Home: Educational Supplement: Appendix

Traditional and Newer Pathological Factors

Stuart J. Schnitt, M.D.

During the last two decades there has been an intensive effort by many investigators to identify prognostic and predictive factors for patients with breast cancer. Prognostic factors are defined as those capable of providing information on clinical outcome at the time of diagnosis, whereas predictive factors are defined as those capable of providing information on the likelihood of response to a given therapeutic modality (Gasparini, Pozza, Harris, 1993). Many recent studies have focused on the potential prognostic and/or predictive role of newer biological and molecular markers, such as growth factors and their receptors, oncogenes and tumor suppressor genes and their products, proteolytic enzymes, adhesion molecules, and markers of cellular proliferation and angiogenesis, among others (Mansour, Ravdin, Dressler, 1994). However, studies of such factors have frequently yielded conflicting results and clinical confusion (Loprinzi, Ravdin, de Laurentiis, et al., 1994). Much of the confusion is due to the fact that even studies evaluating the same prognostic marker often differ in patient selection, treatment methods (including the use of systemic therapy), methods for analyzing the marker, methods of statistical analysis, length of patient followup, and prognostic markers to which the “new” marker is being compared.

There is universal agreement that the status of the axillary lymph nodes as determined by routine pathologic evaluation remains the most important prognostic factor for patients with breast cancer (Goldhirsch, Glick, Gelber, et al., 1998). Although there is increasing interest in the use of ancillary techniques, such as immunohistochemistry, to detect occult tumor cells, the clinical significance of occult axillary lymph node metastases detected exclusively by immunohistochemical staining or any other ancillary technique is at present an unresolved issue (Giuliano, Kelemen, 1998).

Among patients with node-negative disease, the important prognostic factors are generally considered to be tumor size, histologic and/or nuclear grade, histologic type, and hormone receptor status (Goldhirsch, Glick, Gelber, et al., 1998). Hormone receptor status is also the most important predictive factor for response to systemic endocrine therapy. At a recent consensus conference held under the auspices of the College of American Pathologists (Fitzgibbons, Page, Weaver, et al., 2000), a multidisciplinary group of pathologists, clinicians, and statisticians reviewed prognostic and predictive factors in breast cancer and categorized them based on the strength of published evidence into the following groups:

Category I: Factors proven to be of prognostic importance and useful in clinical patient management. Included in this category are tumor size, lymph node status, histologic grade, histologic type, mitotic rate, and hormone receptor status.

Category II: Factors that have been extensively studied biologically and clinically, but whose import remains to be validated in statistically robust studies. This category includes HER-2/neu, p53, lymphovascular invasion, and proliferation markers.

Category III: All other factors not sufficiently studied to demonstrate their prognostic value. Included in this group are DNA ploidy, tumor angiogenesis, epidermal growth factor receptor, transforming growth factor-alpha, bcl-2, pS2, and cathepsin D.

In addition, detailed recommendations for improvement of each factor were made, based on the following goals: (1) to increase the uniformity and completeness of pathologic evaluation; (2) to enhance the quality of data collected about existing prognostic factors; and (3) to improve patient care.

It is of interest to recall that one of the four major issues discussed at the 1990 NIH consensus development conference on the treatment of early breast cancer was the use of prognostic factors to manage patients with node-negative disease. At that conference, a useful prognostic factor was defined as one that had the following characteristics: (1) significant and independent predictive value validated by clinical testing; (2) identification that was feasible, reproducible, and widely available with quality control; and (3) ease of interpretation by clinicians and having therapeutic implications (NIH Consensus Conference, 1991). Even at this time, 10 years later, few, if any, of the numerous reported prognostic or predictive factors fulfill all three of these criteria.

References

Fitzgibbons PL, Page DL, Weaver D, Thor AD, Allred DC, Clark GM, et al. Prognostic factors in breast cancer. College of American Pathologists consensus statement 1999. Arch Pathol Lab Med 2000;124:966-78. Abstract.

Gasparini G, Pozza F, Harris A. Evaluating the potential usefulness of new prognostic and predictive indicators in node-negative breast cancer patients. J Natl Cancer Inst 1993;85:1206-18. Abstract.

Giuliano AE, Kelemen PR. Sophisticated techniques detect obscure lymph node metastases in carcinoma of the breast. Cancer 1998;83:391-3. Abstract.

Goldhirsch A, Glick JH, Gelber RD, Senn HJ. Meeting highlights: International consensus panel on the treatment of primary breast cancer. J Natl Cancer Inst 1998;90:1601-8. Abstract.

Loprinzi CL, Ravdin PM, de Laurentiis M, Novotny P. Do American oncologists know how to use prognostic variables for patients with newly diagnosed primary breast cancer? J Clin Oncol 1994;12:1422-6. Abstract.

Mansour EG, Ravdin PM, Dressler L. Prognostic factors in early breast cancer. Cancer 1994;74:381-400. Abstract.

NIH consensus conference. Treatment of early-stage breast cancer. JAMA 1991;265:391-5. No Abstract Available.