Prognostic and predictive value of centrally reviewed Ki-67 labeling index in postmenopausal women with endocrine-responsive breast cancer: results from Breast International Group Trial 1-98 comparing adjuvant tamoxifen with letrozole.
OBJECTIVE
To evaluate the prognostic and predictive value of Ki-67 labeling index (LI) in a trial comparing letrozole (Let) with tamoxifen (Tam) as adjuvant therapy in postmenopausal women with early breast cancer.


METHODS
Breast International Group (BIG) trial 1-98 randomly assigned 8,010 patients to four treatment arms comparing Let and Tam with sequences of each agent. Of 4,922 patients randomly assigned to receive 5 years of monotherapy with either agent, 2,685 had primary tumor material available for central pathology assessment of Ki-67 LI by immunohistochemistry and had tumors confirmed to express estrogen receptors after central review. The prognostic and predictive value of centrally measured Ki-67 LI on disease-free survival (DFS) were assessed among these patients using proportional hazards modeling, with Ki-67 LI values dichotomized at the median value of 11%.


RESULTS
Higher values of Ki-67 LI were associated with adverse prognostic factors and with worse DFS (hazard ratio [HR; high:low] = 1.8; 95% CI, 1.4 to 2.3). The magnitude of the treatment benefit for Let versus Tam was greater among patients with high tumor Ki-67 LI (HR [Let:Tam] = 0.53; 95% CI, 0.39 to 0.72) than among patients with low tumor Ki-67 LI (HR [Let:Tam] = 0.81; 95% CI, 0.57 to 1.15; interaction P = .09).


CONCLUSIONS
Ki-67 LI is confirmed as a prognostic factor in this study. High Ki-67 LI levels may identify a patient group that particularly benefits from initial Let adjuvant therapy.
Viale
Giuseppe
G
Division of Pathology and Laboratory Medicine, European Institute of Oncology, University of Milan, Milan, Italy. giuseppe.viale@ieo.it
Giobbie-Hurder
Anita
A
Regan
Meredith M
MM
Coates
Alan S
AS
Mastropasqua
Mauro G
MG
Dell'Orto
Patrizia
P
Maiorano
Eugenio
E
MacGrogan
Gaëtan
G
Braye
Stephen G
SG
Ohlschlegel
Christian
C
Neven
Patrick
P
Orosz
Zsolt
Z
Olszewski
Wojciech P
WP
Knox
Fiona
F
Thürlimann
Beat
B
Price
Karen N
KN
Castiglione-Gertsch
Monica
M
Gelber
Richard D
RD
Gusterson
Barry A
BA
Goldhirsch
Aron
A
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D015331:Cohort Studies; D004703:Endocrine System; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis*; D000077289:Letrozole; D009570:Nitriles / Q000627:therapeutic use*; D017698:Postmenopause; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D013629:Tamoxifen / Q000627:therapeutic use*; D014230:Triazoles / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D019394:Ki-67 Antigen; D009570:Nitriles; D014230:Triazoles; D013629:Tamoxifen; D000077289:Letrozole