Therapeutic strategies using the aromatase inhibitor letrozole and tamoxifen in a breast cancer model.
BACKGROUND
The antiestrogen tamoxifen has potent activity against estrogen receptor-positive breast cancer, but two nonsteroidal aromatase inhibitors, letrozole and anastrozole, show considerable advantages over tamoxifen with respect to patient survival and tolerability. To determine the optimal way to use letrozole and tamoxifen, we studied their effects on a breast tumor xenograft model, MCF-7Ca, that is responsive to both antiestrogens and aromatase inhibitors.


METHODS
Female ovariectomized BALB/c athymic nude mice carrying xenograft tumors were treated daily subcutaneously with one of the following first-line therapies for varying durations: no drug (control), tamoxifen (100 microg/day) alone, letrozole (10 microg/day) alone, both drugs at the same time, or alternating 4-week courses of each drug (beginning with a course of tamoxifen or beginning with a course of letrozole). Tumor volumes and weights were estimated using linear mixed-effects models. The time to tumor doubling was calculated, and tumor weights in the treatment groups were compared, with adjustments for multiple comparisons being made with either Tukey's or Dunnett's procedure. Second-line therapies (with tamoxifen, letrozole, or fulvestrant) were initiated when tumors doubled in size under first-line therapies. All statistical tests were two-sided.


RESULTS
The times for doubling of tumor volume were as follows: control, 3-4 weeks; tamoxifen alone, 16 weeks; tamoxifen alternating with letrozole, 17-18 weeks; tamoxifen plus letrozole, 18 weeks; letrozole alternating with tamoxifen, 22 weeks; letrozole alone, 34 weeks. First-line treatment with letrozole was superior to treatment with tamoxifen alone or with the two drugs combined (at week 16, both P<.001). Alternating tamoxifen and letrozole and alternating letrozole and tamoxifen were also not as effective as letrozole alone (at week 16, P =.002 and P<.001, respectively). Tumors progressing on tamoxifen remained sensitive to second-line therapy with letrozole compared with those remaining on tamoxifen at the end of treatment (week 28, P<.001), whereas tumors progressing on letrozole were unaffected by second-line treatment with the antiestrogens tamoxifen or fulvestrant.


CONCLUSIONS
First-line letrozole therapy extends time for tumor progression in this model relative to the other treatment regimens tested. However, further studies are needed to determine the most effective second-line therapy for tumors that progress on letrozole.
Long
Brian J
BJ
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Health Sciences Facility, Baltimore, MD 21201, USA.
Jelovac
Danijela
D
Handratta
Venkatesh
V
Thiantanawat
Apinya
A
MacPherson
Nicol
N
Ragaz
Joseph
J
Goloubeva
Olga G
OG
Brodie
Angela M
AM
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D047072:Aromatase Inhibitors; D001943:Breast Neoplasms / Q000188:drug therapy*; D004195:Disease Models, Animal; D018450:Disease Progression; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000097:blood; D020847:Estrogen Receptor Modulators / Q000008:administration & dosage* / Q000097:blood; D005260:Female; D006801:Humans; D000077289:Letrozole; D016014:Linear Models; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D009570:Nitriles / Q000008:administration & dosage* / Q000097:blood; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D013629:Tamoxifen / Q000008:administration & dosage* / Q000097:blood; D014183:Transplantation, Heterologous; D014230:Triazoles / Q000008:administration & dosage* / Q000097:blood; D014599:Uterus / Q000187:drug effects
D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D020847:Estrogen Receptor Modulators; D009570:Nitriles; D014230:Triazoles; D013629:Tamoxifen; D000077289:Letrozole