Prediction of early relapse and shortened survival in patients with breast cancer by proliferating cell nuclear antigen score

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Abstract
Background. Cell cycle kinetic measures have been shown to have prognostic significance in breast cancer. Methods that have been used to assess the proliferating fraction of tumors include measurements of DNA content with S-phase calculation by flow cytometric analysis, radioisotope-labeled nucleotide incorporation, and cell cycle–associated protein expression. The recent discovery of the S-phase-specific nuclear protein proliferating cell nuclear antigen (PCNA) opens the door for a novel approach to cell kinetic measurement with an immunocytochemical assay. Methods. A quantitative immunocytochemical assay for PCNA was performed on 82 primary invasive breast carcinomas fixed in formaldehyde solution and embedded in paraffin and 18 corresponding axillary metastases. The percentage of tumor cells with strong nuclear staining was determined by visual count. This PCNA score was correlated with histologic parameters, age, relapse intervals, and long-term survival. Results. PCNA scores were distributed normally among primary carcinomas (range, 5–54; mean, 22.5). Carcinomas had much higher scores than adjacent normal epithelium (means, 22.5 and 4.1, respectively; P < 0.0001), and axillary node metastases had slightly higher scores than corresponding primary breast tumors (means, 26.4 and 22.5, respectively; P = 0.05). The PCNA score did not correlate with age, tumor size, axillary node status, intramammary lymphatic–vascular invasion, or estrogen and progesterone binding capacities. Further-more, its variability could not be explained by grade. PCNA values increased as the mitotic rate increased. Cancers with high PCNA scores (≥ 25) were associated with shorter disease-free (P = 0.007) and overall survival times (P = 0.01) than tumors with low PCNA scores (< 25) (median follow-up, 166 months). Conclusions. PCNA score has potential value as a prognostic indicator in breast cancer. This method of assessing the proliferating pool offers advantages over other assays in terms of relative simplicity of the method, applicability to paraffin-embedded fixed tissue, and low cost.