Predictive markers in breast cancer – the future

Abstract

The published literature is awash with examples of new tissue biomarkers promising to predict responses to therapy in breast cancer patients. However, few, if any, of these progress from the laboratory to the clinic. In this review we discuss some of the reasons for this, illustrating our discussion with a selection of biomarkers which are in development and which may be candidates for clinical application within the next few years (topoisomerase II alpha, epidermal growth factor receptor, AKT, phosphatase and tensin homologue). In particular, we explore how our ever increasing knowledge of molecular and pathway biology is facilitating hypothesis-driven biomarker discovery, and the statistical considerations which need to be addressed in order to validate new candidate biomarkers adequately.

Effect of adding gefitinib to neoadjuvant chemotherapy in estrogen receptor negative early breast cancer in a randomized phase II trial

“…there is no clear way to select patients that would benefit from anti-EGFR treatment in breast cancer [12]. However, post-hoc subgroup analysis of our data showed that TNBC were more likely to achieve a pCR than non-TNBC, which is in line with a previously published study [22].…”

“…Whether or not, as indicated by others [12][13][14], an inverse relationship between EGFR and ER expression exists, awaits conduction of further gene expression analysis. If such an inverse relationship exists, the mechanism of action of gefitinib may be, as anticipated by others [10;11;17;18], more than simple inhibition of the EGFR tyrosine kinase.…”

“…Epidermal growth factor receptor (EGFR) is a transmembrane receptor with tyrosine kinase activity, which stimulates a series of intracellular pathways responsible for cell proliferation, downregulating apoptosis, invasion, metastasis and angiogenesis [10;11]. Although studies have demonstrated an inverse relationship between the expression of ER and EGFR [2][3][4][5][6][7][8][9][10][11][12][13][14], and suggested a connection between EGFR and the basal-like phenotype [12;15;16], the function and clinical significance of EGFR in breast cancer are still poorly understood. Preclinical in vivo [7;17] and in vitro [7;13] studies have shown that gefitinib (Iressa , Astra Zeneca), a selective EGFR tyrosine kinase inhibitor, exhibits anti-proliferative and anti-tumor activity in breast cancer.…”

Topoisomerase IIα-dependent and -independent apoptotic effects of dexrazoxane and doxorubicin

“…For several reasons, we focused on the importance of TOP2A. Firstly, both drugs share TOP2A as a major target and the individually variable expression level of TOP2A in breast tumors is being developed as a marker predictive for anthracycline response (9). Further, anthracyclines probably kill cancer cells by several mechanisms independent from TOP2A "poisoning."…”

Engineering Simulations for Cancer Systems Biology

“…These dysregulations confer cancerous cells with the ability to: proliferate at an increased rate; evade differentiation; develop new blood vessels (angiogenesis) within their aggregate tissues; evade death; migrate and metastasise; and resist growth inhibitory factors [5]. These hallmarks of cancer are governed at ultra-and micro-cellular levels by a complex network of signalling regulatory pathways that ultimately dictate the development, maintenance and progression of the cancer [6], as well as its histological and anatomical presentation and organisation [7]. The inherent characteristic and complex heterogeneity of the disease, governed by multivariate spatial and temporal parametric biological (pathways) and environmental (stromal) indices [8,9], make cancer extremely difficult to study and understand.…”