0504 NewsPath Breast Carcinoma Markers

367337416.
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Prognostic and predictive markers for breast carcinoma
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 1930s.
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
NewsPath Editor: Megan J. DiFurio, MD, FCAP
This newsletter is produced in cooperation with the College of American Pathologists Public Affairs Committee and may
be reproduced in whole or in part as a service to the medical community. Copyright 2005
367337416.doc Page 2 of 2
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
chemotherapy.
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.
NewsPath Editor: Megan J. DiFurio, MD, FCAP

This newsletter is produced in cooperation with the College of American Pathologists Public Affairs Committee and may
be reproduced in whole or in part as a service to the medical community. Copyright 2005

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367337416.

Prognostic and predictive markers for breast carcinoma

Major prognostic and predictive factors can be important in choosing appropriate

Estrogen Receptors (ERs) and Progesterone Receptors (PRs): Expression of

While many agree that 5% is considered positive, tumors with a lower

HER2/neu (Immunohistochemistry [IHC] and Fluorescence In-Situ

HER2/neu amplification and protein overexpression can be detected with FISH

tissue. Maximum sensitivity can be achieved by using both methods. HER2

Measures of Tumor Cell Proliferation Rate: Proliferation can be measured by

Other Molecular Markers: Mutation of p53, an oncosuppressor gene, causes

Epidermal growth factor receptor (EGFR) is related to HER2/neu and can be

At a minimum, hormone receptor and HER2 status should be determined for

NewsPath Editor: Megan J. DiFurio, MD, FCAP

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