Brain Metastases Show ‘Divergent Evolution’ From Primary Tumour

Brain metastases show clinically actionable genetic differences from their primary tumours

medwireNews: Genetic analysis demonstrates significant differences between brain metastases and their matched primary tumours that could potentially be used to guide treatment, suggests research presented at the European Cancer Congress in Vienna, Austria.

Recognising that genetic heterogeneity may explain differences in treatment response between primary tumour and brain metastases in patients, the researchers are now using clinically available metastatic samples to investigate whether this strategy could improve patient survival.

Presenting author Priscilla Brastianos, from Massachusetts General Hospital in Boston, USA, explained to medwireNews that alterations, such as PI3K mutations and loss of PTEN, have been previously linked to treatment response, and that research is now ongoing to determine whether agents that cross the blood–brain barrier may be targeted on the basis of brain metastatic alterations.

The initial data set, published simultaneously in Cancer Discovery, included massively parallel sequencing of biopsy samples of healthy tissue, primary tumour and brain metastases taken during clinical care of 104 patients, 15 of whom also had metastatic tissue from other sites available.

“Importantly, 53% of cases […] have a clinically actionable alteration in the brain metastasis branch not detected in the primary site”, reported Priscilla Brastianos. For example, while a patient with primary renal cell carcinoma and brain metastasis detected at the same time showed shared mutations in MTOR and VHL, only the metastatic sample showed a mutation in a “hot spot” of PIK3CA and loss of CDKN2A.

The cyclin-dependent kinase (CDK) pathway was the most commonly affected by mutations in the metastatic samples, with 51% of the patients showing alterations that were associated with sensitivity to CDK inhibitors, while alterations that predicted sensitivity to inhibitors of the PI3K/AKT/mTOR pathway were seen in 43% of patients.

Moreover, regionally, anatomically and temporally distant areas of brain metastases shared the same clinically actionable mutations, explained Priscilla Brastianos.

For example, in a patient with salivary gland ductal carcinoma, two samples of symptomatic metastasis in the cerebellum before surgery and radiotherapy shared the same clinically actionable mutations as those of two samples from a distinct parietal metastasis taken after radiotherapy and before surgery. These mutations were not present in the primary tumour.

However, brain metastases were genetically divergent from those at other sites, with different mutations detected between, for example, brain and lung metastases taken from a patient with colorectal carcinoma.

This indicates that extracranial metastases are not reliable surrogates for brain disease, said Priscilla Brastianos.

Research is now ongoing to determine whether there are mutations that predict brain metastases and whether “liquid biopsy” is able to differentiate between circulating tumour cells or DNA shed from primary tumour and brain metastases, she added.


Brastianos PK, Carter SL, Santagata S, et al.Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets. Cancer Discov 2015; 5; 1–13, advance online publication 26 September.

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