Invasive breast carcinoma - IARC

BRCA1 syndrome
Definition
Inherited tumour syndrome with autosomal
dominant trait and markedly
i n c reased susceptibility to breast and
ovarian tumours, due to germline mutations
in the B R C A 1 gene. Additional organ
sites include colon, liver, endometrium,
cervix, fallopian tube, and peritoneum.
MIM No. 113705 {1835}
Synonyms
Breast cancer 1, early onset breast ovarian
cancer syndrome.
Incidence
The prevalence of BRCA1 mutations in
most Caucasian populations is estimated
to be 1 in 883 {897}. However, in certain
populations, this is higher, e.g. 1% in
Ashkenazi Jews {3065}. Using recombination
techniques, B R C A 1 m u t a t i o n s
have been dated to the early Roman
times {1997}. De novo mutations are rare.
Diagnostic criteria
A definitive diagnosis is only possible by
genetic testing. BRCA1 mutations are
common in certain populations and in
families with numerous early onset breast
cancer cases (≥4 cases of breast cancer
at 30%
because of the need to concentrate
resources.
Breast tumours
Penetrance
Analyses of worldwide data submitted to
the Breast Cancer Linkage Consortium
(BCLC) have provided general estimates
of penetrance {8}. Estimates for specific
populations have shown that the
Ashkenazim have a lower than average
lifetime breast cancer penetrance of
about 50-60% {3065}. Population based
studies in UK breast cancer patients also
revealed a lower penetrance and indicate
that the presence of a mutation within
a familial breast cancer cluster does
confer a higher penetrance {2230}. This
may be due to an association with other
genes or epidemiological factors that are
present in the family. There are also
reports of variable penetrance dependent
on the position of the mutation within
the BRCA1 gene {2914}.
Clinical features
Breast cancer in BRCA1 mutation carriers
occurs more often at a younger age,
typically before age 40 {1687}. It tends to
p ro g ress directly to invasive disease
without a precancerous DCIS component
{8,1574}. Accordingly, there appears to
be a lower chance of early detection by
mammographic screening and a higher
proportion of invasive cancers {1025}.
There is an almost linear increase in the
lifetime risk of contralateral breast cancer
from the age of 35 years, reaching a level
of 64% by the age of 80 {742}.
Pathology
Certain morphological types of breast
cancer, including medullary carcinoma,
tubular carcinoma, lobular carcinoma in
situ, and invasive lobular carc i n o m a ,
Table 8.02
Probability of BRCA1/2 mutation in women with breast/ovarian cancer.
Chance of mutation
Clinical criteria
D. Goldgar R.H.M. Verheijen
R. Eeles C. Szabo
D. Easton A.N. Monteiro
S.R. Lakhani
P. Devilee
S.Piver
S. Narod
J.M. Piek E.H. Meijers-Heijboer
P.J. van Diest
N. Sodha
have been reported more commonly in
patients with a positive family history of
b reast cancer {191,1566,1684,1724,
2441}.
Patients with BRCA1 germline mutations
have an excess of medullary or atypical
medullary carcinoma compared to controls
{8,764,1767}. Tumours in BRCA1
mutation carriers are generally of a higher
grade than their sporadic counterparts
{8,764,1767}. Ductal carcinoma in situ
(DCIS) adjacent to invasive cancer is
observed less frequently while the frequency
of lobular neoplasia in situ is similar
in both groups {8}. However, in a multifactorial
analysis of the BCLC database,
the only features significantly associated
with BRCA1 were total mitotic count, continuous
pushing margins, and lymphocytic
infiltrate. All other features, including
the diagnosis of medullary and atypical
medullary carcinoma, were not found
to be significant {1572}.
B R C A 1-associated tumours are more
likely to be estrogen (ER) and progest
e rone receptor (PgR) negative {766,
1352,1574,2121}. Data on ERBB2 are
limited but BRCA1-linked tumours are
more likely to be negative than controls
{1352,1574}. B R C A 1-linked tumours
show a higher frequency of TP53 mutations
and p53 expression than sporadic
b reast cancer {580,581,765,1574}.
BRCA1-associated tumours show very
low expression of Cyclin D1 in both the
invasive and in situ components {2122}.
The absence of Cyclin D1 in these
tumours could be an additional evidence