Journal Reading

PATIENTS WITH BRCA MUTATIONS HAVE SUPERIOR OUTCOMES

AFTER INTRAPERITONEAL CHEMOTHERAPY IN OPTIMALLY
RESECTED HIGH GRADE OVARIAN CANCER

Presentator : Handri Rezki Vebrian

Supervisor :
Prof. dr. M fauzie sahil, Sp.OG(K)

Department of Obstetric and Gynecology

Oncology Division
Faculty of Medicine – Universitas Sumatera Utara
H. Adam Malik General Hospital
Medan – 2019

R. Wendel Naumann, Jacob C. Morris, David L. Tait, Robert V. Higgins, Erin

K. Crane, Lane K. Drury, Lisa Amacker-North, Megan Templin, Jubilee Brown
INTRODUCTION
Epithelial ovarian cancer is the leading cause of death from gynecologic
malignancy [1].

High grade epithelial ovarian cancer responds well to chemotherapy

with response rates to primary therapy >70% [2].

Advances in treatment have led to excellent short term outcomes and

the overall 5-yr survival has improved to 46% [3].

Several trials conducted by the Gynecologic Oncology Group (GOG)

demonstrated that intraperitoneal (IP) chemotherapy provides an
advantage over standard intravenous (IV) chemotherapy [4–6].
A retrospective study This analysis suggested the author sought to review
.

.
reported the outcomes that the survival their experience with IP
of patients enrolled advantage identified in chemotherapy relative to
onto GOG 172 based on the study may have BRCA status by genetic
pathogenic mutations in been driven almost sequencing to determine
BRCA1 as determined by exclusively by whether IP chemotherapy
immunohistochemistry improvements in was more beneficial in
[10]. outcomes in patients patients who have
with pathogenic pathogenic mutations in
mutations in BRCA1. BRCA and BRCA-related
genes.
MATERIALS AND METHODS
 identified through billing compared with relation to risk

(BRCA+ and BRCA−)

Patients

records between January 1st, factors for recurrence, and

2005 and December 31, 2016. toxicity of the IP regimen
Inclusion criteria for the study using log likelihood ratios.
were as: Progression-free survival (PFS)
• patients must have been and Overall survival (OS)
optimally resected <2 cm, All causes of death were used
• received at least 1 cycle of IP in the calculation of overall
chemotherapy in the survival.
primary chemotherapy Estimates of the cumulative
regimen; proportions of survival were
• must have records adequate based on the methods of
to determine the details of Kaplan–Meier. [11]
therapy; Significance was set at P =
• must have at least 6 months 0.05.
of follow-up; and
• must have a designated
BRCA status.
RESULTS
We identified 131 patients
who were treated with at
31 patients did not meet
least 1 cycle of IP
the criteria for inclusion.
chemotherapy and were
optimally resected.

25 patients were found to

Leaving 100 patients
have a pathogenic BRCA
eligible for inclusion in the
mutation. 75 patients in the
analysis.
BRCA−.
 There was a significant cohort of both the BRCA+ and BRCA− patients
with a prolonged progression free survival.

Only one patient in either cohort recurred after 5 years of disease free
survival.

In the 25 BRCA + patients, 12 recurred within 5-years, 7 were censored

leaving 6 of 18 (33%) patients disease free at >5 years. We feel that these
patients have an excellent chance of permanent remission.
In the BRCA− patients, 11 of the 69 patients were disease free after 5
years (16%).

Assuming that patients who remain disease free at 5 years are likely
to achieve a permanent remission, it appears that BRCA+ patients are
twice as likely to achieve this milestone with IP therapy.
DISCUSSION
This study demonstrates that patients with pathogenic mutations in BRCA
and BRCA-related genes have significantly better PSF and OS when treated
with IP therapy compared to those without such mutations.

Previous studies have demonstrated that deleterious mutations in BRCA-

related genes are associated with an improved response to IV
chemotherapy.

The improvement we have noted in current study for the BRCA+ cohort
receiving IP therapy shows a hazard ratio for PFS of 0.38 and a hazard ratio
for OS of 0.28.

In our experience, many of the BRCA+ patients had a dramatic and durable
response to IP therapy with a median OS of over 9 years.

One third of the patients with BRCA mutations treated with IP therapy are
disease free at 5 years and have an excellent chance at a permanent
remission.
The mechanism of action of the benefit for IP therapy is not clear.

It has been proposed that the advantage to IP therapy is an increase

in the intraperitoneal concentration of cytotoxic chemotherapy.

Other mechanisms that lead to better outcomes for IP therapy in

BRCA patients are not known.

Possible explanations

• include better long term intra-peritoneal control,

• delayed systemic absorption which provides a phramokinetic advantage, or
• other mechanisms such as peritoneal inflammation with an improved
immune response after IP therapy.
The strength of this study is that all of the BRCA+ patients had proven pathogenic
mutations detected by genomic sequencing.

Patients with germline mutations develop ovarian tumors that are devoid of the
BRCA repair mechanism and thus are more sensitive to DNA damaging agents
such as cisplatin.

Patients with pathogenic mutations in BRCA appear to have cancers that are
particularly sensitive to IP chemotherapy and have an excellent PFS and OS after
treatment.

Any future clinical trials of IP therapy should stratify for BRCA status and pre-
specify a subset analysis of this population.
CONFLICT OF INTEREST
 Dr. Brown has received
Dr. Naumann has
personal fees from
received personal fees
Caris and Inivitae,
from Caris, outside the
outside of the
submitted work.
submitted work.

No other author
reports a potential
conflict of interest.
DIAGNOSTIC CRITICAL
APPRAISAL
Comments:

• Patients with high grade ovarian cancer who were treated

with adjuvant IP chemotherapy in the initial setting between
2005 and 2016 were identified.
• Outcomes were compared between patients with pathogenic
mutations in BRCA (BRCA+) and those who tested negative or
were unknown (BRCA−).
Comments:

• Patients with ovarian cancer were identified through billing records and all cases
were reviewed to see if they were treated with IP chemotherapy between January
1st, 2005 and December 31, 2016.
• Inclusion criteria for the study were as follows:
• patients must have been optimally resected >2 cm,
• Received at least 1 cycle of IP chemotherapy in the primary chemotherapy
regimen;
• Must have records adequate to determine the details of therapy;
• Must have at least 6 months of follow-up; and
• Must have a designated BRCA status.
Comments:

• all patients with ovarian cancer were offered genetic testing.

• Somatic testing was performed sporadically and at the discretion of the attending
physician, often to offer targeted therapy to patients with recurrent cancer.
• Patients who did not have sequencing performed because of an unremarkable
family history were included in the BRCA− cohort.
• BRCA testing was performed by one of several different commercial CLIA
approved testing labs throughout the course of the study.
Comments:

• Progression-free survival (PFS) was measured from

the date of diagnosis to either the date of last contact,
date of progression, or date of death.
• Overall survival (OS) was measured to either the date
of last contact or the date of death. All causes of
death were used in the calculation of overall survival.
• Estimates of the cumulative proportions of survival
were based on the methods of Kaplan–Meier.
Significance was set at P = 0.05.
Comments:
• the authors did not mention about any cofounding
factor or disease that affected the outcome of
patients.
 Comments:

Comments:
• One of inclusion criteria mention that must have at
least 6 months of follow-up
• the study is reviewed to see if they were treated with
IP chemotherapy between January 1st, 2005 and
December 31, 2016.
Comments

• A total of 100 eligible patients were identified.

• The median follow-up was 47.0 months (range, 6.6–144.1 months).
• Of these 100 patients, 77 patients underwent BRCA testing; 25
patients (32%) were BRCA+ (23 germline, 2 somatic).
• No differences were noted between groups with respect to number
of IP cycles, stage, or residual disease after surgery.
• The median progression-free survival (PFS) was longer in the BRCA+
group; median PFS was not reached in the BRCA+ group compared to
17.3 months in the BRCA− group (HR = 0.38; 95% CI 0.20–0.73, P =
0.003).
• Median overall survival (OS) was longer in the BRCA+ group at 110.4
months versus 67.1 months (HR = 0.28, 95% CI 0.11–0.73, P = 0.009).
Comments:

• The median progression-free survival (PFS) was

longer in the BRCA+ group; median PFS was not
reached in the BRCA+ group compared to 17.3
months in the BRCA− group (HR = 0.38; 95% CI
0.20–0.73, P = 0.003).
• Median overall survival (OS) was longer in the
BRCA+ group at 110.4 months versus 67.1 months
(HR = 0.28, 95% CI 0.11–0.73, P = 0.009).
Comments:

• The median progression-free survival (PFS) was longer

in the BRCA+ group; median PFS was not reached in
the BRCA+ group compared to 17.3 months in the
BRCA− group (HR = 0.38; 95% CI 0.20–0.73, P = 0.003).
• Median overall survival (OS) was longer in the BRCA+
group at 110.4 months versus 67.1 months (HR = 0.28,
95% CI 0.11–0.73, P = 0.009).
Comments:

• We can offer this BRCA test to the

patients with diagnosis of ovarian
cancer, and if they are willing to
pay for the test by themselves.
Comments:

• Previous studies have demonstrated that

deleterious mutations in BRCA-related genes
are associated with an improved response to
IV chemotherapy. [12]
• A meta-analysis showed patients with BRCA1
mutations have a hazard ratio for death from
ovarian cancer of 0.78 and for BRCA2 this
hazard ratio is reduced to 0.65 [13].
Comments:

• Patients with pathogenic mutations in BRCA appear to have

cancers that are particularly sensitive to IP chemotherapy and
have an excellent PFS and OS after treatment.
• The magnitude of benefit in the BRCA+ group is large enough
to strongly consider IP therapy in this specific subpopulation.
• Any future clinical trials of IP therapy should stratify for BRCA
status and prespecify a subset analysis of this population.
Thank You