Mass General Researchers Uncover Biomarkers that Could Lead to More Patients Getting Immunotherapy

A breakthrough class of cancer treatments – immunotherapies – may become available to a wider range of patients thanks to new research from the Massachusetts General Hospital (MGH).

Microsatellite-high (MSI-H) tumors, which have a high rate of mutations (hypermutant), are more responsive to immunotherapy. Patients with these types of tumors are more likely to be recommended such treatment.

This new finding suggests that even more patients can be identified for immunotherapy by using a small number of genes that are already routinely tested for other therapeutics.

"We found that by testing genes BRCA1/2 and a small number of their family members, we can accurately identify tumors that are microsatellite stable (MSS) and hypermutant without resorting to costly tumor mutation burden assays," says Manish K. Gala, MD, senior author of the study.

Dr. Gala is a gastroenterologist and cancer genetics researcher at MGH. His team's paper, Homologous recombination Repair Truncations Predict Hypermutation in Microsatellite Stable Colorectal and Endometrial Tumors, was published in the March 2020 issue of Clinical and Translational Gastroenterology.

BRCA1/2 are homologous recombination repair (HRR) genes that can fix errors in DNA. These genes have been associated with sensitivity to a class of drugs called PARP inhibitors and/or platinum agents in other tumor types such as breast, ovarian, and pancreatic cancers.

Meanwhile, hypermutant tumors caused by alterations in POLE, or mismatch repair genes, have demonstrated robust responses to immunotherapy. Patients who are responsive to immunotherapies for cancer can have excellent responses, surviving for years even with previously untreatable cancers.

The researchers investigated the relationship between mutations in HRR genes, such as BRCA1/2, in colorectal cancer (CRC) and endometrial cancer (EC).

They determined certain mutations in HRRs can accurately fingerprint MSS tumors that are hypermutators with or without known pathogenic mutations in POLE. Testing for these HRR genes, along with POLE, may serve as a low-cost biomarker for immunotherapy decisions in MSS CRC and EC.

The team developed a classifier, or predictive algorithm, that identified MSS hypermutators from thousands of publicly available cancer samples. Overall, the classifier demonstrated an accuracy of positive detection in 100% in CRC and 98.0% in EC and a false-positive rate of 0.07% and 0.63%. In addition, the classifier accurately reassigned multiple POLE variants of unknown significance as pathogenic and identified MSS hypermutant samples without POLE exonuclease domain mutations.

The study was funded the American College of Gastroenterology (M.K.G.) and the National Institutes of Health (T32CA009476 to S.R.B., ES015869 to P.V.S., and DK103119 to M.K.G.)

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."