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)-selec tive ligand (a rexinoid), called LGD1069, is highly efficacious in both the chemoprevention and the chemotherapy for N-nitrosomethylurea-induced rat m ammary carcinomas. To evaluate a possible role for rexinoids in breast canc er therapy further, me have designed and characterized a novel carcinogen-i nduced model to mimic the clinical situation in which the tumors of patient s 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 respon d completely to the drug. Once the failure of tamoxifen therapy had been es tablished, LGD1069 was added to the treatment regimen, and the tumors in th ese animals were compared with tumors in a group of animals that remained o n 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 pri mary tumors compared with a rate of 33% (95% CI = 11%-56%) in primary tumor s treated with tamoxifen alone, a statistically significant difference (two -sided P<.0001). In addition, the LGD1069 and tamoxifen combination was ass ociated with a statistically significant decrease in total tumor burden (tw o-sided P =.03), In a second study, tumors that failed to respond to tamoxi fen therapy exhibited a 51% (95% CI = 34%-71%) objective response rate when treated with LGD1069 alone for 6 weeks after tamoxifen therapy was withdra wn. Conclusion: 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 t umors that may have developed resistance to antihormonal therapies such as tamoxifen.