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Primary tumor, lymph node biopsies do not detect targetable mutations of brain metastases
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Biopsies of primary tumors routinely failed to capture clinically significant genetic alterations in brain metastases, potentially missing actionable mutations, according to study results presented at European Society of Medical Oncology’s European Cancer Congress.
Further, regional lymph nodes and distal extracranial metastases did not serve as reliable genetic surrogates for brain metastases, according to the researchers.
“Brain metastases are a devastating complication of cancer,” Priscilla Brastianos, MD, director of the brain metastasis program at Massachusetts General Hospital, said in a press release. “Approximately 8% to 10% of patients with cancer will develop brain metastases, and treatment options are limited — even where treatment is successfully controlling cancer elsewhere in the body, brain metastases often grow rapidly.”
Brastianos and colleagues sought to elucidate the evolutionary patterns that lead to brain metastases and to identify whether brain metastases harbor clinically significant genetic differences compared with primary tumors or other extracranial metastatic sites. Further, they wished to examine the extent of genetic heterogeneity across regionally separated and anatomically distinct sites of brain metastasis.
The researchers studied tissue samples from 104 patients with cancer, which included matched primary tumor biopsies, brain metastases and normal tissue samples from each patient. Further, 20 patients had available data on distal extracranial metastases and regional lymph nodes.
Brastianos and colleagues performed an integrative analysis of somatic single nucleotide variants and copy number alterations to reconstruct phylogenetic trees relating to subclones from each patient. They analyzed evolutionary relationships between related cancer samples and annotated phylogenetic trees with clinically significant drivers.
Each brain metastasis likely developed from a single clone with divergent evolution, signaling that the brain metastasis and primary tumor shared a common ancestor but continued to evolve independently, according to the researchers. In 56% of cases, researchers found novel, clinically actionable genetic alterations exclusive to brain metastases.
These brain metastases were enriched for several pathways, including pathways with therapeutic targets.
Further, the researchers found that distal extracranial metastases and regional lymph nodes appeared greatly divergent from brain metastases. They did not observe an extracranial site that closely resembled the brain metastasis sample in any of the cases.
By contrast, regionally and anatomically separated brain metastasis sites appeared genetically homogenous and shared nearly all alterations detected. As such, the researchers recommend that when clinically possible, characterization of even a single brain metastasis lesion are superior to primary tumor or lymph node biopsy for selection of targeted therapeutic agents.
“Brain metastases represent an unmet need in current cancer care,” Brastianos said. “More than half of the patients diagnosed with brain metastasis will die within a few months. The clinical relevance of this finding needs to be studied more in prospective clinical trials. We still need to determine whether targeting the genetic mutations in the brain will lead to improved clinical outcomes.” – by Cameron Kelsall
Reference:
Brastianos P, et al. Abstract 2905. Presented at: European Cancer Congress; September 25-29, 2015; Vienna.
Disclosure: The researchers report no relevant financial disclosures.