Annals of Oncology
Breast cancer in young women (YBC): prevalence of
BRCA1/2 mutations and risk of secondary malignancies
across diverse racial groups
B. G. Haffty1
*, D. H. Choi2
, S. Goyal1
, A. Silber3
, K. Ranieri4
, E. Matloff5
, M. H. Lee6
, D. Toppmeyer7
& M. S. Moran8
Department of Radiation Oncology, UMDNJ-RWJMS and Cancer Institute of New Jersey, New Brunswick, NJ, USA; 2
Department of Radiation Oncology, Samsung
Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 3
Section of Medical Oncology, Department of Medicine, Yale University School of
Section of Medical Genetics, Cancer Institute of New Jersey; 5
Department of Medical Genetics, Yale University School of Medicine; 6
Department of Surgery,
Soonchunhyang University College of Medicine, Seoul, South Korea; 7
Section of Medical Oncology, Department of Medicine, UMDNJ-RWJMS and Cancer Institute of
New Jersey and 8
Department of Therapeutic Radiology, Yale University School of Medicine
Received 6 December 2008; revised 26 January 2009; accepted 9 February 2009
Background: Despite signiﬁcant differences in age of onset and incidence of breast cancer between Caucasian
(CA), African-American (AA) and Korean (KO) women, little is known about differences in BRCA1/2 mutations in these
populations. The purpose of this study is to evaluate the prevalence of BRCA1/2 mutations and the association
between BRCA1/2 mutation status and secondary malignancies among young women with breast cancer in these
three racially diverse groups.
Methods: Patients presenting to our breast cancer follow-up clinics selected solely on having a known breast cancer
diagnosis at a young age (YBC deﬁned as age <45 years at diagnosis) were invited to participate in this study. A total of
333 eligible women, 166 CA, 66 AA and 101 KO underwent complete sequencing of BRCA1/2 genes. Family history
(FH) was classiﬁed as negative, moderate or strong. BRCA1/2 status was classiﬁed as wild type (WT), variant of
uncertain signiﬁcance (VUS) or deleterious (DEL).
Results: DEL across these three racially diverse populations of YBC were nearly identical: CA 17%, AA 14% and KO
14%. The type of DEL differed with AA having more frequent mutations in BRCA2, compared with CA and KO. VUS
were predominantly in BRCA2 and AA had markedly higher frequency of VUS (38%) compared with CA (10%) and KO
(12%). At 10-year follow-up from the time of initial diagnosis of breast cancer, the risk of secondary malignancies was
similar among WT (14%) and VUS (16%), but markedly higher among DEL (39%).
Conclusions: In these YBC, the frequency of DEL in BRCA1/2 is remarkably similar among the racially diverse groups
at 14%–17%. VUS is more common in AA, but aligns closely with WT in risk of second cancers, age of onset and FH.
Key words: BRCA1, BRCA2, breast cancer, genetics, race
The incidence of breast cancer varies widely across geographic
regions and racial groups, with the highest incidence in
Caucasian (CA) women and lower incidences among African-
American (AA) and Korean (KO) women. In addition,
there are known and marked differences in the age of onset of
breast cancer among racial groups, with CA having an average
age of onset in their 50s, AA in the late 40s and KO even
There are likely multiple environmental, biological and
genetic factors that contribute to the variability in incidence
and age of onset of disease . Despite these marked
differences, little is known about the racial diversity in BRCA1
and BRCA2 and the contribution of these mutations to breast
cancer and secondary malignancies in younger women (YBC)
among racially diverse groups [5–14].
While there is no clearly established age cutoff for young
women, we have chosen in this study to use 45 years of age as
a cutoff, as the vast majority of women affected at this age are
in the premenopausal years and a majority of families with
BRCA1/2 mutations have breast cancers presenting at or below
this age. Although BRCA1 and BRCA2 mutations represent
a relatively small component of breast cancers overall, YBC
present with a higher frequency of BRCA1 and BRCA2
mutations. It remains unclear whether there is variability
*Correspondence to: Dr B. G. Haffty, Department of Radiation Oncology, Cancer
Institute of New Jersey, Robert Wood Johnson Medical School-UMDNJ, 195 Little
Albany Street, New Brunswick, NJ 08901, USA. Tel: +1-732-235-5203;
These authors contributed equally to this work.
ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: firstname.lastname@example.org
Annals of Oncology Advance Access published June 2, 2009
among racially diverse populations in the prevalence and
spectrum of BRCA1/2 mutations. Such data may be useful in
clinical decision making regarding genetic testing in YBC.
The purpose of the current study was twofold. First, we
sought to determine the prevalence and spectrum of mutations
in BRCA1/2 among racially diverse populations of YBC from
a general breast cancer clinic population, and secondly, we
sought to evaluate the association of wild-type (WT),
deleterious (DEL) mutations and variants of uncertain
signiﬁcance (VUS) in BRCA1/2 on secondary malignancies and
family history (FH) among these populations of YBC. While
there are inherent selection biases in any study of this nature,
we sought to minimize selection bias by recruiting YBC who
were presenting for routine evaluation or follow-up in our
breast cancer clinics and not selected from high-risk familial
breast cancer clinics.
methods and materials
For the CA and AA cohorts, YBC under age 45 from breast cancer clinics at
Yale (New Haven, CT) and Cancer Institute of New Jersey (New Brunswick,
NJ) were recruited for the study from January 2000 to December 2007.
Patients were recruited during routine follow-up who met the eligibility
criteria of age <45 years, with a known previous diagnosis of breast cancer.
Many of the women seen had been treated >10 years before enrollment,
which allowed for a median follow-up of >10 years after initial diagnosis.
Women were classiﬁed as AA by self-description. The KO were all recruited
from the Soonchunhyang University Hospital (Seoul, Korea). There were
no speciﬁc exclusion or inclusion criteria other than diagnosis of breast
cancer at a young age. Other racial groups were excluded from this analysis
as they represented a very small proportion of patients seen at these clinics.
Since AA in the two US locations represented a smaller proportion of breast
cancers, accrual among AA was expectedly lower than CA. In order to
increase accrual, recruitment was limited to AA in the ﬁnal 3 years of the
study at the two US locations. While there always inherent selection biases
in recruitment of patients to these studies, the proportion of patients
enrolling in the studies represented 40% of patients meeting the eligibility
criteria at the two US locations for both the CA and AA groups and nearly
100% of patients approached at the KO location, as these patients were
recruited during a ﬁxed time interval from a single clinic by their treating
physician. Of note, patients who had no FH or predisposing factors for
familial breast cancer were routinely included in the study. Therefore,
the cohorts were felt to reasonably reﬂect a representative sample of young
women diagnosed with breast cancer from these racially diverse
After informed consent was obtained, complete FHs through three
generations as well as details of demographic, staging, histology, pathology
and treatment data was entered into a computerized database. Blood
samples were drawn and patients underwent complete sequencing of
genomic DNA for BRCA1 and BRCA2 through standard commercial
testing [15, 16]. For this study, samples underwent routine sequencing
through the Myriad Genetics Laboratories. More recent technologies,
including the BRACAnalysisÒ Rearrangement Test, which detects rare,
large cancer-associated rearrangements of the DNA in the BRCA1 and
BRCA2 genes, which were previously undetected by standard genetic
testing, were not carried out in this study. The funding agencies had no role
in the design of the study or the analysis of the data.
BRCA1 and BRCA2 mutations were classiﬁed in accordance with the
breast cancer information core (BIC) database . Patients with known
DEL in BRCA1 or BRCA2 were classiﬁed as having hereditary breast cancer.
Patients with genetic changes in BRCA1 or BRCA2 that are not known to be
DEL were classiﬁed as VUS, in accordance with the BIC database. These
changes may contribute to disease risk or may be polymorphisms that are
not associated with disease risk. Patients with known polymorphisms or no
mutations detected on complete sequencing of BRCA1 and BRCA2 were
classiﬁed as sporadic or WT. FH was classiﬁed as none, moderate (one or
more second-degree relatives with a FH of breast cancer) or strong (one or
more ﬁrst-degree relatives with a FH of breast cancer).
At the time of entry into the study and at the time of data analysis, the
details of second malignancies diagnosed before or following the diagnosis
of breast cancer were entered into the database. Only biopsy-documented
second malignancies as reﬂected in the medical record and/or the tumor
registry were entered. Time to second malignancy was calculated from the
date of the initial breast cancer diagnosis to the date of biopsy of the second
All demographic, clinical, pathological treatment and outcome data were
entered into a computerized database.
As of December 2007, a total of 333 patients were recruited in
these three populations. Characteristics of the overall patient
population are summarized by group in Table 1. All patients in
the study were younger than age 45 years at the time of initial
diagnosis of breast cancer and the majority of patients had stage
Table 1. Patient characteristics by racial group
Caucasian African-American Korean P value
Age (mean) 37 39 35 0.001
Family history (%) 0.001
None 46 48 69
Moderate 32 25 10
Strong 22 27 21
AJCC (%) 0.001
0 (DCIS) 11 8 2
I 55 28 36
II 34 61 58
III 0 3 4
Nodal status (%) 0.06
Negative 74 62 60
Positive 26 38 40
ER status (%) 0.21
Negative 49 59 59
Positive 51 41 41
PR status (%) 0.29
Negative 51 63 52
Positive 49 37 48
Her2/neu (%) 0.49
Negative 66 76 72
Positive 34 24 27
Triple negative 29 58 26 0.008
Histology (%) 0.04
Intraductal 13 14 3
Invasive ductal 75 76 91
Medullary 7 3 4
Other invasive 5 6 2
AJCC, American Joint Commission on Cancer; DCIS, ductal carcinoma in
situ; ER, estrogen receptor; PR, progesterone receptor.
original article Annals of Oncology
2 | Haffty et al.
I or stage II. Median age at diagnosis was 37 years in this
population of YBC.
There are several differences of note between the three racially
diverse populations of YBC. Although all women were by
deﬁnition in a younger age group, the KO were of a slightly
younger age (mean 35 versus 37 years in CA and 39 years in AA)
consistent with the known younger age of onset of disease in KO
women with breast cancer . Despite the younger age of KO, a
FH of breast cancer was less frequent among this group (no
FH 69%), compared with CA (no FH 47%) or AA (no FH 44%).
Although the majority of patients in all three cohorts
presented with stage I or stage II disease, there were less patients
with ductal carcinoma in situ presenting in KO and more
patients with stages II and III disease in the KO and AA
compared with CA. Although there were no signiﬁcant
differences in individual variables of estrogen receptor,
progesterone receptor or Her2/neu status among the three
populations, AA had a higher proportion of triple-negative
cancers, consistent with previous studies which report a high
frequency of triple-negative cancers in AA [18–20].
Table 2 summarizes the results of the genetic testing in the
three racial groups. Of note, the frequency of DEL in BRCA1 or
BRCA2 was remarkably similar in these three racially diverse
populations, varying between 14% and 17%. The high
frequency of DEL mutations among YBC of Jewish ancestry is
well documented. Our data are consistent with this where the
frequency of DEL was 50% among 24 women classiﬁed as of
Jewish ancestry (all Jewish women were in the CA cohort).
Among the non-Jewish Caucasian YBC, DEL mutations were
observed in 13%, as shown in Table 2.
As demonstrated in Table 2 and Figure 1, there were
signiﬁcant differences in the spectrum of mutations, with
a greater proportion of DEL BRCA2 mutations in the AA
cohort (4% BRCA1 versus 8% BRCA2), whereas the
distribution of mutations in CA was 12% BRCA1 versus 4%
BRCA2 and KO was 8% BRCA1 and 6% BRCA2. Of particular
note, there were substantially higher rates of VUS in AA, where
38% of AA were found to have VUS compared with only 10%
of CA and 12% of KO. Speciﬁc mutations detected in the entire
cohort are summarized in Table 3.
As demonstrated in Table 4 and as anticipated, DEL were
more prevalent among patients with a positive FH than in
patients with no FH and were more prevalent among the
youngest patients in the cohorts. Among patients with a strong
FH, DEL were observed in 28% of the patients, whereas DEL
were observed in 7% of patients with no FH. However, in this
group of YBC, even for those with no known FH of breast
cancer, the frequency of DEL varied between 6% and 10% in all
three racial groups. The strong correlation between FH and
DEL held across all the racial groups. Speciﬁcally, DEL were
found in patients with strong FHs in 37%, 23% and 22% of the
CA, AA and KO, respectively, while DEL were observed in
patients with no FH in 7%, 6% and 10% in the CA, AA and KO
groups, respectively. Across all three racial groups, the prevalence
of DEL was higher among the younger cohorts with DEL ranging
from 28% of women under the age of 30 to 11% of women
over age 35. Although numbers get smaller when the results are
broken down by BRCA1 and BRCA2, it appears that the
relationship between DEL BRCA status, young age and FH are
stronger in the BRCA1, compared with the BRCA2 patients.
The AA group had a much higher incidence of VUS than the
CA or KO. These VUS are nontruncating mutations, but until
further data are obtained regarding their linkage with familial
patterns of disease, and/or functional assays, their clinical
signiﬁcance with respect to cancer susceptibility remains
unclear. While it is likely that many of these variants are not
DEL or associated with breast cancer risk, it can be unsettling
for the patient faced with the VUS as a test result.
A secondary aim of this study was to assess the association of
WT, DEL and VUS BRCA mutation status with age, FH and
risk of secondary cancers among these racially diverse
populations. With a median follow-up from original breast
cancer diagnosis of over 10 years, there were a total of 65
biopsy-documented second malignancies recorded. The vast
majority of these were contralateral breast cancers, followed by
gynecological malignancies and a variety of gastrointestinal,
lung and other malignancies. As demonstrated in Table 5, at 10
years the risk of second malignancy in the DEL group was over
twice that of the WT and VUS. Figure 2 demonstrates the risk
of second malignancies as a function of testing results over 15
years in this patient population. It is evident that the VUS track
much more closely with the WT than the DEL, which suggests
that a majority of these VUS are less likely to be functional with
respect to risk of secondary cancers and less likely to be
associated with strong familial history. These data are
important for the large portion (38%) of AA, as well as the
smaller portion of CA and KO (10%–12%), who are faced with
the result of a VUS.
BRCA1/2 DEL appear to be present in 1% of the general
population and it is estimated that DEL in BRCA1 and BRCA2
contribute to 5% of breast cancers in the general population
Table 2. Results of genetic testing by racial group
Caucasian African-American Korean P
Deleterious mutation 17% (28)a
14% (9) 14% (14) 0.73
Jewish 50% NA NA
Non-Jewish 13% NA NA
83% (138) 86% (57) 86% (87)
of BRCA status
Wild type 73% (121) 48% (32) 74% (75)
17% (28) 14% (9) 14% (14)
BRCA1 (21) (3) (8)
BRCA2 (7) (6) (6)
10% (17) 38% (25) 12% (12)
BRCA1 (5) (7) (4)
BRCA2 (12) (18) (8)
Number of mutations in parenthesis.
Annals of Oncology original article
doi:10.1093/annonc/mdp051 | 3
and 10%–20% of YBC [21–30]. There are inherent biases in
estimating the prevalence of BRCA1/2 mutations in YBC since
testing is often based on screening for familial patterns of breast
cancer and/or data from patients presenting to high-risk familial
breast cancer clinics. However, available data suggest that
between 10% and 20% of YBC may be BRCA1/2 associated,
which is in agreement with the overall frequency of DEL in 14%
of our young breast cancer population [10, 11,21–24].
In our study, the frequency of mutations in YBC exceeds
10% and increases with earlier age of onset and increasingly
positive FH, and this association was evident among all three
racially diverse populations. Our results are consistent with the
population-based study from the Breast Cancer Family Registry
by John et al.  which reported in women diagnosed with
breast cancer under age 35 a mutation frequency of 16.7% in 30
AA, 8.9% in 56 Hispanic women, 2.4% in 41 KO and 9.3% in
86 non-Hispanic Whites.
Nanda et al.  reported DEL from families presenting to
a high-risk clinic in 12 of 43 (27%) AA families and 36 of 78
(46%) white families. Given that this was a high-risk clinic, the
higher mutation rate compared with our study is expected. The
frequency of VUS was remarkably similar to our study with
44% of AA and 11% of CA with VUS .
In a population-based study of breast cancer cases and
controls, which was not based out of high-risk clinics, Malone
et al.  reported DEL of 10.3% (6% BRCA1 and 4.3%
BRCA2) in women aged 35–44 years, which is similar to
the rate reported in our study. Their report is also consistent
with our studies and others in reporting a higher rate of
BRCA2 mutations in AA, though they did not report on VUS
In our study even in patients with no FH of breast cancer, the
frequency of DEL disease-associated mutations was between
6% and 10%. While we acknowledge the possibility of selection
biases, patients presenting to our follow-up breast clinics were
offered testing solely based on a diagnosis of breast cancer at
a young age. While there is no clearly deﬁned threshold, genetic
testing has been proposed for patients whose mutation risk
is 10% and certainly would be strongly considered for those
with a risk of between 6% and 10% . These data indicate
that even in women without a strongly suggestive FH, genetic
testing could be considered based on presentation with breast
cancer at a young age. This would be particularly true if
treatment decisions or prevention strategies may be dependent
on the results of genetic testing [31–38]. In addition, since the
frequency of DEL among these three racially distinct groups
was nearly identical, our results suggest that when counseling
patients with YBC regarding genetic testing, racial background
may not be a contributing factor in the decision-making
process. While our study was limited to three speciﬁc racial
groups and we cannot necessarily extrapolate these results to
other racial groups, there is no reason to assume that other
populations would differ. Indeed a study of Hispanic women
from a high-risk clinics at MD Anderson reported by Vogel
et al.  demonstrated DEL mutations in 17% of 78 tested
women and John et al.  reported mutations in 8.9% of 56
tested Hispanic women under age 35 and 3.2% of tested
Hispanic women aged 35–49 years.
Figure 1. (A–D) Frequency of mutations in population and among racial groups: overall population (A), Caucasian population (B), African-American
population (C) and Korean Population (D).
original article Annals of Oncology
4 | Haffty et al.
Although the frequency of DEL mutations was nearly
identical across the racial groups, AA had a much higher
frequency of VUS. The high frequency of VUS among AA
women has previously been reported, and the incidence of 38%
in our population is similar to the 44.2% reported by Nanda
et al. . While these are nontruncating mutations that may
have no functional implications, their clinical signiﬁcance
remains to be elucidated as data accumulate from linkage to
familial patterns of disease. Functional studies and other
biological, mathematical and epidemiologic methods are likely
to further reﬁne our understanding of the clinical signiﬁcance
of these VUS [40–42]. Over time, these VUS may be reclassiﬁed
as polymorphism or perhaps DEL. Our analysis of VUS
Table 4. Age and family history among deleterious mutation patients
30 7/25 = 28%a
6/25 = 20% 2/25 = 8%
30–35 17/74 = 23% 13/74 = 18% 4/74 = 5%
35 27/234 = 11% 14/234 = 6% 13/234 = 5%
None 14/177 = 8% 9/177 = 5% 5/177 = 3%
Moderate 14/78 = 18% 7/78 = 9% 7/78 = 9%
Strong 23/76 = 30%a
18/76 = 24% 6/76 = 8%
One patient in this group had deleterious mutations in both BRCA1 and
Table 5. Comparison of variants with wild-type and deleterious
Wild type Deleterious
Median age 38.5 37 35
Family history (%)
None 62 57 27
Moderate 19 24 27
Strong 19 19 46
Risk of second malignancy
at 10 years (%)
16 14 39
Table 3. List of mutations detected
Deleterious 3875del4 (C·2) 1222delA (CA)
IVS8 + 2TA (C·2) 984delCA (CA)
IVS+1GA (CA) 6626delA (CA)
185delAG (C·8) 6174delT (CA · 2)
C61G (CA) 1417ins4 (CA)
187delAG (C·3) 984delCA (CA)
6174delT (CA) 9017delA (AA)
5438insC (CA) Q3037X (AA)
3825del8 (CA) R3128X (AA)
1294del40 (CA) 6828delTT(AA)
IVS23 + 1GA (AA) 6174delT(AA)
R71G (AA) IVS13-2AG (AA)
S1796X (AA) 1775delT (KO)
1041del3insT (KO) L2080X (KO)
5589del8 (KO) R2494X (KO)
IVS17 + 1GT (KO) 3026delCA (KO)
IVS12 + 1GT (KO) K467X (KO)
Y130X (Kx2) K1533N (KO)
R496H (CA) K2950N (CA · 2)
R1347K (CA) K3392T (CA)
R1443G (CA) S2247G (CA)
R1347G (CA) S1172L (CA · 2)
P568L (CA) S1424C (CA)
V191I (CA) A1170V (CA)
M1137T(CA) F1524V (CA)
V772A (AA) M192T (CA)
R1645S (AA) C1365Y (CA)
T37R (AA) A2466V (CA)
V191I (AA) A2466V (AA)
IVS23 + 1GA (AA) Q2384K (AA)
S1140G (AA) V3079I (AA)
D1739G (AA) I1364L (AA)
S645Y (AA) H114R(AA)
Q1395R (AA) E462G(AA)
M1775R (AA) Q713L (AA)
L1780P (KO) V2010G (AA)
S1577P (K·2) N1880K (AA)
G275D (KO) I379M (AA)
P1150S (KO) D935H (AA)
M1628T (KO) E2571G (AA)
IVS19 + 8GA (AA)
21-4 AC (AA)
Table 3. (Continued)
E2029G (KO · 2)
T582P (KO · 2)
I1929V (KO · 2)
Number of variants exceeds number of patients reported as several patients
had multiple variants
CA, Caucasian; AA, African-American; KO, Korean.
Annals of Oncology original article
doi:10.1093/annonc/mdp051 | 5
indicated that the risk of second malignancies, familial history
and age of onset was more closely aligned with the WT than
with the DEL, which suggests that a majority of these VUS are
less likely to be associated with hereditary breast cancer. These
data may be helpful to clinicians in guiding their patients in
interpreting the implications of a VUS result.
The data presented here have several implications. First, it
would appear that in YBC the indications for BRCA1/2 testing
should be approached without regard to racial group. It
appears that YBC whether of CA, AA or KO background have
similar rates of DEL mutations in BRCA1/2. Furthermore, and
as expected, even among this cohort of YBC, the younger the
patient, and the stronger the FH, the more likely the patient is
to have DEL, and this relationship holds across all the racial
groups. It is also notable that the frequency of mutations even
among patients with no FH was between 6% and 10%, which
itself may be a high enough frequency to warrant genetic
It is notable that the frequency of DEL was as high in KO as it
was in CA and AA, despite the fact that KO women tended to
have lower rates of breast cancer in their families. This is
consistent with previous observations that Asian women with
BRCA mutations are less likely associated with strong FHs [14,
43]. Furthermore, as recently reported by Kurian et al. ,
modeling programs such as BRACAPRO, a BRCA mutation
carrier prediction model, may not be as reliable in predicting
for BRCA1 mutations in Asian women. Although all patients
tested in this study carried a diagnosis of breast cancer, even in
those KO women with DEL, the FHs were notably low in breast
and ovarian cancers. We acknowledge, however, that
underreporting of FHs or less informative families may
potentially inﬂuence this result. Since other family members are
likely to be carrying the DEL, it is possible that other genetic
and/or environmental factors contribute to the lower
penetrance of breast cancer in these families.
As previously discussed, these three racially diverse
populations have unique epidemiologic proﬁles with respect to
breast cancer. The highest incidence of breast cancer is in CA
whereas they have the latest age of onset of disease. AA have
a slightly lower incidence of breast cancer, with a younger
average age of onset, while KO have the lowest incidence of the
three groups, with an even lower average age of onset. In our
study, all the women selected had early-onset disease, and the
frequency of DEL was nearly identical. Several studies estimate
the underlying prevalence of combined BRCA1 and BRCA2
DEL mutations to be between 0.4% and 0.6%, with selected
populations such as Ashkenazi Jewish populations having
prevalence rates of 1.2% [7, 45, 46]. While it is difﬁcult to
extrapolate our results in this selected population of YBC to
overall population genetics, our data indicate that the
underlying frequency of DEL in all three of these racially
distinct groups is similar and contributes equally to early-onset
breast cancer in these populations.
Susan B. Komen Foundation (POP0403085); Ethel
F. Donaghue Women’s Health Investigator Program at Yale;
Patterson Trust and Breast Cancer Alliance.
The funding agencies had no role in the design of the study,
evaluation, presentation of the data or review or writing of the
manuscript. The authors have nothing to disclose.
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Annals of Oncology original article
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