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.
Viale
Giuseppe
G
Division of Pathology and Laboratory Medicine, European Institute of Oncology, University of Milan, Milan, Italy. giuseppe.viale@ieo.it
Regan
Meredith M
MM
Maiorano
Eugenio
E
Mastropasqua
Mauro G
MG
Dell'Orto
Patrizia
P
Rasmussen
Birgitte Bruun
BB
Raffoul
Johnny
J
Neven
Patrick
P
Orosz
Zsolt
Z
Braye
Stephen
S
Ohlschlegel
Christian
C
Thürlimann
Beat
B
Gelber
Richard D
RD
Castiglione-Gertsch
Monica
M
Price
Karen N
KN
Goldhirsch
Aron
A
Gusterson
Barry A
BA
Coates
Alan S
AS
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