The baseline evidence for the variation in breast cancer behavior comes from studies from many years ago of women who had no treatment and of those that were before the advent of systemic (i.e. adjuvant) treatment following surgery. Bloom et al1 reported on a series of 250 women seen at the Middlesex Hospital, London, UK between 1805 and 1933; 74% had advanced (stage IV) disease at the time of admission but 18% of these were still alive at 5 years without any treatment. The number of patients is small but this demonstrates the variation in the natural history of untreated breast cancer. The importance of having large series of patients to derive valid information was appreciated; it is from pre-adjuvant therapy studies that amassed information from one or more centers that data on the clinical importance of tumor size and node status comes.2-7 A criticism of some of the studies, e.g. The National Cancer Institute Surveillance, Epidemiology and End Results (SEER) Program,7 is that staging was based on a combination of clinical and pathological data, and that the reporting pathologists data was used with no review by one or a small number of individuals.

To gain important clinically relevant information about outcome it is necessary for studies to have sufficient numbers of pathologically staged patients who are categorized by age, surgical and adjuvant treatment, and whose cancers are assessed clinically and pathologically using standardized, clearly defined criteria. The derivation of the Nottingham Prognostic Index is an excellent example of this.8 It was established by the long-term follow-up in a dedicated breast unit of patients who did not receive adjuvant therapy, had a standard management, and whose cancers were assessed using defined criteria9,10 by a small number of pathologists.

The drive to find newer/different markers of breast cancer behavior has resulted in innumerable studies, many of limited value. Evaluation guidelines for breast cancer prognostic factors were proposed in 199111 and still apply today: the factor should possess clear biological significance; the study should be defined as a pilot, definitive or confirmatory; there should be an adequate sample size for meaningful calculations; the patient population must be defined and not biased, for example, in relation to size, node status or age; there must be methodological validation; clinical cut-off values must be defined; assays must be reproducible. Problems with tumor-marker prognostic studies (generally, not just breast) have been recognized in reporting recommendations (REMARK),12 that were published simultaneously in US and European journals in 2005. These also emphasize the need for information about study design, preplanned hypotheses, patient and specimen characteristics, assay methods, and statistical analysis methods.

The American Society of Clinical Oncology first published evidence-based clinical practice guidelines for the use of tumor markers in breast cancer in 1996. In the 2007 update,13 13 categories of markers were considered, but not all had enough evidence to support routine use in clinical practice. Those that did included estrogen receptor (ER) and progesterone receptor (PR) (see Chapter 9) human epidermal growth factor receptor 2 (HER2) (see Chapter 13), and also certain gene expression assays (see Chapter 11).

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