The non-steroidal, selective estrogen receptor modulator tamoxifen is current ly the most extensively used hormonal agent for the prevention and treatment of estrogen receptor-positive breast cancer. Epidemiologic stu...The non-steroidal, selective estrogen receptor modulator tamoxifen is current ly the most extensively used hormonal agent for the prevention and treatment of estrogen receptor-positive breast cancer. Epidemiologic studies and clinical tr ials 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 e ndometrial cancer. Twenty-nine breast cancer patients with a history of tamoxif en use who subsequently developed endometrial cancer were retrospectively identi fied and matched for endometrial histologic subtype and grade to 29 endometrial cancers from breast cancer patients never exposed to tamoxifen. Endometrial tumo r tissue was microdissected and genomic DNA extracted for each case. Direct DNA sequencing of the most commonly mutated genes in sporadic endometrial cancer, PT EN, K- RAS, TP53, and CTNNB1, was performed in addition to microsatellite instability (MI) studies. Fisher’s Exact Test was utilized for statistical analyses. 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 muta tions were found in tumors with endometrioid histology, reflecting what is seen in sporadic endometrial cancers. Mutations of K-RAS, TP53, and microsatellite i nstability were present in similar frequencies between the two breast cancer gro ups, and moreover, these were similar to mutational frequencies found in sporadi c endometrial cancer. Tamoxifen and non-tamoxifen-associated endometrial carci nomas arising in women with breast cancer contain similar genetic alterations to those of sporadic endometrial carcinomas.展开更多
文摘The non-steroidal, selective estrogen receptor modulator tamoxifen is current ly the most extensively used hormonal agent for the prevention and treatment of estrogen receptor-positive breast cancer. Epidemiologic studies and clinical tr ials 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 e ndometrial cancer. Twenty-nine breast cancer patients with a history of tamoxif en use who subsequently developed endometrial cancer were retrospectively identi fied and matched for endometrial histologic subtype and grade to 29 endometrial cancers from breast cancer patients never exposed to tamoxifen. Endometrial tumo r tissue was microdissected and genomic DNA extracted for each case. Direct DNA sequencing of the most commonly mutated genes in sporadic endometrial cancer, PT EN, K- RAS, TP53, and CTNNB1, was performed in addition to microsatellite instability (MI) studies. Fisher’s Exact Test was utilized for statistical analyses. 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 muta tions were found in tumors with endometrioid histology, reflecting what is seen in sporadic endometrial cancers. Mutations of K-RAS, TP53, and microsatellite i nstability were present in similar frequencies between the two breast cancer gro ups, and moreover, these were similar to mutational frequencies found in sporadi c endometrial cancer. Tamoxifen and non-tamoxifen-associated endometrial carci nomas arising in women with breast cancer contain similar genetic alterations to those of sporadic endometrial carcinomas.
