The DNA mismatch repair (MMR) pathway holds the responsibility for correcting post-replication errors and ultimately the necessary burden of maintaining genomic fidelity and stability. While scientists have been aware for some time that abnormalities within the MMR pathway lead to a variety of cancerous phenotypes, recent results from investigators at the Johns Hopkins Kimmel Cancer Center show that mutations in MMR genes may accurately predict a patient’s response to immunotherapy drugs known as PD-1 inhibitors.
“This study gives us a solid clue about how immunotherapy may work in cancer and how to guide immunotherapy treatment decisions based on the genetic signatures of a cancer rather than class of cells or organ of origin,” said senior author Luis Diaz Jr., M.D., an oncologist at the Johns Hopkins Kimmel Cancer Center and director of the Swim Across America Laboratory at Johns Hopkins.
The findings from this study were published recently in the New England Journal of Medicine through an article entitled “PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.”
“Defects in mismatch repair genes are found in a small percentage of many cancer types, and this type of biomarker for immunotherapy response could apply to tumors containing errors in other DNA repair genes, as well,” explained Dung Le, M.D., oncologist at the Johns Hopkins Kimmel Cancer Center and lead author on the current study. “Using a predictive biomarker can help us direct the use of immunotherapy drugs to patients who are more likely to respond, avoiding giving people expensive and time-consuming treatments that are not likely to work or delaying the use of other treatments.”
PD-1 is a part of a tightly regulated pathway that typically represses the cytotoxic immune response, which if left unchecked can damage host cells. However, many of the proteins are up-regulated in tumor cells and the blockade of this pathway with antibodies has shown significant clinical response in an array of cancer types.
Knowing the effectiveness of PD-1 inhibitors, the Johns Hopkins team conducted a Phase II study in order to evaluate the clinical activity of the PD-1 inhibitor pembrolizumab in 41 patients with progressive metastatic cancers with or without MMR deficiencies.
In one group of patients with advanced colon and rectal cancers and MMR deficiencies, 60% had partial responses to the drug treatment with shrinkage of tumors by at least 30%. However, in a group of 25 patients with no MMR defects, all failed to respond to the pembrolizumab treatment.
The Johns Hopkins researchers were encouraged by the results of their study, but caution that larger studies are needed to assess the potential for clinical use. Additionally, since chemotherapy regimens using pembrolizumab and other PD-1 inhibitors can reach more than $100,000 per year per patient, being able to sort out which patients will benefit from the treatment is paramount.
“It's rare for patients with colon cancer who have failed all standard therapies to respond and most of them only have a few months to live,” stated Kenneth W. Kinzler, Ph.D., co-director of the Ludwig Center at Johns Hopkins and coauthor on the current study. “While it's promising to see that patients with mistakes in mismatch repair genes responded more often to immunotherapy than those who did not have these mistakes, we need to test this idea in more patients and potentially earlier on in the sequence of therapies for these advanced cancers.”