title: Tamoxifen may prevent both ER+ and ER- breast cancers and select for ER- carcinogenesis: an alternative hypothesis.
abstract: BACKGROUND
  Breast Cancer Prevention Trial (BCPT) and Multiple Outcomes of Raloxifene (MORE) data have been interpreted to indicate that tamoxifen reduces the risk of ER+ but not ER- breast carcinogenesis. We explored whether these data also support an alternative hypothesis, that tamoxifen influences the natural history of both ER+ and ER- cancers, that it may be equally effective in abrogating or delaying ER- and ER+ carcinogenesis, and place selection pressure, in some cases, for the outgrowth of ER- cancers.
  
  
  METHODS
  BCPT and MORE data were used to investigate whether: first, tamoxifen could reduce equally the emergence of ER- and ER+ tumors; and second, tamoxifen could select a fraction of emerging ER+ cancers and promote their transformation to ER- cancers. Assuming that some proportion, Z, of ER+ tumors becomes ER- after tamoxifen exposure and that the risk reduction for both ER- and ER+ tumors is equal, we solved for both the transformation rate and the risk reduction rate.
  
  
  RESULTS
  If tamoxifen equally reduces the incidence of ER+ and ER- tumors by 60%, the BCPT results are achieved with a transformation of approximately Z = 20% of ER+ to ER- tumors. Validation with MORE data using an equal risk reduction of 60% associated with tamoxifen produces an almost identical transformation rate Z of 23%.
  
  
  CONCLUSIONS
  Data support an alternative hypothesis that tamoxifen may promote ER- carcinogenesis from a precursor lesion that would otherwise have developed as ER+ without tamoxifen selection.
authors.affiliation: Deptartment of Surgery, University of California San Francisco Medical Center, San Francisco, CA, USA. laura.esserman@ucsfmedctr.org
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Esserman
authors.forename: Elissa M
authors.initials: EM
authors.lastname: Ozanne
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
authors.forename: Joyce M
authors.initials: JM
authors.lastname: Slingerland
mesh_terms: D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D018890:Chemoprevention; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D016609:Neoplasms, Second Primary / Q000139:chemically induced / Q000503:physiopathology; D010052:Ovariectomy; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000502:physiology*; D012307:Risk Factors; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D011960:Receptors, Estrogen; D013629:Tamoxifen