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

J Natl Cancer Inst. 2014 Sep 30;106(11):dju296. doi: 10.1093/jnci/dju296. Print 2014 Nov.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 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


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