title: [A case of metastatic gastrointestinal stromal tumor developing a resistance to STI571 (imatinib mesylate)].
abstract: Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors of the gastrointestinal tract characterized by the expression of a receptor that activates tyrosine kinase called c-kit. Since malignant GISTs are resistant to conventional radiation therapy and chemotherapy, recurrent or malignant GIST has an extremely poor prognosis even after surgical resection. The development of a tyrosine kinase inhibitor, STI571 (imatinib mesylate, Glivec, Gleevec), which inhibits the BCR-ABL, PDGF-R alpha and c-kit receptors, has changed the management of unresectable malignant GIST and has improved the survival of patients with metastatic disease. We report a patient with GIST and diffused peritoneal metastases, whose tumor initially responded to STI571 and eventually became resistant. A 45-year-old woman underwent partial jejunostomy on September 3, 1998, under a diagnosis of submucosal tumor of the jejunum. Pathological examination of the primary tumor revealed a strong c-kit expression and GIST was diagnosed. The patient underwent an excision of peritoneal recurrences on October 31, 2000; April 17, 2001; and August 28, 2001. A treatment with STI571 (400 mg/day) was initiated on October 15, 2001, and she was free from peritoneal masses for 8 months after the fourth operation. However, the patient herself suspended the STI571 therapy for one month and multiple peritoneal metastases developed. Although the treatment with STI571 was restarted at 400 mg/day, the peritoneal masses did not respond this time. She died of liver, lung, and peritoneal metastases after the seventh cytoreductive operation on February 11, 2004. Several mechanisms of the resistance to STI571 have been identified. Amplification or an overexpression of KIT has been proposed to be involved in the resistance development. Several mutations of KIT were also correlated with the clinical outcome. Her tumors showed mutations in exons 9 or 11 of KIT, which had longer event-free and overall survival times than those tumors that had mutations of exons 13 or 17. In this case, an exon 11 mutation of KIT was initially noted. After the interruption of the treatment, an additional point mutation arose in exon 13 that caused a resistance to STI571. Currently STI571 is the first-line therapy for non-resectable GISTs, but a single-agent therapy often leads to tumor resistance. It is our hope that we will be able to design an alternative treatment to overcome such resistance.
authors.affiliation: Dept. of Surgery, Osaka National Hospital.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Miyake
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Takeda
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Hasuike
authors.forename: Masaki
authors.initials: M
authors.lastname: Kashiwazaki
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Mishima
authors.forename: Masakazu
authors.initials: M
authors.lastname: Ikenaga
authors.forename: Masayuki
authors.initials: M
authors.lastname: Mano
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Takada
authors.forename: Seiichi
authors.initials: S
authors.lastname: Hirota
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Tsujinaka
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D005091:Exons / Q000235:genetics; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D008875:Middle Aged; D010534:Peritoneal Neoplasms / Q000556:secondary; D010879:Piperazines / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases