Posted April 1, 2005
Breast carcinoma is the most common malignancy and the leading cause
of cancer death in women. In this country, there has been a sharp
increase in its detection, largely due to the widespread use of mammography.
Despite detection of smaller (and presumably earlier) disease, the
survival rate has improved very little since the 1930’s.
Major prognostic and predictive factors can be important in choosing
appropriate treatment, determining the risk of recurrence and classifying
patients for clinical trials. Below is a review of markers routinely
offered by most reference laboratories.
Estrogen Receptors (ERs) and Progesterone Receptors (PRs): Expression
of ERs and/or PRs within tumors correlates well with low histologic
grade and responsiveness to hormonal manipulation, especially in
postmenopausal women. ERs and PRs are evaluated with immunohistochemistry
(IHC) on paraffin embedded tissue, where staining of cell nuclei
is considered positive. The percentage of cells staining and strength
of the stain needed for a positive test is controversial, so most
labs will report the actual percentage of positive cells.
While many agree that ≥5% is considered positive, tumors with
a lower percentage (1-4%), or even no staining, may show a borderline
response to hormonal therapy. The American Society of Clinical Oncology
(ASCO) Tumor Marker Panel of 1995 concluded: (1) ER and PR should
be measured on every primary breast cancer (and metastatic lesions
if it would influence treatment planning), (2) in metastatic disease,
ER and PR positivity supports use of hormonal therapy, (3) regardless
of menopausal status, ER and PR positivity helps to identify patients
likely to benefit for adjuvant hormonal therapy and (4) ER and PR
receptors are weak prognostic indicators and should not be used to
determine whether to treat a patient with adjuvant therapy.
HER2/neu (Immunohistochemistry [IHC] and Fluorescence
In-Situ Hybridization [FISH]): HER2/neu is a
proto-oncogene that encodes the production of HER2, a cell surface
protein important in cell regulation. Abnormalities of HER2/neu occur
in 25-30% of breast carcinomas, especially those that are poorly
differentiated, lymph node positive, hormone receptor negative,
flow aneuploid and/or show high proliferation rates.
HER2/neu amplification and protein overexpression can be
detected with FISH and IHC, respectively, both of which can be performed
on paraffin-embedded tissue. Maximum sensitivity can be achieved
by using both methods. HER2 status is used as an eligibility criterion
for anti-HER2 immunotherapies, such as Herceptin™. While some
studies have shown a positive dose-response effect with adjuvant
chemotherapy for tumors showing gene amplification, elevated HER2
may actually be a negative predictor of response to adriamycin-based
Measures of Tumor Cell Proliferation Rate: Proliferation
can be measured by flow cytometry (S-phase fraction), thymidine labeling
index, mitotic counts or IHC detection of cellular proteins (e.g.
Ki-67/MIB-1). Most evidence supports that tumors with a high proliferation
rate have a worse prognosis. Manual mitotic counts have shown to
be an important part of the standard grading system (Scarff-Bloom-Richardson).
Nonetheless, the best technique to use remains unclear as it has
not been determined which can be most accurately measured and will
provide results that correlate well with overall survival.
DNA Ploidy: DNA content in cells can be determined
by flow cytometry, image analysis or laser scanning cytometry. Aneuploid
DNA content has been shown to be associated with a worse prognosis,
but it is uncertain whether this parameter adds independent information
of prognostic value.
Other Molecular Markers: Mutation of p53, an oncosuppressor
gene, causes variant p53 proteins to have an increased half-life,
thus accumulating in the cell. These excess proteins can be detected
with IHC in about 90% of cases by increased nuclear staining. Although
over accumulation of p53 protein has been associated with shortened
survival in breast carcinoma patients, it also correlates with cell
proliferation and thus may not be an independent prognostic factor.
Epidermal growth factor receptor (EGFR) is related to HER2/neu and
can be detected with IHC. The expression of EGFR is associated with
shorter survival, but there is very little evidence to support its
routine use at this time.
At a minimum, hormone receptor and HER2 status should be determined
for every new breast cancer diagnosis. These tests are, of course,
in addition to major prognostic factors such as axillary lymph node
status, tumor size and distant metastasis (the basis of clinical
staging), as well as tumor grade and lymph vascular invasion.
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NewsPath® Editor: Megan
J. DiFurio, MD, FCAP
This newsletter is produced in cooperation with the College of American
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