Discovery of novel treatment predictive biomarkers for individualized therapy of breast cancer patients

Reidun Aesoy, Betzabe Chavez-Sanches, Kristina Viktorsson, Janne Lehtiö, and Rolf Lewensohn.

Lena Kanter-Lewensohn, Lambert Skoog, Torsten Hägerström (Pathology/cytology); Thomas Hatschek, Tommy Fornander, Eva von Schoultz (Oncology). Birgitta Holmlund, Olle Stål, Bo Nordenskjöld, (Oncology, Linköpings University Hospital).

Breast cancer is the leading cause of death among women under age of 55 years in developed countries. Initially breast cancer therapy involved only local treatments as surgery and radiotherapy. However since more than three decades, several attempts to increase breast cancer survival by introduction of systemic adjuvant therapies (chemotherapy and/or endocrine therapy) have been successful. Tamoxifen, a non steroidal selective oestrogen receptor modulator (SERM), initially developed as a contraceptive, has been the corner stone in breast cancer treatment, both adjuvant and at recurrent disease. The effect of endocrine therapy is highly dependent on the expression of steroid receptors; approximately 60% of patients at first relapse will benefit, decreasing to 45% for those that express one of the receptors and no effect in the receptor negative group. There is obviously a need for complementary treatment predictive information also for this therapy. For the effect of chemotherapy the situation is even worse; we have today no biomarkers in clinical routine giving guidelines neither for type of drug, nor for different scheduling.

Discovery

The breast cancer project in KBC is focused on discovery and validation of new treatment predictive biomarkers, which already is up-and-running for several other diseases such as lung cancer and leukaemia. The project is based on internal extended knowledge in protein chemistry, proteomics technologies, and bioinformatics. Collection of material from relevant patient populations necessary to solve these questions have been made in collaboration with the department of pathology/cytology at the Karolinska University Hospital and the department of Oncology, Linköpings University Hospital. Thanks to participation in several national and international clinical trials, we also have been able to do prospective sampling with our questions put in up front. For patients with advanced disease, it is not possible or ethical to do repeated biopsies from metastasis; by use of proteomics we overcome this problem as blood samples, easily taken, can be used. Here we can study possible changes in protein profiles over time; during regress or progressive disease.

Discovery and validation

Using mass spectrometry-based proteomic techniques we are identifying proteins or protein profiles which can predict sensitivity to different types of commonly used breast cancer therapies. Before any clinical use, all markers have to pass a rigorous validation, showing a benefit on different laboratory platforms used at different institutions. Due to collaboration within international groups we have the possibility to validate or withdraw any new predictive biomarkers. We have started with smaller pilot studies aiming at find differences in protein expression between patients responding, or resistant to, a specific therapy. This is followed by an internal enlarged validation within our own population. The potential new biomarkers are then tested in larger patient populations from other institutions in Sweden as well as in international collaboration including several centres in Europe. We will use standard techniques but also newer methods as a multi-ELISA and tissue micro arrays (TMA), both which can be used with smaller amount of patient (sample) material.

Translational preclinical studies in cell lines

Abnormalities in cellular signalling are proposed as one part in endocrine resistance, while loss of the steroid receptors is seldom seen. As part of our project, we study in more detail specific signalling pathways that we have found to be of importance for endocrine resistance in clinical patient materials. For this purpose, breast cancer cell lines sensitive or resistant to endocrine therapies are used.

Clinical significance of the project Our goal to identify novel biomarkers with predictive information regarding the possible effect of a specific therapy will hopefully result in a more optimal and individualised therapy for each breast cancer patient.

Last updated: 2009-09-10