Comparative effectiveness of screening and prevention strategies among BRCA1/2-affected mutation carriers.

Abstract

Comparative effectiveness research has become an integral part of health care planning in most developed countries. In a simulated cohort of women, aged 30-65, who tested positive for BRCA1 or BRCA2 mutations, we compared outcomes of mammography with and without MRI, prophylactic oophorectomy with and without mastectomy, mastectomy alone, and chemoprevention. Methods: Using Treeage 9.02 software, we developed Markov models with 25,000 Monte Carlo simulations and conducted probabilistic sensitivity analysis. We based mutation penetrance rates, breast and ovarian cancer incidence, and mortality rates, and costs in terms of 2009 dollars, on published studies and data from the Surveillance, Epidemiology, and End Results (SEER) Program and the Centers for Medicare and Medicaid Services. We used preference ratings obtained from mutation carriers and controls to adjust survival for quality of life (QALYs). Results: For BRCA1 mutation carriers, prophylactic oophorectomy at $1,741 per QALY, was more cost effective than both surgeries and dominated all other interventions. For BRCA2 carriers, prophylactic oophorectomy, at $4,587 per QALY, was more cost effective than both surgeries. Without quality adjustment, both mastectomy and BSO surgeries dominated all other interventions. In all simulations, preventive surgeries or chemoprevention dominated or were more cost effective than screening because screening modalities were costly. Conclusion: Our analysis suggested that among BRCA1/2 mutation carriers, prophylactic surgery would dominate or be cost effective compared to chemoprevention and screening. Annual screening with MRI and mammography was the most effective strategy because it was associated with the longest quality-adjusted survival, but it was also very expensive.

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EPIDEMIOLOGY
Comparative effectiveness of screening and prevention strategies
among BRCA1/2-affected mutation carriers
Victor R. Grann•Priya R. Patel•Judith S. Jacobson•
Ellen Warner•Daniel F. Heitjan•Maxine Ashby-Thompson•
Dawn L. Hershman•Alfred I. Neugut
Received: 30 June 2010/Accepted: 2 July 2010
? Springer Science+Business Media, LLC. 2010
Abstract
become an integral part of health care planning in most
developed countries. In a simulated cohort of women, aged
30–65, who tested positive for BRCA1 or BRCA2 muta-
tions, we compared outcomes of mammography with and
without MRI, prophylactic oophorectomy with and without
mastectomy, mastectomy alone, and chemoprevention.
Methods: Using Treeage 9.02 software, we developed
Markov models with 25,000 Monte Carlo simulations and
conducted probabilistic sensitivity analysis. We based
mutation penetrance rates, breast and ovarian cancer inci-
dence, and mortality rates, and costs in terms of 2009
dollars, on published studies and data from the Surveil-
lance, Epidemiology, and End Results (SEER) Program
Comparativeeffectivenessresearch has
and the Centers for Medicare and Medicaid Services. We
used preference ratings obtained from mutation carriers
and controls to adjust survival for quality of life (QALYs).
Results: For BRCA1 mutation carriers, prophylactic
oophorectomy at $1,741 per QALY, was more cost effec-
tive than both surgeries and dominated all other interven-
tions. For BRCA2 carriers, prophylactic oophorectomy, at
$4,587 per QALY, was more cost effective than both
surgeries. Without quality adjustment, both mastectomy
and BSO surgeries dominated all other interventions. In all
simulations, preventive surgeries or chemoprevention
dominated or were more cost effective than screening
because screening modalities were costly. Conclusion: Our
analysis suggested that among BRCA1/2 mutation carriers,
prophylactic surgery would dominate or be cost effective
compared to chemoprevention and screening. Annual
screening with MRI and mammography was the most
effective strategy because it was associated with the
Electronic supplementary material
article (doi:10.1007/s10549-010-1043-4) contains supplementary
material, which is available to authorized users.
The online version of this
V. R. Grann ? J. S. Jacobson ? M. Ashby-Thompson ?
D. L. Hershman ? A. I. Neugut
Herbert Irving Comprehensive Cancer Center,
Columbia University, New York, NY, USA
V. R. Grann ? D. L. Hershman ? A. I. Neugut
Department of Medicine, College of Physicians and Surgeons,
Columbia University, New York, NY, USA
V. R. Grann (&) ? J. S. Jacobson ? D. L. Hershman ?
A. I. Neugut
Department of Epidemiology, Joseph L. Mailman School of
Public Health, Columbia University, Room 734, 722 West 168th
Street, New York, NY 10032, USA
e-mail: VRG2@columbia.edu
V. R. Grann
Department of Health Policy and Management, Joseph L.
Mailman School of Public Health, Columbia University,
New York, NY, USA
P. R. Patel
Department of Obstetrics and Gynecology, University of
Pennsylvania School of Medicine, Philadelphia, PA, USA
E. Warner
Sunnybrook Health Sciences Centre, University
of Toronto, Toronto, ON, Canada
D. F. Heitjan
Department of Biostatistics and Epidemiology, University
of Pennsylvania School of Medicine, Philadelphia, PA, USA
123
Breast Cancer Res Treat
DOI 10.1007/s10549-010-1043-4

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longest quality-adjusted survival, but it was also very
expensive.
Keywords
Cost-effectiveness ? Mastectomy ? Oophorectomy or both ?
Tamoxifen ? Screening with MRI and mammography ?
BRCA1/BRCA2
Comparative effectiveness ?
Introduction
Among women with BRCA1 or BRCA2 genetic mutations,
contrast-enhanced magnetic resonance imaging (MRI)
combined with mammography has been recommended by
the American Cancer Society and other authoritative
groups for breast screening [1]. Many women who test
positive for these mutations now choose to be followed
with annual MRI combined with mammography rather
than using chemopreventive agents or undergoing pro-
phylactic mastectomy [2–6]. Although randomized trials
have not been conducted, observational studies have found
that prophylactic mastectomy and/or prophylactic bilateral
salpingoophorectomy (BSO) can delay or prevent cancers
of the breast and ovary among mutation carriers [7–10].
Mammography alone has not been found to be reliable
enough for screening BRCA mutation carriers, in part,
because they are at risk for breast cancer at much younger
ages than non-carriers, and mammography does not accu-
rately detect cancer in the dense breasts of young women.
Recent observational studies have found that screening by
MRI with mammography was effective in detecting early-
stage breast cancers among BRCA1/2 mutation carriers
[11–15]. Currently, mutation carriers who have not been
diagnosed with cancer may choose among or combine
several preventive strategies: primary prevention with
chemopreventive agents (e.g., tamoxifen), prophylactic
mastectomy or prophylactic BSO; and secondary preven-
tion with mammography and MRI [2, 16]. Comparative
effectiveness analysis is increasingly being used to deter-
mine the relative merits of therapeutic interventions in
specific patient populations. In a previous analysis, we
showed that among mutation carriers, BSO with or without
mastectomy was more cost effective than surveillance with
annual mammograms [17–19]. Other analyses compared
MRI with mammography to mammography alone and
found that, although expensive, limited use of MRI might
be more cost effective than mammography [20–22]. Using
recent cancer risk data on women with BRCA1 and BRCA2
mutations, we have now developed new models to estimate
the comparative effectiveness, including quality-adjusted
and unadjusted cost effectiveness, of the primary and
secondary preventive interventions available to mutation
carriers. For quality adjustment, we have used new
preference ratings obtained from both women without
known high risk and a Canadian cohort of BRCA1 or
BRCA2 mutation carriers [23, 24].
Methods
We developed a Markov process [25] and used 25,000
Monte Carlo simulations with TreeAge ProSuite 2009 to
estimate the survival, quality-adjusted survival, and costs
associated with preventive interventions for BRCA1 and
BRCA2 mutation carriers who had no cancer diagnosis at
baseline [26]. The interventions (Fig. 1) were prophylactic
mastectomy, prophylactic BSO, Prophylactic mastectomy
and BSO (both surgeries), tamoxifen, mammography,
mammography plus MRI (MRI), and prophylactic BSO
plus MRI. (We assumed that women who had MRI would
also have mammography because screening with both
modalities is now the standard of care for women aged 30?
years, who have a BRCA1/2 mutation [2].) In previous
studies, we assumed that mammography alone was the
standard of care. We chose five health states as outcomes:
good health, breast cancer, ovarian cancer, both breast and
ovarian cancer, their complications, and death. We used
25,000 simulations for the base case of this study and fol-
lowed individuals for new primary breast and ovarian
cancers from age 30 (base case) to 65 for survival. We
assumed that women who had prophylactic surgery did so at
age 35 and that all women started screening with MRI or
mammogram at age 30 [27]. For each year of each strategy,
we calculated the age-dependent probabilities of developing
breast cancer, developing ovarian cancer, dying from breast
or ovarian cancer, dying from any cause, or remaining well.
We followed all women up to age 100 or death.
Health parameters
We included in our model published estimates of the
cumulative incidence of breast cancer and ovarian cancer
Side
Effects
Breast
Cancer
Ovarian
Cancer
Death
Well
Tamoxifen
Mammography
MRI
Prophylactic
Mastectomy
Prophylactic
Oophorectomy
Prophylactic
Mastectomy/
Oophorectomy
Prophylactic
Oophorectomy/
MRI
Fig. 1 Markov model of BRCA1/2 health states
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among BRCA1/2-positive women by decade [28]. We
converted these 10-year risks to annual conditional prob-
abilities of cancer, assuming constant instantaneous
increases in incidence rates per year (Table 1) [19].
We assumed that among BRCA1/2 mutation carriers,
thosewithbreastcancerhadthesameconditionalprobability
of developing ovarian cancer as those who were well. Using
the U.S. National Cancer Institute’s Surveillance, Epidemi-
ology, and End Results (SEER) program data for the period
1973–2004, we also computed estimates of dying with
and without cancer [29]. Assuming that BRCA1/2-positive
women who developed cancer would have the same
Table 1 Incidence, preventive
strategy risk reduction, and
mortality assumptions used in
the Markov model
* No ovarian cancer in one
study of BRCA2? women, but
not statistically significant.
Assumed 96 ± 0.03 [8]
Variable Value
Health states per 100 persons per year ± SE, n
Breast cancer [19, 28]
BRCA 1 mutation carrier 3.32 ± 0.63
BRCA 2 mutation carrier 3.79 ± 1.07
BRCA 1 and BRCA 2
3.43 ± 0.556
Ovarian cancer [19, 28]
BRCA 1 mutation carrier 1.55 ± 0.304
BRCA 2 mutation carrier0.523 ± 0.031
BRCA 1 and BRCA 2
1.12 ± 0.285
Endometrial cancer due to tamoxifen [33] 0.401 ± 0.019
Pulmonary embolism due to tamoxifen [33]0.320 ± 0.180
Cataracts due to tamoxifen [33]0.110 ± 0.050
Preventive strategies ± SE, %
Breast cancer risk reduction due to
Prophylactic bilateral mastectomy [19, 51] 90 ± 5
Mastectomy and oophorectomy [9, 51]95 ± 5
Tamoxifen [19, 33] 49 ± 7
Oophorectomy before age 50 years
[8, 9, 37, 52]
47 ± 1
Ovarian cancer risk reduction due to
Oophorectomy BRCA1 [6, 8, 36, 37] 96 ± 3
Oophorectomy BRCA2 [6, 8, 36] 96 ± 3*
Oral contraceptives [47]54 ± 11
Estrogen receptor? by age and mutation % [35]
BRCA1
30–49 18% ± 2
50–6922% ± 2
C7024% ± 2
BRCA2
30–49 62% ± 2
50–6975% ± 2
C7083% ± 2
Mortality
Breast cancer1 - SEER survival rates B0–16 years after diagnosis;
U.S. population mortality rates thereafter [29]
Ovarian cancer1 - SEER survival rates B0–10 years after diagnosis;
U.S. population mortality rates thereafter [29]
Endometrial cancer1 - SEER survival rates B5 years after diagnosis;
U.S. population rates[5 years, includes 15% of mixed
Mullarian tumors 0–5 years after diagnosis [31];
U.S. population rates [29, 33]
Pulmonary embolism 3% in first year; U.S. population rates after 1 year
[29, 33]
CataractsU.S. population rates [29, 33]
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conditionalprobabilityofdeathaswomenwith cancerinthe
general population, we used SEER data to calculate the
probabilities of dying [29]. We did not adjust our ovarian
cancer survival estimates for screening because heightened
surveillance does not appear to alter the prognosis of this
cancer [30–32].
For women diagnosed with breast cancer, who were not
being screened by MRI, we based our stage distribution
assumptions on the cases among participants in the Breast
Cancer Prevention Trial (BCPT). Of the BCPT participants
in the control arm who developed breast cancer, 70% had
localized (node-negative) and 30% regional (node-positive)
disease [33].
We assumed that patients who had annual MRI
screening would have the same stage distribution as the
cases diagnosed in a cohort of 236 BRCA1 and BRCA2
mutation carriers, aged 25–65 years, who underwent
annual MRI imaging, ultrasound, mammography, and
clinical breast examinations from November 3, 1997 to
March 31, 2003 [2, 3, 14, 34 We applied to our model the
distributions of pathological TNM stages, tumor size,
lymph node status, grade, and hormone receptor status
observed in their cancers [14, 35]. For both groups, we
computed mortality risk based on SEER data for those
distributions [29].
We updated our estimates of the health effects of pre-
ventive strategies to reflect the findings of studies pub-
lished since our previous report. These studies suggest that
prophylactic BSO may reduce the risk of ovarian cancer by
96% for BRCA1 and BRCA2 mutation carriers, respec-
tively, and may reduce the risk of breast cancer among
premenopausal women by 53% for both [8, 36, 37]. Other
studies suggest that prophylactic bilateral mastectomy may
reduce the risk of breast cancer by 90% [8]. Table 1
describes our risk assumptions. For our base case, the risk
reductions associated with these strategies were assumed to
last indefinitely.
We assumed that after prophylactic oophorectomy,
most women would take hormone replacement therapy
(HRT) until age 50, and that HRT would not affect their
risks of breast cancer, cardiovascular disease, or osteo-
porosis [38].
Cost parameters
We obtained age-stratified data on screening and cancer
care costs from the literature and expressed the costs in
terms of 2009 US dollars (Table 2). Drug cost data were
obtained from the Drug Topics Redbook: Pharmacy’s
Fundamental Reference [39]. Patient care costs associated
with cancer were obtained from the literature and are given
in terms of 2009 dollars.
Quality-of-life adjustment
We adjusted our survival estimates for quality of life based
on preference ratings of cancer- and preventive treatment-
related states obtained from both mutation carriers in the
previously described MRI cohort and women without
known high risk (Table 3) [14, 35, 40]. We interpreted the
preferences of the latter group as representing a societal
standard. The preference ratings were derived from
responses to a time trade-off questionnaire, which pre-
sented vignettes or scenarios involving various cancer-
related states and asked respondents how much of their life
expectancy they would trade to avoid those states. The
states were breast cancer, ovarian cancer, bilateral mas-
tectomy, BSO, both surgeries, use of a chemopreventive
medication (tamoxifen), mammography, and MRI. The
cancer state vignettes quantified the risk of recurrence and
the effect of the cancer on life expectancy. Each vignette
was based on literature review, patient interviews, and
professional oncological experience. The preference rating
was calculated as total life expectancy minus traded time,
divided by total life expectancy.
Comparative effectiveness analysis
We computed the mean cost (SD) of each intervention for a
BRCA1 or BRCA2 mutation carrier to those who chose it.
We then listed the interventions in the order of costs from
the least to the most expensive. We computed the incre-
mental cost of each intervention over that of the next most
expensive one. We computed the mean survival (SD) in
life years (LYs) or quality-adjusted life years (QALYs)
associated with each intervention, and their incremental
LYs or QALYs (positive or negative) above that associated
with the least expensive intervention. Interventions that
were more expensive and less effective (in LYs or QALYs)
were designated as dominated. Extended dominance rep-
resents the percentage of the population that receives the
less effective treatment and is considered dominated
(Appendix Figure 4).
Results
Table 4 presents the results of the comparative effective-
ness analyses, which we conducted separately for BRCA1
and BRCA2 mutation carriers. Based on the preferences of
women without known high risk for breast or ovarian
cancer, the optimal strategy for BRCA1 mutation carriers
was BSO, with an incremental cost effectiveness ratio
(ICER) of $1,741 per QALY compared to both surgeries;
for BRCA2 mutation carriers, BSO had an ICER of $4,587
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(Table 4). With quality adjustment based on mutation
carriers’ preferences, the optimal strategy for BRCA1
mutation carriers was still BSO, with an ICER of $1,677
per QALY. For BRCA2 mutation carriers, prophylactic
oophorectomy had extended dominance over bilateral
mastectomy with an ICER of $4,535 per QALY (Table 4).
MRI plus BSO was associated with the most QALYs of
any strategy for BRCA1 carriers, but at a cost of $170,899
and an unacceptable ICER of $736,788 per QALY com-
pared to prophylactic oophorectomy alone.
Without quality adjustment, using LYs saved, the opti-
mal strategy adopted for both BRCA1 and BRCA2 was
prophylactic surgery, as it was the most effective and the
least expensive (Table 4).
Table 2 Medical costs used in
the Markov model in terms of
2009 dollarsa,b
aThe discount rate (range) was
3% (0–5%). DRG diagnosis-
related group, NCCN National
Comprehensive Cancer
Network, V/Q ventilation-
perfusion
bAdjusted by the Medical
Consumer Price Index into 2009
US$ [65]
cYearly costs for patients with
breast cancer apply to years
2–16 after diagnosis. Cost for
years[16 are the same as those
for healthy women
Variable (reference)Total costs (direct ? indirect),
US$
First year after diagnosis [53–59]22,375b(DCIS)
74,149b(breast cancer)
107,619b(ovarian cancer)
6,506c(breast cancer)
11,831b(ovarian cancer)
Subsequent yearly costs [54, 56, 58–60]
Terminal care costs, last year of life [54, 58–61] 54,991 (breast cancer)
75,188 (ovarian cancer)
Surveillance (per NCCN guidelines) [61] 4,476 (without breast or
ovarian cancer)
Terminal care costs, last year of life [59, 60, 62]36,199 (without breast or
ovarian cancer)
Other medical costsb
Endometrial cancerb[19]
Pulmonary embolib[19, 39]
Cataract surgeryb[19]
6,211
5,173
3,987
Genetic testing and counseling [63]3,175
Preventive strategies
Tamoxifen cost per year for premenopausal women (for 5 years) [39] 727
Letrozole cost per year for postmenopausal women (for 5 years) [39, 64] 3,516
Prophylactic mastectomy [5, 6] 10,591
Prophylactic salpingo-oophorectomy [5, 6]6,373
Both prophylactic mastectomy and salpingo-oophorectomy
Prophylactic salpingo-oophorectomy and tamoxifen\age 50
(includes cost per year for 5 years of tamoxifen) [39]
16,964
10,008
Screening strategies including work and 2009 dollars [20, 27, 54, 65]
Bilateral screening mammogram
Initial screening mammogram 129
Follow-up mammogram120
Ultrasound 112
Mammographic-guided surgical biopsy 1,667
Ultrasound-guided core needle biopsy716
Stereotactic biopsy997
Ultrasound-guided fine needle biopsy581
Average total diagnostic cost following mammographic screening31
Bilateral screening MRI
Initial screening MRI1,219
Short interval follow-up MRI 940
MRI-guided surgical biopsy 2,131
MRI-guided core needle biopsy 1,199
Average total diagnostic cost following initial MRI373
Average total diagnostic cost following subsequent MRI209
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