Breast cancer prognostic classification in the molecular era: the role of histological grade

Abstract

Breast cancer is a heterogeneous disease with varied morphological appearances, molecular features, behavior, and response to therapy. Current routine clinical management of breast cancer relies on the availability of robust clinical and pathological prognostic and predictive factors to support clinical and patient decision making in which potentially suitable treatment options are increasingly available. One of the best-established prognostic factors in breast cancer is histological grade, which represents the morphological assessment of tumor biological characteristics and has been shown to be able to generate important information related to the clinical behavior of breast cancers. Genome-wide microarray-based expression profiling studies have unraveled several characteristics of breast cancer biology and have provided further evidence that the biological features captured by histological grade are important in determining tumor behavior. Also, expression profiling studies have generated clinically useful data that have significantly improved our understanding of the biology of breast cancer, and these studies are undergoing evaluation as improved prognostic and predictive tools in clinical practice. Clinical acceptance of these molecular assays will require them to be more than expensive surrogates of established traditional factors such as histological grade. It is essential that they provide additional prognostic or predictive information above and beyond that offered by current parameters. Here, we present an analysis of the validity of histological grade as a prognostic factor and a consensus view on the significance of histological grade and its role in breast cancer classification and staging systems in this era of emerging clinical use of molecular classifiers.

Figure 1

Histological grade of breast cancer as assessed by the Nottingham Grading System. (a) A well-differentiated tumor (grade 1) that demonstrates high homology to the normal breast terminal duct lobular unit, tubule formation (>75%), a mild degree of nuclear pleomorphism, and low mitotic count. (b) A moderately differentiated tumor (grade 2). (c) A poorly differentiated (grade 3) tumor with a marked degree of cellular pleomorphism and frequent mitoses and no tubule formation (<10%).

Figure 2

Relationship between histological grade and breast cancer-specific survival. (a) In the old Nottingham series (1977 to 1989), no systemic therapy was offered to the patients. Of the 1,816 patients, 404 (17.7%) had grade 1 tumors (gray curve), 621 (36.2%) had grade 2 (blue curve), and 791 (46.1%) had grade 3 (black curve) (χ² = 97.5, P < 0.0001). (b) In the recent Nottingham series (1990 to 2002), systemic therapy was offered to the patients according to Nottingham Prognostic Index and estrogen receptor expression as described previously [11]. Of the 3,579 patients, 677 (18.9%) had grade 1 tumors (gray curve), 1,383 (38.6%) had grade 2 (blue curve), and 1,519 (42.4%) had grade 3 (black curve) (χ² = 195.5, P < 0.0001). Analysis of grade 1 and 2 only showed statistical survival difference (χ² = 20.7, P < 0.0001). Both series are consecutive and included estrogen receptor-positive and -negative and lymph node-negative and -positive cases [11,75,76].