title: Which patients benefit most from adjuvant aromatase inhibitors? Results using a composite measure of prognostic risk in the BIG 1-98 randomized trial.
abstract: BACKGROUND
  On average, aromatase inhibitors are better than tamoxifen when used as initial or sequential therapy for postmenopausal women with endocrine-responsive early breast cancer. Because there may be contraindications to their use based on side-effects or cost, we investigated subgroups in which aromatase inhibitors may be more or less important.
  
  
  METHODS
  Breast International Group 1-98 trial randomized 6182 women among four groups comparing letrozole and tamoxifen with sequences of each agent; 5177 (84%) had centrally confirmed estrogen receptor (ER) positivity. We assessed whether centrally determined ER, progesterone receptor (PgR), human epidermal growth factor receptor 2, and Ki-67 labeling index, alone or in combination with other prognostic features, predicted the magnitude of letrozole effectiveness compared with either sequence or tamoxifen monotherapy.
  
  
  RESULTS
  Individually, none of the markers significantly predicted differential treatment effects. Subpopulation treatment effect pattern plot analysis of a composite measure of prognostic risk revealed three patterns. Estimated 5-year disease-free survival for letrozole monotherapy, letrozole→tamoxifen, tamoxifen→letrozole, and tamoxifen monotherapy were 96%, 94%, 93%, and 94%, respectively, for patients at lowest risk; 90%, 91%, 93%, and 86%, respectively, for patients at intermediate risk; and 80%, 76%, 74%, and 69%, respectively, for patients at highest risk.
  
  
  CONCLUSIONS
  A composite measure of risk informs treatment selection better than individual biomarkers and supports the choice of 5 years of letrozole for patients at highest risk for recurrence.
authors.affiliation: International Breast Cancer Study Group Central Pathology Office, Division of Pathology and Laboratory Medicine, European Institute of Oncology, University of Milan, Milan, Italy. giuseppe.viale@ieo.it
authors.forename: G
authors.initials: G
authors.lastname: Viale
authors.forename: M M
authors.initials: MM
authors.lastname: Regan
authors.forename: P
authors.initials: P
authors.lastname: Dell'Orto
authors.forename: M G
authors.initials: MG
authors.lastname: Mastropasqua
authors.forename: E
authors.initials: E
authors.lastname: Maiorano
authors.forename: B B
authors.initials: BB
authors.lastname: Rasmussen
authors.forename: G
authors.initials: G
authors.lastname: MacGrogan
authors.forename: J F
authors.initials: JF
authors.lastname: Forbes
authors.forename: R J
authors.initials: RJ
authors.lastname: Paridaens
authors.forename: M
authors.initials: M
authors.lastname: Colleoni
authors.forename: I
authors.initials: I
authors.lastname: Láng
authors.forename: B
authors.initials: B
authors.lastname: Thürlimann
authors.forename: H
authors.initials: H
authors.lastname: Mouridsen
authors.forename: L
authors.initials: L
authors.lastname: Mauriac
authors.forename: R D
authors.initials: RD
authors.lastname: Gelber
authors.forename: K N
authors.initials: KN
authors.lastname: Price
authors.forename: A
authors.initials: A
authors.lastname: Goldhirsch
authors.forename: B A
authors.initials: BA
authors.lastname: Gusterson
authors.forename: A S
authors.initials: AS
authors.lastname: Coates
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D047072:Aromatase Inhibitors / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000096:biosynthesis; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis; D000077289:Letrozole; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage; D011379:Prognosis; D011960:Receptors, Estrogen / Q000096:biosynthesis; D011980:Receptors, Progesterone / Q000096:biosynthesis; D013629:Tamoxifen / Q000008:administration & dosage; D014230:Triazoles / Q000008:administration & dosage
chemical_list: D047072:Aromatase Inhibitors; D019394:Ki-67 Antigen; D009570:Nitriles; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D014230:Triazoles; D013629:Tamoxifen; D000077289:Letrozole; D066246:ErbB Receptors