ECC 2013

Molecular biology guiding treatment of gastrointestinal stromal tumours (GISTs)

Dr Javier Martin-Broto - Son Espases Hospital, Palme de Mallorca, Spain

The aim of our investigation was to improve the GIST outcomes we have with the present drugs, so with three different angles. We have now more knowledge from pathogenic mechanisms of disease; we have now more details about wild-type GIST, and that represents 15% of GIST cases and is considered now a very different entity, and we have now relevant information compared with five years ago, for instance. We know within this wild-type GIST that KIT is important but not as relevant compared with mutant GIST. So we need new approaches and we know that in this subset of patients the loss of SDH complex induced to cellular hypoxic status where genes involved with angiogenesis are important. So antiangiogenic treatment in this specific subset of GIST is relevant and it should be tested in the clinical setting.

What can you tell us about your study into combination therapy?

In wild-type GIST there is no combination because imatinib is not working so we can offer in the clinical setting just sunitinib or regorafenib but we think it’s relevant to explore other options under clinical research in a phase I/II trial, along with this antiangiogenic treatment alone, as the first step. So combination is important in mutant GIST where we are looking for greater response rates. For instance, the apoptosis in GIST is remarkably delayed compared with other tumours so one important topic of research is how we can improve the apoptosis in GIST.

What was the design in this investigation?

There is very complex apoptosis in GIST, it’s not related just with the shutdown of kinase activity and there is one histone, one molecule, that drives GIST cells into apoptosis. So this is a good target also to be treated in advanced disease.

What have your results achieved?

We are offering targeted therapies so imatinib is the first line, sunitinib is the second line and regorafenib is the third line in advanced GIST. But doxorubicin is just working in some subsets but it’s not usually done in this entity.

What are your findings in the study you have presented at the ECC?

We have presented several findings from several authors and one also important research we have personally implicated is in the prognostic relevance of genotype because 80% of GISTs are presented as localised disease and it’s very relevant to offer prognostic information to these patients. So genotype can offer a robust information because specific mutations which involve a specific carrier of columns within exon 11 of KIT entails a very worse prognosis. So this is also very important to take into account and our challenge is to integrate this information within the pathologic and clinical information that we are giving to the patients usually in the clinical setting. We need more details, more robust information stemming from molecular research.