Improving Mesothelioma Survival by Targeting New Genetic Mutations

Research from Brigham and Women’s Cancer Center in Boston recently identified a distinct spectrum of genetic mutations in pleural mesothelioma tumors, a blockbuster finding that should significantly improve future treatment of the disease.

It was the breakthrough the mesothelioma community was anticipating.

“This is probably the most significant advancement in the treatment of mesothelioma since the advent of cytoreductive surgery,” thoracic surgeon Dr. David Sugarbaker, director of the Lung Institute at Baylor College of Medicine and America’s foremost authority on pleural mesothelioma, told Asbestos.com. “This is very exciting. It could mean long-term survival is a reality for a large number of patients.”

Sugarbaker co-authored the research study published this month in Nature Genetics. He led the International Mesothelioma Program (IMP) and started the tissue bank at Brigham that was used in the research. He moved to Baylor College of Medicine in 2014 after more than two decades in Boston.

The study identified previously unknown genetic alternations within mesothelioma and 10 mutated genes of significance, opening a much-clearer path for new therapies.

“We now have targets to really go after, and really launch the missiles of therapy, knowing we will be more accurate because we have a better guidance system,” he said. “We have missiles with a better guidance system now.”

A More Personalized Approach to Treatment

The study showed that several of the targeted mutations discovered are sometimes found in individual patients, which will further personalize the treatment approach to mesothelioma.

Many of the mutations uncovered already have been found in other cancers, and drugs that target those mutations have been used effectively against other cancers. Patients with specific mutations may benefit now from existing drugs not used previously for mesothelioma.

Specific immunotherapy drugs can be developed more accurately to target other mutations.

“Now a medication that had maybe only a 5-10 percent success rate for a particular malignancy can have an 80 percent response rate if a specific subtype can be identified,” Sugarbaker said. “We can start, in a real comprehensive way, being able to identify subgroups of patients who will respond to certain therapies.”

The inhalation or ingestion of asbestos fibers causes mesothelioma, a rare and aggressive cancer. It is diagnosed in an estimated 3,000 Americans annually. The typical prognosis is 6-18 months. With even the most aggressive treatment approach today, the five-year survival rate can be as high as 10 percent, but the most recent data shows it can drop to 3.7 percent.

Genotyping Becomes Important

The recent findings raise the importance of genotyping patients, where genetic alterations that underlie the cancer are identified in each patient.

Genomic analysis uses the most updated DNA sequencing technology to measure, identify and contrast information that influences cell behavior.

For this study, researchers used 216 tissue bank samples from the IMP, comparing them to paired normal tissue samples.

The Genome Sequencing Center at Baylor College of Medicine is one of the largest in the world, and it provides genetic testing for patients at its Mesothelioma Treatment Center in Houston.

“These finding were the result of the tissue bank, and the willingness of patients and their families to participate,” Sugarbaker said. “They have allowed us to make this jump. It’s been a long road, but we’re now moving forward.”

Help for Sarcomatoid Mesothelioma Subtype

The genetic mutation research was particularly relevant to those with the sarcomatoid cell type of mesothelioma, which affects an estimated 10-20 percent of the patients and is the most aggressive and resistant to current therapies.

The study identified a highly expressed molecule (PD-L1), which represents a defined target for a cancer immunotherapy pathway that already is being explored with several cancers.

“This is the next level of therapy. We’re fairly certain that most patients will fit into one of these categories. We’ve identified the mutations. Now can we identify effective therapies for each one of the subtypes?” Sugarbaker said. “If we can, we’ve hit the home run.”