NcXHF

CHEMOTHERAPY FOR PATIENTS WITH BMOC
in other genes, such as ATM, CHEK1, CHEK2, NBN, and
RAD51D, can also affect HR function and increase sensitivity
to DNA-damaging agents and PARPi. 11
WHAT ARE THE MECHANISMS OF PLATINUM
RESISTANCE IN BMOC TUMORS?
Recent evidence suggests that secondary (reversion) BRCA1/2
mutations are a mechanism of acquired resistance to platinum
and PARPi in BRCA1/2-mutated cancer cells. 15,16 Reversion of
BRCA1/2 germ-line mutations also have been found in
platinum-resistant tumors, 17 but it is unclear which functions of
BRCA1/2 proteins are required for therapy resistance and
which BRCA1/2 genotypes are more likely to undergo reversion
mutations. Furthermore, it is unclear if a spectrum of platinum
and PARPi sensitivity exists among BRCA1/2 mutant cancers,
such that, independent of reversion mutations, certain
BRCA1/2 genotypes may be associated with a phenotype that is
intrinsically less sensitive to these therapies than others or may
be associated with heterogeneity in their response to these therapies,
such that the tumors are platinum resistant but still retain
sensitivity to PARPi and vice versa. Heterogeneity in clinical response
also may be explained by other mechanisms of (PARPi)
resistance, including enhanced P-glycoprotein-mediated drug
efflux or reduced 53BP1 expression. 18
Evidence to support the notion that all BRCA1/2-mutated
cancers may not have a uniform clinical phenotype has
KEY POINTS
Improved prognosis and response to platinum-based
chemotherapy are hallmarks of BRCA1/2-mutated ovarian
cancer (BMOC).
Increased platinum sensitivity is attributed to underlying
homologous-recombination repair deficiency in BMOC,
leading to impaired ability to repair platinum-induced
double-strand breaks, thereby conferring increased
sensitivity to chemotherapy.
Chemotherapeutic strategies for patients with BMOC should
focus on platinum-based chemotherapy at first-line and
recurrent-disease settings, and include measures to
increase the platinum-free interval in patients with early
platinum-resistant relapse (i.e., progression-free survival
of 6 months from last platinum-based chemotherapy) by
using nonplatinum cytotoxic agents, with the aim of
reintroducing platinum at a later date.
In recurrent disease, patients with BMOC appear to have
increased sensitivity to pegylated liposomal doxorubicin
and other DNA-damaging agents, including trabectedin and
mitomycin C, also may have a therapeutic role.
With recent approval for the use of the poly(ADP-ribose)
polymerase (PARP) inhibitor (PARPi) olaparib in BMOC in
Europe and the United States, further work to define the
optimal choice, timing, and sequence of chemotherapy and/
or PARPi therapy will be crucial to improve outcomes for
patients with BMOC.
emerged from survival data showing that patients with EOC
who carry a germ-line BRCA2-mutation have a better prognosis
than patients with EOC who carry a germ-line BRCA1-
mutation. 6 Furthermore, recent in vivo data from a BRCA1-
defıcient mouse mammary carcinoma model suggest that the
BRCA1C61G mutation (a common pathogenic missense
variant) may be associated with poor response and rapid development
of resistance to platinum drugs and PARP inhibition
but still retain the BRCA1C61G mutation. 19 This
suggests that ab initio resistance to specifıc chemotherapeutic
agents may also exist in certain BRCA1/2-mutated breast
and ovarian cancers depending on the patient’s BRCA1/2 genotype.
In a recent meta-analysis of clinical outcome data in
patients with BMOC, BRCA1/2 mutations and low BRCA1
expression by immunohistochemistry or reverse transcription
polymerase chain reaction were statistically signifıcantly
better prognostic factors for survival (hazard ratio [HR]
0.51 to 0.67), whereas BRCA1- promoter methylation was
not associated with improved prognosis (HR 1.59). 10
Therefore, given the potential effect of the mechanisms of
BRCA1/2 inactivation and genotype on the heterogeneity of
treatment responses and outcome, the ability to correlate
BRCA genotype with its clinical “BRCAness” phenotype will
be crucial to facilitate patient stratifıcation according to underlying
BRCA1/2 defıciency in each patient to optimize
management in the future.
WHAT DATA EXIST FOR INCREASED SENSITIVITY
TO SINGLE AGENT CHEMOTHERAPEUTIC DRUGS
OTHER THAN PLATINUM COMPOUNDS IN PATIENTS
WITH BMOC?
Limited data are available presently to fully address the question
of whether chemosensitivity to platinum salts observed
in patients with BMOC can be extended to other nonplatinum
agents, including pegylated liposomal doxorubicin
(PLD), paclitaxel, topotecan, and gemcitabine, which commonly
are used as monotherapy in the platinum-resistant/
refractory setting (Table 1).
The most convincing information comes from two retrospective
analyses on patient outcomes following treatment
with PLD in BMOC. Both have demonstrated improved response
rates and PFS when compared with patients who are
non-BMOC. 22,28 Safra et al combined the outcomes of
patients who received either PLD as a single agent or in combination
with platinum-based chemotherapy and demonstrated
improved median time to treatment failure (15.8 vs.
8.1 months; p 0.009) and OS (56.8 vs. 22.6 months; p
0.002) for patients with BMOC vs. patients who are non-
BMOC. 28 Adams et al examined the response rates of 23 patients
with BMOC following treatment with single-agent
PLD and reported an improved response rate of 56.5% (3 by
RECIST criteria and 10 by CA125 levels) in patients with
BMOC compared with only 19.5% (2 by RECIST criteria and
6 by CA125 levels; p 0.004) in patients who are non-
BMOC. 22 Notably, 71% (10/14) of BMOC patients with
platinum-resistant disease in this study responded to PLD,
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