Brain metastases evolve ‘clinically actionable’ mutations

By Lynda Williams, Senior medwireNews Reporter

Brain metastatic disease shows branched evolution from the primary tumour, suggest preliminary findings from the largest massively parallel sequencing study of paired samples performed so far.

The study, presented at the European Cancer Congress in Vienna, Austria, and published simultaneously in Cancer Discovery, identified genetic mutations specific to brain metastases from different types of primary tumour and raises the possibility of treatment targeting these alterations.

Presenting author, Priscilla Brastianos, from Massachusetts General Hospital in Boston, USA, explained that matched samples of primary tumour, brain metastases and distant disease at other sites showed a “common ancestor” but had site-specific mutations indicating “divergent evolution”.

For example, a patient with renal cell carcinoma showed common germline mutations in MTOR and VHL in the primary and brain metastases samples, with additional loss of function mutations in PIK3CA and CDKN2A/B that were found only at the distant site.

Indeed, of 104 number of brain metastases sequenced, 56% were found to have a “clinically actionable alteration” that was not present in the primary tumour; 51% of mutations suggested the metastasis might be sensitive to CDK inhibitors and 43% of mutations indicated potential efficacy of PI3K, AKT or mTOR inhibitors.

Further analysis revealed that metastases from “regionally, anatomically and temporally distinct areas of the brain” shared the same clinically actionable mutations, whereas there was genetic divergence between metastases in the brain and distant disease at other sites.

“Genetic divergence between primary and metastatic samples poses a major challenge to clinical decision-making for precision medicine in oncology in brain metastases”, said Brastianos, explaining that extracranial metastases are not reliable surrogates for disease detected in the brain.

Speaking at a press conference, Brastianos said that the “genetic heterogeneity was daunting” and that further research is ongoing to determine whether liquid biopsy will be able to differentiate between circulating tumour cells or DNA from primary tumour, brain metastases and distant disease from other sites.

Brastianos also told medwireNews that further investigations are now underway to find out whether mutations in PI3K, PTEN and other genes previously linked to treatment response can be used to identify which patients with brain metastases will respond to molecularly targeted treatments that can cross the blood–brain barrier.

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