10.1576/toag.7.1.023.

27038

The role of prophylactic

salpingo-oophorectomy
in women who carry
mutations of the
BRCA genes
S Eliza Griffiths, Tito Lopes, Richard J Edmondson
There is increasing awareness among women and healthcare
professionals of the increased risk of cancer related to certain genetic
traits; in particular, mutations of the BRCA genes and their
predisposition towards breast and ovarian cancer. It is not always
clear, however, how best to manage women with these familial
tendencies. In this article we discuss the implications of carrying a
mutation in one of these genes and focus on the role and timing of
risk-reducing surgery. We also examine the available evidence
regarding the use of hormone replacement therapy after surgery in
these women.
BRCA incidence and implications

Screening

Ovarian cancer has an annual incidence of 22.3

per 100 000 women in the UK. It is the most
common cause of death from gynaecological
malignancy and the fourth leading cause of
cancer death in women in the UK. It is estimated
that one in ten ovarian cancers is hereditary,
involving BRCA1 and BRCA2 genetic
mutations in the majority of cases.1 It has been
estimated that between 0.07% and 0.09% of the
UK population are BRCA1 carriers and between
0.14% and 0.22% are BRCA2 carriers.2 Metaanalysis has shown the cumulative risks in
BRCA1 mutation carriers by the age of 70 years
to be 65% for breast cancer and 39% for ovarian
cancer. For BRCA2 carriers the estimates are
45% for breast and 11% for ovarian cancer.3 With
increasing awareness of the role of genetics in the
development of breast and ovarian cancers, more
women are becoming aware of their high-risk
status. These women may wish to explore options
that might prevent them from developing the
disease. This article focuses on the management
options available to women who are found to be
carriers of mutations in the BRCA genes, with
particular regard to the role of prophylactic
salpingo-oophorectomy and the subsequent use
of hormone replacement therapy (HRT).

There are two main methods currently in use to

screen women for ovarian cancer: transvaginal
ultrasound and measurement of serum CA125
antigen. Interpretation of transvaginal ultrasound
is difficult and inaccurate in the premenopausal
woman because of cyclical variation in ovarian
morphology, but it may have a role in
postmenopausal women. The limitation of
transvaginal ultrasound is the high number of
false positive results, which can lead to
unnecessary
surgery.4
Serum
CA125
measurement alone also produces false positive
results, as levels can rise in benign conditions
such as endometriosis.A combination of the two
tests, which is thought to produce fewer false
positive results, is currently being trialled in the
UK Familial Ovarian Cancer Screening Study
(UKFOCSS). These screening methods are
designed to detect early invasive disease, not a
premalignant lesion, and the effectiveness of this
strategy in terms of survival is not yet proven.

Treatment
It is known that the use of oral contraceptives is
protective against the development of ovarian
cancer in the general population.5 There is

2004 Royal College of Obstetricians and Gynaecologists

2005

www.rcog.org.uk/togonline

REVIEW
The Obstetrician
& Gynaecologist
2005;7:2327

Keywords
BRCA genes,
hormone
replacement
therapy, prophylactic
surgery,
oophorectomy,
ovarian cancer

Author details

S Eliza Griffiths Medical student,

University of Newcastle-upon-Tyne,
UK.

Tito Lopes FRCOG, Consultant

Gynaecological Oncologist, Queen
Elizabeth Hospital, Gateshead, UK.

Richard J Edmondson MD,

Consultant and Senior Lecturer in
Gynaecological Oncology,
Northern Gynaecological Oncology
Centre, Queen Elizabeth Hospital,
Sheriff Hill, Gateshead, NE9 6SX,
UK. email:
richard.edmondson@ghnt.nhs.uk
(corresponding author)

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REVIEW
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& Gynaecologist
2005;7:2327

also some evidence that the use of oral

contraceptives can reduce the incidence of
ovarian cancer in BRCA1 and BRCA2
carriers.6 A Canadian study6 of 207 women
with ovarian cancer and 161 of their sisters as
controls, found that oral contraceptive use for
six or more years was associated with a 60%
reduction in the risk of developing ovarian
cancer. A larger Israeli study,7 involving 840
women with ovarian cancer and 751 controls,
found that oral contraceptive use only decreased
the incidence of ovarian cancer in non-BRCA
carriers. As such, the evidence is not yet
conclusive and it is too early to recommend the
use of combined oral contraceptives in BRCA1
and BRCA2 carriers. It is important to consider
the effect that oral contraceptive use has on the
incidence of breast cancer in BRCA carriers,
especially if oral contraceptives are recommended as a chemopreventative treatment
against the development of ovarian cancer. A
link between the oral contraceptive and breast
cancer has been established in well women.8
Research into the implications of oral
contraceptive use and breast cancer is limited.
Early research suggests that the effects of oral
contraceptive use in women with a familial
breast cancer risk may be similar to the effects in
the general population.9
The only definitive treatment currently available is
prophylactic salpingo-oophorectomy. A 96%
reduction in the incidence of pelvic cancers has
been reported in BRCA carriers after prophylactic
oophorectomy.10 A 100% reduction is not possible
because these women retain a risk of developing
other pelvic cancers. It has been shown that 1.8%
of women who undergo prophylactic salpingooophorectomy will subsequently develop a
primary peritoneal cancer.11
BRCA carriers who undergo prophylactic
oophorectomy before the menopause have a
50% reduction in the incidence of breast
cancer.10 Although intuitively it would be
sensible to suggest that the earlier the surgery is
performed the greater the benefit in terms of
risk reduction, there is no evidence to support
this hypothesis.
If it is accepted that prophylactic salpingooophorectomy is a BRCA carriers best chance
of avoiding the development of ovarian cancer,
the discussion then centres on the age at which
these women should be advised to have their
ovaries removed. The age range of presentation
of hereditary ovarian cancer is wide. A US
study12 looking at the clinicopathological
features of BRCA-linked ovarian cancer found
cases presenting from 3179 years. The study

24

found the mean age of BRCA2 carriers

presenting (62 years) was similar to the sporadic
cases (63 years), while BRCA1 carriers presented
on average 8 years earlier (54 years).12 Hereditary
breast cancers also presented significantly earlier
than sporadic cases.A Japanese study13 found the
mean age of presentation of BRCA mutation
breast cancer (44 years) to be 10 years younger
than the mean age of presentation of sporadic
breast cancer (54 years).
At the moment, the UK does not have any specific
guidelines for these high-risk women. Decisions
are made on a case-by-case basis using each
departments own criteria. In the USA, guidelines
are driven by the effect that prophylactic salpingooophorectomy has on the incidence of breast
cancer in BRCA carriers. The guidelines
consequently advise women to undergo
oophorectomy at the age of 35 years or after
childbearing has been completed.14 It is clear
from these guidelines that a significant number of
women will undergo a premature surgical
menopause as a result of their prophylactic surgery.

Risk of menopause
When women are placed into a surgical
menopause, vasomotor symptoms often present
suddenly, which may be distressing.Women who
undergo a premature surgical menopause are at
significantly increased risk of developing
osteoporosis if they are not given HRT.15 An
osteoporotic hip fracture affects life expectancy;
case fatality following hip fracture is in the order
of 12.5% at 90 days and 23.7% at 1 year.16
Inducing a premature menopause without the
prescription of HRT could be distressing and
dangerous for women who may not have gone
on to develop a cancer. This goes against the
foundation of medical ethics, non-malevolence,
despite the intended beneficence.

Type of surgery
There has been some discussion about the actual
procedures that should be performed as part of
risk-reducing surgery. Clearly, the ovaries should
be removed.There seems little doubt, given that
the risk of fallopian tube cancer is also increased
in carriers of BRCA mutations, that the tubes
should also be removed. Some authors have
suggested that, without hysterectomy, the
intramural portion of the tube will be conserved
and the woman remains at risk of developing
fallopian tube cancer.To date, there has been no
recorded case of such a cancer.
There is conflicting evidence as to whether
uterine cancers are over-represented in mutation

2004 Royal College of Obstetricians and Gynaecologists

carriers. The majority of evidence suggests that

mutation carriers have no increased risk,17
although one report has suggested that the risk
of uterine papillary serous carcinoma, a highgrade variant of endometrial cancer, is increased
in these women.18 At present, given the
increased
morbidity
associated
with
hysterectomy even by the laparoscopic route,19
there seems insufficient evidence to recommend
hysterectomy for these women.20

Womens views and concerns

One of the main concerns expressed by highrisk women before prophylactic surgery is the
onset of menopausal symptoms.21 This concern
would appear to be justified, as up to 35% of
women complain of extremely bothersome
vaginal dryness and hot flushes up to 2 years after
their surgery, and 34% of women report a
worsening of sexual function after surgery.22
Although over 80% of women remain satisfied
with their decision to undergo surgery, 20% of
women will continue to show high anxiety levels
regarding developing subsequent ovarian cancer.22
A consistent theme is that women feel that they
were often not given as much information as they
would have liked.23 The women in this study were
part of the UKFOCSS study investigating the
benefits of screening in this population. Only
one-third of these women received specific
genetic counselling, which suggests that practice
in the UK is suboptimal. There is probably a
genuine desire for knowledge in these women
who are undertaking elective surgery for
preventative reasons without an immediate
obvious health benefit. More importantly,
information given to women must be consistent
between health professionals. In an unpublished
survey of our own patients, several women
reported that they had received conflicting advice
from geneticists and gynaecologists, particularly
regarding HRT use after surgery.

HRT after surgery

The dilemma faced by a clinician presented with
a woman who is a known carrier of a gene
mutation is to decide on the timing of surgery.
There are three principal options.

Delay surgery
The first option is to delay surgery until after the
woman has completed a natural menopause, in
order to reduce the risk of inducing
osteoporosis. Doing this does, however, negate
the beneficial effect of salpingo-oophorectomy
on the reduction of the incidence of breast

cancer in these high-risk women.10 Some

women, particularly BRCA1 carriers, may
develop their hereditary ovarian cancer prior to
the
menopause. Operating
only
on
postmenopausal women would result in some
women developing possibly preventable cancers.

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Perform surgery without HRT

A second option is to operate on premenopausal
women and accept an increased risk of
osteoporosis. In this situation, women could be
advised to undertake other strategies to reduce
the incidence of osteoporosis. The combination
of a high calcium diet and weight-bearing
exercise are low-risk interventions which have
demonstrated benefits in reducing the risks of
osteoporosis.24 The use of bisphosphonates has
also been suggested but currently there are no
data regarding their safety with long-term use.

Perform surgery and prescribe

HRT
The third option is to prescribe HRT to all
BRCA carriers who undergo a premature
surgical
menopause
after
salpingooophorectomy. Prescribing HRT would solve
the problems of sudden, postoperative
menopausal symptoms and reduce the risk of
osteoporosis. However, there is a lack of evidence
of safety of HRT in this population. Evidence
does exist for the postmenopausal population: in
this group it is known that there is an increased
risk of deep venous thrombosis in low-risk
women taking HRT.25 There is also evidence of
an increased risk of breast cancer in long-term
users of HRT.26 Where HRT is used to replace
oestrogen lost as the result of a prematurely
induced menopause, it is tempting to suggest
that these risks are reduced but unfortunately
few data exist to support this suggestion.
That said, there remains no evidence that HRT
harms BRCA carriers.27 In fact, prophylactic
salpingo-oophorectomy significantly reduces the
risk of BRCA carriers developing breast cancer,
a reduction not negated by the use of HRT.27
Although HRT does not negate the benefits of
risk-reducing surgery it is worth noting that the
effect is blunted. For many doctors this may not
seem relevant but the population requesting
risk-reducing surgery is highly motivated to
undergo such treatment and will often seek to
achieve the maximum benefit from this surgery.
These women may not, therefore, be prepared to
accept even the smallest reduction in benefit
from such surgery. Many of them may feel
uncomfortable with taking HRT, knowing that
the risk of breast cancer is thereby increased.

2004 Royal College of Obstetricians and Gynaecologists

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HRT is, however, currently thought to be

contraindicated in women who have already had
breast cancer.28 Compliance has also been an
issue for HRT in postmenopausal women with
one study finding only one-third to one-half of
women taking the medication as directed.29
When long-term compliance is lacking,
prophylactic salpingo-oophorectomy leads to a
shorter life expectancy, if performed prior to the
age of 45 years.30
No studies have directly looked at compliance
with HRT in high-risk women after surgery
but, while some have suggested that all women
will continue for 5 years,31 others have
suggested that as many as 4 of 23 women
stopped HRT within 18 months of surgery.23 In
our own practice, it appears that two-thirds of
women take HRT as directed, having evidently
understood the importance of HRT in the
prevention of osteoporosis. Problems occurred
in women who received conflicting advice from
gynaecologists and geneticists. It would be
interesting to know what effect publicity about
the increased risk of breast cancer in HRT users
has had on these women and whether this has
influenced women or their doctors to counsel
stopping HRT.
Various attempts have been made to provide
advice about the timing of surgery based on
modelling of risks.32,33 These models suffer from
severe limitations in that they are based on
assumptions of risk, which in many cases are not
evidence based. Other drawbacks include the
assumption that all women will take oestrogen
replacement therapy after surgery and that this
will confer the same degree of risk of osteoporosis
as the general population.As previously discussed,
there is no evidence that women take HRT until
the time of the natural menopause.
Notwithstanding these drawbacks, however,
the models mentioned above have estimated
that a salpingo-oophorectomy in a 30-yearold may result in an overall increased survival
of between 2.6 and 4.7 years. In the latest
published model the effects of HRT have
been included but the overall effects of this
are not clear, leading to a change in survival of
between 0.34 years and +0.17 years. The
suggestion from these models is that survival
is increased the earlier the prophylactic
surgery is performed but this is based on the
assumption that women continue to take
HRT until the time of the natural menopause
and that taking HRT is safe in this
population. These models overall would
appear to be too primitive to help a clinician
or a woman arrive at a conclusion as to the

26

timing of surgery or whether postoperative

HRT is safe or advantageous.
In our own practice, prophylactic salpingooophorectomy is performed at a median age of
48 years; however, the age range is wide
(3667 years), indicating that we do not have a
consistent policy. Furthermore, women are
currently being referred at a wide range of ages
for consideration of surgery. As families become
more aware of their carrier status it is likely that
women will present at ever younger ages wanting
to discuss options and it is therefore important
that we begin to develop more robust protocols
for the management and timing of surgery.

Conclusions
Increasing numbers of women are becoming
aware of their high-risk status.This is resulting in
increased numbers of referrals to discuss riskreducing surgery. As noted above, in many areas
there is a paucity of information but it seems
reasonable at present to offer prophylactic
bilateral salpingo-oophorectomy either at the
age of 45 years or 5 years before the index case
in the family, whichever is the earlier. There
seems little justification for offering surgery at a
much earlier age, as advocated in North
America, although more data about breast cancer
risk reduction are needed. In those women
undergoing surgery, HRT can be offered for
relief of symptoms but there is no evidence to
support its use after the age of 50 years and many
women may choose not to use HRT.

The future
It is likely that, with increasing knowledge of the
implications of specific mutations, more
individualised risks will be available for members
of specific families. For instance, certain
mutations predispose more towards ovarian
cancer than breast cancer and vice versa. This
may enable more individualised management
strategies to be developed. Nevertheless, in the
interim it is important that data are collected
regarding HRT use and its safety in this
population (which has, to date, been underinvestigated in this regard) in order that the
riskbenefit balance of surgery versus continued
observation can be measured more accurately.
Given the current paucity of data it is unlikely that
national guidelines can be formulated but as
information accrues this area should be revisited.
All professionals involved in the care of these
women can expect to see their workload increase
as a greater number of women, and their families,
become aware of their heightened risk.

2004 Royal College of Obstetricians and Gynaecologists

Box 1. Key points

Prophylactic surgery remains the only therapeutic strategy to reduce the risk of ovarian cancer in women
who carry BRCA gene mutations.

Prophylactic salpingo-oophorectomy also reduces the risk of breast cancer.

In women with previous breast cancer this may not be appropriate.

Timing of surgery will depend partly on the balance of ovarian cancer and breast cancer in each family.
The majority of surgeries will be performed on women between 40 and 50 years.
It seems reasonable to offer HRT for relief of short-term symptoms, probably up to the age of 50 years,
but there seems little justification beyond this point.
Some women will not want HRT and this may be reasonable.
Advice about HRT must be consistent between all members of the team caring for these women.

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