Download Therapy-orienting testing of BRCA1 and BRCA2 germline mutations

Practice Guidelines
Therapy-orienting testing of BRCA1
and BRCA2 germline mutations in
women with ovarian cancer
K. Claes, PhD1, H. Denys, MD, PhD2, M. Huizing, MD, PhD3, I. Vergote, MD, PhD4, F. Kridelka, MD, PhD5,
J. De Grève, MD, PhD6, V. Bours, MD, PhD7
On behalf of the BRCA Testing Working Group.
With the aim to optimally position poly-(adenosine diphosphate-ribose) polymerase inhibitors in the treatment
of ovarian cancer, a panel of Belgian Experts came to a national multidisciplinary consensus: (i) germline
BRCA1/2 testing should be indicated for all women with high-grade serous epithelial ovarian cancer, who are
in good general condition (i.e. eligible for systemic treatment with low toxicity); BRCA1/2 mutation detection
ratios being about 15–20% in this group; (ii) as the finding of a BRCA1/2 germline mutation has therapeutic
implications in ovarian cancer patients, the request for therapy-orienting testing should be made as soon as
possible during the course of first-line treatment. Pre-test genetic counselling is important because positive
testing has implications for both the patients and their relatives, and the nature of the discussions depends
on whether they take place in a therapeutic or familial context. The organisation of consultations should be
coordinated in a collaborative effort between clinical geneticists, and gynaecological and medical oncologists,
keeping in mind that ‘fast-track’ pre-test genetic counselling and short turnaround times are required for
patients for whom the test results will have a therapeutic impact. Offering germline BRCA1/2 testing to all
patients with high-grade serous epithelial ovarian cancer who are eligible for systemic treatment with low
toxicity will lead to a limited increase in the number of patients eligible for this test in Belgium.
(Belg J Med Oncol 2015;9(2):65-70)
Introduction
The treatment of ovarian cancer, which is the main
cause of gynaecological cancer death in developed
1
countries, is based on combinations of optimal cytoreductive surgery, systemic chemotherapy and antiangiogenic therapy.1,2 Almost all women with epithelial
Center for Medical Genetics, Universitair Ziekenhuis Gent, Ghent, Belgium, 2Department of Medical Oncology, Universitair Ziekenhuis Gent, Ghent,
Belgium, 3Department of Oncology, Universitair Ziekenhuis Antwerpen, Edegem, Belgium, 4Department of Obstetrics and Gynaecology & Gynaecologic Oncology, Universitair Ziekenhuis Leuven, Leuven, Belgium, 5Department of Obstetrics and Gynaecology, Centre Hospitalier Universitaire
de Liège, Liège, Belgium, 6Department of Medical and Molecular Oncology, Universitair Ziekenhuis Brussel, Brussels, Belgium, 7Department of
Human Genetics, Centre Hospitalier Universitaire de Liège, Liège, Belgium.
Please send all correspondence to: K. Claes, PhD, Centre for Medical Genetics, Universitair Ziekenhuis Gent, De Pintelaan 185, B-9000 Gent,
Belgium, email: [email protected].
Conflict of interest: AstraZeneca was the funding source and funded all costs associated with the development and the publishing of the present manuscript. M. Huizing and F. Kridelka participated in the PARP inhibition advisory board for AstraZeneca.
Keywords: Belgium, BRCA1 / BRCA2 germline mutations, high-grade serous epithelial ovarian cancer, therapy-orienting genetic testing.
Acknowledgements: The authors would like to thank the members of the BRCA Testing Working Group for their input and critical discussion
during the working group meetings: Prof M. Abramowicz, Prof K. Dahan, Dr H. Pascale, Prof G. Matthijs, Dr J. van den Ende, Dr K. Segers and Prof
E. Teugels.
The authors thank Melissa McNeely (XPE Pharma & Science, Belgium c/o AstraZeneca) for publication management and Claire Verbelen (XPE
Pharma & Science, Belgium) for drafting the manuscript.
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ovarian cancer are treated frontline with platinumbased chemotherapy. The majority of relapsing tumours remain platinum-sensitive, and re-treatment
with platinum-based chemotherapy is frequent. However, cumulative toxicities and emergence of resistance
suggest that maintenance therapy with an inhibitor of
poly-(adenosine diphosphate [ADP]-ribose) polymerase (PARP), which is the enzyme involved in the
base-excision repair of single-strand errors, could be a
sound alternative approach.3,4
Previous studies have shown that up to 20% of ovarian
cancers are associated with mutations in BRCA1,
BRCA2 or both (BRCA1/2), with lower detection ratios
in non-high grade serous ovarian cancer and among
patients without a family history of breast or ovarian
cancer.5-8 The BRCA1 and BRCA2 genes are needed for
the repair of double-stranded DNA damage through
homologous recombination. Germline mutations in
BRCA1/2 confer an increased risk for ovarian cancer,
but are associated with longer survival rates after diagnosis and high responses rates to both chemotherapy
(e.g. platinum-based therapy and pegylated liposomal
doxorubicin) and PARP inhibitors.4,9-14 PARP inhibitors
cause significant tumour lethality in carriers of BRCA1/2
germline mutations because they have a cumulative effect on the DNA integrity of cancer cells.1,5,15
Various PARP inhibitors, of which olaparib has been
the most extensively studied, are currently under investigation.16-20 Phase I and phase II studies have shown
that olaparib, such as other PARP inhibitors, has a high
anti-tumour activity in patients with ovarian cancer
and BRCA1/2 germline mutations, and in patients with
high-grade serous ovarian cancer with or without
BRCA1/2 mutations.21-24 Another study has shown that
maintenance treatment with olaparib improves the duration of progression-free survival among patients with
platinum-sensitive high-grade serous ovarian cancer in
relapse (median 8.4 months in patients treated with
olaparib versus 4.8 months in patients who received a
placebo).25 Since the presence of a BRCA1/2 mutation is
a major determinant of the response to olaparib, the
knowledge of the BRCA1/2 mutation status in women
with ovarian cancer may guide treatment choices.3
Since the identification of the BRCA1/2 genes in 1994–
1995, germline BRCA1/2 testing has been offered in
Belgium to thousands of patients. Inclusion criteria
were typically based on family history of breast or ovarian cancer and the age at diagnosis, leading to the detection of a BRCA1/2 mutation in a minority of tested
patients.26 Knowledge of the BRCA1/2 mutation status
has very important implications for both patients and
their relatives; BRCA1/2 germline mutations are inherited in an autosomal dominant way, and each first degree relative has a 50% chance of having the mutation.
Once a BRCA1/2 germline mutation is identified in probands, predictive testing could be offered to relatives
who may benefit from preventive medical management
options, such as intensive screening or prophylactic
surgery. In addition, patients and relatives carrying a
BRCA1/2 germline mutation may seek advice on family
planning, including pre-implantation genetic or prenatal diagnosis.
With the arrival of PARP inhibitors, an evolution towards therapy-orienting germline BRCA1/2 testing is
ongoing. In this manuscript, we present a summary of
the topics discussed by a panel of Belgian gynaecologists and gynaecological/medical oncologists who met
on April 17th and November 13th, 2014, and who were
invited for their expertise and knowledge in ovarian
cancer treatment. Clinical and molecular geneticists
from the eight Belgian medical centres for human genetics were also invited. The following topics were
discussed:
• Which patients should be tested?
• When should patients be tested?
• How can the germline BRCA1/2 testing be integrated
in the patient pathway?
• Which practical implementations would be needed?
Epidemiology and pathology of epithelial
ovarian cancer
Ovarian cancer is predominantly a disease of postmenopausal women with the majority (>80%) of cases
being diagnosed in women over 50 years.4 The exact
cause of ovarian cancer remains unknown but many associated risk factors have been identified (such as age,
hormonal and reproductive factors, obesity, or ethnicity).4 Family history also plays an important role in the
risk of developing ovarian malignancies. The prognosis
for ovarian cancer is determined by the following patient
characteristics: stage of disease, debulking surgery to no
residual disease, response to systemic treatment, histological subtype, and degree of differentiation in stage I
disease.31 The most powerful indicator of prognosis remains the staging system of the International Federation
of Gynaecology and Obstetrics (FIGO), which identifies
the extent of the disease at the time of diagnosis.4 Epithelial ovarian cancers are classified into five histological types of various prognosis: serous, endometrioid,
mucinous, clear cell, and mixed tumours.32,33
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Practice Guidelines
In Belgium, the number of new patients with invasive
ovarian and fallopian tube epithelial tumours is constant (about 800–900 per year), and their five-year relative survival remains unfavourable (<50%).34,35 This
can be partially explained by the fact that epithelial
ovarian cancer is often diagnosed at a late stage, as
more than 75% of patients are diagnosed with FIGO
stage III or IV epithelial ovarian cancer. The most common histological subtype, which is reported in approximately 70% of women with epithelial ovarian cancer,
is high-grade serous ovarian cancer.36 This is an important finding since BRCA1/2 germline mutations are
mainly found in women with high-grade serous ovarian cancers, and the expected proportion of BRCA1/2
germline mutations is 15–20% in this group (with
lower detection ratios expected among patients who do
not have a family history of breast or ovarian cancer).
Of note, several other types of ovarian cancer, as well
as fallopian tube and primary papillary peritoneal cancers, have also been found in BRCA1/2 germline mutation carriers.37,38
BRCA1/2 testing in Belgium – From
familial risk to therapy-orienting testing
The Belgian Society of Human Genetics has developed
guidelines for germline testing in hereditary breast or
ovarian cancer conditions.39 In Belgium, people with a
family history of cancer suggesting the possible presence of a BRCA1/2 mutation are currently referred for
germline BRCA1/2 testing (familial risk BRCA1/2 testing). In addition, inclusion criteria for patients who
should be tested for germline BRCA1/2 mutations include (i) women with both breast and ovarian cancer,
and (ii) women with epithelial ovarian cancer. These
guidelines are currently in the process of being updated by the Belgian Health Care Knowledge Centre in
collaboration with geneticists and oncologists.
In Belgium, the current BRCA1/2 testing pathway includes the following steps: (i) patients with a suggestive family history of breast/ovarian cancer are referred
by their medical/gynaecological oncologist for germline
BRCA1/2 testing; (ii) in most centres, patients have a
pre-test genetic counselling appointment with a clinical geneticist approximately two to three months later
to discuss whether germline BRCA1/2 testing may be
appropriate and to explain the medical implications of
positive or negative test results for themselves and their
relatives; (iii) blood samples of the patients are tested
by the genetic laboratories, and results are analysed
and interpreted; (iv) when results are validated
(another two to six months later), patients are invited
to discuss the results (post-test genetic counselling).
The turnaround time of this genetic testing process is
four to nine months and fast-track is available for a limited number of requests. The discussion of Experts on
therapy-orienting testing in Belgium is summarised
topic-by-topic below.
Which patients should be tested?
The Experts highlighted the fact that women with
high-grade serous epithelial ovarian cancer and in a
good general condition (i.e. eligible for systemic treatment with low toxicity) should be eligible at any age for
therapy-orienting germline BRCA1/2 testing. This is in
line with a previous Australian study, where it has been
suggested that germline BRCA1/2 testing should be offered to all women diagnosed with non-mucinous,
ovarian carcinoma, regardless of family history.40 In
Canada and Australia, women with non-mucinous epithelial ovarian cancer are routinely tested for BRCA1/2
mutations. In Scotland, testing has recently been extended to all women with high-grade serous ovarian
cancer. In England, testing is offered only to women
with a strong family history of breast or ovarian cancer
and those in whom the cancer develops at an unusually
young age.15
The Experts suggest that (i) women with tumours of
borderline histology, low-grade ovarian cancer or mucinous tumours should not be systematically tested for
BRCA1/2 as the mutation detection ratio in this group
is very low, but testing might still be considered in the
presence of a relevant family history of breast and ovarian cancer; and (ii) women with a poor general condition, who are not eligible for systemic treatment with
low toxicity, should only be tested for BRCA1/2 if the
presence of the mutation may have a benefit for their
relatives.
When should patients be tested?
The Experts recommend that the request for germline
BRCA1/2 testing is made as soon as possible during the
course of first-line treatment. Germline BRCA1/2 mutation status affects significantly the survival in ovarian
cancer patients, and treatment strategies can be better
planned if results are available as early as possible or at
least at the time of first recurrence.
This recommendation is supported by the results of a
population-based case-control study conducted in
Australia, where the need for re-evaluation of the timing and coverage of germline BRCA1/2 testing for
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ovarian cancer patients was highlighted.40 The authors
of this study suggest that women should be routinely
referred for genetic counselling and BRCA1/2 testing
either during or soon after completion of their primary
systemic therapy, so that the BRCA1/2 gene mutation
status can be taken into account when planning the
treatment of a potential future relapse.
How can germline testing be efficiently integrated into the
patient treatment pathway?
Currently, the total turnaround time of the BRCA1/2
testing pathway, including pre- and post-test counselling, laboratory testing and validation, is between four
and nine months, with a limited number of ‘fast-track’
available for patients for whom the BRCA1/2 test results
will have therapeutic implications. While the turnaround time for genetic testing and validation can be
expected to be reduced to a maximum turnaround
time of two months in the near future, different options
can be proposed to reduce counselling turnaround
times, with the aim of reducing the total turnaround
time for germline BRCA1/2 testing to less than four
months.
The first option would be that genetic centres keep a
few slots every week to receive and inform patients
with a recent diagnosis of ovarian cancer within short
delays. Each of the eight Belgian genetic centres could
probably offer two or three slots per week, giving a total
of more than 800 slots per year. Pre-test counselling is
important because positive test results have implications for both the patients and their relatives, and discussions are different in a therapeutic versus a familial
context. Therefore, an appropriate therapy-oriented
training should be given to geneticists willing to counsel ovarian cancer patients.
A second option would be to combine the pre-test
counselling visit with a consultation with the patient’s
medical/gynaecological oncologist. Medical or gynaecological oncologists should receive appropriate training regarding the genetic aspects of the diseases they
are treating and should provide explanatory leaflets or
websites to the patients during the pre-test genetic
counselling. This has been successfully tested by oncologists at the Royal Marsden Hospital in London,
who offered the test and explained its implications to
114 patients with ovarian cancer. During this sixmonth pilot study, only patients with a positive result
were then referred to a genetic expert for post-test
counselling.41 A similar study was performed in the
same hospital on 119 patients and showed that pre-test
counselling could be successfully given by oncologists
who completed a 30 minute online training. This solution was highly appreciated by the patients and allowed
the discovery of 20 patients with BRCA1/2 mutation,
amongst which only one had been referred for genetic
testing.42
Finally, counselling turnaround time could be decreased
by increasing the number of trained genetic counsellors,
potentially leading to the creation of a new profession,
or by creating familial cancer clinics in which patients
would receive pre- and post-test counselling by physicians trained in cancer genetic counselling.
Which practical implementations would be needed?
There is an immediate need for publication of a new
guideline recommending that therapy-orienting germline BRCA1/2 testing should be offered to women with
high-grade serous epithelial ovarian cancer who are in
good general condition (who are eligible for systemic
treatment with low toxicity). Belgian genetic centres,
gynaecologists and oncologists should further evaluate
the different options for the organisation of qualitative
services to these patients. This should take into account the need to obtain BRCA1/2 test results within
short time frames to allow adequate treatment, and
should also guarantee adequate medical information
for patients and their relatives, before and after
testing.
The number of requests for genetic testing will probably gradually increase in the coming years as women
with ovarian cancer are increasingly referred for germline BRCA1/2 mutation testing. Moreover, increased
public awareness on hereditary aspects of breast cancer
is also leading to a higher number of patients in the
genetic centres or familial cancer clinics.
The quality of the service provided by the Belgian genetic laboratories is high: all obtained the ISO15189
accreditation and moved to a next generation sequencing approach. Although new generation sequencing
technologies have lowered the price of genetic testing,
the current budget of the RijksInstituut voor Ziekte en
InvaliditeitsVerzekering (RIZIV) / Institut National
d’Assurance Maladie-Invalidité (INAMI) for reimbursement of genetic testing will need to increase alongside
the increasing number of tests to be performed in Belgium. However, better genetic assessment would reduce the treatment costs through more personalised
decisions and would facilitate preventive management
of family members, leading to an overall cost reduction
on the long-term.
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Practice Guidelines
Key messages for clinical practice
1. As positive test results do not only have implications for the patient but also for relatives, all patients
should receive adequate pre- and post-test genetic counselling.
2. Women with high-grade serous epithelial ovarian cancer and in good general condition (i.e. eligible
for systemic treatment with low toxicity) should be eligible at any age for therapy-orienting germline
BRCA1/2 testing.
3. The request for germline BRCA1/2 testing should be made as soon as possible in the course of
first-line treatment.
4. For patients for whom the BRCA1/2 test results will have therapeutic implications, the turnaround
time could be shortened if pre-test genetic counselling visits are organised in a collaborative effort
between adequately trained clinical geneticists, and gynaecological and medical oncologists. The
input of well-trained genetic counsellors, who would deal with counselling of all aspects of hereditary
forms of breast/ovarian cancer, may be required in the future.
5. Offering testing for germline BRCA1/2 mutations to all patients with high-grade serous epithelial
ovarian cancer who are eligible for systemic treatment with low toxicity will lead to a limited increase
in the number of requests for germline BRCA1/2 testing in the coming years in Belgium.
Conclusion
With the aim to optimally position PARP inhibitors in
the treatment of ovarian cancer, Belgian Experts highlight the fact that germline BRCA1/2 testing should be
made as soon as possible in the course of first-line
treatment for all women with high-grade serous epithelial ovarian cancer who are in good general condition
(i.e. eligible for systemic treatment with low toxicity).
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BRCA1 mutation in a patient diagnosed with late onset breast and ovarian
cancer: implications for genetic testing. Breast Cancer Res Treat 2012;132(1):8795.
9. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J
Clin Oncol 2007;25(11):1329-33.
10.Vencken PM, Kriege M, Hoogwerf D, et al. Chemosensitivity and outcome
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