NcXHF

CHEMOTHERAPY FOR PATIENTS WITH BMOC
rate in platinum-sensitive patients was reported as 29% to
36%. 34,35 A second piece of clinical data has suggested a correlation
between BRCA1/2-mutation status and the improved effıcacy
of trabectedin/PLD over PLD alone in a subgroup analysis
of 41 patients in the OVA-301 trial. This observation may merit
further exploration of that combination. 36
Clinical data on smaller numbers of patients were reported in
support of preclinical results suggesting increased sensitivity to
other DNA-damaging agents such as mitomycin-C 37 and melphalan
38 for BRCA1/2-defıciency. Moiseyenko et al recently reported
that administration of mitomycin-C (10 mg/m 2 , 4 doses
per week), which induces DNA cross-links, resulted in one CR
(duration 36 weeks), two PRs (duration 36 and 48 weeks) and six
instances of disease stabilization of between 12 to 24 weeks duration
in patients with BMOC with recurrent disease. 26 Melphalan
is a bifunctional alkylating agent that induces inter- and
intrastrand DNA cross-links. It has been shown to be selectively
toxic to BRCA2-defıcient breast cancer cell lines. 38 Single doses
of melphalan also have resulted in longer relapse-free survival in
mice xenografted with BRCA2-defıcient cells than with cisplatin
or olaparib in vivo. 38 Osher et al reported a case of a patient who
was a BRCA2 mutation carrier with platinum-resistant EOC
who responded to treatment with oral melphalan (8 mg per day,
5 days per month for 1 year) and has remained disease-free for
more than 25 years. 27
Paclitaxel is a well-established therapeutic agent for treating
patients with EOC in the fırst-line 39 and relapsed settings.
40 In the context of patients with BMOC, however, the
sensitivity of BRCA1-mutated cancer cells to platinum chemotherapy
has been reported to correlate inversely with sensitivity
to microtubule-interfering agents such as taxanes. 41
Furthermore, inhibition of BRCA1-expression in ovarian cancer
cell lines has shown to increase cellular sensitivity to platinum
compounds but reduce antitumor activity of taxanes. 42,43
Clinical data were also provided to suggest that overall survival
for patients with higher BRCA1-expressing ovarian cancers improved
following taxane-containing chemotherapy, albeit nonsignifıcantly
(23.0 vs. 18.2 months; p 0.12; HR, 0.53), 42 thus
suggesting that higher BRCA1-expression levels may be required
for a clinical response to taxanes. In vitro data suggest
that BRCA1-mutated breast cancer cells are resistant to paclitaxel,
in contrast to BRCA1 wild-type cells, 44 and MCF-7 cells
transfected with BRCA1 siRNA display a signifıcant 9-fold increase
in resistance to paclitaxel (p 0.001). 45 Taken together,
these data imply that patients with BMOC who harbor defects in
BRCA1/2 function through germ-line or sporadic mutations
also may be potentially resistant to paclitaxel. 43 However, conflicting
preclinical published studies indicate reduced BRCA1
expression actually may confer increased sensitivity to paclitaxel.
46,47 In this context, a study by Tan et al of 26 patients with
BMOC who received paclitaxel monotherapy for relapsed disease
described an overall response rate of 46% (12 of 26 patients).
21 The clinical benefıt rate (defıned as RECIST PR or CR,
or stable disease after 18 weeks of treatment) was signifıcantly
higher (80 vs. 36%, p 0.04) in patients who are platinum sensitive
than in patients who are platinum resistant. 21 These data
do not suggest any adverse effect of BRCA1/2 mutation carrier
status on the activity of paclitaxel. The study also showed that
patients with BMOC who were platinum sensitive had signifıcantly
longer median PFS compared with patients who were
platinum resistant (42 vs. 21 weeks, p 0.003). 21 In the retrospective
study by Safra et al, PFS for patients with BMOC
following paclitaxel monotherapy was not signifıcantly different
from that of patients who are non-BMOC (p
0.572). 30 Overall, the data suggest that equivalent paclitaxel
effıcacy is seen in both groups of patients, and taxanes should
continue to have a therapeutic role in patients with EOC regardless
of BRCA1/2 carrier status.
ARE THERE ANY CHEMOTHERAPY COMBINATION
DATA IN THIS CONTEXT?
In a retrospective single-institute review of 256 patients, the
combination of PLD and platinum or gemcitabine and platinum
was associated with signifıcantly improved PFS in patients
with BMOC compared with patients who are non-BMOC (p
0.001 and p 0.02, respectively); however, there were no differences
in outcome when taxanes were used in combination with
platinum. 30 As such, it is tempting to speculate that a PLD/platinum
combination potentially may be a better option than a taxane/platinum
combination at some stage of treatment for
patients with BMOC. However, no prospective comparative
data presently support this. The two randomized trials that
compared their effıcacy in the fırst-line (MITO-2 trial) 48 and recurrent
(CALYPSO trial) 49 settings did not include subgroup
analyses of patients with BMOC vs. patients who are non-
BMOC. There is a good case, however, to retrieve samples in
these trials for BRCA1/2-mutation testing.
HOW SHOULD PATIENTS WITH BMOC BE TREATED
AT PRESENT?
First-Line Chemotherapy for Patients with BMOC
In recurrent disease, the retrospective data appear to suggest
that PLD may be superior to paclitaxel as a single agent, but
the situation for carboplatin-based combinations in fırst-line
treatment may be quite different. Although some may consider
the option of PLD/carboplatin as the fırst-line treatment
of choice in newly diagnosed patients with BMOC,
there are no randomized data to support this approach. Data
from the JGOG3016 study demonstrating signifıcantly superior
PFS and OS outcomes when carboplatin is combined
with dose-dense weekly paclitaxel instead of thrice weekly
paclitaxel also should be taken into account (PFS, p 0.0037;
OS, p 0.039). 50 Therefore, although the PLD/carboplatin
combination represents a viable alternative to the current
standard of paclitaxel/carboplatin in patients with BMOC
who wish to reduce the risk of neuropathy, which is in line
with the data from MITO-2, 48 there are currently no data to
support dropping paclitaxel routinely from fırst-line chemotherapy
for patients with BMOC.
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