Effect of the retinoid X receptor-selective ligand LGD1069 on mammary carcinoma after tamoxifen failure.
BACKGROUND
We have previously shown that a retinoid X receptor (RXR)-selective ligand (a rexinoid), called LGD1069, is highly efficacious in both the chemoprevention and the chemotherapy for N-nitrosomethylurea-induced rat mammary carcinomas. To evaluate a possible role for rexinoids in breast cancer therapy further, we have designed and characterized a novel carcinogen-induced model to mimic the clinical situation in which the tumors of patients stop responding to tamoxifen therapy and develop resistance to this drug.


METHODS
Rats with experimentally induced mammary tumors were treated with tamoxifen to select a population with primary tumors that failed to respond completely to the drug. Once the failure of tamoxifen therapy had been established, LGD1069 was added to the treatment regimen, and the tumors in these animals were compared with tumors in a group of animals that remained on tamoxifen alone.


RESULTS
LGD1069 in combination with tamoxifen for up to 20 weeks yielded an overall objective response rate of 94% (95% confidence interval [CI] = 86%-100%) (includes complete and partial responses) in primary tumors compared with a rate of 33% (95% CI = 11%-56%) in primary tumors treated with tamoxifen alone, a statistically significant difference (two-sided P<.0001). In addition, the LGD1069 and tamoxifen combination was associated with a statistically significant decrease in total tumor burden (two-sided P =.03). In a second study, tumors that failed to respond to tamoxifen therapy exhibited a 51% (95% CI = 34%-71%) objective response rate when treated with LGD1069 alone for 6 weeks after tamoxifen therapy was withdrawn.


CONCLUSIONS
We have demonstrated that the RXR-selective ligand LGD1069 in combination with tamoxifen is a highly efficacious therapeutic agent for tumors that fail to respond completely to tamoxifen. This finding suggests that rexinoid therapy offers a novel approach to the treatment of breast tumors that may have developed resistance to antihormonal therapies such as tamoxifen.
Bischoff
E D
ED
Department of Retinoid Research, Ligand Pharmaceuticals Inc., San Diego, CA 92121, USA.
Heyman
R A
RA
Lamph
W W
WW
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000077610:Bexarotene; D002273:Carcinogens; D018450:Disease Progression; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D008770:Methylnitrosourea; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000627:therapeutic use*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D017211:Treatment Failure; D016896:Treatment Outcome
D016588:Anticarcinogenic Agents; D018931:Antineoplastic Agents, Hormonal; D002273:Carcinogens; D013764:Tetrahydronaphthalenes; D013629:Tamoxifen; D008770:Methylnitrosourea; D000077610:Bexarotene