ECC 2015

Brain metastases genomic analysis could reveal new targets for treatment

Prof Priscilla Brastianos - Massachusetts General Hospital, Boston, USA

Brain metastases can come from a whole lot of different primary sites but you’ve been looking specifically at brain mets. What were you trying to establish in the study that you’ve just reported?

So the most common histologies that go to the brain are lung, breast and melanoma although many other cancers can go to the brain. So what our study did was evaluate the genetics or genomics of brain metastases and compare them to matched primary tumours to map out the evolutionary patterns in brain metastases.

This was after resection so you’ve got samples to work on.

Exactly. We used biopsy samples that were collected as part of clinical care.

What were the big findings of your study?

The major finding was that we saw divergent evolution and what does that mean, or branched evolution, what does that mean? It means that the brain metastases and the primary tumours although they shared a common ancestor there was continued evolution in each of the brain metastases and each of the primary tumours. So they continued to evolve separately and what does that mean, how is that important clinically? We found clinically attributable alterations in brain metastases that were not present in the primary tumour biopsy.

Now, you could find some alterations in the brain mets which were in common with the primary and you could find ones that are completely different. What’s the policy when you find particular features?

We found that in 53% of cases the brain metastases had additional clinically attributable alterations that were not present in the primary tumour. What we found across the entire cohort, there were some commonalities across the entire cohort. We found that there were a lot of mutations in the CDK pathway or alterations that predict sensitivity or are associated with sensitivity to CDK inhibitors. We also found alterations that were associated with sensitivity to PI3 kinase inhibitors. Those were the two most common pathways that we saw across the entire cohort, across all histologies that we evaluated.

How might this knowledge affect the way that doctors would be treating their patients?

This knowledge actually has significant implications for clinical care. Often decisions for personalised medicine in cancer patients are made from looking at the primary tumour biopsy. We’re showing now that by looking at a brain metastasis we may uncover more clinical possibilities or more therapeutic targets. So whether targeting what we see in the brain will have a survival benefit, that needs to be studied prospectively. However, what we’re saying is that if there is brain metastasis tissue available, so brain metastasis tissue that was collected as part of clinical care, either because the patient had a craniotomy for a single metastasis or had a craniotomy for a mass lesion in the brain, we should be looking into that brain metastasis tissue for potential new therapeutic targets.

Of course, brain metastases are, generally speaking, a late stage of disease so how much hope does this give to patients if they get a more appropriate individualised therapy at this stage?

Not all brain metastases are a late manifestation of disease. So in many lung cancer patients patients will develop brain metastases synchronously with the primary tumour, meaning the brain metastases will happen around the same time as the diagnosis of the primary tumour. In breast cancer, on the other hand, so the HER2 breast cancer patients, they will develop brain metastases later in their course of disease. So if we find genetic alterations that are present in the brain metastases there is hope that by targeting those brain metastases or targeting those mutations in the brain metastases we may be able to improve survival outcomes. However, that needs to be studied prospectively.

If you get the treatment right for brain mets can you improve quality of life?

If we get the treatment right for brain metastases I would hope that we could significantly improve quality of life for patients.

So what’s the short take-home message for doctors coming out of your work?

The short take-home message is if there is brain metastasis tissue available we should be looking into that tissue to look for potential actionable targets for these patients.

Thank you very much.