Systematic Evidence Review for the U.S. Preventive Services Task Force
Heidi D. Nelson, M.D., M.P.H.; Laurie Hoyt Huffman, M.S.; Rongwei Fu, Ph.D.; and Emily L. Harris, Ph.D., M.P.H.
The authors of this article are responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the Agency for Healthcare Research and Quality, the Centers for Disease Control and Prevention, or the U.S. Department of Health and Human Services.
This article was originally published in Ann Intern Med. 2005;143:362-379.
Contents
Abstract
Introduction
Methods
Data Synthesis
Discussion
References
Notes
Appendix 1
Appendix 2
Appendix 3
Abstract
Background: Clinically significant mutations of BRCA1 and
BRCA2 genes are associated with increased susceptibility for
breast and ovarian cancer. Although these mutations are uncommon,
public interest in testing for them is growing.
Purpose: To determine benefits and harms of screening for inherited
breast and ovarian cancer susceptibility in the general
population of women without cancer presenting for primary health
care in the United States.
Data Sources: MEDLINE (1966 to 1 October 2004), Cochrane
Library databases, reference lists, reviews, Web sites, and experts.
Study Selection: Eligibility was determined by inclusion criteria
specific to key questions about risk assessment, genetic counseling,
mutation testing, prevention interventions, and potential adverse
effects.
Data Extraction: After review of studies, data were extracted,
entered into evidence tables, and summarized by using descriptive
or statistical methods. Study quality was rated by using predefined
criteria.
Data Synthesis: Tools assessing risks for mutations and referral
guidelines have been developed; their accuracy, effectiveness, and
adverse effects in primary care settings are unknown. Risk assessment,
genetic counseling, and mutation testing did not cause
adverse psychological outcomes, and counseling improved distress
and risk perception in the highly selected populations studied.
Intensive cancer screening studies are inconclusive. Chemoprevention
trials indicate risk reduction for breast cancer in women with
varying levels of risk, as well as increased adverse effects. Observational
studies of prophylactic surgeries report reduced risks for
breast and ovarian cancer in mutation carriers.
Limitations: No data describe the range of risk associated with
BRCA mutations, genetic heterogeneity, and moderating factors;
studies conducted in highly selected populations contain biases;
and information on adverse effects is incomplete.
Conclusions: A primary care approach to screening for inherited
breast and ovarian cancer susceptibility has not been evaluated,
and evidence is lacking to determine benefits and harms for the
general population.
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Introduction
Clinically significant, or deleterious, mutations of
BRCA1 and BRCA2 genes are associated with increased
susceptibility for breast and ovarian cancer.1,2
These mutations increase a woman's lifetime risk for breast
cancer to 60% to 85%3,4 and risk for ovarian cancer to
26% (BRCA1) and 10% (BRCA2).5-8 Specific BRCA mutations are clustered among certain ethnic groups, such
as Ashkenazi Jews,9-11 and in the Netherlands,12
Iceland,13,14 and Sweden.15 Additional germline
mutations associated with familial breast or ovarian cancer
have been identified, and others are suspected.16,17
BRCA1 and BRCA2 mutations are also associated with increased
risk for prostate cancer, and BRCA2 mutations are
associated with increased risk for pancreatic and stomach
cancer and melanoma.18
Screening for inherited breast and ovarian cancer susceptibility
is a 2-step process: assessment of risk for clinically
significant BRCA mutations followed by genetic testing
of high-risk individuals. Guidelines recommend testing
for mutations only when an individual has personal or
family history features suggestive of inherited cancer susceptibility,
when the test result can be adequately interpreted,
and when results will aid in management.19,20 Several characteristics are associated with an increased likelihood of clinically significant BRCA mutations, including
young age at breast cancer diagnosis, bilateral breast cancer,
history of both breast and ovarian cancer, multiple cases of
breast cancer in a family, both breast and ovarian cancer in
a family, and Ashkenazi Jewish heritage.21-24 Risk status
requires reevaluation when personal or family cancer
history changes. Genetic counseling is recommended before
mutation testing.25 Several approaches are in practice,
including educational; decision-making; and psychosocial
support26,27 provided by genetic counselors,28-30 nurse educators,31-33 or other professionals.
The type of mutation analysis required depends on
family history. Individuals from families or ethnic groups
with known mutations can be tested specifically for them.
Several clinical laboratories in the United States test for
specific mutations or sequence-specific exons. Individuals
without linkages to others with known mutations undergo
direct DNA sequencing. In these cases, guidelines recommend
that testing begin with a relative who has known
breast or ovarian cancer to determine whether a clinically
significant mutation is segregating in the family.19
Myriad Genetic Laboratories provides direct DNA sequencing
in the United States and reports analytic sensitivity
and specificity exceeding 99%.34 Approximately
12% of high-risk families without a BRCA1 or BRCA2 coding-region mutation may have other clinically significant genomic rearrangements34,35 Test results include
not only positive (denoting a deleterious mutation) and
negative (no mutation found) interpretations but also variants
of uncertain clinical significance; this last group represents
up to 13% of results.21 The results of genetic
testing could lead to prevention interventions for reducing
risk or mortality in mutation carriers. Experts recommend
earlier and more frequent cancer screening, chemoprevention,
and prophylactic surgery (Table 1).36-40
Although clinically significant BRCA mutations are estimated
to occur in 1 in 300 to 500 persons in the general
population,41-44 public interest in testing is growing,
and physicians are increasingly faced with this issue while
providing primary health care. Women often overestimate
their risks for breast cancer or BRCA mutations,32,45,46 and most women responding to surveys, including women at average and moderate risk, report a strong desire
for genetic testing,27,47 even though only those at high
risk would potentially benefit. Concerns about cancer,
publicized scientific advances, incomplete understanding of
testing and interventions, and direct-to-consumer advertising
probably influence these perceptions, increasing demand
for genetic testing services47
The objective of this systematic evidence review is to
determine the benefits and harms of screening for inherited
breast and ovarian cancer susceptibility in the general population
of women presenting for primary health care in the
United States. This review was prepared for the U.S. Preventive
Services Task Force (USPSTF) and examines a
chain of evidence about genetic risk assessment in primary
care settings; impact of genetic counseling; ability to predict
cancer risk in women with average, moderate, and
high risks for clinically significant mutations; benefits of
prevention interventions; and potential adverse effects. A
review of studies about Ashkenazi Jewish women specifically is reported elsewhere.48
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Methods
The analytic framework in Figure 1 outlines the patient
population, interventions, and health outcomes. This
report focuses on the following key questions:
1. Do risk assessment and BRCA mutation testing lead to a reduction in the incidence of breast and ovarian cancer and cause-specific or all-cause mortality?
2A. How well does risk assessment for cancer susceptibility by a clinician in a primary care setting select candidates for BRCA mutation testing?
2B. What are the benefits of genetic counseling before testing?
2C. Among women with family histories predicting an average, moderate, or high risk for a deleterious mutation, how well does BRCA mutation testing predict risk for breast and ovarian cancer?
3. What are the adverse effects of risk assessment, genetic counseling, and testing?
4. How well do interventions reduce the incidence and mortality of breast and ovarian cancer in women identified as high risk by history, positive genetic test results, or both?
5. What are the adverse effects of interventions?
We identified relevant papers from multiple searches
of MEDLINE® (1966 to 1 October 2004) and the Cochrane
Library databases; we obtained additional papers by
reviewing reference lists of pertinent studies, reviews, editorials,
and Web sites and by consulting experts (Appendix Figure). Investigators reviewed
all abstracts and determined eligibility by applying
inclusion and exclusion criteria specific to key questions
(Appendix Table). We then reviewed full-text papers of included abstracts for relevance.
Studies about patients with current or past breast or
ovarian cancer were excluded unless they addressed genetic
testing issues in women without cancer. Data were extracted
from each included study, entered into evidence
tables, and summarized by using descriptive or statistical
methods or both. Two reviewers independently rated the
quality of studies using criteria specific to different study
designs developed by the USPSTF (Appendix 1).49 When reviewers disagreed, a final
rating was determined by reevaluations by the 2 initial
reviewers and a third reviewer if needed. Only studies rated
good or fair in quality were included, although studies with
designs that do not have quality rating criteria, such as
descriptive studies, were also included if relevant to the key
questions.
To estimate risks for breast and ovarian cancer due to
clinically significant BRCA mutations, the screening population
was stratified into groups at average, moderate, and
high risk for being a mutation carrier based on history of
breast or ovarian cancer in first- and second-degree relatives.
This approach allows use of published data that describe
risks in similar terms. The following definitions were
used: average risk—no first-degree relatives and no more
than 1 second-degree relative on each side of the family
with breast or ovarian cancer; moderate risk—1 first-degree
relative or 2 second-degree relatives on the same side of the
family with breast or ovarian cancer; and high risk—at
least 2 first-degree relatives with breast or ovarian cancer.
On the basis of pooled data from more than 100 000
women without breast cancer from 52 epidemiologic studies,
approximately 92.7% of the screening population
would be expected to be average risk, 6.9% moderate risk,
and 0.4% high risk according to these definitions.50
Risks for breast and ovarian cancer in mutation carriers
have been primarily calculated from families of women
with existing breast and ovarian cancer. To determine benefits
and adverse effects of genetic testing in average-, moderate-, and high-risk groups, we estimated mutation prevalence as well as the probability of developing cancer given
the presence of the mutation (penetrance) for each risk
group. Penetrance was calculated from data about the prevalence
of BRCA mutations in women with and without
breast and ovarian cancer; the probability of breast or ovarian
cancer in the U.S. population estimated from Surveillance,
Epidemiology, and End Result (SEER) data51 by
using DevCan software;52 and relative risks for breast
and ovarian cancer in moderate- and high-risk groups.
Penetrance estimates were based on the Bayes theorem and
stratified by cancer type (breast or ovarian), risk group (average,
moderate, and high), and age whenever data were
available. Appendix 2 (available at www.annals.org) provides
additional details of this method.48
We also performed a meta-analysis of chemoprevention
trials to more precisely estimate effectiveness and adverse
effects. All chemoprevention trials reported relative
risk (RR) estimates, and the logarithm of the RR (logRR)
and the corresponding standard errors were calculated for each trial and used in the meta-analysis. The overall estimates of RR were obtained by using a random-effects model.53
We developed an outcomes table to determine the
magnitude of potential benefits and adverse effects of testing
for BRCA mutations in the general population based
on best estimates from published studies and results of
analyses when available. Variation associated with these estimates
was incorporated by using Monte Carlo simulations.
The sampling distributions for estimates were either
the underlying distribution on which calculation of the
95% CI was based when available, or one that best approximated
the point estimate and CI (Appendix 3, available at
www.annals.org). The point estimates and 95% CIs of outcome
variables were based on 1 000 000 simulations. Since
there are no direct estimates of BRCA mutation prevalence
for average- and moderate-risk groups, sensitivity analyses
were conducted by assuming a range of prevalence values.
Prevalence values were chosen such that when they were
summed across the 3 risk groups, the total fell within the
range for the general population (1 in 300 to 500).41-44 Calculations assumed that women are cancer free at age 20 years, and outcomes were calculated to age 40 years
for breast cancer, age 50 years for ovarian cancer, and age
75 years for both because results at these ages were most
often reported by studies. We assumed that half of the
mutations would be in BRCA1 and half in BRCA2, and we
did sensitivity analyses to determine whether this ratio
(40/60, 50/50, 60/40) affects outcomes.
This research was funded by the Centers for Disease
Control and Prevention under a contract with the Agency
for Healthcare Research and Quality to support the work
of the USPSTF. Agency staff and Task Force members
participated in the initial design of the study, and, along with content experts, reviewed reports. The authors are
responsible for the content of the manuscript and the decision
to submit it for publication.
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