Genomic study of brain metastases sheds light on unique features relative to primary tumors

A deep sequencing study of brain metastases from MD Anderson revealed many similarities but also distinct differences relative to the primary tumors, which reinforces that these lesions are not identical to the original tumors. The findings were presented today at the American Association for Cancer Research (AACR) Virtual Annual Meeting (abstract #5704) by Olivia Lee, graduate student in Bioinformatics and Computational Biology.

“In our study, brain metastases shared a majority of mutations with primary tumors, but we found evidence that additional mutations accumulate in the metastatic lesions, including mutations typically only found in primary brain tumors,” says Lee. “These variations highlight the need for continued study of brain metastases in order to better understand them and potentially find therapeutic targets.”

Brain metastases represent significant unmet clinical need

Metastases to the brain occur in up to 30% of cancer patients, with roughly 200,000 new cases of brain metastases occurring each year in the U.S. Patients with melanoma, lung cancer, kidney cancer and breast cancer are most likely to be diagnosed with a brain metastasis.

While advances have been made in treating primary tumors for these cancers, treatments for brain metastases are less successful. Most patients are treated with targeted radiation, and survival can range from three months to just over two years. In addition, most clinical trials exclude patients with brain metastases as part of enrollment criteria.

“Despite the increased survival in patients with various primary tumors, a large number of patients eventually succumb to brain metastases and there is a significant clinical need for these patients,” says Andy Futreal, Ph.D., chair of Genomic Medicine and senior author on the study. “We are now studying these lesions to better understand their genetics and interactions with the brain tumor microenvironment with the goal of translating our findings into new therapeutic opportunities.”

Comparing brain metastases to primary tumors gives biological insights

For the current study, the research team worked with the laboratories of Jason Huse, M.D., Ph.D., associate professor of Pathology, and Michael Davies, M.D., Ph.D., chair of Melanoma Medical Oncology.

Whole-exome sequencing was performed on brain metastases and matched tumors from 41 patients with melanoma, kidney cancer, breast cancer and lung cancer. In total, the team analyzed 126 tumor samples, comparing brain lesions to either paired primary tumors or, in some cases, metastases occurring elsewhere in the body.

“We found that the majority of gene mutations were shared between the matched samples,” says Akash Mitra, graduate student in Genomic Medicine and collaborator on the study. “However, there were a few certain circumstances where we did see oncolytic mutations in genes such as KRAS, PIK3CA, IDH1 and ERBB2 which were specific to the brain metastasis.”

These findings indicate that, despite sharing most mutations, there are subpopulations of cancer cells within brain metastases that have developed new mutations independent of their primary tumor, some of which could theoretically be targeted by available therapies. The researchers note that it’s possible these mutations could be missed in sequencing primary tumor biopsies, so follow-up studies are warranted to confirm those findings.

Treating patients with brain metastases has become a special focus of MD Anderson with the launch of our Brain Metastases Clinic. The effort brings together medical oncologists, neurosurgeons and radiation oncologists to collaboratively manage the care of these patients and offer the best available treatment options.

The clinic also includes a research component designed to collect additional samples that will aid in conducting similar translational research.

The research team continues to perform comprehensive profiling of these samples, including gene expression, protein expression and characterizing interactions with the immune microenvironment, to explore the common biology across brain metastases that may reveal therapeutic vulnerabilities that could improve the care of these patients.

A full list of authors and reported disclosures can be found with the abstract here.