YGYNO-976692; No.

of pages: 6; 4C:
Gynecologic Oncology xxx (2017) xxx–xxx

Contents lists available at ScienceDirect

Gynecologic Oncology

journal homepage: www.elsevier.com/locate/ygyno

Mortality reduction and cost-effectiveness of performing hysterectomy

at the time of risk-reducing salpingo-oophorectomy for prophylaxis
against serous/serous-like uterine cancers in BRCA1 mutation carriers
Laura J. Havrilesky a,c,e,⁎, Haley A. Moss a,c, Junzo Chino d,e, Evan R. Myers b,c,e, Noah D. Kauff e
a
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, United States
b
Division of Clinical and Epidemiological Research, Department of Obstetrics and Gynecology, Duke University, United States
c
Department of Obstetrics and Gynecology, Duke University Medical Center, United States
d
Department of Radiation Oncology, Duke University Medical Center, United States
e
Duke Cancer Institute, Durham, NC 27710, United States

H I G H L I G H T S

• A cost-effectiveness model compared RRSO+/−hysterectomy for BRCA1 mutation carriers.

• RRSO + immediate hysterectomy is more effective and less costly than RRSO.
• Delayed risk-reducing hysterectomy is cost-effective for up to 25 years after RRSO.

a r t i c l e i n f o a b s t r a c t

Article history: Objective. To estimate the survival benefit and cost-effectiveness of performing hysterectomy during risk-re-
Received 7 March 2017 ducing salpingo-oophorectomy (RRSO) for BRCA1 mutation carriers.
Received in revised form 28 March 2017 Methods. Based on a recent prospective cohort study indicating an elevated incidence of serous/serous-like
Accepted 29 March 2017
uterine cancers among BRCA1 mutation carriers, we constructed a modified Markov decision model from a
Available online xxxx
payer perspective to inform decisions about performance of hysterectomy during RRSO at age 40. We assumed
Keywords:
patients had previously undergone a risk-reducing mastectomy and had a residual risk of death from breast or
Risk-reducing salpingo-oophorectomy ovarian cancer. Disease-specific survival, age-adjusted competing hysterectomy rates, and deaths from other
Hysterectomy causes were incorporated. Costs of risk-reducing surgery, competing hysterectomy, and care for serous/serous-
Cost-effectiveness like uterine cancer were included.
BRCA1 Results. A 40 year old woman who undergoes RRSO + Hysterectomy gains 4.9 additional months of overall
survival (40.38 versus 39.97 undiscounted years) compared to RRSO alone. The lifetime probabilities of develop-
ing or dying from serous/serous-like uterine cancer in the RRSO group are 3.5% and 2%, respectively. The RRSO
alone strategy has an average cost of $9013 compared to $8803 for RRSO + Hysterectomy, and is dominated
(less effective and more costly) when compared to RRSO + Hysterectomy. In an alternative analysis, delayed
hysterectomy remains a cost-effective prevention strategy with an ICER of less than $100,000/year for up to
25 years following RRSO at age 40.
Conclusions. The addition of hysterectomy to RRSO in a 40 year old BRCA1 mutation carrier results in a mean
gain of 4.9 additional months of life and is cost-effective.
© 2017 Elsevier Inc. All rights reserved.

1. Introduction against development of breast and ovarian/fallopian tube malignancy. Re-

Women who are carriers of a germline BRCA1/2 mutation are
counseled about the options of risk-reducing surgery as prophylaxis
⁎ Corresponding author at: Box 3079 DUMC, Durham, NC 27710, United States.
E-mail address: havri001@mc.duke.edu (L.J. Havrilesky).
moval of the uterus at the time of risk-reducing salpingo-oophorectomy
(RRSO) has been considered elective and professional societies have sug-
gested that the decision to perform hysterectomy at time of RRSO should
be individualized [1,2] The risks of hysterectomy include the known
short-term surgical risks as well as potential impact on the long-term
rates of pelvic organ prolapse and urinary incontinence [3,4]. Benefits of

http://dx.doi.org/10.1016/j.ygyno.2017.03.025
0090-8258/© 2017 Elsevier Inc. All rights reserved.

Please cite this article as: L.J. Havrilesky, et al., Mortality reduction and cost-effectiveness of performing hysterectomy at the time of risk-reducing
salpingo-oophorectomy for proph..., Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.025
2 L.J. Havrilesky et al. / Gynecologic Oncology xxx (2017) xxx–xxx

hysterectomy in this cohort include prevention of uterine cancers and 2. Methods

avoidance of progesterone in cases where hormone replacement therapy
is desired following oophorectomy.
The risk of uterine cancer and the distribution of its subtypes among
BRCA carriers compared to non-carriers has been controversial, with
some studies suggesting no difference in risk [5,6] and others suggesting
greater risk and more aggressive subtypes among mutation carriers [7,
8]. A recently published multicenter prospective cohort study demon-
strated a markedly elevated observed-to-expected ratio of serous and
serous-like endometrial carcinomas among BRCA1 mutation carriers
(22.2; 95% CI 6.1–56.9), but not BRCA2 carriers, compared to the general
population [9]. This data raises the possibility that hysterectomy at the
time of RRSO may confer a long-term survival benefit. We therefore
constructed a decision model to estimate the mortality reduction bene-
fit and cost-effectiveness of hysterectomy performed at the time of
RRSO among BRCA1 carriers.
2.1. Model
A modified Markov state transition model was constructed from a
health care sector perspective to inform the decision of a BRCA1 muta-
tion carrier to pursue RRSO versus RRSO and hysterectomy (RRSO +
Hysterectomy) as surgical prophylaxis against gynecologic cancers at
age 40. Primary model outcomes were undiscounted life expectancy
and discounted cost-effectiveness, calculated using discounted costs
and discounted life expectancy. A lifetime horizon was used. A set of ex-
haustive and mutually exclusive Markov states were constructed: Alive
with no cancer, Alive with no cancer/prior hysterectomy, Alive with se-
rous/serous-like endometrial carcinoma, Long term survivor of serous/
serous-like endometrial carcinoma, Dead of ovarian/fallopian tube/peri-
toneal cancer, Dead of breast cancer, Dead of other causes, Dead of

Fig. 1. Effect of time to delayed hysterectomy on incremental cost-effectiveness ratio.

Please cite this article as: L.J. Havrilesky, et al., Mortality reduction and cost-effectiveness of performing hysterectomy at the time of risk-reducing
salpingo-oophorectomy for proph..., Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.025
 L.J. Havrilesky et al. / Gynecologic Oncology xxx (2017) xxx–xxx 3

Table 1
Model parameters.

Range for sensitivity Distribution

Parameter Estimate analysis type Source

Annual incidence of serous/serous-like endometrial cancer 0.00106 N/A N/A Shu et al. [9].
Survival from serous/serous-like endometrial cancer Variable, age-related N/A beta SEERStat 8.3.2
Annual probability of death from breast cancer follow risk-reducing mastectomy 0.001125 0–0.00575 N/A Kurian et al. [10].
Annual probability of death from ovarian/fallopian tube/peritoneal cancer following RRSO 0.0015375 0–0.0025 N/A
Annual incidence of competing hysterectomy Variable, age-associated 0.00164–0.01103 N/A Babalola et al. [15].

Cost of surgery Median Mean Interquartile range Source

Cost of RRSO $5300 $5988 $4010–$7326 lognormal Wright et al. [16].

Cost of risk-reducing or competing hysterectomy+/−RRSO $7682 $8299 $5977–$9976 lognormal Wright et al. [17].

Cost of care for serous/serous-like endometrial cancer Median Mean 95% Confidence intervals Source

Initial year $23,405 $23,426 $22,459–$24,392 lognormal Yabroff et al. [22]

Annual cost $1310 $1319 $1166–$1473 lognormal
Final year $35,478 $35,497 $34,227–$36,766 lognormal

Adverse events following hysterectomy Median Mean Distribution type Source Clinical rate Distribution type Source

Urinary tract infection (ICD-9 599.0) $6823 $5436 lognormal HCUPnet [24] 5/130 beta Cochrane review [19]
Wound infection (ICD-9 998.59) $13,881 $8658 3/100
Vaginal cuff infection (ICD-9 998.59) $13,881 $8658 3/139
Venous thromboembolism (ICD-9 453.4) $7991 $5753 2/366

SEER, Surveillance, Epidemiology, and End Results; RRSO, risk-reducing salpingo-oophorectomy; ICD, International Classification of Diseases; HCUP, Healthcare Cost and Utilization
Project.

serous/serous-like endometrial carcinoma. The basic model structure is
displayed in Fig. 1. All patients were assumed to start in the Alive with
no cancer state at age 40, following risk-reducing bilateral mastectomy
and RRSO+/−hysterectomy. We assumed that risk-reducing hysterec-
tomy was completely protective against subsequent uterine cancer. The
annual risks of dying from breast or ovarian/fallopian tube/peritoneal
cancer (henceforth referred to as ovarian cancer) were assigned based
on a previously published model by Kurian et al. [10]. Non-serous/se-
rous-like endometrial carcinomas were not included in the model as
they do not occur at higher rates among BRCA1 mutation carriers. In
the RRSO arm, the risk of serous/serous-like cancers was modeled
using the recently published data of Shu et al. [9] as a constant annual
incidence of 0.00106. The annual probability of dying from serous/se-
rous-like (henceforth referred to as serous) endometrial cancer during
years 0–10 following diagnosis was modeled using Surveillance, Epide-
miology and End Results (SEER) 18 registries, 1973–2013. Data was
accessed via SEER*Stat v 8.3.2(Surveillance Research Program, NCI)
[11]. Cancer-specific survival was modeled for all stages together but
stratified by decade of cancer diagnosis. Survival data were modeled an-
nually as beta distributions as previously described [12]. Women who
survived more than 10 years after a diagnosis of serous endometrial car-
cinoma were considered to be long-term survivors and could no longer
die from this cancer. Death from other causes was modeled using US Life
Tables [13]. In order to express the true expected clinical benefit of each
strategy to providers and patients, life expectancy was undiscounted for
the primary analysis. In order to conform with the standards of cost-ef-
fectiveness analysis, life expectancy was discounted at 3% annually for
calculation of incremental cost-effectiveness ratios (ICERs) [14]. In the
RRSO arm, the annual age-associated risk of competing hysterectomy
for indications other than serous endometrial carcinoma was modeled
from a retrospective cohort study of women in Olmsted County, MN be-
tween 1995 and 2002 [15]. Table 1 displays model input parameters.
2.2. Costs
The costs of surgery were estimated using previously published
claims data from a third party payer database [16,17]. Costs of surgical
procedures were estimated as total costs incurred during the primary
surgical encounter. The cost of RRSO was estimated as the cost of lapa-
roscopic oophorectomy for benign indications; costs of prophylactic
hysterectomy and competing hysterectomy were estimated as the
cost of total laparoscopic hysterectomy [16,18]. Rates of conversion to
laparotomy were incorporated based on conversion rates reported in a
2015 Cochrane review [19]; the additional costs associated with lapa-
rotomy were estimated at 20% based on several studies comparing lap-
aroscopic to open hysterectomy [20,21]. The costs of care for
endometrial carcinoma were estimated using a retrospective analysis
of longitudinal Medicare claims data from cancer patients, divided
into cost of the first year of care, annual cost of ongoing care, and the
cost in the final year of life [22]. All costs were inflated to 2015 US dollars
using medical inflation [23] and modeled as lognormal distributions
using available confidence intervals and interquartile ranges (Table 1).
Costs were discounted at a rate of 3% annually [14].
2.3. Complications of hysterectomy
To account for the additional costs of delayed adverse events associ-
ated with hysterectomy, we incorporated the rates and costs of the fol-
lowing post-hysterectomy complications that might be expected to
incur costs after the initial surgical hospital encounter: urinary tract in-
fection, wound infection, vaginal cuff infection, and venous thrombo-
embolic events. Rates of each adverse event were modeled from a
2015 Cochrane review of laparoscopic hysterectomy [19]. Costs of
these adverse events were estimated using ICD-9 diagnosis-linked inpa-
tient costs from the National Inpatient Sample (NIS), Healthcare Cost
and Utilization Project (HCUP), Agency for Healthcare Research and
Quality [24]. While acknowledging that many delayed adverse events
do not require inpatient treatment, we chose to err on the side of as-
suming higher costs for the hysterectomy strategy.
2.4. Quality of life
In the base case, we assumed equal quality of life for both strategies.
While several studies have suggested that women undergoing premen-
opausal RRSO have a meaningful decrement in quality of life, particular-
ly with regard to vasomotor symptoms and sexual functioning [25,26],
available data suggests that hysterectomy for benign medical indica-
tions is generally associated with improvements in quality of life [27,
28]. Given this, while there are no prospective data directly comparing
QOL between RRSO and RRSO + Hysterectomy, there are no compelling

Please cite this article as: L.J. Havrilesky, et al., Mortality reduction and cost-effectiveness of performing hysterectomy at the time of risk-reducing
salpingo-oophorectomy for proph..., Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.025
4 L.J. Havrilesky et al. / Gynecologic Oncology xxx (2017) xxx–xxx

data to suggest that QOL would be significantly lower in the RRSO + (6.1) as the true HR and explored the cost-effectiveness of RRSO + im-
Hysterectomy arm. However, we performed a sensitivity analysis in mediate or delayed hysterectomy at that lower bound HR.
which RRSO with risk-reducing hysterectomy resulted in a small long-
term QOL decrement compared to RRSO alone. 3. Results

2.5. Sensitivity analyses 3.1. Undiscounted survival and mortality

To account for uncertainty around estimates, the primary model was
run as a Monte Carlo probabilistic sensitivity analysis with 1000
microsimulations and 1000 second order parameter samples per run.
This allowed construction of cost-effectiveness acceptability curves
(CEACs), which provide effective confidence intervals around cost-ef-
fectiveness estimates. In addition, we varied the expected probability
that a BRCA1 mutation carrier will develop breast or ovarian/fallopian
tube/peritoneal cancer following risk-reducing surgery over clinically
plausible ranges (Table 1). For breast cancer, we simulated a higher
rate of death from breast cancer over a lifetime (upper estimate 23%) ef-
fectively also simulating breast screening without risk-reducing mas-
tectomy over a lifetime. Finally, the discount rate was varied between
2 and 5% for sensitivity analysis.
2.6. Alternative analyses
2.6.1. Delayed hysterectomy
To address the question of whether hysterectomy for prophylaxis
against serous endometrial cancer improved life expectancy or might
be considered cost-effective when considered some time period after
performance of RRSO, we constructed a delayed hysterectomy scenario
in which the time between RRSO and prophylactic hysterectomy was
varied between 5 and 30 years. We also examined the effects of time
to delayed hysterectomy on an alternative cost-benefit metric, the num-
ber of prophylactic hysterectomies performed per serous or serous-like
uterine cancer prevented.
2.6.2. Competing hysterectomy rates
Based on observed trends of a decrease in the incidence of hysterec-
tomy over time [15], we examined a scenario in which competing hys-
terectomy are lower by 50% than rates modeled using available
population-based data.
2.6.3. Incidence of serous uterine cancers
To address the alternative method, described by Shu et al. [9], of es-
timating serous uterine cancer incidence using a constant hazard ratio
rather than a constant annual incidence rate, we modeled the incidence
of serous uterine cancers in each 5 year age bracket by applying the ob-
served to expected HR of 22.2 (95% CI 6.1–56.9) to the age-associated
observed incidence of serous/serous-like cancers reported within the
SEER registries (Surveillance Research Program, National Cancer Insti-
tute SEER*Stat software (seer.cancer.gov/seerstat) version 8.3.2) [11]
We then modeled the lower bound of the described confidence interval
In the base case, a 40 year old woman gains 4.9 undiscounted
months of life if she undergoes RRSO + Hysterectomy (40.38 years)
compared to RRSO (39.97 years).
The lifetime probability of hysterectomy for other indications is 23%.
The lifetime probability of death from breast cancer is 4.4% in each arm,
and from ovarian cancer, 6% in each arm. The probability of dying from
other causes is 87.6% for RRSO and 89.4% for RRSO + Hysterectomy. The
lifetime probabilities of developing and dying from serous endometrial
cancer in the RRSO arm are 3.5% and 2.0%, respectively, compared to 0%
and 0% in the RRSO + Hysterectomy arm.
3.2. Cost-effectiveness
In the base case with 3% discounting, RRSO costs $9013 (95% CI
$8597–$9574) and RRSO + Hysterectomy costs $8803 (95% CI
$7942–$11,526). RRSO results in 22.73 discounted life years (95% CI
22.35–23.08) while RRSO + Hysterectomy results in 22.89 discounted
life years (95% CI 22.53–23.25), for a difference of 2 months. RRSO +
Hysterectomy dominates (is both less costly and more effective than)
RRSO. In acceptability curve analysis using a willingness to pay of either
$50,000 or $100,000/year of life saved, RRSO + Hysteretomy is the cost-
effective strategy in 79% of simulations.
3.3. One-way sensitivity analyses
When the probability of death from ovarian cancer following risk-re-
ducing surgery is varied from 0 to 0.0025 annually (varying up to 10%
the lifetime probability of dying from cancer), or the risk of death
from breast cancer varied from 0 to 0.00575 (varying up to 23% the life-
time probability of dying from breast cancer), RRSO remains dominated
by RRSO + Hysterectomy.
When the discount rate is reduced to 2%, RRSO is dominated. At a 5%
discount rate, RRSO + Hysterectomy becomes more costly but remains
more effective with an ICER of $598/YLS compared to RRSO. Similarly,
when the rate of competing hysterectomy is decreased by 50%, RRSO
+ Hysterectomy is also more costly but more effective than RRSO,
with an ICER of $1924/YLS.
3.4. Delayed hysterectomy after RRSO
In the alternative scenario of a woman who has already undergone
RRSO at age 40 and is considering hysterectomy at a later time,
undiscounted life expectancy gained with the addition of hysterectomy
drops from 3.8 additional months at age 45 to less than 1 additional

Table 2
Cost-effectiveness of delayed hysterectomy.

Develop serous/serous-like Die of serous/serous-like Additional months undiscounted ICERa compared to

Strategy uterine cancer (%) uterine cancer (%) life expectancy RRSO ($/YLS)

RRSO age 40 3.5 2.0

RRSO + Hysterectomy age 40 0 0 4.9 Dominant
Delay hysterectomy to age:
45 0.5 0.2 3.8 $45,757
50 1.0 0.45 3.0 $56,276
55 1.4 0.7 1.9 $67,487
60 1.8 0.9 1.4 $79,916
65 2.2 1.1 0.8 $91,580
70 2.5 1.3 0.6 $152,445

RRSO, risk-reducing salpingo-oophorectomy; ICER, incremental cost-effectiveness ratio; YLS, year of life saved.
a
ICER calculated using discounted costs and discounted life expectancy.

Please cite this article as: L.J. Havrilesky, et al., Mortality reduction and cost-effectiveness of performing hysterectomy at the time of risk-reducing
salpingo-oophorectomy for proph..., Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.025
 L.J. Havrilesky et al. / Gynecologic Oncology xxx (2017) xxx–xxx
Fig. 2. Decision tree with Markov states. RRSO, risk-reducing salpingo-oophorectomy.
month at age 70. Delayed hysterectomy remains cost-effective with an
ICER of less than $100,000/YLS until after age 65 (Table 2). Both the
ICER and the number of risk-reducing hysterectomies performed per se-
rous uterine cancer prevented rise as the time to risk-reducing hysterec-
tomy increases. The immediate hysterectomy at age 40 strategy results
in 25 risk-reducing hysterectomies per case of serous uterine cancer
prevented. At a 30 year delay to risk-reducing hysterectomy, 61 hyster-
ectomies must be performed to prevent one case of serous uterine can-
cer (Fig. 2).
3.5. Alternative assumptions
3.5.1. Cancer incidence
When the incidence of uterine cancer is alternatively modeled by
applying Shu et al.’s HR of 22.2 to the observed age-associated inci-
dence, the lifetime risk of developing or dying from serous uterine can-
cer in the RRSO arm are 3.5% and 2.2%, respectively. In this analysis,
RRSO remains dominated by RRSO + Hysterectomy. When we vary
the HR to 6.1 (the lower bound of the 95% CI), RRSO is no longer domi-
nated. However, RRSO + Hysterectomy remains cost-effective with an
ICER of $25,697/YLS compared to RRSO. When assuming this lower
HR, delayed risk-reducing hysterectomy is no longer cost-effective,
with an ICER of $223,697/YLS compared to RRSO if hysterectomy is de-
layed by 1 year.
3.5.2. Quality of life
In an alternative scenario, we varied quality of life following risk-re-
ducing hysterectomy to a minimal clinically meaningful utility decre-
ment of 0.03 and assumed persistence of this decrement until the
normal age of menopause, while assuming no quality of life decrement
results from RRSO. In this scenario, RRSO is both more effective and
cost-effective compared to RRSO + Hysterectomy, with an ICER of
$13,479/QALY.
4. Discussion
Hysterectomy is commonly offered as an elective procedure when
salpingo-oophorectomy is indicated. However, the medical indications
for hysterectomy in the face of a newly diagnosed BRCA mutation are
not straightforward. Decisions about prophylactic surgery are complex
and require consideration of the risks of developing several different
cancers, surgical complications and long-term side effects, as well as
the effects of surgery on sexual function and overall quality of life. The
Please cite this article as: L.J. Havrilesky, et al., Mortality reduction and cost-effectiveness of performing hysterectomy at the time of risk-reducing
salpingo-oophorectomy for proph..., Gynecol Oncol (2017), http://dx.doi.org/10.1016/j.ygyno.2017.03.025
5
current analysis suggests that hysterectomy is highly cost-effective,
and even cost-saving, in the setting of risk-reducing surgery for a
BRCA1 mutation. Further, delayed hysterectomy appears to be cost-ef-
fective for up to 25 years after an RRSO performed at age 40. Strengths
of our model include detailed accounting of the costs of surgery and
its complications, the cost of treating serous uterine cancer, the risk of
competing hysterectomy, the risks of breast and ovarian cancer follow-
ing both RRSO and risk-reducing mastectomy, and the risk of dying from
another cause.
The clinical significance of the 5 additional months of undiscounted
life expectancy provided by the addition of hysterectomy to RRSO at age
40 may seem modest. However, this represents an average benefit
among all women who undergo risk-reducing hysterectomy. Ultimate-
ly, the 3.5% of women who would otherwise develop serous endometri-
al cancer over a lifetime would each accrue a large survival benefit from
hysterectomy. The presentation of such risk information in ways that
women can understand and relate to is critical to shared decision
making.
Shu et al. estimated that women with a BRCA1 mutation have a 2.6 to
4.7% risk of developing serous uterine cancer through age 70, and sug-
gested that prophylactic hysterectomy be considered along with
salpingo-oophorectomy. Our model uses Shu et al.’s more conservative
estimate of a constant annual risk for serous endometrial cancer of 1.06
per 1000 woman years. This results in a modeled lifetime probability of
3.5% that a serous uterine cancer will develop and a 2% chance of
resulting death in the absence of risk-reducing hysterectomy. If we in-
stead use Shu et al.’s less conservative constant mortality ratio of 22.2
(95% CI 6.1–59.9) to model the incidence of serous uterine cancers in
women with a BRCA1 mutation compared to expected rates from
SEER, RRSO is associated with a 2.2% risk of dying of a serous uterine
cancer and remains both more costly and less effective than RRSO +
Hysterectomy.
Our model's results were robust to most alternative and sensitivity
analyses, including increasing the discount rate to 5% and varying the
risk of death from other BRCA-associated cancers. The only scenario in
which our cost-effectiveness model did not favor immediate hysterec-
tomy was under the assumption that hysterectomy significantly de-
creases long-term quality of life beyond the effects of RRSO alone.
Kwon et al. previously demonstrated that the quality of life decrement
associated with risk-reducing surgery for Lynch syndrome has a signif-
icant effect of the cost-effectiveness of cancer prevention strategies [29].
While there are no data specifically comparing quality of life between
women undergoing RRSO and RRSO + Hysterectomy, a long-term
6 L.J. Havrilesky et al. / Gynecologic Oncology xxx (2017) xxx–xxx
additional decrement related to the hysterectomy alone is unlikely. In a
second alternative analysis, immediate, but not delayed, risk-reducing
hysterectomy was cost-effective when the lowest HR estimate (6.1)
was used to model serous uterine cancer incidence.
There are a number of limitations to the current model. First, we did
not incorporate non-serous uterine cancers. While the competing hys-
terectomy risk used in our model includes hysterectomy for any malig-
nancy, adjuvant therapies for lower risk uterine cancers are not
included here. While inclusion of the costs of treating these lower risk
cancers in the model would be expected to make risk-reducing hyster-
ectomy even more economically attractive than is represented here,
they would not be expected to add significantly to uterine cancer mor-
tality. Second, competing hysterectomy rates may be decreasing over
time due to the availability of alternative treatments for conditions
such as fibroids [15]. In our sensitivity analysis, we examined the setting
of a 50% lower rate of competing hysterectomy. Under these assump-
tions, RRSO + immediate hysterectomy was more costly than RRSO
but remained very cost-effective. Third, in assigning costs to the risks
of hysterectomy, we assumed that the costs of some short term surgical
complications, such as hemorrhage events, would be included in part
the cost of the initial surgical encounter. While late hemorrhage is un-
likely, it may occur and would be unaccounted for by our model. For ad-
verse events assumed to occur after the primary surgical encounter for
hysterectomy, such as venous thromboembolic events, we assigned an
inpatient cost for their treatment. This would, however, tend to increase
the cost of hysterectomy in the model. Finally, we did not incorporate
the risks of treating breast and ovarian cancers that occur after RRSO
and risk-reducing mastectomy. However, the rates of these cancers
should be approximately equivalent regardless of the performance of
prophylactic hysterectomy.
In summary, our model suggests that hysterectomy performed ei-
ther at the time of RRSO or as a subsequent procedure by age 65 is a
cost-effective intervention to prevent mortality from BRCA1-associated
serous uterine cancer. Immediate and earliest delayed hysterectomy
are both most cost-effective and provide the highest life expectancy.
As is the case with all risk-reducing strategies, cost-effectiveness is
only one component of a complex decision making process. The specific
approach that makes the most sense for an individual woman is still
best determined in the setting of a comprehensive discussion between
the specific woman and a health care provider experienced in the man-
agement of individuals at inherited risk.
Conflict of interest statement
None of the authors have any conflict of interest related to this work.
Appendix A. Supplementary data
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.ygyno.2017.03.025.
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