title: The outcome and predictive factors of sunitinib therapy in advanced gastrointestinal stromal tumors (GIST) after imatinib failure - one institution study.
abstract: BACKGROUND
  Gastrointestinal stromal tumors (GIST) mutational status is recognized factor related to the results of tyrosine kinase inhibitors therapy such as imatinib (IM) or sunitinib (SU). Arterial hypertension (AH) is common adverse event related to SU, reported as predictive factor in renal cell carcinoma. The aim of the study was to analyze the outcomes and factors predicting results of SU therapy in inoperable/metastatic CD117(+) GIST patients after IM failure.
  
  
  METHODS
  We identified 137 consecutive patients with advanced inoperable/metastatic GIST treated in one center with SU (2nd line treatment). Median follow-up time was 23 months. Additionally, in 39 patients there were analyzed selected constitutive single nucleotide polymorphisms (SNPs) of VEGFA and VEGFR2 genes.
  
  
  RESULTS
  One year progression-free survival (PFS; calculated from the start of SU) rate was 42% and median PFS was 43 weeks. The estimated overall survival (OS, calculated both from start of SU or IM) was 74 weeks and 51 months, respectively. One-year PFS was 65% (median 74 weeks) in 55 patients with AH vs. 22% (median 17 weeks) in patients without AH. Patients with primary tumors carrying mutations in KIT exon 9 or wild-type had substantially better 1-year PFS (68% and 57%; median 65.5 and 50.5 weeks, respectively) than patients having tumors with KIT exon 11 or PDGFRA mutations (34% and 15%; median 36.8 and 9 weeks, respectively). We identified two independent factors with significant impact on PFS and OS in univariate and multivariate analysis: primary tumor genotype and presence of AH. The most common adverse events during therapy were: fatigue, AH, hypothyroidism, hand and foot syndrome, mucositis, skin reactions, dyspepsia, and diarrhea. Two deaths were assessed as related to tumor rupture caused by reaction to SU therapy. The presence of C-allele in rs833061 and the T-allele in rs3025039 polymorphism of VEGFA were associated with significantly higher risk of hypothyroidism (OR: 10.0 p = 0.041 and OR: 10.5; p = 0.015, respectively).
  
  
  CONCLUSIONS
  We confirmed that many advanced GIST patients benefit from SU therapy with OS > 1.5 year. Primary tumor KIT/PDGFRA genotype and SU-induced AH, as surrogate of its antiangiogenic activity are two independent factors influencing both PFS and OS.
authors.affiliation: Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland. rutkowskip@coi.waw.pl
authors.forename: Piotr
authors.initials: P
authors.lastname: Rutkowski
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Bylina
authors.forename: Anna
authors.initials: A
authors.lastname: Klimczak
authors.forename: Tomasz
authors.initials: T
authors.lastname: Switaj
authors.forename: Sławomir
authors.initials: S
authors.lastname: Falkowski
authors.forename: Jacek
authors.initials: J
authors.lastname: Kroc
authors.forename: Iwona
authors.initials: I
authors.lastname: Lugowska
authors.forename: Magdalena
authors.initials: M
authors.lastname: Brzeskwiniewicz
authors.forename: Wojciech
authors.initials: W
authors.lastname: Melerowicz
authors.forename: Czesław
authors.initials: C
authors.lastname: Osuch
authors.forename: Ewa
authors.initials: E
authors.lastname: Mierzejewska
authors.forename: Kacper
authors.initials: K
authors.lastname: Wasielewski
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Woźniak
authors.forename: Urszula
authors.initials: U
authors.lastname: Grzesiakowska
authors.forename: Zbigniew I
authors.initials: ZI
authors.lastname: Nowecki
authors.forename: Janusz A
authors.initials: JA
authors.lastname: Siedlecki
authors.forename: Janusz
authors.initials: J
authors.lastname: Limon
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D018572:Disease-Free Survival; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010879:Piperazines / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use*; D000077210:Sunitinib; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D007211:Indoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068877:Imatinib Mesylate; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077210:Sunitinib