ABSTRACT:
BACKGROUND: The vast majority of patients with
HER2-positive metastatic breast cancer (MBC) treated with trastuzumab
eventually develop resistance to this agent. There is an unmet need therefore,
for identifying biological markers with possible prognostic/predictive value in
such patients. The aim of this study was to investigate the prognostic role of
topoisomerase II alpha gene (TOP2A) amplification and protein (TopoIIa)
expression in patients treated with trastuzumab-containing regimens.
METHODS:
Formalin-fixed paraffin-embedded tumor tissue
samples were retrospectively collected from 225 eligible patients treated with
trastuzumab. Protein expression of ER, PgR, Ki67, PTEN, HER2 and TopoIIa were
centrally assessed by immunohistochemistry. HER2 and TOP2A gene amplification
was evaluated by fluorescence in situ hybridization. PIK3CA mutations were identified
by single nucleotide polymorphism genotyping. Survival was evaluated from the
initiation of trastuzumab as 1st line treatment to the date of last follow-up
or death.
RESULTS:
Among the 225 samples analyzed, only 137 (61%)
were found to be HER2-positive. TOP2A was amplified in 41% and deleted in 16%
of such tumors. TOP2A gene amplification was more frequent in ER-negative
tumors. TopoIIa protein expression was observed in the majority (65%) of the
samples and was associated with ER-positive status, high Ki67 expression,
presence of PTEN protein and PIK3CA mutations. Median follow-up for patients
treated in the 1st line was 51 months. Survival was more prolonged with
trastuzumab-containing treatment in HER2-positive patients (50 months,
log-rank, p=0.007). TOP2A non-amplified or deleted tumors were associated with
increased risk for death compared to TOP2A amplified tumors (HR=2.16, Wald's
p=0.010 and HR=2.67, p=0.009, respectively). In multivariate analysis, a
significant interaction of TOP2A with anthracycline treatment (either in the
adjuvant or the 1st line setting) was observed for survival (Wald's p=0.015).
Among the TOP2A amplified subgroup, anthracycline-treated patients were
associated with decreased risk for death.
CONCLUSIONS:
TOP2A gene amplification was shown to be a
favorable prognostic marker in HER2-positive MBC patients treated with
trastuzumab, such an effect however, appears to rather be related to treatment
with anthracyclines (predictive marker for benefit from anthracyclines). The
results of the present retrospective study warrant validation in larger cohorts
of patients treated in the context of randomized trials.
Source: Topoisomerase ii alpha gene
amplification is a favorable prognostic factor in patients with HER2-positive metastatic
breast cancer treated with trastuzumab. Fountzilas G (fountzil@auth.gr), Christodoulou C, Bobos M,
Kotoula V, Eleftheraki AG, Xanthakis I, Batistatou A, Pentheroudakis G, Xiros
N, Papaspirou I, Koumarianou A, Papakostas P, Bafaloukos D, Skarlos DV,
Kalogeras KT. J Transl Med. 2012 Oct 23;10(1):212.
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