Linking estrogen-induced apoptosis with decreases in mortality following long-term adjuvant tamoxifen therapy

• Published in: JNCI : Journal of the National Cancer Institute Vol. 106; no. 11; p. dju296
• Main Author: Jordan, V Craig
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.11.2014
• Subjects: Adult; Aged; Antineoplastic Agents, Hormonal - administration & dosage; Antineoplastic Agents, Hormonal - pharmacology; Apoptosis; Breast Neoplasms - drug therapy; Breast Neoplasms - epidemiology; Breast Neoplasms - mortality; Chemotherapy, Adjuvant - methods; Cytochrome P-450 CYP2D6 - metabolism; Estrogens - administration & dosage; Estrogens - metabolism; Female; Humans; Menopause; Middle Aged; Receptors, Estrogen - metabolism; Signal Transduction - drug effects; Tamoxifen - administration & dosage; Tamoxifen - pharmacology; Time Factors
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/dju296

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.