Activity and safety of the antiestrogen EM-800, the orally active precursor of acolbifene, in tamoxifen-resistant breast cancer.
OBJECTIVE
To determine the efficacy and safety of EM-800 (SCH-57050), the precursor of acolbifene, a new, highly potent, orally active, pure antiestrogen in the mammary gland and endometrium, for the treatment of tamoxifen-resistant breast cancer.


METHODS
Forty-three post menopausal/ovariectomized women with breast cancer who had received tamoxifen, either for metastatic disease or as adjuvant to surgery for > or = 1 year, and had relapsed were treated in a prospective, multicenter, phase II study with EM-800 (20 mg/d [n = 21] or 40 mg/d [n = 22] orally). Results Thirty-seven patients had estrogen receptor (ER)-positive tumors (>10 fmol/mg; mean, 146 fmol/mg cytosolic protein), three patients had ER-negative/progesterone receptor-positive tumors, and three patients had undetermined ER status. The objective response rate to EM-800 was 12%, with one complete response and four partial responses. Ten patients (23%) had stable disease for > or = 3 months, and 7 patients (16%) had stable disease for > or = 6 months. With a median follow-up of 29 months, median duration of response was 8 months (range, 7 to 71+ months). Treatment with EM-800 was well tolerated. No significant adverse events related to the study drug were observed clinically or biochemically.


CONCLUSIONS
EM-800 produced responses in a significant proportion of patients with tamoxifen-resistant breast cancer, thus showing that this highly potent, selective estrogen receptor modulator, which lacks estrogenic activity in the mammary gland and endometrium, has incomplete cross-resistance with tamoxifen, thus suggesting additional benefits in the treatment of breast cancer.
Oncology and Molecular Endocrinology Research Center, Laval University Medical Center, 2705 Laurier Blvd, T-3-67, Quebec City, Quebec, G1V 4G2, Canada. fernand.labrie@crchul.ulaval.ca
Fernand
F
Labrie
Pierre
P
Champagne
Claude
C
Labrie
Jean
J
Roy
Jacques
J
Laverdière
Louise
L
Provencher
Martin
M
Potvin
Yvan
Y
Drolet
Michael
M
Pollak
Lawrence
L
Panasci
Bernard
B
L'Espérance
Jean
J
Dufresne
Jean
J
Latreille
Jean
J
Robert
Benoît
B
Samson
Jacques
J
Jolivet
Louise
L
Yelle
Lionel
L
Cusan
Pierre
P
Diamond
Bernard
B
Candas
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001578:Benzopyrans / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001682:Biological Availability; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002277:Carcinoma / Q000188:drug therapy* / Q000556:secondary*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D004965:Estrogen Antagonists / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D011355:Prodrugs; D011422:Propionates / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011446:Prospective Studies; D018570:Risk Assessment; D016019:Survival Analysis; D013629:Tamoxifen / Q000008:administration & dosage; D016896:Treatment Outcome
D001578:Benzopyrans; D004965:Estrogen Antagonists; D011355:Prodrugs; D011422:Propionates; D013629:Tamoxifen; C106945:EM 800