Prognostic and predictive value of centrally reviewed expression of estrogen and progesterone receptors in a randomized trial comparing letrozole and tamoxifen adjuvant therapy for postmenopausal early breast cancer: BIG 1-98.
OBJECTIVE
To evaluate locally versus centrally assessed estrogen (ER) and progesterone (PgR) receptor status and the impact of PgR on letrozole adjuvant therapy compared with tamoxifen in postmenopausal women with early breast cancer.


METHODS
Breast International Group (BIG) 1-98 randomly assigned 8,010 patients to four arms comparing letrozole and tamoxifen with sequences of each agent. The Central Pathology Office received material for 6,549 patients (82%), of which 79% were assessable (6,291 patients). Prognostic and predictive value of both local and central hormone receptor expression on disease-free survival (DFS) were evaluated among 3,650 assessable patients assigned to the monotherapy arms. Prognostic value and the treatment effect were estimated for centrally assessed ER and PgR expression levels using the Subpopulation Treatment Effect Pattern Plot.


RESULTS
Central review confirmed 97% of tumors as hormone receptor-positive (ER and/or PgR > or =10%). Of 105 tumors locally ER-negative, 73 were found to have more than 10% positive cells, and eight had 1% to 9%. Of 6,100 tumors locally ER positive, 66 were found to have no staining, and 54 had only 1% to 9%. Discordance was more marked for PgR than ER. Patients with tumors reclassified centrally as ER-negative, or as hormone receptor-negative, had poor DFS. Centrally assessed ER and PgR showed prognostic value. Among patients with centrally assessed ER-expressing tumors, letrozole showed better DFS than tamoxifen, irrespective of PgR expression level.


CONCLUSIONS
Central review changed the assessment of receptor status in a substantial proportion of patients, and should be performed whenever possible in similar trials. PgR expression did not affect the relative efficacy of letrozole over tamoxifen.
Division of Pathology and Laboratory Medicine, European Institute of Oncology, University of Milan, Milan, Italy. giuseppe.viale@ieo.it
Giuseppe
G
Viale
Meredith M
MM
Regan
Eugenio
E
Maiorano
Mauro G
MG
Mastropasqua
Patrizia
P
Dell'Orto
Birgitte Bruun
BB
Rasmussen
Johnny
J
Raffoul
Patrick
P
Neven
Zsolt
Z
Orosz
Stephen
S
Braye
Christian
C
Ohlschlegel
Beat
B
Thürlimann
Richard D
RD
Gelber
Monica
M
Castiglione-Gertsch
Karen N
KN
Price
Aron
A
Goldhirsch
Barry A
BA
Gusterson
Alan S
AS
Coates
D000328:Adult; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D000077289:Letrozole; D009570:Nitriles / Q000627:therapeutic use*; D017698:Postmenopause / Q000378:metabolism*; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D013629:Tamoxifen / Q000627:therapeutic use*; D014230:Triazoles / Q000627:therapeutic use*
D009570:Nitriles; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D014230:Triazoles; D013629:Tamoxifen; D000077289:Letrozole