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Diseases of the Breast
Prognostic and Predictive Factors
Gary M. Clark

G. M. Clark: Breast Care Center, Baylor College of Medicine, Houston, Texas

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Introduction
Historical Perspective
Histopathologic Features
 
Histologic Type
 
Axillary Lymph Nodes
 
Tumor Size
 
Tumor Grade
 
Other Histologic Factors
Patient Characteristics
 
Age at Diagnosis
 
Ethnicity
Measures of Proliferation
 
Mitotic Index
 
Thymidine-Labeling Index
 
S-Phase Fraction by Flow Cytometry
 
Ki67 Staining
 
Proliferating Cell Nuclear Antigen
 
Comparison of Measures of Proliferation
Steroid Receptors and Estrogen-Regulated Factors
 
Estrogen and Progesterone Receptors
 
pS2
 
Heat Shock Proteins
Growth Factors and Receptors
 
Epidermal Growth Factor Receptor
Her-2/neu
Tumor-Suppressor Genes
 
p53
 
nm23
Measures of Invasiveness
 
Cathepsin D
 
Plasminogen Activators and Inhibitors
 
Laminin Receptors
Angiogenesis
Microarray Technology
Models of Prognostic Factors
Management Summary
Chapter References

INTRODUCTION
The diagnosis of breast cancer presents several dilemmas for the patient and the physician. What type of surgery should be performed? Is radiation therapy necessary? Should additional systemic adjuvant therapy be used? If so, which therapy is best for this particular patient? To address these questions, one must first determine the likelihood that this patient will have a recurrence of the disease in the future if no additional therapy is administered. Then, the efficacy of the available therapies must be estimated and weighed against the potential side effects to determine the probable benefit for this patient. Unfortunately, the clinical course of primary breast cancer varies from patient to patient. Some patients have long disease-free survival times, whereas others experience a rapid deterioration with early recurrence of breast cancer, followed shortly by death. Some of this variability is undoubtedly explained by differences in tumor growth rates, invasiveness, metastatic potential, and other mechanisms that are not yet fully understand. Knowledge of biomarkers that could measure these functions, either directly or indirectly, would obviously be useful so individual patients could be classified into subsets with varying risks of disease recurrence.
Throughout this chapter, the terms prognostic factor and predictive factor are used. A prognostic factor is defined as any measurement available at the time of diagnosis or surgery that is associated with disease-free or overall survival in the absence of systemic adjuvant therapy. Potential prognostic factors include demographic characteristics (e.g., age, menopausal status, ethnicity), tumor characteristics (e.g., lymph node status, tumor size, pathologic subtype), biomarkers that measure or are associated with biological processes purportedly involved in tumor progression (e.g., altered oncogenes, tumor-suppressor genes, growth factors, measures of proliferation), and other factors. Prognostic factors can be used to predict the natural history of the tumor. A predictive factor is defined as any measurement associated with response or lack of response to a particular therapy. An example of a predictive factor is the estrogen receptor (ER) status of a tumor, which predicts response to hormonal therapy in the adjuvant setting and in metastatic disease.
This chapter describes the current standard prognostic and predictive factors for primary breast cancer and details several newer markers that are still being evaluated but have the potential for becoming standard factors in the future. Pitfalls to be considered when evaluating these new markers are also described.

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HISTORICAL PERSPECTIVE
The role of prognostic factors in optimizing treatment for breast cancer patients has clearly changed with the trend toward general use of systemic adjuvant therapy. Several years ago, patients with axillary node–negative breast cancer were considered to have a relatively good prognosis, and few received adjuvant therapy after local surgery. In 1985, a National Cancer Institute (NCI) consensus development conference concluded that no standard therapy existed for patients with node-negative breast cancer.1 Some of these patients were destined to have early recurrences of their disease, but despite attempts by several groups to identify subsets of patients at an increased risk of disease recurrence and death using prognostic factors, a consensus could not be reached concerning the identity of such high-risk patients. With the publication of early results from several randomized clinical trials showing a benefit from adjuvant therapy for patients with node-negative breast cancer2,3,4 and 5 and the publication of the overview analysis by the Early Breast Cancer Trialists' Collaborative Group,6 however, many clinicians began to adopt the treatment strategy of administering systemic adjuvant therapy to all breast cancer patients regardless of prognostic factors. A subsequent NCI consensus development conference7 in 1991 recognized that clinical outcomes varied among patients with primary breast cancer, but the panelists generally concluded that, aside from the standard factors of nodal status, tumor size, and histopathologic subtype, none of the newer prognostic factors had been proved to have clinical use. Thus, one might question whether any new prognostic factors for breast cancer are really needed.
Today, prognostic or predictive factors are useful in at least three clinical situations.8 The first is to identify patients whose prognosis is so good after local surgery that the addition of systemic adjuvant therapy would not be cost-effective. The second is to identify patients whose prognosis is so poor with conventional treatment that other forms of more aggressive therapy might be warranted. The third is to ascertain which patients are or are not likely to benefit from specific therapies. As more is learned about the biology of breast tumors, these characteristics might be therapeutic targets for new treatments for patients with breast cancer.
The standard prognostic factors currently applied in cases of primary breast cancer include the following:

Axillary lymph node status

Histologic subtype

Tumor size

Nuclear or histologic grade

Estrogen and progesterone receptor status

Measure of proliferation
Unfortunately, none of these factors, alone or in combination, completely separates patients who are cured by local therapy from those whose cancer is destined to recur and who will die without intervention. Therefore, to accomplish this objective, newer markers that have not yet been fully evaluated must be considered. Special issues of the journal Breast Cancer Research and Treatment (1998, vol. 51, no. 3; 1998, vol. 52, nos. 1–3) have been published that describe many new prognostic and predictive factors. Caution must be exercised when interpreting results of published studies that have evaluated potential prognostic and predictive factors. McGuire9 proposed guidelines for the design and conduct of prognostic factor studies, and Gasparini et al.10 gave more details on evaluation of these factors. Hayes et al. created a tumor marker use grading system to evaluate the clinical use of tumor markers11 and described a process for assessing the clinical impact of prognostic factors.12
Statistical p values, especially those from univariate analyses, can be misleading, because they depend on the number of patients included in the study and, more importantly, on the number of events. In this chapter, whenever possible, other statistics, including relative risks and absolute survival or recurrence rates, are presented to give the reader some estimates of the magnitude of the effects that have been observed for the various factors. In addition, emphasis is placed on multivariate analyses that at least partially take into account the prognostic significance of established factors and often of newer putative prognostic factors.
HISTOPATHOLOGIC FEATURES
Histologic Type
Infiltrating ductal and infiltrating lobular carcinomas, either in their pure form or in combination with other tumor types, are the most common types of breast cancer. When cells of two or more histologic types are present, the tumor is usually evaluated according to its most malignant-appearing elements, although Fisher et al.13 have questioned the appropriateness of this practice. Patients with infiltrating ductal tumors generally have a higher incidence of positive axillary lymph nodes and poorer clinical outcomes than patients with the less common types of infiltrating tumors. With increased use of mammography and other screening programs, more and more noninvasive breast tumors are diagnosed. Although these tumors generally portend a favorable clinical outcome, some do recur as invasive carcinomas. Considerable interest exists in identifying prognostic factors for these noninvasive tumors. Because of the low relapse rates and relatively long disease-free survival times, however, large studies must be conducted to address this question, and such studies are currently being performed. The remainder of this chapter focuses on invasive, infiltrating ductal carcinomas.
Axillary Lymph Nodes
The presence or absence of metastatic involvement in the axillary lymph nodes is the most powerful prognostic factor available for patients with primary breast cancer. Although most clinical trials stratify patients into three nodal groups (those with negative nodes, those with one to three positive nodes, and those with four or more positive nodes), several groups have demonstrated a direct relationship between the number of involved nodes and clinical outcome.14,15 and 16 Figure 32-1 displays disease-free survival time as a function of the number of positive lymph nodes for patients in the San Antonio Database. Although lymph node involvement is associated with larger tumors, it is relatively independent of other biomarkers, including presence of steroid receptors and measures of proliferation; for this reason, the conjecture has been put forward that axillary node status may merely reflect the relative chronologic age of the tumor and that the various biological prognostic factors might influence prognosis through other mechanisms.17

FIG. 1. Disease-free survival (DFS) by number of positive axillary lymph nodes. Data from San Antonio Database; median follow-up, 51 months.

Although axillary lymph node dissection provides important prognostic information, debate exists about its therapeutic use for local and regional control. Some studies have found a modest benefit, whereas others have not. Consensus has been reached, however, that not all patients need undergo this procedure. Patients with small, pure, noninvasive ductal carcinoma in situ derive little benefit from an axillary dissection because their incidence of axillary involvement is low and their clinical prognosis is good. The value of axillary dissection in patients who present with systemic, metastatic disease is also questionable.

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