Biomedical Engineering Reference
In-Depth Information
BCIRG 005 study and found no amplification of TOP2A and only 2.6%
with TOP2A deletion in 1,614 HER-2 non-amplified breast cancer
[124]. From this study it would appear that TOP2A amplification
only occurs in the context of HER-2 amplification. A second study
evaluated patients from the Danish Breast Cancer Cooperative Group
(DBCCG) 89D study, which tested the efficacy of CEF compared with
CMF in pre- and post-menopausal early-stage breast cancer patients
[125]. HER-2 and TOP2A amplification was assessed by FISH as
above, but using different reagents from the paper by Press
et al.
[125]. This group found TOP2A amplification in 32% and TOP2A
deletion in 25% of 246 patients with HER-2 amplification but only
found TOP2A amplification in 2.7% and TOP deletion in 4.9% of
527 samples without HER-2 amplification. A third group, using
FISH to evaluate samples from the CCTG MA.5 study found TOP2A
amplification in 28% and TOP2A deletion in 15% of 116 samples
with HER-2 amplification but only found TOP2A amplification in 6%
and TOP deletion in 3% of 314 samples without HER-2 amplification
[126]. From these studies, TOP2A amplification in the absence of
HER-2 amplification is rare. TOP2A is the target of anthracyclines, and
cancer cell lines expressing higher levels of TOP2A are more sensitive
to anthracyclines [127-129]. When the last two studies that both
compared CAF with CEF were analyzed for response in relationship
to TOP2A amplification, both found improvement in DFS and OS for
patients with TOP2A amplification treated with CAF compared with
CEF but no such improvement was seen in patients without TOP2A
amplification [125, 126, 130, 131]. Thus, a biologically plausible
hypothesis is that TOP2A amplification, and not HER-2 amplification,
is responsible for the improved outcome when anthracyclines are
used to treat patients with HER-2 amplification. All of these analyses
are based on retrospective analyses and a prospective trial directly
testing this has not been done. The importance of these observations
given the cardiac and leukemogenic toxicities of anthracyclines is
to identify patients in whom anthracyclines can safely be avoided.
In the BCIRG 006 study, patients with early-stage HER-2 positive
breast cancer were randomized to three treatment regimens;
doxorubicin, cyclophosphamide and paclitaxel (ACT), ACT with
trastuzumab (ACTH), or docetaxel, carboplatin, and trastuzumab
(TCH) [80]. When Press
. analyzed these treatment arms with
regard TOP2A amplification for RFS and OS, they found that the
patients with tumors containing TOP2A amplification had improved
survival on ACT compared with those without TOP2A amplification
et al
