Tailoring adjuvant systemic therapy for breast cancer: dream or reality?

Martine J Piccart
Jules Bordet Institute and Université Libre de Bruxelles, Brussels, Belgium

Introduction
Exploiting the great knowledge acquired in the 20th century about cancer genes to develop both molecular biomarkers and molecular therapeutics forms the basis for the development of personalised cancer medicine in the 21st century. In simple words, finding the right treatment for the right patient at the right time is the greatest challenge oncologists are facing nowadays. We will take the example of early breast cancer (BC) therapy to illustrate the most striking clinical advances already accomplished, as well as future directions for clinical and translational research.

Selection of adjuvant systemic therapies: historical perspective
The St-Gallen 2005 paradigm ‘first select the target in the tumour – then think about risk’ is the corner-stone of modern ‘tailored’ adjuvant therapy. While recent progress has been done in evaluating ‘risk’, much work still needs to be done in identifying the Achilles’ heel of each tumour for therapy selection.

Multi-gene prognostic signatures on their way to the clinic
Fairly reliable gene-expression signatures predicting BC outcome have been developed in the last few years. However, strong claims about their clinical value cannot be made without prospective clinical trials that validate their benefit above and beyond the use of standard clinico-pathological prognosis variables. Two gene expression predictors, namely the 21-gene recurrence score (ONCOTYPE DX) and the 70-gene Amsterdam signature (MAMMAPRINT ®) have reached the final step of prospective clinical trial testing: the TAILORx and the MINDACT trials are recruiting patients and will be updated. However, not all the relevant information related to outcome is contained in the primary tumour gene expression profile. This observation calls for the need to reinforce the study of circulating tumour cells and disseminated tumour cells, which constitute a window into the metastatic process … and a potential way of grasping the biology of putative breast cancer stem cells.

Aiming at the target is our next difficult challenge
We will discuss how the development of high throughput platforms, which can provide parallel information on thousands of tumor genes and their correspondent proteins and the use of ‘synthetic lethality screens’ in preclinical experiments should help with the identification of critical pathways and lead to smart combinations and/or sequences of targeted therapies.

The need for a revolution in the design and conduct of cancer clinical trials
Finally, as science is now catching up with clinical needs, a profound revolution needs to take place in the way clinical trials are being designed, conducted and financially supported. This ‘revolution’ will be discussed.