Invasive breast carcinoma - IARC

Extent of ductal carcinoma in situ
The presence of an extensive intraductal
component is a prognostic factor for
local recurrence in patients treated with
conservative surgery and radiation therapy,
when the status of the excision margins
is unknown. However, this is not an
independent predictor when the microscopic
margin status is taken into consideration
{2569}. Its relationship with
metastatic spread and patient survival
remains unclear {2176,2437,2689}.
Tumour stroma
Prominent stromal elastosis has variously
been reported to be associated with a
favourable prognosis {2664,2858}, an
unfavourable prognosis {84,1016}, and
to have no prognostic significance {626,
1266,2393}. The presence of a fibrotic
focus in the centre of an invasive carcinoma
has also been reported to be an
independent adverse prognostic indicator
{545,1153}
Combined morphologic prognostic factors
The best way to integrate histological
p rognostic factors is an unre s o l v e d
issue {1833}. The Nottingham Pro g n o s t i c
Index takes into consideration tumour
size, lymph node status and histological
grade, and stratifies patients into good,
moderate and poor prognostic gro u p s
with annual mortality rates of 3%, 7%,
and 30%, respectively {954}. Another
p roposal for a prognostic index includes
tumour size, lymph node status and
mitotic index (morphometric pro g n o s t i c
index) {2993}.
Molecular markers and gene
e x p r e s s i o n
A large number of genetic alterations
have been identified in invasive bre a s t
c a rcinomas, many of which are of
potential prognostic or predictive value.
Some provide tre a t m e n t - i n d e p e n d e n t
i n f o rmation on patient survival, others
p redict the likelihood that a patient will
benefit from a certain therapy. Some
alterations may have both pro g n o s t i c
and predictive value.
Steroid hormone receptors
(Estrogen receptor (ER) and
Progesterone receptor PR)
E s t rogen is an important mitogen exerting
its activity by binding to its re c e p t o r
(ER). Approximately 60% of breast carc i-
nomas express the ER protein. Initially,
ER-positive tumours were associated
with an improved prognosis, but studies
with long-term follow-up have suggested
that ER-positive tumours, despite having
a slower growth rate, do not have a lower
metastatic potential. Nonetheless, ER
status remains very useful in pre d i c t i n g
the response to adjuvant tamoxifen {4,
368,1304,1833,2120}. Measurement of
both ER and PR has been clinical practice
for more than 20 years. PR is a
s u r rogate marker of a functional ER. In
e s t rogen target tissues, estrogen tre a t-
ment induces PR. Both can be detect
e d by ligand binding assay, or more
commonly nowadays, by immunohistochemical
(IHC) analysis using monoclonal
antibodies. ER/PR-positive
tumours have a 60-70% response rate
c o m p a red to less than 10% for ER/PRnegative
tumours. ER-positive/PR-negative
tumours have an intermediate response
of approximately 40%. Horm o n e
receptor status is the only re c o m m e n d-
ed molecular marker to be used in tre a t-
ment decision {9,886, 1030}. The impact
of hormone receptor status on pro g n o s i s
and treatment outcome prediction is
complex. The finding, in cell lines, that
tamoxifen can interact with the re c e n t l y
identifed ERβ receptor (ERB) may provide
new clues towards improvement of
p redicting tamoxifen re s p o n s i v e n e s s
{ 1 5 2 6 , 1 9 2 5 , 3 2 6 9 } .
Epidermal growth factor receptor (EGFR)
and transforming growth factor alpha
( T G Fα), antiapoptotic protein bcl-2,
cyclin dependent kinase inhibitor p27
a re other potential prognostic markers
that look promising. Elevated expre s s i o n
of EGFR, in the absence of gene amplification,
has been associated with estrogen
receptor negativity {2509}.
The ERBB2 / HER2 oncogene
The prognostic value of ERBB2 overe
x p ression, first re p o rted in 1987
{2719}, has been extensively studied
{2962,3173}. ERBB2 over- e x p ression is
a weak to moderately independent predictor
of survival, at least for node-positive
patients. Gene amplification or
o v e r- e x p ression of the ERBB2 pro t e i n
can be measured by Southern blot
analysis, FISH, diff e rential PCR, IHC
and ELISA {2958}. Studies of the predictive
value of ERBB2-status have not
been consistent. A recent review {3173}
concluded that ERBB2 seems to be a
weak to moderately strong negative
p redictor for response to alkylating
agents and a moderately positive predictive
factor for response to anthracyclines.
There was insufficient data to
draw conclusions on the response to
taxanes or radiotherapy. In an a d j u v a n t
setting, ERBB2 status should not be
used to select adjuvant systemic
chemotherapy or endocrine therapy.
C o n v e r s e l y, when adjuvant chemotherapy
is recommended, anthracyclinebased
therapy should be pre f e r red
for ERBB2 positive patients. A humanized
anti-ERBB2 monoclonal antibody,
trastuzumab (Herceptin), has been
developed as a novel anti-cancer drug
targeting overe x p ressed ERBB2 {529}.
This has been shown to be effective in
20% of patients with ERBB2 amplified
t u m o u r s .
TP53 mutations
A p p roximately 25% of breast cancers
have mutations in the tumour suppre s-
sor gene T P 5 3, most of which are missense
mutations leading to the accumulation
of a stable, but inactive protein in
the tumour cells {1196,2759,2761}.
Both DNA sequencing and IHC have
been used to assess T P 5 3-status in the
t u m o u r. However, some 20% of the
mutations do not yield a stable pro t e i n
and are thus not detected by IHC, while
n o rmal (wildtype) protein may accumulate
in response to DNA damage or cellular
stress signals. Studies using DNA
sequencing all showed a strong association
with survival whereas those
using only IHC did not, or did so only
weakly {5,886,1304,2237,2760}. Given
the diverse cellular functions of the p53
p rotein and the location and type of
alteration within the gene, specific
mutations might conceivably be associated
with a particularly poor pro g n o s i s .
Patients with mutations in their tumours
a ffecting the L2/L3 domain of the p53
p rotein, which is important for DNA
binding, have a particularly poor survival
{251,317,976,1523}.
The role of p53 in the control of the cell
cycle, DNA damage re p a i r, and apoptosis,
provides a strong biological rationale
for investigating whether mutations
a re predictors of response to DNA damaging
agents. Several studies using
DNA sequencing of the entire gene
have addressed this in relation to diff e r-
ent chemotherapy and radiotherapy
regimes {16,241,249,976}. A stro n g
58 Tumours of the breast