BREAST-CANCER METASTATIC PHENOTYPE AS PREDICTED BY HISTOLOGIC TUMOR-MARKERS

PURPOSE Two clinical characteristics of the metastatic cancer phenotyp e are virulence-which reflects the pace of disease growth, clinical ma nifestation, and dissemination-and metastagenicity, the ultimate likel ihood of distant metastasis. Molecular markers map allow distinguishin g between these two cancer phenotypes. The purpose of this study is to determine whether proliferating cell nuclear antigen (PCNA) and tumor nuclear grade are markers of virulence or metastagenicity. PATIENTS A ND METHODS PCNA aad tumor nuclear grade were determined in patients wi th extensive follow-up, treated only with mastectomy, for whom archiva l paraffin-embedded tissue was available. RESULTS There is no signific ant difference in long-term disease-free survival (DFS) as a function of PCNA, but after only 5 years of analysis there are significant diff erences that gradually disappear with further follow-up, reflecting di fferences in virulence. While the likelihood of recurrence is the same , in patients with high PCNA 80% of disease recurrences become evident in the first 2 to 3 years, whereas in patients with low PCNA it takes more than 10 years for 80% of metastases to become clinically detecta ble. There was a significant difference in 20-year DFS for nuclear gra de I compared with nuclear,grade 2 and 3 tumors, indicating a differen ce in metastagenicity. The differences in DFS between nuclear grade 2 and 3 tumors decrease as the length of follow-up increases; thus, like PCNA, these grade differences are also a marker of virulence. Eighty percent of the metastasis became evident within 4 years in grade 3 tum ors and within 12 years in grade 2 tumors. DISCUSSION PCNA and nuclear grade (2 vs 3) are markers of virulence. We have previously shown ang iogenesis to be a marker of metastagenicity as is, in this study, the difference between nuclear grade 1 and nuclear grades 2 and 3. Both ph enotypic characteristics, virulence and metastagenicity, are important to understanding the natural history of the tumors and may influence the nature of the therapy.