Dividing cells face daunting challenges when replicating the billions of letters of DNA in their genomes. For instance, DNA letters in new cells can get mixed up, and then the affected genes don’t function correctly. To fix that problem, healthy cells can deploy so-called mismatch repair (MMR) genes that put scrambled DNA letters back in the correct order. But when those genes are themselves defective, then this repair system breaks down. And as a result, cells develop a progressive condition called microsatellite instability that leaves them vulnerable to cancer.
Those sorts of defects are shared by many different tumor types. The good news is that they are susceptible to the killing effects of an immunotherapy drug called pembrolizumab. The FDA approved that drug last year for all MMR/MSI-positive metastatic cancers, regardless of where they originate in the body. Pembrolizumab works by prompting the immune system’s T cells to recognize and destroy cancer cells bearing this genetic biomarker.
Earlier this year, scientists reported new findings with pembrolizumab in men with prostate cancer. Of the 839 men they evaluated, 2.5% had MMR defects and high levels of microsatellite instability. In about a quarter of the men, those defects were somatic, meaning they had been acquired after conception and were localized to the cancer. In the rest of the men, the defects were inherited and expressed by all the cells in their bodies.
This was the first study to investigate how the drug performs in men with MMR/MSI-positive prostate cancer, and the results were encouraging: Among half the treated men, PSA levels dropped by 60% to 80%. Since prostate cancer cells release PSA, a decline in the level of that hormone shows the drug is working. Moreover, tumors also shrank in as many as 40% of the men whose PSA levels were responding to treatment.
The authors of this study recommended that all metastatic prostate cancer patients be tested for these defects, since pembrolizumab might also work for them. Dr. Marc Garnick, the Gorman Brothers Professor of Medicine at Harvard Medical School and Beth Israel Deaconess Medical Center, and editor in chief of HarvardProstateKnowledge.org, agrees. “This is an exciting development as it opens up therapeutic possibilities that would have never been considered previously,” he said. “Moreover, our own personal experiences in testing for MMR mutations and treatment with pembrolizumab have been remarkable. Testing will likely become mandatory as more experience is gathered.”