Cathepsin D expression detected by immunohistochemistry has independent prognostic value in axillary node-negative breast cancer.
OBJECTIVE
Increased expression of the lysosomal protease cathepsin D (CD) has been implicated in the metastatic progression of breast cancer. This study was designed to determine the prognostic significance of CD expression in axillary node-negative (ANN) breast cancer. The relationship of CD expression and onset of soft tissue recurrences and visceral metastatases was also studied.


METHODS
We analyzed a population-based group of 262 ANN breast cancer patients, none of whom had received any adjuvant chemotherapy or endocrine therapy. An immunohistochemical method based on a new monoclonal antibody (1C11) with a distinct epitope specificity made it possible to study CD expression from archival paraffin-embedded specimens and to distinguish staining in tumor cells from the high-level expression found in tumor-infiltrating macrophages.


RESULTS
High-level CD expression, as defined by cytoplasmic immunoreactivity in greater than 10% of the cancer cells, was found in 95 cases (36%). High-level CD expression was associated with large primary tumor size (P = .014), but not with histologic grade, estrogen and progesterone receptors, DNA index, or S-phase fraction, or with c-erbB-2 and p53 overexpression. Patients with CD-positive tumors developed significantly more often both soft tissue recurrences and visceral metastases (P = .0007) and had a significantly shorter disease-free survival (P < .0001). Eight-year overall survival of patients with high-level CD expression was 64% as compared with 90% in those with low-level expression (relative risk, 2.97; 95% confidence interval [Cl], 1.6 to 4.4; P < .0001). According to a Cox multivariate model and a regression-tree analysis, high-level CD expression was an independent predictor of poor overall survival in conjunction with tumor size and S-phase fraction.


CONCLUSIONS
These results indicate that CD expression determined by immunohistochemistry is a powerful prognostic factor in ANN breast cancer. The most significant prognostic information was obtained when CD expression (predicting metastatic activity) was combined with estimate of cell-proliferation rate (S-phase fraction).
Isola
J
J
Department of Biomedical Sciences, University of Tampere, Finland.
Weitz
S
S
Visakorpi
T
T
Holli
K
K
Shea
R
R
Khabbaz
N
N
Kallioniemi
O P
OP
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D002402:Cathepsin D / Q000032:analysis*; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008207:Lymphatic Metastasis; D008875:Middle Aged; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000032:analysis; D018719:Erb-b2 Receptor Tyrosine Kinases; D012044:Regression Analysis; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D002402:Cathepsin D; D004273:DNA, Neoplasm; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D016159:Tumor Suppressor Protein p53