title: Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status.
abstract: BACKGROUND
  The biological basis for the superior efficacy of neoadjuvant letrozole versus tamoxifen for postmenopausal women with estrogen receptor (ER)-positive locally advanced breast cancer was investigated by analyzing tumor proliferation and expression of estrogen-regulated genes before and after the initiation of therapy.
  
  
  METHODS
  Tumor samples were obtained at baseline and at the end of treatment from 185 patients participating in a double blind randomized Phase III study of neoadjuvant endocrine therapy. These paired specimens were simultaneously analyzed for Ki67, ER, progesterone receptor (PgR), trefoil factor 1 (PS2), HER1 (epidermal growth factor receptor), and HER2 (ErbB2 or neu) by semiquantitative immunohistochemistry.
  
  
  RESULTS
  The treatment-induced reduction in geometric mean Ki67 was significantly greater with letrozole (87%) than tamoxifen (75%; analysis of covariance P = 0.0009). Differences in the average Ki67 reduction were particularly marked for ER-positive tumors that overexpressed HER1 and/or HER2 (88 versus 45%, respectively; P = 0.0018). Twenty-three of 92 tumors (25%) on tamoxifen and 14 of 93 on letrozole (15%) showed a paradoxical increase in Ki67 with treatment, and the majority of these cases was HER1/2 negative. Letrozole, but not tamoxifen, significantly reduced expression of the estrogen-regulated proteins PgR and trefoil factor 1, regardless of HER1/2 status (P < 0.0001). ER down-regulation occurred with both agents, although levels decreased more with tamoxifen (P < 0.0001).
  
  
  CONCLUSIONS
  Letrozole inhibited tumor proliferation to a greater extent than tamoxifen. The molecular basis for this advantage appears complex but includes possible tamoxifen agonist effects on the cell cycle in both HER1/2+ and HER1/2- tumors. A pattern of continued proliferation despite appropriate down-regulation of PgR expression with estrogen deprivation or tamoxifen was also documented. This observation suggests the estrogenic regulation of proliferation and PgR expression may be dissociated in endocrine therapy resistant cells.
authors.affiliation: Duke University Comprehensive Cancer Center, Campus Box 8056, 660 South Euclid, Durham, NC 27710, USA. mellis@lm.wustl.edu
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
authors.forename: Andrew
authors.initials: A
authors.lastname: Coop
authors.forename: Baljit
authors.initials: B
authors.lastname: Singh
authors.forename: Yu
authors.initials: Y
authors.lastname: Tao
authors.forename: Antonio
authors.initials: A
authors.lastname: Llombart-Cussac
authors.forename: Fritz
authors.initials: F
authors.lastname: Jänicke
authors.forename: Louis
authors.initials: L
authors.lastname: Mauriac
authors.forename: Erhard
authors.initials: E
authors.lastname: Quebe-Fehling
authors.forename: Hilary A
authors.initials: HA
authors.lastname: Chaudri-Ross
authors.forename: Dean B
authors.initials: DB
authors.lastname: Evans
authors.forename: William R
authors.initials: WR
authors.lastname: Miller
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D004311:Double-Blind Method; D066246:ErbB Receptors / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis; D000077289:Letrozole; D020360:Neoadjuvant Therapy; D009570:Nitriles / Q000627:therapeutic use*; D014176:Protein Biosynthesis; D011506:Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D011960:Receptors, Estrogen / Q000096:biosynthesis; D011980:Receptors, Progesterone / Q000096:biosynthesis; D013629:Tamoxifen / Q000627:therapeutic use*; D000071163:Trefoil Factor-1; D014230:Triazoles / Q000627:therapeutic use*; D025521:Tumor Suppressor Proteins
chemical_list: D018931:Antineoplastic Agents, Hormonal; D066246:ErbB Receptors; D019394:Ki-67 Antigen; D000077289:Letrozole; D009570:Nitriles; D011506:Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen; D000071163:Trefoil Factor-1; D014230:Triazoles; D025521:Tumor Suppressor Proteins; C051838:TFF1 protein, human