Gene expression profiling can predict
pathological complete response (pCR) to anthracycline-monotherapy in
estrogen-receptor (ER) negative breast cancer (BC) patients.
Desmedt
C, Azambuja E, Di Leo A, Larsimont D, Durbecq V, Antoine D, Lallemand
F, Haibe-Kains B, Cardoso F, Nogaret JM, Fontaine D, Liebens F, Duhem
C, Kains JP, Maerevoet M, Richard V, Vindevoghel A, Delaloge S, Buyse
M, D’Hondt V, Piccart M, Sotiriou C.
Purpose: The TOP trial is an
international study that aims to identify biological markers associated
with pCR to neoadjuvant anthracycline chemotherapy (CT). Its unique
characteristics are: 1/Determination of the predictive factors of
response to single agent epirubicin; 2/Evaluation of response in
ER-negative pts only, eliminating the confounding effect of indirect
ovarian suppression in ER+ BC. 3/Sample size calculation based on
biological hypothesis.
Patients and methods: In an
interim analysis, 81 pts were evaluated (64 early BC pts: epirubicin
100mg/m2 q3wks x4 / 17 inflammatory or locally-advanced pts: 100mg/m2
q2wks x6). pCR was defined as disappearance of all invasive cancer in
the breast and lymph nodes after epirubicin. After surgery, all pts
received docetaxel. We evaluated protein expression of ER, PgR, HER2,
Ki67, CK5/6 and topoII, and gene amplification of HER2 and topoII. Gene
expression profiles were generated from pre-treatment biopsies using
Affymetrix U133 Plus 2.0 chips.
Results: The median age and
tumor size were 46 yrs and 3.0 cm. Of the 69 evaluable pts, 13% showed
a pCR and 60% a clinical response. No association was observed between
pCR and age, size and the evaluated markers, except that all pCR pts
had high Ki67 expression (>25%). Microarray data was available for
62 pts and a student t-test analysis identified 568 genes that were
significantly associated with pCR (p<.001). The probability of
selecting these genes by chance was estimated to be p=0.005 after 1000
random permutations. These genes were mainly involved in cell growth,
death, morphology and signaling. We recently developed gene expression
indices for several hallmarks of BC (Sotiriou et al., ASCO 2006) and
found that pCR’s were associated with the expression of stroma
and topoII index genes.
Conclusions: These results
suggest that a group of genes can identify ER-negative BC pts likely to
respond to epirubicin. Since 400 pts will be enrolled, this gene set
will soon be tested on a larger cohort of pts and a predictor will be
developed. We are also testing whether these genes predict response to
chemotherapy in general or only to anthracyclines.