Sequencing Metastatic Cancers Could Lead to Improved Therapies

        Unravelling the genetic sequences of cancer that has spread to the brain could offer unexpected targets for effective treatment, according to a study (“Genomic characterization of brain metastases and paired primary tumors reveals branched evolution and potential therapeutic targets”) published in Cancer Discovery.

        Scientists say they found that the original, or primary, cancer in a patient’s body may have important differences at a genetic level from cancer that has spread to the patient’s brain. This insight could suggest new lines of treatment.

        Priscilla Brastianos, M.D., a neuro-oncologist and director of the Brain Metastasis program at Massachusetts General Hospital, points out that “brain metastases are a devastating complication of cancer. Approximately eight to ten percent of cancer patients 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.”

        She and her colleagues studied tissue samples from 104 adults with cancer. In collaboration with researchers at the Broad Institute, they analyzed the genetics of biopsies taken from the primary tumor, brain metastases, and normal tissues in each adult. For 20 patients, they also had access to metastases elsewhere in the body.

        The team discovered that, in every patient, the brain metastasis and primary tumor shared some of their genetics, but there were also key differences. In 56% of patients, genetic alterations that potentially could be targeted with drugs were found in the brain metastasis but not in the primary tumor.

        “We found genetic alterations in brain metastases that could affect treatment decisions in more than half of the patients in our study,” notes Dr. Brastianos. “We could not detect these genetic alterations in the biopsy of the primary tumor. This means that when we rely on analysis of a primary tumor we may miss mutations in the brain metastases that we could potentially target and treat effectively with drugs.”

        This study also found that if a patient had more than one brain metastasis, each was genetically similar. The researchers used their findings to map the evolution of a cancer through a patient’s body, and draw up a phylogenetic tree for each patient to demonstrate how the cancer had spread and where each metastasis had come from.

        They concluded that brain metastases and the primary tumor share a common genetic ancestor. Once a cancer cell, or clone, has moved from the primary site to the brain, it continues to develop and amass genetic mutations. The genetic similarity of the brain metastases in individual patients suggests that each brain metastasis has developed from a single clone entering the brain.

        The genetic changes in brain metastases are independent of any occurring at the same time in the primary tumor, and in metastases elsewhere in the body, the researchers said. Characterization of the genetics of a patient’s primary cancer can be used to optimize treatment decisions, so that drugs that target specific mutations in the cancer can be chosen. However, brain metastases are not routinely biopsied and analyzed.

    “When brain metastasis tissue is available as part of clinical care, we are suggesting sequencing and analysis of that sample,” continues Dr. Brastianos. “It may offer more therapeutic opportunities for the patient. Genetic characterization of even a single brain metastasis may be superior to that of the primary tumor or a lymph node biopsy for selection of a targeted treatment.”