Gene expression profiling can predict
pathological complete response (pCR) to anthracycline-based therapy in
estrogen-receptor (ER) negative breast cancer (BC) patients.
Desmedt C, André F, Azambuja E, Haibe-Kains B, Larsimont D, D’Hondt V, Di Leo A, Piccart MJ, Pusztai L and Sotiriou C
Background: Breast cancers show
variable sensitivity to anthracycline (A)-based therapy. Here we aimed
to identify gene expression profiles associated with pCR to this
treatment. As it has repeatedly and consistently been shown that ER is
the most dominant factor influencing the molecular composition of
breast cancer, defining different types of BC disease and because we
wanted to eliminate the confounding effect of indirect ovarian
suppression in ER+ BC, we focused in this study on ER-negative patients
only.
Methods: We analyzed Affymetrix
gene expression profiles generated from 132 ER- pre-treatment samples,
constituting the largest series of ER- preoperatively A-treated BC
(n=132/35 pCR). Sixty-two samples derived from the prospective
multicentric TOP trial (epirubicin single-agent), 41 from Institut G.
Roussy (retrospective selection/ FEC) and 27 from MD Anderson
(prospective study/ FAC).
Results: A student t-test
analysis on the combined population of A-treated pts was performed
identifying 102 genes that were significantly associated with pCR
(p<.01). These genes were mainly involved in cell death, DNA
replication and recombination, molecular transport, cell cycle and
morphology. Interestingly, 14 of these genes were located on the
topoIIα amplicon. Of interest, none of these 14 genes seem to carry any
prognostic value in untreated ER- pts (N=161). When we considered gene
expression indices for specific A-targets such as topoIIα and helicase,
we found that both were associated with pCR. However, subgroup analysis
revealed that topoIIα index was predictive in ERBB2+ but not in ERBB2-
subgroup. None of the genes from the adriamycin predictor (Potti et
al.) or the p53 signature (Miller et al.) were significantly associated
with pCR.
Conclusions: This study
suggests that a group of genes associated with topoIIα can identify
ER-negative BC pts likely to respond to A-based therapy. These
promising results are currently being validated in a larger series.