Prognostic factors in early breast carcinoma

Several investigators, the SEER data, and the ECOG/Intergroup study have shown that patients with small tumors (<0.5 cm) have a recurrence rate of less than 2%, compared to 20–25% for large tumors (≥5 cm). Nuclear grade and tumor differentiation are established indicators; however, the interobserver lack of concordance has thwarted their use in clinical trials. The presence of peritumoral lymphatic and blood vessel invasion (PLBI) is associated with a relative risk of recurrence of 4.7. The predictive value of the presence of hormone receptors in tumors is associated with a favorable disease free and overall survival difference of 8–10%; however, this advantage is being eroded by the early appearance of other factors, such as the epidermal growth factor receptor (EGFR), proliferative capacity (S-phase), nuclear grade, and HER-2/neu oncogene. Concordance among the different methods of hormone-receptor assay (immune-cytochemical, sucrose gradient, and dextran-coated charcoal) is essential to refine the true value of these factors. DNA flow cytometry measurements of ploidy (DNA content) and S-phase fraction are the most characterized of the prognostic factors. There are conflicting reports regarding the clinical significance of ploidy status, while measurements of S-phase fraction clearly indicate a robust association with disease free and overall survival. Our data continue to show that S-phase, but not ploidy, can predict time to recurrence significantly in untreated patients, even when data are stratified for tumor size. HER-2/neu oncogene is expressed in about 50% of ductal carcinoma in situ and 14% of invasive ductal carcinoma. The presence of this oncogene at high copy number may be a useful independent marker of poor prognosis and may be associated with drug resistance and correlated with tumor recurrence and shorter survival. EGFR could be measured in most breast tumors, and the level of its expression has inversely correlated with estrogen receptor protein expression. The value of EGFR as a predictor of prognosis remains controversial and is still being investigated. Cathepsin-D provides a provocative biologic rationale but is hindered by different and incongruent methods of analysis. The majority of large studies with more than 3-years' follow-up suggests that high cathepsin-D levels may be predictive of greater recurrence and lower survival. Angiogenesis has been implicated as a critical component of the metastatic process. Early studies show that tumor angiogenesis is an independent and highly significant prognostic indicator, and its presence may suggest the selection of “anti-angiogenic therapy.” Mutations in the tumor suppressor p53 gene have been detected in 13–15% of primary breast cancers, resulting in overexpression of mutant p53, which is associated with poor prognosis. There also may be a strong relationship between mutant p53 overexpression and high S-phase activity. Although there is a growing understanding of the prognostic significance of individual prognostic factors, the topic of how practically to use multiple prognostic factors in concert is still largely unexplored. The development of practical systems for clinical application will require improvements in the areas of (1) standardization of methodologies and interlaboratory quality control for prognostic factor determinations, (2) definition of a limited set of prognostic markers that are independently predictive, and (3) staging systems or tools that integrate this information. Large studies based on cooperative group material and large data bases will play a vital role in this process.