|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 26, No 12 (April 20), 2008: pp. 2046-2051 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.0707
Major Response to Imatinib Mesylate in KIT-Mutated MelanomaThe Melanoma Program, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
Division of Hematology and Oncology, Oregon Health and Science University, Portland, OR
The Melanoma Program, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
Department of Radiology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
Department of Medical Oncology, Ludwig Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
The Melanoma Program, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA A 79-year-old woman presented having underwent resection of a rectal mass in June 2004. Pathology revealed a rectal melanoma with positive staining for melanoma markers S-100, HMB45, and MART-1. In September 2004, the patient developed a recurrence at the anastomotic site, which was resected with a resulting diverting colostomy. The patient was well until December 2006, when she developed vaginal bleeding. Restaging at that time revealed a large pelvic mass near the anal rectal junction inferior to the uterus. A 3 cm exophytic mass was also present superior to the left kidney. Core biopsy of the pelvic mass was consistent with metastatic melanoma. The patient received palliative radiation to the pelvis. Pathologic review of the tumor removed in 2004 (Figs 1A and 1B) confirmed a polypoid mass involving the rectal mucosa consisting of epithelioid cells with large nuclei, prominent nucleoli, and immunohistochemical staining for HMB45 and Melan-A (Fig 1C). The tumor was also found to have strong, uniform staining for KIT (CD117) by immunohistochemistry (Fig 1D). Tumor tissue was manually dissected from 5-µm unstained sections of formalin-fixed, paraffin-embedded tissue, and DNA was extracted and purified as previously described.1 KIT gene exons 11, 13, and 17 were each amplified by polymerase chain reaction and the products were screened for mutations by denaturing high-performance liquid chromatography (Transgenomic WAVE system; Transogenomic, Omaha, NE).1 This revealed an additional peak in the exon 11 amplicon (Fig 1E). Direct sequencing confirmed a seven-codon duplication (Fig 2). The week before treatment, the patient noted recurrence of vaginal and rectal bleeding. Within 3 days of initiation of oral imatinib mesylate 400 mg daily (supplied by Novartis Pharmaceuticals Corp, Basel, Switzerland), the bleeding stopped. Two weeks later, the patient complained of mild bilateral lower extremity edema and skin changes over both shins consistent with venous stasis. Echocardiogram and noninvasive lower extremity Doppler images were normal. Serum lactate dehydrogenase decreased from 447 u/L to normal within the first 2 weeks of treatment. Four weeks after the initiation of imatinib mesylate, the patient maintained a good performance status, had no further bleeding, and had mild bilateral lower extremity edema with resolution of venous stasis changes. At that time, restaging [18F]fluorodeoxyglucose–positron emission tomography/computed tomography (FDG-PET/CT) revealed marked response of pre-existing disease (Fig 3). FDG-PET/CT images are depicted before (Figs 3A, 3C, 3E, and 3G) and 4 weeks after (Figs 3B, 3D, 3F, and 3H) initiation of imatinib mesylate. Sites of disease are depicted by arrows. Normal bladder is depicted by dotted arrow. There was complete resolution of a FDG-avid right epicardial soft tissue mass. There was also complete resolution of an FDG-avid right adrenal mass. Significant improvement in a left posterior pararenal soft tissue mass was noted, having measured 5.0 x 4.0 cm (maximum standardized uptake value 9.5) pretreatment, subsequently measuring 2.5 x 2 cm (maximum standardized uptake value 3.4) after 4 weeks of treatment. A left anterior peritoneal mass decreased from 3.7 x 3.4 cm to 1.7 x 1.5 cm, demonstrating residual low-grade tracer uptake post-treatment. A deep pelvic mass lost FDG avidity, with size changing from 7.8 x 8.8 cm to 6.2 x 6.1 cm. Subsequent CT imaging of chest, abdomen, and pelvis on day 42 of treatment confirmed a continuing response (Fig 4). CT images demonstrate disease before (Figs 4A, 4C, 4E, 4G) and after (Figs 4B, 4D, 4F, 4H) initiating imatinib mesylate treatment. Sites of disease are depicted by arrows. Noted are significant decreases in size and number of pulmonary nodules. The 2.2 x 1.5 cm right epicardial mass completely resolved. The left suprarenal mass decreased from 4.5 cm to 2.5 cm; the pelvic mass decreased from 8.7 to 5.7 cm; and the left iliac fossa mass decreased from 4 to 1.4 cm. At 4 months, the patient has continued stabilization of this response, having required a 1-week delay in treatment and dose reduction to 300 mg per day of imatinib mesylate due to angioedema and desquamating rash. She is currently tolerating 300 mg daily of imatinib mesylate.
Melanomas arising from mucosal surfaces, palms, soles, and nailbeds do not result from the usual risk factors of sun exposure and family history.2 No effective treatment options exist for patients who develop metastatic disease. Mucosal melanomas are rare and can arise in the sinuses, oropharynx, vagina, and anal regions. Acral melanomas (approximately 5% of all melanomas), arise on the non–hair-containing palms, soles, and nailbeds.3 Given their unique distribution and similar incidence across races, mucosal and acral melanomas likely have different genetic alterations and biologic behavior compared with cutaneous melanomas. Recently, KIT-activating mutations were reported in 21% of mucosal melanomas, 11% of acral melanomas, and 16.7% of melanomas arising in chronically sun-damaged skin as determined by the presence of solar elastosis.4 Additional cases showed increased KIT copy number or amplification. In a separate report, 15% of anal melanomas harbored a KIT mutation.5 Most mutations affect the juxtamembrane region of the KIT protein, which predicts responsiveness to imatinib mesylate. The receptor tyrosine kinase KIT acts on a cascade of substrates leading to key intracellular signals of cellular proliferation. Mutations in KIT have been reported in 75% to 80% of GI stromal tumors (GIST),6 resulting in ligand-independent kinase activity. Imatinib mesylate inhibits enzymatic activity of several tyrosine kinases including KIT and platelet-derived growth factor  . Importantly, clinical studies have demonstrated 75% to 90% stable and responding disease rates in patients with advanced GIST.7-9 Imatinib mesylate has also been shown to be an inhibitor of BCR-Abl–dependent cell proliferation in chronic myelogenous leukemia by competitively inhibiting the binding of adenosine triphosphate to the Abl kinase domain at sub-micromolar concentrations.10,11 The response rate nears 100% for patients in chronic phase. Given the lack of effective treatments, recent discoveries of KIT aberrations, and prior clinical success of targeted tyrosine kinase inhibitors, we initiated a phase II study of imatinib mesylate for the treatment of patients with mucosal or acral melanoma and an activating KIT mutation in the tumor at the Dana-Farber Cancer Institute (Boston, MA). We report here the first patient treated with a primary anal melanoma harboring a seven-codon duplication in exon 11 of KIT. The clinical trial details and results of the phase II study will be reported separately. Malignant melanoma is a disease typified by exceedingly poor responses to therapies. Given that evidence exists for melanoma being an immunogenic tumor, much prior clinical investigation focused on immune-based therapies. Molecular analyses of melanomas have brought to light a number of oncogenic mutations that are potential therapeutic targets, including BRAF, NRAS, and KIT.12 Although certainly an important and promising area of active investigation, reported successful targeting of BRAF continues to be challenging.13 In addition, three phase II trials of imatinib mesylate have proven disappointing.14-16 Several possible explanations for these clinical observations exist. First, melanoma cells may be so resistant to death signals that the dependence on oncogenic mutations may be fundamentally different than that for other cancers. Second, drugs of greater specificity or potency may be necessary. Third, it is possible that uncharacterized molecular features of the tumors (in addition to a kinase mutation) are critical in predicting responsiveness. Patient selection may provide an answer at least in certain important cases. The KIT mutation identified in our patient's tumor involved the juxtamembrane domain (exon 11), which is the most frequent site of mutation in GIST and predicts imatinib mesylate response.6,17 The patient had a near complete metabolic response by FDG-PET/CT and much greater than 50% reduction in tumor volume 4 weeks after initiation of imatinib mesylate. These observations suggest that melanomas are unlikely to be intrinsically less dependent on such oncogenic events than other cancers, a finding that renews enthusiasm for other targeted strategies against melanoma. KIT and its ligand stem-cell factor are essential to melanocyte development and expression of KIT (CD117) is common in early-stage melanoma in a variety of primary sites. However, data on KIT mutations in melanoma are limited. Among CD117-positive melanomas (primarily cutaneous) screened by high-resolution melting curve analysis, only three mutations were identified in 35 cases (8.6%).18,19 The mutation frequency seems to be higher among melanomas of the mucosa, acral skin, and chronically sun-damaged skin, ranging from 11% to 21%.4,5 It is interesting to note that in one of the reported phase II trials of imatinib mesylate, the only patient who benefited significantly from treatment had metastatic acral melanoma.15 Increased KIT copy number and amplification have been reported in some melanomas, both with and without mutations.4,5 It remains to be determined whether genomic over-representation of KIT correlates with treatment sensitivity independent of mutation status. From the GIST experience with imatinib mesylate, most patients eventually develop progressive disease, with tumors acquiring secondary mutations that confer treatment resistance. Use of later-generation kinase inhibitors or novel therapeutic combinations in melanoma requires additional investigation. Only by expanding investigation of KIT inhibition–targeted therapies to larger numbers of patients can the frequency of KIT mutations and amplification in this patient population be understood and efficacy of a number of targeted therapies appreciated. Given the low incidence of mucosal and acral melanomas as well infrequent mutational rate of KIT, this will require collaborative efforts by many clinical investigators. Comparisons of primary versus metastatic melanomas have underscored the genomic complexity of the disease.20 The ability to selectively inhibit with clinical meaningfulness an activating mutation in a receptor tyrosine kinase such as KIT within the background of such complexity suggests an ongoing dependency of this oncoprotein within tumor cells. It remains particularly urgent to identify the full extent of KIT mutations in melanoma, and enlist such patients into treatment protocols with available highly effective targeted therapies. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Christopher L. Corless, Novartis Pharma (C), Pfizer Inc (C); Michael C. Heinrich, Novartis Pharma (C), Pfizer Inc (C); George Demetri, Novartis Pharma (C), Pfizer Inc (C); David E. Fisher, Novartis Pharma (C) Stock Ownership: Michael C. Heinrich, molecularMD Honoraria: F. Stephen Hodi, Novartis Pharma; Christopher L. Corless, Novartis Pharma, Pfizer; Michael C. Heinrich, Novartis Pharma, Pfizer Inc; George D. Demetri, Novartis Pharma, Pfizer Research Funding: Michael C. Heinrich, Novartis Pharma, Pfizer Inc; George D. Demetri, Novartis Pharma, Pfizer Inc; David E. Fisher, Novartis Pharma Expert Testimony: None Other Remuneration: None
ACKNOWLEDGMENTS Supported in part by The Ron Gelb Melanoma Research Fund at Dana-Farber Cancer Institute. REFERENCES
1. Corless CL, McGreevey L, Haley A, et al: KIT mutations are common in incidental gastrointestinal stromal tumors one centimeter or less in size. Am J Pathol 160:1567-1572, 2002 2. Patrick RJ, Fenske NA, Messina JL: Primary mucosal melanoma. J Am Acad Dermatol 56:828-834, 2007[CrossRef][Medline] 3. Barnhill RL: Textbook of Dermatopathology (ed 2). New York, NY, McGraw-Hill Health Pub Division, 2004 4. Curtin JA, Busam K, Pinkel D, et al: Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 24:4340-4346, 2006 5. Antonescu CR, Busam KJ, Francone TD, et al: L576P KIT mutation in anal melanomas correlates with KIT protein expression and is sensitive to specific kinase inhibition. Int J Cancer 121:257-264, 2007[CrossRef][Medline] 6. Rubin BP, Heinrich MC, Corless CL: Gastrointestinal stromal tumour. Lancet 369:1731-1741, 2007[CrossRef][Medline] 7. Verweij J, Casali PG, Zalcberg J, et al: Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: Randomised trial. Lancet 364:1127-1134, 2004[CrossRef][Medline] 8. Demetri GD, von Mehren M, Blanke CD, et al: Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472-480, 2002 9. van Oosterom AT, Judson I, Verweij J, et al: Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: A phase I study. Lancet 358:1421-1423, 2001[CrossRef][Medline] 10. Druker BJ, Talpaz M, Resta DJ, et al: Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031-1037, 2001 11. Druker BJ, Tamura S, Buchdunger E, et al: Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 2:561-566, 1996[CrossRef][Medline] 12. Fecher LA, Cummings SD, Keefe MJ, et al: Toward a molecular classification of melanoma. J Clin Oncol 25:1606-1620, 2007 13. Eisen T, Ahmad T, Flaherty KT, et al: Sorafenib in advanced melanoma: A phase II randomised discontinuation trial analysis. Br J Cancer 95:581-586, 2006[CrossRef][Medline] 14. Wyman K, Atkins MB, Prieto V, et al: Multicenter phase II trial of high-dose imatinib mesylate in metastatic melanoma: Significant toxicity with no clinical efficacy. Cancer 106:2005-2011, 2006[CrossRef][Medline] 15. Eton O, Billings L, Kim K, et al: Phase II trial of imatinib mesylate (STI-571) in metastatic melanoma (MM). J Clin Oncol 22:717s, 2004 (suppl; abstr 7528) 16. Ugurel S, Hildenbrand R, Zimpfer A, et al: Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer 92:1398-1405, 2005[CrossRef][Medline] 17. Heinrich MC, Corless CL, Demetri GD, et al: Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342-4349, 2003 18. Willmore-Payne C, Holden JA, Tripp S, et al: Human malignant melanoma: Detection of BRAF- and c-kit-activating mutations by high-resolution amplicon melting analysis. Hum Pathol 36:486-493, 2005[CrossRef][Medline] 19. Willmore-Payne C, Holden JA, Hirschowitz S, et al: BRAF and c-kit gene copy number in mutation-positive malignant melanoma. Hum Pathol 37:520-527, 2006[CrossRef][Medline] 20. Chin L, Garraway LA, Fisher DE: Malignant melanoma: Genetics and therapeutics in the genomic era. Genes Dev 20:2149-2182, 2006
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
