Tipifarnib plus tamoxifen in tamoxifen-resistant metastatic breast cancer: a negative phase II and screening of potential therapeutic markers by proteomic analysis.
OBJECTIVE
Tipifarnib, a farnesyltransferase inhibitor, has antitumor activity in heavily pretreated metastatic breast cancer patients. Preclinical data suggest that FTIs could restore tamoxifen responsiveness in tamoxifen-resistant disease. Thus, combining FTIs and tamoxifen may be a promising clinical approach after relapse or progression on tamoxifen.


METHODS
Postmenopausal patients with measurable estrogen receptor- and/or progesterone receptor-expressing metastatic breast cancers were enrolled. Only patients with disease progression on tamoxifen were eligible, but there was no limitation regarding prior chemotherapy or hormone therapy regimens. Patients were immediately treated with 300 mg (n = 12) or 200 mg (n = 10) tipifarnib twice daily for 21 of 28-day cycles plus tamoxifen once daily. Serum was collected at baseline and after 8 weeks of treatment to enable proteomic comparison and identify possible predictive response markers.


RESULTS
Twenty patients were enrolled and evaluated for efficacy: one patient had an objective response (liver metastasis) and nine had stable disease after 6 months for a clinical benefit rate of 50%; median duration of benefit was 10.3 (range, 7.4-20.2) months. The proteomic analysis by SELDI-TOF and LTQ-FT-Orbitrap identified a known peptide of fibrinogen alpha, the intensity of which was significantly increased in patients with progression compared with patients who benefited from the combined treatment after 8 weeks.


CONCLUSIONS
Because the primary end point of efficacy (three objective responses) was not achieved, the study is negative. Nevertheless, the identified peptide could be of interest in discriminating, at 8 weeks of treatment, responders from nonresponders.
Dalenc
Florence
F
Institut Claudius Regaud, Université Paul Sabatier, Toulouse, France.
Doisneau-Sixou
Sophie F
SF
Allal
Ben C
BC
Marsili
Sabrina
S
Lauwers-Cances
Valérie
V
Chaoui
Karima
K
Schiltz
Odile
O
Monsarrat
Bernard
B
Filleron
Thomas
T
Renée
Nicole
N
Malissein
Emilie
E
Meunier
Elise
E
Favre
Gilles
G
Roché
Henri
H
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy; D019008:Drug Resistance, Neoplasm; D051231:Farnesyltranstransferase / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D017698:Postmenopause; D040081:Protein Array Analysis; D015363:Quinolones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013629:Tamoxifen / Q000008:administration & dosage*
D015363:Quinolones; D013629:Tamoxifen; D051231:Farnesyltranstransferase; C402769:tipifarnib