Efficacy and safety of imatinib mesylate (Gleevec®) and immunohistochemical expression of c-Kit and PDGFR-β in a Gynecologic Oncology Group Phase Il Trial in women with recurrent or persistent carcinosarcomas of the uterus

• Published in: Gynecologic oncology Vol. 117; no. 2; pp. 248 - 254
• Main Authors: Huh, Warner K., Sill, Michael W., Darcy, Kathleen M., Elias, Kevin M., Hoffman, James S., Boggess, John F., Alvarez, Ronald D., Long, Harry J., O'Malley, David M., Birrer, Michael J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2010
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Benzamides; c-Kit; Carcinosarcoma; Carcinosarcoma - drug therapy; Carcinosarcoma - metabolism; Disease-Free Survival; Female; Hematology, Oncology and Palliative Medicine; Humans; Imatinib; Imatinib Mesylate; Immunohistochemistry; Middle Aged; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - metabolism; Obstetrics and Gynecology; PDGFR; Piperazines - adverse effects; Piperazines - therapeutic use; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-kit - biosynthesis; Pyrimidines - adverse effects; Pyrimidines - therapeutic use; Receptor, Platelet-Derived Growth Factor beta - biosynthesis; Treatment Outcome; Uterine Neoplasms - drug therapy; Uterine Neoplasms - metabolism; Uterus; PDGFR; Imatinib; c-Kit; Uterus; Carcinosarcoma
• ISSN: 0090-8258; 1095-6859; 1095-6859
• DOI: 10.1016/j.ygyno.2010.01.002

This multi-institutional phase II trial assessed the activity and toxicity of imatinib mesylate and explored c-Kit and platelet-derived growth factor receptor (PDGFR)-β in recurrent or persistent uterine carcinosarcoma. Women with measurable uterine carcinosarcoma, who had a performance status of 0, 1, or 2 and had received up to two prior treatment regimens, were eligible and treated with a 600-mg daily oral dose of imatinib mesylate until disease progression or unacceptable toxicity. Endpoints included progression-free survival (PFS) ≥ 6 months, overall toxicity, PFS, overall survival (OS), and response. c-Kit and PDGFR-β were evaluated by immunohistochemistry in archival tumor. Twenty-six women were enrolled, 23 were eligible/evaluable, 1 was ineligible (wrong primary), and 2 were inevaluable (never treated). One subject had a PFS time ≥ 6 months, yielding the only patient with stable disease. All other patients had progressive disease ( n = 17) or were inevaluable for tumor response ( n = 5). Adverse events included grade 4 hypocalcemia ( n = 1) and grade 3 fatigue, dehydration and anorexia, genitourinary/renal, lymphatic, metabolic, and ocular toxicity ( n = 1 each, 4%). Positive expression of c-Kit or PDGFR-β was observed in 88% (14/16) or 40% (6/15) and in 56% (9/16) or 73% (11/15) of cases in the sarcoma and carcinoma component of the tumor, respectively. Expression of c-Kit in the carcinoma component appeared to be associated with worse OS. No other associations were notable. Imatinib mesylate was generally well tolerated but had minimal activity as a single agent in unscreened patients. The potential association between carcinomatous c-Kit and OS requires validation.