New research published today in the Journal of Clinical Investigation, led by scientists at the Institute of Cancer Research in the UK and Dana-Farber Cancer Institute in Boston, suggests that men with specific DNA defects in their prostate cancers may respond especially well to immunotherapy agents.
“Our study found that some men with advanced prostate cancers have genomic mutations in their tumors that make the disease unstable, aggressive and resistant to standard therapies,” said Professor Johann de Bono, Director of the Drug Development Unit at the Institute of Cancer Research and the lead author of the study.
These mutations are defects in genes which control a process called DNA mismatch repair. Occasionally as a result of normal errors in DNA replication or damage by external factors such as carcinogens, DNA bases are arranged in a haphazard way, with DNA letters not arranged opposite to their intended pairs. This is called a mismatch and is often repaired in healthy cells, but in people with defects in their mismatch repair genes, this process is impaired or even absent altogether, meaning that these mismatch mutations progressively accumulate in the cancer cell DNA.
“These men with ‘mismatch’ repair mutations only live about half as long as others who also have advanced prostate cancer but whose tumors don’t carry such mutations,” said de Bono.
DNA mismatch repair defects are common in some types of cancer, notably colorectal cancers, but the new study showed that these defects were also present in 8.1% of men with advanced prostate cancer. The men with DNA mismatch repair mutations in their tumors survived for under four years after diagnosis, compared with seven years for men with advanced prostate cancer with no detectable mismatch repair defects, but the new research suggests that the men with the mismatch repair defects may respond particularly well to immunotherapy agents known as immune checkpoint inhibitors.
“We discovered that tumors with mismatch repair mutations have key hallmarks which make them particularly likely to respond to checkpoint inhibitor immunotherapy,” said de Bono.
The researchers looked at the prostate cancer cells from tumor biopsies of 124 men and tested for the levels of a protein called PD-L1, which is essentially a warning light to the immune system, telling it to leave the cell alone. High levels of PD-L1 can make cancer cells especially resistant to this immune system monitoring, but treatment with immune checkpoint inhibitors can target this protection, unleashing the immune system on the cancer cell.
The study found that half of all men with mismatch repair defects in their tumors had high PD-L1 levels, compared to less than 10 percent of men with normal mismatch repair. The published work builds upon results presented at the American Society for Clinical Oncology meeting in June, which indicated that DNA mismatch repair defects were responsible for favorable responses to Keytruda and the scientists are currently running new clinical trials to test the effectiveness of immune checkpoint inhibitors in these patients.
“We are now developing tests that could pick out patients with these mutations, and we’re running new clinical trials to see if immunotherapy can offer new hope for these men,” said de Bono.