Targeting Molecular Drivers in Breast Cancer Brain Metastases Could Have Therapeutic Potential

Patients with breast cancer who develop brain metastases tend to have poor prognosis with short overall survival. Although new therapies continue to emerge, disease progression in the brain remains common, even in the setting of stable extracranial disease.

According to Priscilla Brastianos, MD, Director, Central Nervous System Metastasis Program, Massachusetts General Hospital, Harvard Medical School, Boston, MA, understanding of how intracranial metastases genetically evolve from the primary tumors remains limited. However, data from large-scale genomic efforts to characterize brain metastases have revealed that targeting common genetic mutations in patients with breast cancer brain metastases—particularly CDK and PI3K pathway alterations—could have therapeutic potential.

At the 37th Annual Miami Breast Cancer Conference, she discussed these targetable mutations and brought attendees up to speed on her research in the field.

Dr Brastianos and colleagues conducted whole-exome sequencing of 104 brain metastases matched with primary and normal tissue, including 15 with additional extracranial sites, as well as temporally, regionally, and anatomically separated brain metastases. In looking for commonalities across their sample in an attempt to inform future clinical trials, they found that despite significant genetic divergence between the brain metastases and extracranial sites, there were some common clinically actionable genetic alterations across brain metastases that could be potential therapeutic targets.

PI3K pathway alterations were very common; approximately 40% of cases had alterations associated with sensitivities to PI3K inhibitors. “We wanted to explore that in the lab, so we looked at the efficacy of a CNS-penetrant PI3K inhibitor, GDC0084, in vivo in a PIK3CA-mutant cell line compared with PIK3CA-wild type,” Dr Brastianos explained.

In this mouse model, GDC0084 showed promising activity in the brain metastases, inhibiting tumor growth in a PIK3CA-mutant cell line, but not in a PIK3CA–wild-type cell line. The researchers are now working to translate these findings to the setting of a clinical trial.

Other commonalities included CDK pathway alterations in more than 50% of the cases. “So CDK inhibitors are promising in brain metastases,” she added.

To further explore whether targeting alterations in the brain could lead to improved survival outcomes, Dr Brastianos and colleagues have initiated a national biomarker-driven trial in which they will target patients based on the alterations found in their brain metastases. If a patient in the trial has a particular alteration, he or she will receive that inhibitor (ie, CDK). “This is an Alliance trial,” Dr Brastianos added. “So, it can be opened at any site affiliated with an [National Cancer Institute] cooperative group.” This genomically guided brain metastasis trial is now underway.

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