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Risks of breast, ovarian, and
contralateral breast cancer
for BRCA1- and BRCA2-
mutation carriers
JAMA: The Journal of the American Medical Association
Take-home message
•
This prospective study evaluated the impact of mutation type, location, and family
history on the incidence and risk of breast, ovarian, and contralateral breast cancer.
Analysis of 6030 BRCA1 female carriers revealed a rapid increase in the incidence
of breast cancer until ages 30 to 40, which stabilized until age 80, resulting in a
72% cumulative risk of breast cancer in BRCA1 carriers. Analysis of 3820 BRCA2
carriers revealed an increasing incidence of breast cancer until age 40 to 50,
which stabilizes through age 80, leading to a 69% cumulative risk of breast cancer
in BRCA2 carriers. For BRCA1 and BRCA2 carriers up to 80 years of age, the
cumulative risk of ovarian cancer was 44% and 17%, respectively, and the cumulative
risk of contralateral breast cancer was 40% and 26%, respectively. There was a
significant trend between the number of close relatives diagnosed with breast
cancer and increased risk.
•
The study highlights the importance of mutation location and family history during
risk assessment of breast cancer patients.
Abstract
IMPORTANCE
The clinical management of BRCA1
and BRCA2 mutation carriers requires accurate,
prospective cancer risk estimates.
OBJECTIVES
To estimate age-specific risks of
breast, ovarian, and contralateral breast can-
cer for mutation carriers and to evaluate risk
modification by family cancer history and muta-
tion location.
DESIGN, SETTING, AND PARTICIPANTS
Prospective
cohort study of 6036 BRCA1 and 3820 BRCA2
female carriers (5046 unaffected and 4810 with
breast or ovarian cancer or both at baseline)
recruited in 1997–2011 through the International
BRCA1/2 Carrier Cohort Study, the Breast Can-
cer Family Registry and the Kathleen Cuningham
Foundation Consortium for Research into Famil-
ial Breast Cancer, with ascertainment through
family clinics (94%) and population-based stud-
ies (6%). The majority were from large national
studies in the United Kingdom (EMBRACE), the
Netherlands (HEBON), and France (GENEPSO).
Follow-up ended December 2013; median fol-
low-up was 5 years.
EXPOSURES
BRCA1/2 mutations, family cancer
history, and mutation location.
MAIN OUTCOMES AND MEASURES
Annual inci-
dences, standardized incidence ratios, and
cumulative risks of breast, ovarian, and con-
tralateral breast cancer.
RESULTS
Among 3886 women (median age, 38
years; interquartile range [IQR], 30–46 years)
eligible for the breast cancer analysis, 5066
women (median age, 38 years; IQR, 31–47 years)
eligible for the ovarian cancer analysis, and 2213
women (median age, 47 years; IQR, 40–55 years)
eligible for the contralateral breast cancer analy-
sis, 426 were diagnosed with breast cancer, 109
with ovarian cancer, and 245 with contralateral
breast cancer during follow-up. The cumulative
breast cancer risk to age 80 years was 72%
(95% CI, 65–79%) for BRCA1 and 69% (95% CI,
61–77%) for BRCA2 carriers. Breast cancer inci-
dences increased rapidly in early adulthood
until ages 30 to 40 years for BRCA1 and until
ages 40 to 50 years for BRCA2 carriers, then
remained at a similar, constant incidence (20–30
per 1000 person-years) until age 80 years. The
cumulative ovarian cancer risk to age 80 years
was 44% (95% CI, 36–53%) for BRCA1 and 17%
(95% CI, 11–25%) for BRCA2 carriers. For con-
tralateral breast cancer, the cumulative risk 20
years after breast cancer diagnosis was 40%
(95% CI, 35–45%) for BRCA1 and 26% (95% CI,
20–33%) for BRCA2 carriers (hazard ratio [HR]
for comparing BRCA2 vs BRCA1, 0.62; 95% CI,
0.47–0.82; P=0.001 for difference). Breast can-
cer risk increased with increasing number of
first- and second-degree relatives diagnosed as
having breast cancer for both BRCA1 (HR for ≥2
vs 0 affected relatives, 1.99; 95% CI, 1.41–2.82;
P<0.001 for trend) and BRCA2 carriers (HR, 1.91;
95% CI, 1.08–3.37; P=0.02 for trend). Breast can-
cer risk was higher if mutations were located
outside vs within the regions bounded by posi-
tions c.2282–c.4071 in BRCA1 (HR, 1.46; 95% CI,
1.11–1.93; P=0.007) and c.2831–c.6401 in BRCA2
(HR, 1.93; 95% CI, 1.36–2.74; P<0.001).
CONCLUSIONS AND RELEVANCE
These findings
provide estimates of cancer risk based on
BRCA1 and BRCA2 mutation carrier status using
prospective data collection and demonstrate
the potential importance of family history and
mutation location in risk assessment.
Risks of breast, ovarian, and contralateral breast
cancer for BRCA1 and BRCA2 mutation carri-
ers.
JAMA
2017 Jun 20;317(23)2402-2416, KB
Kuchenbaecker, JL Hopper, DR Barnes, et al.
COMMENT
By Lee S. Schwartzberg
MD, FACP
W
omen with hereditary BRCA1/2
mutations have an increased
lifetime risk of developing
breast cancer and ovarian cancer. With
increased availability and affordabil-
ity of testing, more women are being
informed that they are mutation carriers.
It is therefore critical to counsel them
correctly as to their risk of developing
these diseases and the timing of risk-re-
ducing interventions such as surgery.
For the first time, investigators have pub-
lished in
JAMA
the results of a large
prospective cohort study of BRCA1/2 muta-
tion carriers, which clearly defines the risk
of cancer with much less intrinsic bias and
more precise estimates than previous retro-
spective studies. Several findings stand out:
1) The cumulative lifetime risk of breast can-
cer is high at about 70% to age 80 in both
BRCA1 and -2 carriers, while the risk of
ovarian cancer is far lower in BRCA2 than
BRCA1 carriers. BRCA2 ovarian incidence
does not begin until after age 50, while
the risk starts at age 35 to 40 with BRCA1.
For young carriers who wish to have chil-
dren, this information is important.
2) Family history matters – there is approxi-
mately a doubling of risk of breast cancer
if at least one first-degree relative also has
the disease. Similarly, family history of ovar-
ian cancer increases the risk of that disease.
3) Contralateral breast cancer rates are high,
up to 50% to 60% overall, but much lower
for BRCA2 carriers if the first breast can-
cer occurred after the age of 50 years.
4) Mutation location matters – there are areas
in the genes that are associated with rel-
atively higher or lower risk of breast and
ovarian cancer. All mutations are not equal.
These results will aid the decision-mak-
ing process for women identified as BRCA
mutation carriers. Perhaps, most importantly,
risk reduction bilateral salpingo-oophorec-
tomy should be approached differently in
BRCA1 vs 2 patients, while bilateral prophy-
lactic mastectomy recommendations should
probably be similar regardless of the gene
involved. More accurate estimations of risk
will reduce the uncertainty inherent in the
shared decision-making process. Compre-
hensive family history and careful analysis
of the mutation location are important and
are best accomplished by utilizing genetic
counselors in the result delivery discussion
when surveillance and treatment decisions
are being made.
BREAST
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