PEI; lung, endocrine Εxon 17 skin toxicity PEI metastasectomy; brain G2 IFO-ADR; longostatina; RT 2 M 61 Debulking; IVB lung B2 Wild-type 0 PD Diarrhea G2; 12 None 60 RT; PEI. HFS G2 3 F 75 ADOC; RT; IVB lung Epidermoid Wild-type 0 RP HFS G3; 28 None 76 ADOC Diarrhea G3 4 M 70 CHOP; DDP-VP; IVB lung, Thymus Wild-type 2 SD None 32 Novantrone 92 Debulking; adrenal carcinoma Mitoxantrone; PEI. 5 F 66 Debulking; IVB pleura,B2 Wild-type 1 SD None 16 Adriamicina- 116 PEI; RT; soft tissue 5FU; Metastesectomy; Imatinib; PEI; RT. w

PR, Partial response; PD, progressive disease; SD, stable disease; RT, radiotherapy; PEI, cisplatin, etoposide, ifosfamide; IFO-ADR, ifosfamide, adriamicina; CHOP, adriablastina, cisplatin, vincristine, prednisone; DDP-VP, cisplatin, etoposide; ADOC, cisplatin, doxorubicin, vincristine, cyclophosphamide; TTP, time-to-progression.

Patients and Methods embedded block were applied on noncover-slipped slides for microdissection and DNA extraction. Briefly, microdissection was Patients. From October 2007 to August 2011 5 patients with performed under direct observation with an inverted microscope metastatic TC refractory to conventional treatment were treated with using a sterile needle. Each microdissected sample was directly sorafenib in our Institution. transferred to an Eppendorf tube containing digestion buffer (2 All patients had a diagnosis of type C TC according to the 2004- mg/ml proteinase K in 50 mM Tris (pH 8.5), 1 mM EDTA, 0.5% World Health Organization (WHO) classification of thymic tumors. Tween 20). The tubes were then incubated overnight at 56˚C and In all cases, surgical specimens were fixed in 10% buffered-formalin followed by 10 min of incubation at 95˚C to eliminate any remaining and then routinely paraffin-embedded. Immunohistochemistry was proteinase K activity. Polymerase chain reaction) (PCR) was performed using an automated immunostainer (BenchMark, Ventana, performed in 20 μl reactions containing 2.0 μl DNA, 2 μl of Tucson, AZ, USA). The primary antibodies used in all cases were commercial PCR buffer (Applied Biosystems, Foster City, CA, the following: CD117 (clone A4502, Dakopatts, Glostrup, Denmark; USA), 1.0 to 2.0 mM of MgCl2, 200 mM of each dNTP, 20 pmol of 1:200 dilution without antigen retrieval), CD5 (clone SP19, Ventana; each primer, and 3 units of AmpliTaq Gold polymerase (Applied prediluted with microwave antigen retrieval), p63 (clone 4A4, Biosystems). The PCR reaction was carried out on Uno II NeoMarkers, Fremont, CA, USA; 1:400 dilution with microwave Thermoblock (Biometra, Gottingen, Germany). Initial denaturation antigen retrieval), chromogranin (clone LK2H10, Ventana; prediluted at 95˚C for 10 minutes was followed by 41 cycles and a final with microwave antigen retrieval), synaptophysin (polyclonal, extension step (10 minu at 72˚C). The cycles included denaturation Ventana; prediluted with microwave antigen retrieval). at 95˚C for 1 minute, annealing at 55˚C to 66˚C for 1 minute, and The institutional Ethical Committee of our Hospital (Comitato extension at 72˚C for 2 min. The amplified DNA was Etico Provinciale – IRCCS Arcispedale S. Maria Nuova – Reggio electrophoresed on 2% agarose gel for 1 hour at 110 V. The Emilia) approved the treatment and patients gave written informed amplification products were then purified by using the MinElute consent. PCR purification Kit (Qiagen, Valencia, CA, USA) as indicated by All clinicopathological features are reported in Table I. the manufacturer’s instructions. PCR products were then sequenced in both directions with ABI Prism BigDye Terminator v1.1 Cycle Treatment. Treatment consisted in 400 mg of sorafenib orally twice Sequencing (Applied Biosystems), using the same primers as daily continuously until progression or unacceptable toxicity. The those employed for PCR. The PCR products were finally purified by response to treatment was evaluated according to Response Centri-Sep Spin Columns (Applied Biosystems) and subsequently Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria and the ran on the ABI Prism 310 automatic sequencer (Applied toxicity was monitored as clinical practice. Biosystems). The data were analyzed with the Sequencing Analysis 5.2 Software (Applied Biosystems). The forward and reverse DNA extraction and mutational analysis. Five-μm thick, oligonucleotide primers used to amplify c-KIT exons 9, 11, 13, 14 hematoxylin-eosin-stained sections from a representative paraffin- and 17, and PDGFRα exons 12, 14 and 18 are listed in Table II.

5106 Pagano et al: Sorafenib Efficacy in Thymic Carcinomas

Table II. Oligonucleotide primers used in the study.

Primer Name Primer sequence Annealing temperature Product size (bp)

Exon 9 c-KIT Forward 5’- ATG CTC TGC TTC TGT ACT GCC -3’ Reverse 5’- CAG AGC CTA AAC ATC CCC TTA-3’ 58˚C 238 bp Exon 11 c-KIT Forward 5’- GAT CTA TTT TTC CCT TTC TC -3’ Reverse 5’- AGC CCC TGT TTC ATA CTG AC-3’ 57˚C 174 bp Exon 13 c-KIT Forward 5’- GCT TGA CAT CAG TTT GCC AG -3’ Reverse 5’- AAA GGC AGC TTG GAC ACG GCT TTA-3’ 66˚C 193 bp Exon 14 c-KIT Forward 5’- GTC TGA TCC ACT GAA GCT G -3’ Reverse 5’- ACC CCA TGA ACT GCC TGT C-3’ 59˚C 151 bp Exon 17 c-KIT Forward 5’- TAC AAG TTA AAA TGA ATT TAA ATG GT -3’ Reverse 5’- AAG TTG AAA CTA AAA ATC CTT TGC-3’ 63˚C 228 bp Exon 12 PDGFRα Forward 5’- TCC AGT CAC TGT GCT GCT TC -3’ Reverse 5’- GCA AGG GAA AAG GGA GTC TT-3’ 61˚C 260 bp Exon 14 PDGFRα Forward 5’- GTA GCT CAG CTG GAC TGA TA -3’ Reverse 5’- AAT CCT CAC TCC AGG TCA GT-3’ 60˚C 180 bp Exon 18 PDGFRα Forward 5’- TAC AGA TGG CTT GAT CCT GAG T -3’ Reverse 5’- AGT GTG GGA GGA TGA GCC TG-3’ 65˚C 211 bp

Results sorafenib. No mutational events were identified in the other patient showing a PR as well as in patients with stable At histology, type C carcinomas were classified as squamous disease. cell carcinomas in 3 cases and undifferentiated in 2 cases. All cases showed immunoreactivity for p63, CD5 and Discussion CD117, whereas neuroendocrine markers (chromogranin and synaptophysin) were entirely negative (Figure 1). Thymic carcinomas are uncommon and aggressive Median age was 66 years (range=50-75) and 60% (3 neoplasms with a poor prognosis. When diagnosed in early patients) were male. All patients have received at least 1 stages, surgery is the treatment of choice with a 95% to previous line of chemotherapy (1 line in 1 case, 2 lines in 100% OS at 5 years (19). In advanced disease, the survival two patients, 4 lines in two subjects). dramatically drops to 28-68% at 5 years, and the main Partial response was obtained in 2 of 5 patients (40%). therapeutic strategy is palliative chemotherapy (20, 21). Stable disease was observed in two patients (40%). One The best results have been obtained with platinum-based patient progressed during sorafenib treatment. The median regimes like PAC (cisplatin, doxorubicin and duration of treatment was 7 months (3-29); the median PFS cyclophosphamide), ADOC (cisplatin, doxorubicin, and OS were 28 weeks (12-116) and 92 weeks (60-180), vincristine and cyclophosphamide) or PE (cisplatin, respectively. In 3 patients an ulterior line of therapy was etoposide) with response rates from 50 to 90% (22, 23). administered after sorafenib progression (Table I). Neither molecular targets nor targeted-therapies have been Concerning drug toxicity, in three cases a reduction to 600 identified in TC until now, but some published data suggest mg of the daily dose of sorafenib was necessary, in one case a key role of the proto-oncogene c-KIT among various due to and skin toxicity, in the other two cases molecular pathways (24, 25). In particular, the presence of due to diarrhea G3 and hand food syndrome (HFS) G2. c-KIT mutations, although rare in TC, have been well- Because of permanent HFS G3, sorafenib was finally demonstrated in the literature and c-KIT-mutated cases have discontinued in one of these three patients. In the other two a significant clinical response to different tyrosine kinase cases, sorafenib was administrated with the full 800 mg dose. inhibitors (TKI). At mutational analysis, only the case harbouring a Two case reports have described a successful response to missense mutation in c-KIT exon 17 (D820E) experienced a the TKI imatinib in metastatic TC patients heavily pre- PR (Figure 2). treated with a c-KIT mutation in exon 11 (11, 16). All the other 4 cases were c-KIT wild-type. No PDGFR- In another two published reports, sorafenib efficacy has alpha mutations were found. Of the two cases with a PR, the been described in patients with metastatic TC with two longest response (29 months) was observed in a patient with different c-KIT mutations, involving exon 17 and 11 (17, 18). c-KIT mutated tumor. This case was further successfully Of note, in a recent work by Girard et al. (26), the authors treated with sunitinib for 12 months after progression to identified 2 c-KIT mutations involving exons 11 (V560

5107 ANTICANCER RESEARCH 34: 5105-5110 (2014)

Figure 1. Thymic carcinoma, undifferentiated type, (A, Haematoxylin-Eosin stain ×200) expressing p63 (B, immunohistochemistry ×200), CD5 (C, immunohiostochemistry ×200) and CD117/c-KIT (D, immunohistochemistry ×200).

deletion) and 14 (L576P) in 2 out of 7 type-C thymic carcinomas, but not in thymomas. However, clinical responses have been demonstrated even in c-KIT wild-type TC. Interestingly, Strobel et al. has described sunitinib activity in a limited series of c-KIT and PDGFR-alpha wild- type TC, possibly suggesting an anti-angiogenetic mechanism, as previously demonstrated in (14). Similarly to Strobel et al. (14), we did not find an obligatory correlation between mutational status and clinical Figure 2. Electropherogram derived from molecular analysis by direct response, although the only c-KIT-mutated patient had the sequncing of tumor cells from a case showing a missense mutation on c- longest clinical response. KIT exon 17 (D820E). Therefore, it is important to note that sorafenib demonstrated an 80% disease control rate (2 PR and 2 SD). As suggested by Strobel et al. (14), apart from c-KIT, sorafenib may also inhibit vascular endothelial to represent the treatment-of-choice in TC harbouring c-KIT receptor-1 (VEGFR-1), VEGFR-2, and VEGRF-3, supporting mutations in exons 9 and 11, patients with mutations in exons the hypothesis of an anti-angiogenetic activity even in TC. 13 and 14 could have a major clinical benefit using sunitinib. Schirosi et al. (27), after a review of all metastatic TCs Finally, sorafenib demonstrated the best response in TC treated with TKI inhibitors published in literature, harbouring an exon 17 mutation. On the other hand, wild-type hypothesized an interesting and practical therapeutic patients could be treated with sorafenib or sunitinib in algorithm based on the type of c-KIT mutations in order to of their consistent anti-angiogenetic action. Unfortunately, guide the best choice of specific TKIs. While imatinib seems this intriguing proposal is based on a very limited number of

5108 Pagano et al: Sorafenib Efficacy in Thymic Carcinomas cases and clearly requires further observation on larger 2 Giaccone G, Wilmink H, Paul MA and Van der Valk P: Systemic prospective series of patients with TC. Another open question treatment of malignant thymoma. A decade experience at a concerns how to continue the treatment when the disease single institution. Am J Clin Oncol 29: 336-344, 2006. progress after an initial response to a specific TKI. 3 Marx A, Rieker R, Toker A, Länger F and Ströbel P: Thymic carcinoma: is it a separate entity? From molecular to clinical In the current series, it is noteworthy that the patient with evidence. Thorac Surg Clin 21: 25-31, 2011. c-KIT-mutated TC was successfully treated with sunitinib 4 Srirajaskanthan R, Toubanakis C, Dusmet M and Caplin ME: A during 12 months after sorafenib progression. To our review of thymic tumours. Lung Cancer 60: 4-13, 2008. knowledge, this is the second case described in the literature 5 Marx A, Strobel P, Zetti A and Muller-Hermelink HK: Tumours showing a successful response to a TKI-TKI sequence of the thymus. In Travis W, Brambilla E, Harris CC (eds.).: strategy for a metastatic TC patient. A similar experience was WHO Classification of Tumours. Pathology and Genetics of recently described by Rossi et al. (28) demonstrating the Tumours of the Lung, Thymus and Heart, Vol 10, 3rd edition. Lyon, France: IARC 93-145, 2004. efficacy of sunitinib after progression on imatinib in a type-C 6 Loehrer PJ Sr, Jiroutek M, Aisner S, Aisner J, Green M, Thomas TC harbouring a c-KIT mutation in exon 11. CR Jr, Livingston R and Johnson DH: Combined etoposide, Although anecdotic, these cases seem to support the idea ifosfamide, and cisplatin in the treatment of patients with that, as happen in gastrointestinal stromal tumours or in renal advanced thymoma and thymic carcinoma: an intergroup trial. cell carcinomas, the TKI-TKI sequence could be a viable Cancer 91: 2010-2015, 2001. therapeutic proposal in patients with metastatic TC having a 7 Schmitt J and Loehrer PJ Sr: The role of chemotherapy in good response and tolerance to a previous TKI therapy. advanced thymoma. J Thorac Oncol 10(suppl 4): s357-s360, 2010. With regard to toxicity data, a dose reduction of the 8 Rajan A and Giaccone G: for advanced thymic tumors. J Thorac Oncol 5 10(suppl 4): s361-s364, 2010. sorafenib daily dose from 800 mg to 600 mg was necessary 9 Pan cc, chen PC and Chiang H: KIT (CD117) is frequently in three patients, but it should be kept in mind that these overexpressed in thymic carcinomas but is absent in thymomas. patients had been heavily pre-treated. As a matter of fact, the J Pathol 202: 375-381, 2004. therapy with sorafenib was in general well-tolerated and 10 Nakagawa K, Matsuno Y, Kunitoh, Maeshima A, Asamura H and observed toxicities were easily manageable. Tsuchiya R: Immunohistochemical KIT (CD117) expression in In conclusion, although based on few cases, we consider a thymic epithelial tumors. Chest 128: 140-144, 2005. treatment with sorafenib a good option for metastatic type-C 11 Strobel P, Hartmann M, Jakob A, Mikesch K, Brink I, Dirnhofer S and Marx A: Thymic carcinoma with overexpression of TC previously undergoing chemotherapy, even in cases with mutaded KIT and the response to imatinib. N Engl J Med 350: c-KIT and PDGRF alpha wild-type mutational status. 2625-2626, 2004. Incidentally, testing c-KIT mutations in KIT-positive type-C 12 Yoh K, Nishiwaki Y, Ishii G, Goto K, Kubota K, Ohmatsu H, TC is mandatory and the type of c-KIT mutation could guide Niho S, Nagai K and Saijo N: Mutational status of EGFR and the initial choice of the TKI. By contrast, PDGFR-alpha KIT in thymoma and thymic carcinoma. Lung Cancer 62: 316- does not seem to have a role in TC. Treatment with a 320, 2008. different TKI is to be considered after progression and 13 Tsuchida M, Umezu H, Hashimoto T , Shinohara H, Koike T, Hosaka Y, Eimoto T and Hayashi JI : Absence of gene mutations sorafenib therapy seems promising even in wild-type cases. in KIT- positive thymic epithelila tumors. Lung Cancer 62: 321- These promising clinical results in the current and previous 325, 2008. limited series of TC studies seem to support the feasibility 14 Strobel P, Bargou R, Wolff A, Spitzer D, Manegold C, of a prospective trial on a larger series of patients. Dimitrakopoulou-Strauss A, Strauss L, Sauer C, Mayer F, Hohenberger P and Marx A: Sunitinib in metastatic thymic Conflicts of interest carcinomas: laboratory findings and initial clinical experience. Br J Cancer 103: 196-200, 2010. Dr C. Boni declares honoraria as member of advisory board 15 Lorusso PM and Eder JP: Therapeutic potential of novel selective-spectrum kinase inhibitors in oncology. Expert Opin for ; other authors declare no conflict of interest. This Investing Drugs 17: 1013-28, 2008. research project was conduct without financial assistance. 16 Buti S, Donini M, Sergio P, Garagnani L, Schirosi L, Passalacqua R and Rossi G: Impressive response with imatinib Acknowledgements in a heavily pretreated patient with metastatic c-Kit mutated thymic carcinoma. J Clin Oncol 29: e803-e805, 2011. We thank Dr Giorgio Gardini for your help in the research paper. 17 Bisagni G, Rossi G, Cavazza A Sartori G, Gardini G and Boni C: Long lasting response to the multikinase inhibitor bay 43- 9006 (sorafenib) in a heavily pretreated metastatic thymic References carcinoma. J Thorac Oncol 4: 773-775, 2009. 18 Disel U, Oztuzcu S, Besen AA, Karadeniz C, Köse F, Sümbül 1 Eng TY, Fuller CD, Jagirdar J, Bains Y and Thomas CR Jr.: AT, Sezer A, Nursal GN, Abalı H and Ozyılkan O: Promising Thymic carcinoma: state of the art review. Int J Radiat Oncol efficacy of sorafenib in a relapsed thymic carcinoma with C-KIT Biol Phys 59: 654-664, 2004. exon 11 delection mutation. Lung Cancer 71: 109-112, 2011.

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19 Chen G, Marx A, Chen WH, Yong J, Puppe B, Stroebel P and 25 Natali PG, Nicotra MR, Sures I, Santoro E, Bigotti A and Ullrich Mueller-Hermelink HK: New WHO histologic classification A: Expression of c-kit receptor in normal and transformed predicts prognosis of thymic epithelial tumors: a human nonlymphoid tissues. Cancer Res 52: 6139-6143, 1992. clinicopathologic study of 200 thymoma cases from China. 26 Girard N, Shen R, Guo Tianhua, Zakowski MF, Heguy A, Riely Cancer 95: 420-429, 2002. G.J, Huang J, Lau C, Lash AE, Ladanyi M, Viale A, Antonescu 20 Tseng YL, Wang ST, Wu MH, Lin MY, Lai WW and Cheng FF: CR, Travis WD, Rusch VW, Kris MG and Pao W: Thymic carcinoma: involvement of great vessels indicates poor Comprehensive Genomic Analysis reveals clinically relevant prognostic. Ann Thorac Surg 76: 1041-1045, 2003. molecular distinctions between thymic carcinomas and 21 Kondo K and Monden Y: Therapy for thymic epithelial tumors: thymomas. Clin Cancer Res 15(22): 6790-6799, 2009. a clinical study of 1,320 patients from Japan. Ann Thorac Surg 27 Schirosi L, Nannini N, Nicoli D, Cavazza A, Valli R, Buti S, 76: 878-85, 2003. Garagnani L, Sartori G, Calabrese F, Marchetti A, Buttitta F, 22 Yokoi K, Matsuguma H, Nakahara R, Kondo T, Kamiyama Y, Felicioni L, Migaldi M, Rea F, Di Chiara F, Mengoli MC and Mori K and Miyazawa N: Multidisciplinary treatment for Rossi G: Activating c-kit mutations ina asubset of thymic advanced invasive thymoma with cisplatin, doxorubicin, and carcinoma and response to different c-kit inhibitors. Ann Oncol methylprednisolone. J Thorac Oncol 2: 73-78, 2007. 23: 2409-2414, 2012. 23 Lemma GL, Loehrer PJ, Lee JW, Langer CJ, Tester WJ and 28 Rossi V, Donini M, Sergio P, Passalacqua R, Rossi G and Buti S: Johnson DH: A phase II study of plus paclitaxel in When a thymic carcinoma "becomes" a GIST. Lung Cancer 80: advanced thymoma or thymic carcinoma: E1C99. J Clin Oncol 106-108, 2013. ASCO Annual Meeting Proceedings; 26 [abstract 8018], 2008. 24 Yarden Y, Kuang WJ, Yang-Feng T, Coussens L, Munemitsu S, Dull TJ, Chen E, Schlessinger J, Francke U and Ullrich A: Received May 15, 2014 Human protooncogene c-kit: a new cell surface receptor tyrosine Revised June 28, 2014 kinase for an unidentified ligand. EMBO J 6: 3341-335, 1987. Accepted July 1, 2014

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