New Insights into Genetics May Soon Guide Targeted Therapies for Patients with Breast Cancer and Central Nervous System Metastases

According to Priscilla Brastianos, MD, Director, Central Nervous System Metastasis Program, Massachusetts General Hospital, Harvard Medical School, Boston, MA, there remains several unanswered clinical questions regarding the treatment of patients with breast cancer and central nervous system (CNS) metastases.

At the 37th Annual Miami Breast Cancer Conference, Dr Brastianos took a deep dive into some of the most pressing questions on this topic, including: Is intracranial progression caused by incomplete drug penetration or different genetic drivers? Can we rely on a primary biopsy to make decisions for systemic targeted agents in brain metastases?

“Historically, we’ve had a limited understanding of how brain metastases genetically evolve from their primary tumor,” she said. “But research shows that brain metastases harbor distinct clinically actionable genetic alterations compared to their primary tumors and extracranial metastases.”

Branched Evolution: Brain Metastasis and Primary Tumors Evolve Separately

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.

For each brain metastasis and primary tumor, the researchers mapped out the genetic evolution to try to understand where different genetic changes occurred—in the brain metastasis only, in the primary tumor only, or shared by the brain metastasis and the primary tumor.

“What we found across the entire board of samples was a pattern of branched evolution, meaning the brain metastasis and the primary tumor shared a common ancestor, but there was then continued significant genetic evolution, such that there were new mutations in the brain metastasis,” Dr Brastianos explained.

How Is This Clinically Significant?

Dr Brastianos presented a case study to explore whether brain metastases harbor clinically significant genetic differences compared with their primary tumors, noting that the example used was not an unusual clinical scenario.

In a patient with HER2-positive breast cancer who developed a cerebellar tumor in the setting of stable extracranial disease on trastuzumab therapy, the cerebellar tumor harbored an EGFR mutation that was exclusive to the brain metastasis.

“This is the same mutation known to predict sensitivity to EGFR inhibitors in lung cancers, but in this case, we detected it in the breast cancer cerebellar tumor,” she said. “If the EGFR mutation is exclusive to the cerebellar tumor, this probably represents a mutation that was a resistant subclone during trastuzumab therapy, but importantly, when we looked across the entire cohort, more than half the cases had clinically actionable alterations in the brain metastasis that were not detected in the primary tumor biopsy.”

Therefore, if targetable mutations exist in brain metastases that are not in the primary tumor, the targeted therapy appropriate for the primary tumor may not be appropriate for the brain metastasis.

“One could imagine that genetic divergence between primary metastatic samples poses a major challenge to clinical decision-making in oncology,” Dr Brastianos added.

What About Heterogeneity Within CNS Metastatic Disease?

The next logical step would be addressing regional heterogeneity throughout the brain itself. So how representative of all CNS metastatic disease is a single brain metastasis sample?

“To answer this question, we sequenced regionally, anatomically, and temporally distinct areas in the brain metastases,” Dr Brastianos said.

Dr Brastianos and colleagues sequenced a cerebellar tumor removed from a patient before whole-brain radiation and a parietal metastasis removed after whole-brain radiation. They found that all anatomically distinct regions of the brain metastases shared the same clinically actionable drivers. “They were more related to each other than to the primary tumor biopsy, so they’re relatively homogenous,” she said.

And Extracranial Sites?

So, if metastases within the CNS are genetically homogenous, to what extent do extracranial sites recapitulate genetic vulnerabilities in brain metastases?

“To answer that question, we looked at lymph nodes and other metastatic sites from the same patient,” Dr Brastianos continued.

In evaluating the primary tumor sample, a regional lymph node and the brain metastasis, the researchers found that lymph nodes are not a reliable genetic surrogate of brain metastasis, nor is the primary tumor. They were able to demonstrate that intracranial metastases have branched evolution, whereby the brain metastasis and primary tumor share a common ancestor, yet both continue to evolve independently.

“It looks like extracranial disease is genetically divergent from brain metastasis,” she said. This is clinically relevant, as it creates important opportunities for precision medicine.

“We know that patients often develop progressive brain metastases in the setting of stable extracranial disease. The question has always been whether it’s a blood–brain barrier issue or an issue of genetic heterogeneity. Our data suggest that, at least in part, genetic divergence is a contributing factor,” Dr Brastianos said.

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