Clinical Breast Cancer February 2003 • 381 Introduction Breast cancer is a major public health problem, and its in- cidence is increasing in all Western countries. Because of its biological heterogeneity and wide spectrum of responsive- ness to different therapeutic options, it is a complex disease of difficult clinical management. Important advances in the understanding of the molecular mechanisms involved in tu- morigenesis and progression of breast cancer have been made, providing new insights in the pathways modulating tumor cell cycle, apoptosis, angiogenesis, growth factors, regulation of hormone receptors, and oncogene and tumor suppressor genes. 1 The complexity of molecular mechanisms involved in the stimulation or suppression of the growth of breast cancer via endocrine, autocrine, or paracrine path- ways might explain why TNM staging or any other single clinicopathologic feature cannot retain an absolute prognos- tic or predictive value. 2 The availability of several adjuvant therapy options provides the opportunity to select different treatments for well-defined subgroups of patients. There- fore, in addition to the conventional prognostic indicators, a number of markers have been proposed to predict the re- sponse to selective treatments. Prognostic and Predictive Factors A prognostic indicator is defined as a factor able, at the time of diagnosis, to give significant information on the nat- ural history of the disease and on clinical outcome of each single patient, in the absence of systemic adjuvant therapy. 3 To provide such evidence, a prognostic indicator must be re- lated to molecular mechanisms involved in tumor growth, progression, and/or metastasis. A new prognostic indicator must not only demonstrate statistical significance as a single variable, but it should also be independent in multivariate analysis studies in which the conventional clinicopathologic indicators are evaluated. A profile of a possible ideal new prognostic indicator for patients with breast cancer is sum- marized in Table 1. Currently, no single prognostic indicator with all the characteristics required exists, but there are sev- eral potentially useful prognostic indicators, including clini- copathologic, biochemical, genetic, and molecular character- istics of the tumor (Table 2). Most of these factors are under evaluation, and others need to be better defined, either by standardization of the method or by exploring relations be- tween new and conventional prognosticators. The clinical Prognostic and Predictive Indicators in Operable Breast Cancer Submitted: Sep 27, 2002; Revised: Jan 24, 2003; Accepted: Feb 7, 2003 1 Division of Medical Oncology, Azienda Ospedaliera San Filippo Neri, Rome, Italy 2 Centro Regionale Indicatori Biochimici di Tumore, Ospedale Civile USL 12 Veneziana, Venezia, Italy Because of its biological heterogeneity and wide spectrum of responsiveness to different treatments, breast cancer is a complex disease of difficult clinical management. Over the past several years, knowledge of the molecular mechanisms regulating normal and aberrant cell growth leading to cancer has been enhanced. These advances have enabled the identification of an increasing number of surrogate biomarkers, which have been correlated with prognosis or used as predictors of response to specific treatments. Axillary nodal status, age, tumor size, pathologic grade, and hormone receptor status are the established prognostic and/or predictive factors for selection of adjuvant treatments. The role of new biomarkers, such as p53, HER2/neu, angiogenesis, and the proliferation index value, is promising; however, the clinical value of their determina- tion must be provided by prospective clinical studies. Clinical Breast Cancer, Vol. 3, No. 6, 381-390, 2003 Key words: Angiogenesis, Axillary nodal status, Biomarkers, HER2/neu, Hormone receptor, p53, Proliferation index review Abstract comprehensive Address for correspondence: Prof. Giampietro Gasparini, Division Medical Oncology, Hospital San Filippo Neri, Via Martinotti 20 00135 Rome, Italy. Fax: 39 06 33062445; e-mail: gasparini.oncology@tiscalinet.it Alessandro Morabito, 1 Elena Magnani, 1 Massimo Gion, 2 Roberta Sarmiento, 1 Barbara Capaccetti, 1 Raffaele Longo, 1 Domenico Gattuso, 1 Giampietro Gasparini 1