Defects in these so-called “mismatch repair genes” were originally discovered in 1993 by a team that included Albert de la Chappelle, MD, PhD, of the OSUCCC – James. Defects, or mutations, in mismatch repair genes occur in both sporadic and hereditary forms of colorectal, endometrial, stomach, biliary tract, pancreas, ovarian and small intestine cancer. The mutations disable a cell’s ability to repair small errors in its DNA that occur during cell division. Loss of the repair mechanism helps lead to the unchecked cellular growth that is a hallmark of cancer.
The study suggests that patients with mutations in mismatch repair genes respond better to pembrolizumab than patients with normal mismatch repair genes.
“This study is a real-life example of how gene sequencing of tumor cells and precision cancer medicine can improve our approach to treating cancers with immunotherapy agents based on the genetic signatures of a cancer, rather than on the class of cells or the organ in which the tumor occurs,” says Goldberg, physician-in-chief at The OSUCCC – James. “Pembrolizumab is showing remarkable promise and doing so with fewer side effects for patients.”
Study Design and Results
This initial report includes data on 48 patients with colon cancer recruited at five cancer center, the majority of which were recruited at Johns Hopkins.
In one group of 13 patients with advanced colorectal cancer and mutations/defects in mismatch repair genes, eight had partial responses to pembrolizumab, meaning their cancers shrunk by at least 30 percent in diameter. Four patients had no change in tumor growth and one patient experienced disease progression. Among the patients who responded the improvement has been both substantial and long lasting leading to improved quality of life and prolonged survival.
In another group of 25 patients with colorectal cancer who had no defects in mismatch repair genes, tumors in all of those patients failed to respond. In a third group of 10 patients with a variety of other cancers that tested positive for mismatch repair gene defects, one patient with uterine cancer had a complete response, meaning there was no radiographic evidence of cancer, five had partial responses, one had stable disease and three experienced cancer progression. (Of these patients, four had pancreatic/bile duct cancers, two had uterine cancer, two had small-bowel cancer, one had stomach cancer and one had prostate cancer).
All patients enrolled in this study had stopped responding to previous therapies.
“What has been done in this study is nearly unprecedented — taking the story from detection of the genetic basis some 22 years ago through clinical, screening and counseling studies in the ensuing decades and now to a new, highly promising therapy,” adds de la Chapelle, distinguished professor and researcher with The OSUCCC – James Molecular, Immunology and Medical Genetics Research Program.
Phase 2 Testing Ongoing in Columbus
The OSUCCC – James is currently enrolling patients with progressive, metastatic colon cancer to this ongoing phase 2 pembrolizumab trial. The study is open at six centers across the United States. The OSUCCC – James is the only testing site for this trial in Ohio.
In order to be eligible for this study, the patient’s tumors must harbor this genetic change known as “microsatellite instability” that leads to defective repair of mismatches in DNA. This occurs as cells reproduce and that change is what transforms them into cancer cells. The immunotherapy agent targets the PDL-1 pathway. Certain cancer cells have been shown to hijack this pathway to hide from the immune system’s normal processes of detecting and fighting off infections and diseases.
“This study details a potential new biomarker for patients who respond best to therapy based on DNA-level information. The research also sheds light on which patients might even do better if the immunotherapy drug (prembrolizumab) is combined with chemotherapy that causes additional DNA damage,” adds Goldberg.
Funding for this study was provided by the cancer philanthropy Swim Across America, the Lustgarten Foundation for Pancreatic Cancer Research, the Banyan Gate Foundation, the Commonwealth Fund, the Sol Goldman Pancreatic Cancer Research Center, and the National Institutes of Health’s National Cancer Institute (P50CA062924, CA163672, CA43460, CA67941, CA16058 and CA57345).