Although the worldwide incidence of breast cancer is increasing, death from this disease is now declining in a number of Western countries.2 This decrease in mortality is likely to result from a combination of mammographic screening and increased use of systemic adjuvant treatments. For optimum care of patients with breast cancer, a multidisciplinary approach is necessary. This approach should involve surgery, histopathology, medical oncology, radiotherapy, radiology and the use of tumour markers.

Tumour markers are substances that can be measured in blood, tumour tissue or other body fluid and that aid cancer detection and/or management. Tumour markers are potentially useful in screening for early cancer (e.g. prostatespecific antigen (PSA) in prostate cancer), aiding diagnosis (tumour markers almost never replace histopathology for the primary diagnosis of cancer), determining prognosis, predicting likely response or resistance to therapy, post-operative surveillance and monitoring therapy in patients with advanced cancer.

For breast cancer, the existing markers are of little value for screening or aiding early diagnosis. In contrast, markers are available for determining prognosis, predicting likely response to therapy, post-operative follow-up and monitoring therapy in metastatic disease. Prognostic and predictive marker use is usually determined on tumour tissue whereas surveillance and monitoring markers are measured in blood. The aim of this article is to review the role of both tissue and serum markers in the care of patients with breast cancer.

Tissue Markers

Hormone Receptors
Hormone receptors (i.e. oestrogen and progesterone receptors) are carried out in order to determine endocrine-sensitivity of newly diagnosed breast cancers. For hormone receptor-positive patients, endocrine therapy should be administered, i.e. tamoxifen and/or an aromatase inhibitor for postmenopausal patients and tamoxifen and/or ovarian suppression/ablation for premenopausal patients. Hormone receptor-negative tumours should not be treated with endocrine therapy but are candidates for treatment with adjuvant chemotherapy. It is generally recommended that both oestrogen and progesterone receptors be measured together as patients derive maximum benefit from hormone therapy when both receptors are present.

While the primary use of hormone receptors is for selecting for endocrine sensitivity, oestrogen receptors may also be used to determine prognosis. Generally, for the first five years following diagnosis, receptor-positive patients have a better outcome than receptor-negative patients. However, as a prognostic factor, the impact of oestrogen receptor is relatively weak, especially in patients with lymph node-negative disease. Furthermore, the favourable prognostic impact of hormone receptors disappears after about five years of follow-up.

Human Epidermal Growth Factor Receptor-2
Human epidermal growth factor receptor-2 (HER- 2) is primarily measured in order to select patients for treatment with Herceptin (trastuzumab). Herceptin is a therapeutic monoclonal antibody directed against the HER-2 oncoprotein. When administered with chemotherapy to HER-2- positive patients, Herceptin significantly improved both progression-free and overall survival in patients with advanced breast cancer. When given either with or after chemotherapy to patients with HER- 2-positive early breast cancer, Herceptin reduced the risk of recurrence by approximately 50%.

As well as predicting response to Herceptin, HER- 2 may be used for determining prognosis in patients with breast cancer. Generally, patients with HER- 2-positive tumours have a worse outcome than those with HER-2-negative cancers. Indeed, in the 2005 St Gallen Consensus statement, assay of HER-2 was recommended for classifying risk in newly diagnosed breast cancer patients.

uPA and PAI-1

uPA and PAI-1 are two proteins that promote cancer invasion and metastasis. More than 20 independent studies have shown that high levels of uPA or PAI-1 in breast cancer are associated with aggressive disease and poor outcome. Most importantly, the prognostic value of these proteins has been validated in the highest available level evidence studies, i.e. in level I evidence studies. These high-level evidence studies included a multicentre randomised prospective trial carried out in 14 centres in Germany and a pooled analysis involving data from 18 different centres across Europe.

Currently, the main clinical use of uPA and PAI-1 is for selecting lymph node-negative breast cancer patients that may not need to undergo treatment with adjuvant chemotherapy, i.e. lymph nodenegative breast cancer patients with low levels of uPA and PAI-1 have such a good prognosis that the benefit of chemotherapy would be sufficiently small that they could avoid the toxic side effects and high costs of this therapy. On the other hand, patients with high levels of uPA and/or PAI-1 have a poor prognosis (similar to that of patients with three positive lymph nodes) and thus should be treated with adjuvant chemotherapy.