Imatinib mesylate (Gleevec) in advanced breast cancer-expressing C-Kit or PDGFR-beta: clinical activity and biological correlations.
BACKGROUND
Novel molecular therapies for metastatic breast cancer (MBC) are necessary to improve the dismal prognosis of this condition. Imatinib mesylate (Gleevec) inhibits several protein tyrosine kinases, including platelet-derived growth factor receptor (PDGFR) and c-kit, which are preferentially expressed in tumor cells. We tested the activity of imatinib mesylate in MBC with overexpression of PDGFR or c-kit. Additionally, we sought to determine the biological correlates and immunomodulatory effects.


METHODS
Thirteen patients were treated with Imatinib administered orally at 400 mg p.o. b.i.d. (800 mg/day), until disease progression. All patients demonstrated PDGFR-beta overexpression and none showed c-kit expression.


RESULTS
No objective responses were observed among the 13 patients treated in an intention-to-treat analysis. All patients experienced disease progression, with a median time to progression of 1.2 months. Twelve patients have died, and the median overall survival was 7.7 months. No patient had a serious adverse event. Imatinib therapy had no effect on the plasma levels of the angiogenesis-related cytokines, vascular endothelial growth factor, PDGF, b-fibroblast growth factor, and E-selectin. Immune studies showed imatinib inhibits interferon-gamma production by TCR-activated CD4(+) T cells.


CONCLUSIONS
Imatinib as a single agent has no clinical activity in PDGFR-overexpressing MBC and has potential immunosuppressive effects.
Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. mcristof@mdanderson.org
M
M
Cristofanilli
P
P
Morandi
S
S
Krishnamurthy
J M
JM
Reuben
B-N
BN
Lee
D
D
Francis
D J
DJ
Booser
M C
MC
Green
B K
BK
Arun
L
L
Pusztai
A
A
Lopez
R
R
Islam
V
V
Valero
G N
GN
Hortobagyi
D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D018567:Breast Neoplasms, Male / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D007155:Immunologic Factors / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010879:Piperazines / Q000627:therapeutic use*; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis*; D011743:Pyrimidines / Q000627:therapeutic use*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000096:biosynthesis*
D000970:Antineoplastic Agents; D001549:Benzamides; D007155:Immunologic Factors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020797:Receptor, Platelet-Derived Growth Factor beta