Invasive breast carcinoma - IARC

esemble those identified in invasive
ductal carcinoma, adding weight to the
t h e o ry that DCIS is a direct pre c u r s o r.
L O H
In DCIS, loss of heterozygosity (LOH)
was frequently identified at several loci
on chromosomes 1 {1942}, 3p21 {1743},
and chromosomes 8p, 13q, 16q, 17p,
17q, and 18q {924,2317,3036}. The
highest re p o rted rates of LOH in DCIS
a re between 50% and 80% and involve
loci on chromosomes 16q, 17p, and
17q, suggesting that altered genes in
these regions may be important in the
development of DCIS {72,924,3036}.
Among more than 100 genetic loci studied
so far on chromosome 17, nearly all
DCIS lesions showed at least one LOH
{72,301,924,1942,2071,2317,2475}. By
CGH and FISH, low and some interm e d i-
ate grade DCIS and invasive tubular carcinoma
(G1) show loss of 16q, harbouring
one of the cadherin gene clusters,
w h e reas some intermediate grade and
high grade DCIS and nearly all G2 and
G3 invasive ductal carcinomas show no
loss of genetic material on this locus but
have alterations of other chromosomes
(-13q, +17p, +20q). Based upon this
data, a genetic pro g ression model was
p roposed {301}.
E R B B 2
The E R B B 2 (Her2/neu) oncogene has
received attention because of its association
with lymph node metastases, short
relapse free time, poor survival, and
d e c reased response to endocrine and
chemotherapy in breast cancer patients
{72,1567}. Studies of ERB B2 have used
mainly FISH technique to identify amplification
and immunohistochemistry (IHC)
to detect over expression of the oncogene,
which are highly correlated {72}.
Amplification and/or over expre s s i o n
was observed on average in 30% of
DCIS, correlating directly with diff e re n t i-
ation {72}; it was detected in a high prop
o rtion of DCIS of high nuclear grade
(60-80%) but was not common in low
nuclear grade DCIS {196}. Patients with
ERBB2 positive tumours may benefit
f rom adjuvant treatment with monoclonal
antibody (Herc e p t i n ) .
Cyclin D1
This protein plays an important part in
regulating the pro g ress of the cell during
the G1 phase of the cell cycle. The gene
A
B
Fig. 1.95 Unusual intraductal proliferation.
A The lesion shows a uniform cell population proliferating
in a solid pagetoid pattern similar to lobular
neoplasia, but the cells appear more adherent
than in typical lobular neoplasia (LN).
B Double immunostain is positive for both
C K 34βE12 (purple) and E-cadherin (brown), qualifying
the lesion as a hybrid positive type that may
suggest the diagnosis of DCIS.
(C C N D 1) is considered a potential oncogene,
but in clinical studies of invasive
b reast cancer, overe x p ression of cyclin
D1 was found to be associated with
e s t rogen receptor expression and low
histological grade, both markers of good
p rognosis {1007}. Amplification of
CCND1 occurs in about 20% of DCIS
and is more commonly found in high
grade than in low grade DCIS (32% versus
8%) {2700}. The cyclin D1 pro t e i n
was detected in 50% of cases, and high
levels were more likely in low grade than
in the intermediate and high grade DCIS
{2700}. Although so far no oncogene has
been identified on chromosome 20q13,
amplification of this region was fre q u e n t-
ly found in DCIS {134,856}.
TP53 mutations
The TP53 protein is a transcription factor
involved in the control of cell pro l i f-
eration, response to DNA damage,
apoptosis and several other signaling
pathways. It is the most commonly
mutated tumour suppressor gene in
sporadic breast cancer {196} and this is
generally associated with aggre s s i v e
biological features and poor clinical
outcome. Most T P 5 3 mutations are missense
point mutations resulting in an
inactivated protein that accumulates in
the cell nucleus {72,712}. In DCIS, T P 5 3
mutations were found with diff e rent frequency
among the three histological
grades, ranging from rare in low grade
DCIS, 5% in intermediate-grade, and
common (40%) in high grade DCIS
{ 7 1 2 , 3 0 4 8 } .
Prognosis and predictive factors
The most important factor influencing
the possibility of re c u r rence is persistence
of neoplastic cells post-excision;
p r i m a ry and re c u r rent DCIS generally
have the same LOH pattern, with acquisition
of additional alterations in the latter
{1670} The significance of margins is
mainly to ascertain complete excision. In
randomized clinical trials, comedo
n e c rosis was found to be an import a n t
p redictor of local re c u r rence in the
NSABP-B17 trial {2843}, while solid and
c r i b r i f o rm growth patterns along with
involved margin of excision were found
to be predictive of local re c u r rence in
E O RTC-10853 trial {270,271}. In re t rospective
trials, on the other hand, high
nuclear grade, larger lesion size, comedo
necrosis and involved margins of
excision were all found to be pre d i c t i v e
of local re c u r rence following breast conservative
treatment for DCIS.
Although mastectomy has long been the
traditional treatment for this disease, it
likely re p resents over- t reatment for many
patients, particularly those with small,
mammographically detected lesions.
C a reful mammographic and pathologic
evaluation are essential to help assess
patient suitability for breast conserving
t reatment.
While excision and radiation therapy of
DCIS (with or without Tamoxifen) have
significantly reduced the chances of
re c u r rence {866,870}, some patients
with small, low grade lesions appear to
be adequately treated with excision
alone, whereas those with extensive
lesions may be better served by mast
e c t o m y. Better prognostic markers are
needed to help determine which DCIS
lesions are likely to recur or to pro g re s s
to invasive cancer following breast conserving
treatment. The optimal management
is evolving as data accumulates
f rom a variety of prospective studies.
Intraductal proliferative lesions
73