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: V Craig Jordan
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 106 Issue 11 (Nov 2014) ISSN: 1460-2105 [Electronic] United States
• PMID: 25269699 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].

Chemical References

• Antineoplastic Agents, Hormonal
• Estrogens
• Receptors, Estrogen
• Tamoxifen
• Cytochrome P-450 CYP2D6

Topics

• Adult
• Aged
• Antineoplastic Agents, Hormonal (administration & dosage, pharmacology)
• Apoptosis
• Breast Neoplasms (drug therapy, epidemiology, mortality)
• Chemotherapy, Adjuvant (methods)
• Cytochrome P-450 CYP2D6 (metabolism)
• Estrogens (administration & dosage, metabolism)
• Female
• Humans
• Menopause
• Middle Aged
• Receptors, Estrogen (metabolism)
• Signal Transduction (drug effects)
• Tamoxifen (administration & dosage, pharmacology)
• Time Factors