Uterine carcinosarcoma/malignant mixed Müllerian tumor incidence is increased in women with breast cancer, but independent of hormone therapy

Uterine carcinosarcoma/malignant mixed Mullerian tumor (UC/MMMT) is an uncommon and aggressive gynecological malignancy with poor prognosis. Tumors arise from monoclonal carcinoma cells derived from embryonal mesoderm, which exhibit sarcomatous metaplasia. UC/MMMT usually occurs in postmenopausal women and accounts for 2%-5% of all uterine malignancies [1,2]. The five-year survival rates are particularly poor (21%-39%). Several case reports and case series describe UC/MMMT occurring after tamoxifen therapy for breast cancer [3,4,5,6,7,8,9]. Retrospective studies suggest that the increased incidence of these high-risk malignancies is greater than the observed increase in incidence of endometrial tumors generally following tamoxifen therapy [10,11,12,13], though the number of subjects with UC/MMMT in any of these studies is small. The increase in uterine cancers generally following tamoxifen therapy is thought to be driven by the estrogen receptor alpha (ERα) through a positive trophic effect on the uterine corpus. Although tamoxifen binds ERβ with equal affinity, there is no observed activation of this receptor [14,15]. Whether ER activation exerts any positive effect on UC/MMMTs remains equivocal. Other studies suggest that tamoxifen may upregulate expression of the HER2/neu oncogene in UC/MMMT cells [16,17], although any potential effect on the behavior of these malignancies is far from clear. As tamoxifen metabolites can covalently bind DNA, principally forming (E)- and (Z)-α-(deoxyguanosin-N2-yl)-4-hydroxytamoxifen adducts [18], the possibility that tamoxifen therapy is inherently carcinogenic has also been considered. However, tamoxifen-DNA adduct formation in uterine tissues following oral administration occurs at levels too low to be consistent with this being the mechanism driving such endometrial cancers [19]. We identified two unrelated women who developed UC/MMMT as a second primary malignancy following BRCA1-associated breast cancer. Neither of these women received hormone therapy, as their tumors were histologically determined to be unresponsive to hormone therapy (i.e., ER-/progesterone receptor [PR]-). Patient 1 had BRCA1 c.5503C>T (p.Arg1835*), developed breast cancer at 36 years, which was managed with lumpectomy and local radiotherapy, and subsequently developed UC/MMMT at 48 years. Patient 2 had BRCA1 c.2560_2561dupGC (p.Gln855fs), developed breast cancer at 34 years, again treated with lumpectomy and local radiotherapy, and was found to have UC/MMMT at 56 years. Although BRCA1 mutation carriers are at increased risk of developing endometrial cancers compared to the general population, most of this risk is attributable to tamoxifen use [20]. It has also been suggested that BRCA1 mutations may predispose carriers to uterine papillary serous carcinoma specifically [21,22]. However, UC/MMMT is not recognized as part of the BRCA1 phenotype. Prompted by this unexpected finding, we conducted a retrospective population-based study to establish whether an association exists between breast cancer and UC/MMMT generally and whether a breast tumor being ER-/PR- has any bearing on this.