Diverging Cancer Paths

Brain metastases are a devastating complication of cancer, leading to the death of more than half of patients whose cancer spreads to the brain. A new study finds that while brain metastases share some genetic characteristics with the primary tumors from which they originated, they also carry unique genetic mutations.

The diverging evolutionary pathways of the metastatic and the primary tumors may change sensitivities to targeted therapy drugs, an international collaboration led by Harvard Medical School scientists at Massachusetts General Hospital report in Cancer Discovery.

“Our study demonstrates that while brain metastases and primary tumors share a common ancestry, they continue to evolve separately,” said Priscilla Brastianos, HMS instructor in medicine at Mass General and co-lead author of the paper.

“This is tremendously important, as we demonstrate that brain metastases may have clinically significant mutations that have not been detected either in the primary tumor biopsy or in metastases from other parts of the body,” she said. “We also showed that multiple brain metastases from the same patient share nearly all clinically significant mutations.”

Brain metastases commonly develop from melanoma, lung cancer or breast cancer and can appear despite the primary tumor’s being well controlled by drugs that target mutations driving its growth. Once brain metastases develop, patients usually die within a matter of months, and patients with brain metastases are typically excluded from most clinical trials.

“While brain metastases and primary tumors share a common ancestry, they continue to evolve separately.” —Priscilla Brastianos

In treating cancers known to be driven by targetable gene mutations, treatment planning is usually based on genetic analysis of tissue from the primary tumor. Because treatment of brain metastases often involves removal of the metastasis, samples of that tumor are often available for analysis. The current study was designed to investigate whether the genetic profiles of brain metastases are identical to those of the primary tumors.

The research team conducted whole-exome gene sequencing on three tissue samples—primary tumor, brain metastasis and normal tissue—from each of 86 patients with lung, breast or kidney cancers. The exome is the tiny portion of the genome that encodes proteins.

In each instance, while the investigators found that the primary tumor and the metastasis shared some mutations, the brain metastases had new mutations that were not related to those of the primary tumors. In four of the 86 patients, the brain metastases actually appeared to have originated from additional primary tumors.

The new mutations detected in the metastases often signaled potential sensitivity to targeted therapy drugs that would not have been effective against the primary tumors. Overall, more than half of the patients appeared to have clinically targetable new mutations in their brain metastases.

Analysis of multiple brain metastases samples from the same patient showed that nearly all of the significant mutations appeared in all of the brain metastases. In contrast, metastases from other parts of the body differed significantly from the brain metastases.

“It has been unclear whether brain metastases from well-controlled primary tumors develop because the chemotherapy drugs don’t cross the blood-brain barrier or because of different genetic mutations in the metastasis,” said Brastianos. “Our data suggest that genetic differences may contribute to the formation and treatment resistance of brain metastases.”

The clinical impact of directly targeting brain-metastasis specific mutations needs to be evaluated more fully, she said, and it is something the scientists are now investigating.

“We believe that routinely looking for clinically significant alterations in brain metastases may open the door to new therapeutic options for these patients,” Brastianos said.

Support for the study includes National Institutes of Health grants U54 HG003067, 5U24 CA143687 and U54 CA143798, and grants from the Brain Science Foundation, Susan G. Komen for the Cure, Terri Brodeur Breast Cancer Foundation, Conquer Cancer Foundation, the American Brain Tumor Association, Breast Cancer Research Foundation and the Mary Kay Foundation.

Adapted from a Mass General news release.