Regional Laboratory
AllianceRegional Laboratory
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It has been known for a number of years that breast cancer stage and, in particular, lymph node status and tumor grade are the strongest predictors of prognosis. With no lymph node involvement, 10 year disease free survival is 75-80%. When 1-3 nodes are involved, this drops to 35-40%. The difference in survival between high and low histologic grade tumors can be 81% vs. 16% over 15 years. There has also been an increasing amount of data addressing tumor markers. This information can theoretically be used to predict prognoses as well as to tailor chemotherapy to the patient’s particular needs. Among the markers, which have been studied, are cathepsin-D, HER-2/neu (c-erbB-2), p53, and the more traditional markers of estrogen and progesterone receptor, DNA ploidy and cell cycle analysis. The following represents a brief review of these markers:
Estrogen (ER) and progesterone receptors (PR): Presently these are done primarily by image analysis and flow cytometry using fluorescent labeled antibodies to the estrogen and progesterone receptors. Tumors are considered to be positive when at least 10% of cells analyzed are reactive. ER and PR positive tumors are usually of lower histologic grade than negative tumors, are diploid and have a low S-phase fraction and can be treated with hormone therapy. ER and PR negative tumors tend to have a higher histologic grade, aneuploidy, have a high S-phase fraction and are not responsive to hormone therapy.
DNA Ploidy: This parameter is a measure of the degree of abnormality of the DNA content of the tumor cells. This again can be studied by flow cytometry or image analysis. It is reported as a function of comparison to the normal diploid DNA content of cells. For example a normal ploidy value is 1.0 (range of 0.9-1.1). Aneuploid values would represent such values as 1.73 or 2.35 etc. In general aneuploidy is a predictor of more aggressive breast carcinoma behavior.
Cell Cycle Analysis: This represents a measure of the number of cells which are in the process of cell division or S-phase. This can be studied by flow cytometry or by antibodies to proliferative proteins (i.e.: PCNA) in the cell by image analysis. Up to 10% of cells in division is considered to be compatible with a less aggressive behavior.
Cathepsin D: This is a protein with collagenase-like activity which was initially reported to predict a higher likelihood of stromal invasion when overexpressed. More recent studies have found this to be of questionable significance.
p53: Wild type (non-mutated) p53 appears to play a role in tumor suppression by blocking cellular division after DNA damage. Mutations in this gene are one of the better described molecular events in a number of carcinomas. A number of reports have indicated an association between p53 mutations in breast cancer with increased recurrence and death rates. P53 is usually studied using immunohistochemical or molecular techniques.
HER-2/neu (c-erbB-2): This is a transmembrane protein receptor similar to epidermal growth factor receptor. Overexpression of HER-2/neu has been found to be present in up to 30% of patients with breast carcinoma. Overexpression has been linked to shorter survival independent of other factors. Lack of overexpression would tend to predict a less aggressive behavior. This is usually studied by immunohistochemical methods in tissue biopsies. New chemotherapeutic agents designed to interfere with HER-2/neu expression have recently been reported. These are usually used in conjunction with standard chemotherapeutic agents and appear to increase response rates and tumor shrinkage.
Our current recommendation for primary breast cancer analysis would include:
The following represents a summary table of current markers from CA-A Cancer Journal for Clinicians:
|
Prognostic Factor |
Favorable |
Unfavorable |
|---|---|---|
|
Axillary lymph nodes |
No metastasis |
Metastasis present |
|
Positive axillary nodes |
1-3 |
4 or more |
|
IM lymph nodes |
No metastasis |
Metastasis present |
|
Tumor size |
Small |
Large |
|
Histologic grade |
I (well differentiated) |
III (poorly differentiated) |
|
Nuclear grade |
I (well differentiated) |
III (poorly differentiated) |
|
Estrogen receptor |
> 10 fmol/mg protein |
< 10 fmol/mg protein |
|
Progesterone receptor |
> 10 fmol/mg protein |
< 10 fmol/mg protein |
|
pS2 protein |
High (> 11 ng/mg) |
Low (< 11 ng/mg) |
|
S-phase fraction |
Low |
High |
|
Ploidy |
Diploid |
Aneuploid |
|
Mitotic index |
Low |
High |
|
TLI |
Low |
High |
|
HER-2/neu (c-erbB-2) |
Absent |
Present |
|
p53 |
Absent |
Present |
|
Ki-67 |
Low |
High |
|
PCNA/cyclin |
Low |
Low |
|
Cathepsin-D |
Low |
High |
|
uPA |
Low |
High |
Reference: Masood, S, "Prognostic Factors in Breast Cancer, " Journ Surg Path, 1995:1:45-61, 1995.