title: Linking estrogen-induced apoptosis with decreases in mortality following long-term adjuvant tamoxifen therapy.
abstract: The impressive first results of the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) and the adjuvant Tamoxifen To offer more (aTTom) trials both demonstrate that 10 years of tamoxifen is superior to five years of treatment. Tamoxifen is a nonsteroidal antiestrogen that blocks estrogen-stimulated tumor growth. Paradoxically, mortality decreases dramatically only in the decade after long-term tamoxifen is stopped. It is proposed that the evolution and clonal selection of micrometastases that acquire tamoxifen resistance now become increasingly vulnerable to endogenous estrogen-induced apoptosis. Laboratory and clinical studies confirm the concept, and supporting clinical evidence from the estrogen-alone trial in the Women's Health Initiative (WHI), demonstrate that long-term estrogen-deprived women given exogenous physiologic estrogen have a decreased incidence of breast cancer and decreased mortality. It is proposed that a natural process of apoptosis is recruited to execute the long-term survival benefit of stopping ten years of adjuvant tamoxifen, but only after clonal selection of vulnerable breast cancer cells in an estrogen-deprived environment.
authors.affiliation: Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC. vcj2@georgetown.edu.
authors.forename: V Craig
authors.initials: VC
authors.lastname: Jordan
mesh_terms: D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage* / Q000494:pharmacology*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000453:epidemiology / Q000401:mortality*; D017024:Chemotherapy, Adjuvant / Q000379:methods; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D004967:Estrogens / Q000008:administration & dosage* / Q000378:metabolism*; D005260:Female; D006801:Humans; D008593:Menopause; D008875:Middle Aged; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000008:administration & dosage* / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004967:Estrogens; D011960:Receptors, Estrogen; D013629:Tamoxifen; D019389:Cytochrome P-450 CYP2D6