My research focuses on breast cancer translational research and also some clinical research. The research that I will present here today is on a transcription factor known as Signal Transduction and Activation of Transcription 3, it’s STAT3. It’s part of the IL-6/JAK2-STAT signal transduction pathway. This transcription factor is usually activated by cytokines from the IL-6 family and translocates to the nucleus in the phosphorylated state where it activates as transcription factors. But in breast cancer we have found that around 40% of the breast tumours are constitutively activated for the phosphorylated STAT3 protein. We can detect it by specific antibodies that identify the phosphorylated status of this transcription factor. Quite a lot of studies in the preclinical setting show that STAT3 is an oncogene associated with proliferation, oncogenesis, angiogenesis, anti-apoptotics, so it’s associated with progression of the disease. On the other hand there are retrospective studies and clinical studies and other studies not in breast cancer but in other cancers that show that STAT3 has a tumour suppressor effect. So actually we are quite in a dilemma whether STAT3 is associated with improved outcome, better prognosis or whether it is associated with a worse outcome. It’s becoming extremely important because compounds that inhibit this pathway are at a different stage of development. So we have inhibitors for the IL-6 upstream pathway, for the JAK and the STAT3 pathway. Even currently we have clinical trials evaluating a JAK1/2 inhibitor, ruxolitinib, in the setting of oestrogen receptor positive breast cancer. So actually it’s very timely now to evaluate whether STAT3 has a good prognostic role or a bad prognostic role and this was the major purpose of the study that I will present today.
Did you find pSTAT3 pathway to be beneficial to treatment in your research?
We integrated a proteomic and gene expression approach and used a pooled analysis with a metagene that we developed using machine learning tools. This was the first approach and the second approach was to validate the results in the setting of a prospective randomised trial. We used a [?? 2:32] prospective randomised trial and its data for the validation in both the pooled analysis and the validation set from the randomised trial showed that phosphorylated STAT3 is associated with improved outcome in luminal breast cancer, namely ER positive breast cancer, whether they are luminal A or whether they are luminal B.
Can we expect a change in the treatment of luminal breast cancer in the near future?
First, this is an important observation because, as I said before, we are now trying to target this pathway. So even if we find it useful to target STAT3 or the upstream JAK2 or IL-6 still we need to take into account the fact that tumours that have an activated STAT3 pathway have better prognosis, whether inhibiting the pathway will be detrimental or effective, this has to be seen. But any trial that is evaluating inhibitors of this pathway need to take into account our observations.
What would be your take home message?
My take home message is that phosphorylated STAT3 in luminal breast cancer is associated with improved outcome. Any trial that is going to evaluate compounds that inhibit this pathway this should be taken into account as a stratification factor or as a biomarker.
