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CHEMOTHERAPY FOR PATIENTS WITH BMOC
relapse could conceivably be platinum-resistant. In Europe, but
not in the United States, this would deprive the patient
with BMOC of the opportunity to receive a PARPi. Thus,
in Europe it might be tempting to recommend olaparib
fırst because bevacizumab could be given later in the context
of platinum resistance (where it is approved according
to the AURELIA data 55 ). However, if the next relapse in
that situation was still platinum sensitive, bevacizumab
could not be given. According to the current label, it only
can be used for the fırst platinum-sensitive relapse. The
dilemma in Europe is clear, and this common clinical scenario
will require careful discussion with patients with
BMOC when the choice of chemotherapy in the platinumsensitive
relapse situation occurs. One way forward is to
consider carefully the platinum-free interval in these patients
as a way of predicting whether the next relapse is
likely to be platinum sensitive or platinum resistant. However,
this is an inexact science. The situation will best be
resolved when more data are available from further studies
to permit a more uniform and flexible approach from the
regulatory authorities in Europe and the United States.
WHAT EFFECT WILL THE USE OF A PARP INHIBITOR
HAVE ON RESPONSE TO SUBSEQUENT CHEMOTHERAPY?
This is a particularly pertinent question in view of the previously
discussed preclinical data suggesting that the development
of PARPi resistance also may compromise benefıt to
subsequent chemotherapy, particularly platinum-based regimens,
in patients with BMOC through the acquisition of reversion
mutations in BRCA1/2. 15 A recently published study
of chemotherapeutic response in patients with BMOC following
progression on olaparib demonstrated a response rate
of 36% (24 of 67 patients) by RECIST and 45% (35 of 78 patients)
by RECIST and/or Gynaecologic Cancer Inter-Group
(GCIG) CA125 criteria following postolaparib chemotherapy,
with a median PFS and OS of 17 weeks and 34 weeks,
respectively. 59 Response rates to platinum-based chemotherapy
were 40% (19 of 48 patients) and 49% (26 of 53 patients),
respectively, with a median PFS of 22 weeks and OS of 45
weeks. For patients who received single-agent paclitaxel, response
rates were 40% (4 of 10 patients) by RECIST and 50%
(5 of 10 patients) by RECIST and/or GCIG criteria. Patients
who received postolaparib PLD had a 0% (0 of 5 patients)
response by RECIST and 30% (3 of 10 patients) response by
RECIST and/or GCIG criteria. Notably, no evidence of secondary
BRCA1/2 mutation was detected in tumor samples of
six PARPi-resistant patients, suggesting that other yet to be
determined mechanisms of resistance to PARPi may be involved.
These data suggest that a proportion of BMOC tumors
will retain chemosensitivity, particularly to platinum and
paclitaxel despite progression on PARPi therapy. However,
it is still not known completely how resistance to
PARPi will affect the subsequent duration of chemotherapy
response. To understand more fully the mechanistic
interplay between PARPi and chemotherapy resistance, it
will be important to systematically collect tumor samples
and treatment outcome data to defıne the optimal chemotherapeutic
options and relevant predictive biomarkers
for patients with BMOC in the post-PARPi setting.
CONCLUSIONS: CHEMOTHERAPY FOR PATIENTS
WITH BRCA1/2 MUTATION AND OVARIAN
CANCER: SAME, BUT DIFFERENT
The hallmarks of BMOC are a high response rate to
platinum-based chemotherapy at fırst and subsequent relapses,
long treatment-free intervals between relapses, and
improved OS. These features describe the clinical signature
of BRCAness in the context of EOC; however, so far
they have been less well documented in other BRCA1/2-
mutant carrier– related cancers including breast, pancreatic,
and prostate cancer. This suggests that the context of
the BRCA1/2-mutant genotype has a signifıcant bearing
on disease behavior and outcome. Nonetheless, very encouraging
data on responses to PARPi in BRCA1/2-
mutant carriers with prostate, 60 pancreatic, 56,61 and breast
cancer 62 have been reported and are likely to be associated
with platinum sensitivity. 63 It remains to be seen if an assay
for HR-defıciency can be identifıed that will predict for
platinum and PARPi sensitivity in a broad range of cancers.
In the meantime, however, it is clear that establishing
the germ-line and/or tumor BRCA1/2 mutation status in
patients with cancers known to be associated with
BRCA1/2 mutations is of paramount importance because
of the potential therapeutic options.
Our recommendations for chemotherapy for patients with
BMOC are generally based on retrospective analyses, with a
primary emphasis on rechallenging these patients with
platinum-based treatment and prolonging the platinum-free
interval in the event of early relapse following platinumbased
treatment. The welcome arrival of using PARPi to treat
patients with BMOC also provides an additional initial factor
to consider within the context of relapsed disease. Hence, although
a majority of treatment options remain the same for
both patients with BMOC and with non-BMOC, the timing
and sequence of therapy, and the indications for rechallenging
patients with platinum-based chemotherapy, and perhaps
even routes or schedules of administration (IV vs. IP,
weekly vs. thrice weekly) are likely to differ as more data
emerges from post hoc analyses of the mutation status of
BRCA1/2 and other HR-related genes in tumor samples from
previously completed studies. Moreover, stratifıcation based
on HR-defıciency phenotype/genotype may become the
standard in upcoming prospective clinical trials involving
patients with EOC and that will be highly informative in this
respect. Further work to dissect the precise relationship between
BRCA1/2-mutation genotype and clinical phenotype
also will be crucial to delineate the best treatment options in
the future for patients with BMOC.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK 119