Molecular genetic characterization of tamoxifen-associated endometrial cancer

OBJECTIVES: The non-steroidal, selective estrogen receptor modulator tamoxifen is currently the most extensively used hormonal agent for the prevention and treatment of estrogen receptor-positive breast cancer. Epidemiologic studies and clinical trials have shown an increased risk of endometrial cancer with tamoxifen exposure; however, few studies have examined these tumors on a molecular level. We sought to elucidate the molecular genetic alterations found in tamoxifen-associated endometrial cancer. METHODS: Twenty-nine breast cancer patients with a history of tamoxifen use who subsequently developed endometrial cancer were retrospectively identified and matched for endometrial histologic subtype and grade to 29 endometrial cancers from breast cancer patients never exposed to tamoxifen. Endometrial tumor tissue was microdissected and genomic DNA extracted for each case. Direct DNA sequencing of the most commonly mutated genes in sporadic endometrial cancer, PTEN, K-RAS, TP53, and CTNNB1, was performed in addition to microsatellite instability (MI) studies. Fisher's Exact Test was utilized for statistical analyses. RESULTS: Of 29 tamoxifen-associated cancers, 10 (34.5%) contained PTEN mutations compared to 13 (44.8%) of the non-tamoxifen-associated cancers (P = 0.59). All PTEN mutations were found in tumors with endometrioid histology, reflecting what is seen in sporadic endometrial cancers. Mutations of K-RAS, TP53, and microsatellite instability were present in similar frequencies between the two breast cancer groups, and moreover, these were similar to mutational frequencies found in sporadic endometrial cancer. CONCLUSION: Tamoxifen and non-tamoxifen-associated endometrial carcinomas arising in women with breast cancer contain similar genetic alterations to those of sporadic endometrial carcinomas.