BOSTON – Cancer researchers at Massachusetts General Hospital (MGH), Dana-Farber Cancer Institute (DFCI) and affiliated institutions have identified changes in lung cancer-promoting genes that may allow the disease to metastasize (spread) to the brain.Their work, which points to possible therapies for preventing or treating brain metastases from lung cancer, is described in the journal Nature Genetics.

Up to 40% of deaths from lung cancer occur when the disease metastasizes to other organs, most commonly the brain. Nearly one-third of patients with lung adenocarcinoma, which comprises about 40% of all lung cancers, will be found to have brain metastases at the time of diagnosis and more than half of all patients will eventually develop brain metastases.

“It’s a terrible complication of lung cancer, because it’s associated with significant mortality, and the median survival in this patient population is on the order of months. Unfortunately, the treatment options are limited and there is no established standard of care for most patients with brain metastases from lung adenocarcinoma,” says principal investigator Priscilla K. Brastianos, MD, from the MGH Cancer Center.

To better understand the genetic drivers of brain metastases from lung adenocarcinoma, Brastianos, Scott L. Carter, PhD, from DFCI, and colleagues used whole-exome sequencing, a technique for analyzing the protein-coding regions of DNA, to study acquired mutations in tissue samples of brain metastases cases from 73 patients with lung adenocarcinoma, and compared them with control sequences of 503 primary lung adenocarcinomas without brain metastases from a large NCI-funded cancer genetics database. 

“To isolate potential metastasis driver genes, we first looked for regions of the genome with recurrent alterations in brain metastasis cases, but not in primary tumor controls,” Carter explains.

“We used statistical methods to establish that only a handful of such regions were significantly different, and that several regions contained genes already known to play a role in cancer progression, as well as new genes.  While these results were encouraging, we needed to validate whether the same few genes were also recurrently altered in an independent set of brain metastasis cases. Fortunately, our colleagues at the Medical University of Vienna, Austria had a large set of well-annotated samples that we were able to use for this purpose, and those results confirmed the same genes were also frequently altered in the samples from Vienna,” he says. 

“We found potential genetic mutations that contribute to brain metastases, including ones with therapeutic potential,” Brastianos says.

For example, the researchers found that brain metastases with mutations causing over-expression of a gene labeled YAP1 might be effectively treated with a category of drugs currently in development that target the Hippo pathway, a regulator of cell and organ growth.

They also saw that certain genes that were more frequently mutated in brain metastases than in primary lung tumors, including some that might be treated with drugs that are currently FDA-approved for other forms of cancer, including two drugs used to treat advanced breast cancer, and one targeted against inoperable or metastatic tumors solid tumors with an NTRK gene fusion.

Brastianos is chair of an NCI-sponsored 304-center clinical trial (Alliance A071701) studying the use of genetic testing to guide treatment for patients with solid tumors that have spread to the brain.

Brastianos’ co-authors include David J. H. Shih, Naema Nayyar, Ivanna Bihun, Ibiayi Dagogo-Jack, Corey M. Gill, Elisa Aquilanti, Mia Bertalan, Alex Kaplan, Megan D’Andrea, Ugonma Chukwueke, Franziska Maria Ippen, Christopher Alvarez-Breckenridge, Nicholas Camarda, Matthew Lastrapes, Devin McCabe, Ben Kuter, Benjamin Kaufman, Matthew R. Strickland, Juan Carlos Martinez Gutierrez, Deepika Nagabhushan, Magali De Sauvage, Michael White, Brandyn Castro, Kaitlin Hoang, Andrew Kaneb, Emily D. Batchelor, Sun Ha Paek, Sun Hye Park, Maria Martinez-Lage, Anna S. Berghoff, Parker Merrill, Elizabeth R. Gerstner, Tracy T. Batchelor, Matthew P. Frosch, Ryan P. Frazier, Darrell R. Borger, A. John Iafrate, Bruce E. Johnson, Sandro Santagata, Matthias Preusser, Daniel P. Cahill, and Scott L. Carter.

Researcher affiliations include MGH, DFCI, Harvard TF Chan School of Public Health, Broad Institute of MIT and Harvard, Brigham & Women’s Hospital, Seoul National University College of Medicine in South Korea, and Medical University of Vienna, Austria.

The work was supported by grants to Brastianos and Carter from the National Cancer Institute; from grants to Brastianos from the Damon Runyon Foundation, the Conquer Cancer Foundation, the Breast Cancer Research Foundation, the Brain Science Foundation, Susan G. Komen for the Cure, the American Brain Tumor Association; and from grants to Carter from Wong Family Award and the Dana-Farber/Harvard Cancer Center Lung Cancer Program.

Brastianos is a consultant for Lilly, Tesaro and Angiochem, has received honoraria from Merck and Genentech and has received research grants (to MGH) from Merck, Pfizer, Lilly and BMS. Several co-authors have disclosed similar relationships.

About the Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $1 billion and comprises more than 8,500 researchers working across more than 30 institutes, centers and departments. In August 2019 the MGH was once again named #2 in the nation by U.S. News & World Report in its list of "America’s Best Hospitals."