What we are doing now, we are working on the genomic characterisation of metastatic breast cancer. There are some papers that have suggested that the genomic landscape of metastatic breast cancer could be different to the one of early breast cancer and, as we all know, what is going to kill the patient is the metastatic cancer not the primary tumour. So we are having several efforts, the first one is to describe the frequency, the distribution, of the common recurrent genomic alterations in metastatic breast cancer and to see if they are associated with specific clinical outcomes like poor survival or better response to conventional treatment. That is the first part about the conventional common recurrent genomic alterations.
The second part is drug development, the development of targeted therapies but also immunotherapeutics and DNA damage drugs that match to each of these genomic alterations. So this is the second part, this drug development. Then the third part is to understand the biological role, the functional validation, of genomic alterations that have been acquired in metastatic cancer. For example, when a genomic alteration is not present in early breast cancer but becomes recurrent in metastatic breast cancer then we investigate in the lab if this genomic alteration could be involved in the metastatic process.
Then point number four is to work on genomic evolution and genome evolution between the primary and the metastases and for doing that we look at what are the genomic alterations frequent in metastatic samples that we cannot find in the bulk of early breast cancer. We try to understand what has been the evolution of the genome that led to the appearance of this genomic alteration.
What are your key findings?
We have characterised the genomic landscape of more than 200 metastatic breast cancers using whole exome sequencing and there are several new findings. The first one is the fact that there are some recurrent genomic alterations that are specific to the metastatic sample as opposed to the primary. We found eleven genomic alterations and some of them have been characterised and could be involved in the metastatic process. When a patient is presenting these genomic alterations then the outcome is worse as compared to metastatic breast cancers who do not present this metastasis specific genomic alteration. So this is one first finding.
The second finding we had by running the genomic landscape of metastatic breast cancer is that a subset of oestrogen receptor positive metastatic breast cancers present with a very high mutational load and acquired genomic instability and high mutational load, probably because of high expression of APOBEC. We found that around 10-15% of oestrogen receptor positive breast cancer, when they are metastatic, have a very high mutational load. Now there are some attempts to see whether these patients could be more sensitive to immunotherapeutics and there are some attempts to understand what has made this cancer become so mutated. As I mentioned before, APOBEC is one of the hypotheses but there are several other ones.
Then what we are investigating and for which we have some interesting preliminary results is whether these genomic alterations that are enriched in metastatic breast cancer but present at a low frequency in early breast cancer could have some prognostic value when they are present in early breast cancer. Indeed, some of these genomic alterations when they are present in early breast cancer are associated with a worse outcome.
What clinical impact do you see your research having in the future?
The first one is to find new targets that could prevent the development of metastasis because if we understand what are the genomic alterations that are functional and enriched in metastatic breast cancer and led to the development of metastases, that could generate some work about preventing metastases. The second application is to better drive the drug development in metastatic breast cancer by defining what is the genomic landscape of metastatic breast cancer and obviously the genomic landscape of metastatic breast cancer is very different to the one of primary breast cancer. Point number three is to better understand which patients with metastatic breast cancer are going to have a very poor outcome. This is very important because if we can identify some genomic alterations associated with a very poor outcome then the drugs that target this genomic alteration could receive some fast track drug approval. So finding which genomic alterations are associated with worse outcomes, very poor outcomes, is a major challenge to drive drug development.
