The Gene expression Grade
Index: a potential predictor of relapse for endocrine-treated breast
cancer patients in the BIG 1-98 trial
Desmedt C, Giobbie-Hurder 1,
Neven P, Paridaens R, Christiaens M, Smeets A, Lallemand F,
Haibe-Kains B, Viale G, Gelber RD, Piccart MJ, Sotiriou C
Background: We have
previously shown that the Gene expression Grade Index (GGI) was able to
identify two subtypes of estrogen receptor (ER)-positive tumors that
were associated with statistically distinct clinical outcomes in both
untreated and tamoxifen-treated patients. Here, we aim to investigate
the ability of the GGI to predict relapses in postmenopausal women who
were treated with tamoxifen (T) or letrozole (L) within the BIG 1-98
trial.
Methods: We generated gene
expression profiles (Affymetrix) and computed the GGI for a matched,
case-control sample of patients enrolled in the BIG 1-98 trial from the
two hospitals where frozen samples were available. All relapses (cases)
were identified from patients randomized to receive monotherapy or from
the switching treatment arms for whom relapse occurred before the
switch. Each case was randomly matched with four controls based
upon nodal status and treatment (T or L). The prognostic value of
GGI was assessed as a continuous predictor and divided at the
median. Predictive accuracy of GGI was estimated using
time-dependent area under the curve (AUC) of the ROC curves.
Results: Frozen samples
were analyzable for 48 patients (10 cases and 38 controls). Seven
of the 10 cases had been assigned to receive L. Cases and controls were
comparable with respect to menopausal and nodal status, local and
chemotherapy, and HER2 positivity. Cases were slightly older than
controls and had a larger proportion of large, poorly differentiated
ER+/PgR- tumors. The GGI was significantly and linearly related
to risk of relapse: each 10-unit increase in GGI resulted in an
increase of approximately 11% in the hazard rate (p=0.02). Within
the subgroups of patients with node-positive disease or who were
treated with L, the hazard of relapse was significantly greater for
patients with GGI at or above the median. AUC reached a maximum of 78%
at 27 months.
Conclusions: This analysis
supports the GGI as a good predictor of relapse for ER-positive
patients, even among patients who receive L. Validation of these
results, in a larger series from BIG 1-98, is planned using the
simplified GGI represented by a smaller set of genes and tested by
qRT-PCR on paraffin-embedded tissues.