Lynch Syndrome, Research Studies

The new era of Immunotherapy and Lynch Syndrome cancer treatment


Key Points:

  • Mismatch repair deficiency predicted response to the anti–PD-1 antibody pembrolizumab among patients with advanced colorectal, endometrial, and several types of gastrointestinal cancers.
  • Responses occurred in 62% of patients with mismatch repair–deficient colorectal cancers but none of the patients with mismatch repair–proficient tumors.
  • Disease control rates were 92% among patients with mismatch repair–deficient colorectal cancers and 16% in the mismatch repair–proficient group.
  • An overall response rate of 60% was observed in patients with other mismatch repair–deficient cancers.

Figure 2.Mismatch repair genes have long been a source of fascination to basic biologists. Normally, these genes serve to fix the small glitches that occur when DNA is copied as cells divide. Most of the original work was done in bacteria, with no expectation of medical relevance. But, as often happens, basic science studies can provide a profoundly important foundation for advances in human health. The relevance of mismatch repair to cancer was dramatically revealed in 1993, when teams led by Bert Vogelstein of Johns Hopkins School of Medicine, Baltimore, and Richard Kolodner, then of Harvard Medical School, Boston, discovered that mutations in human mismatch repair genes play a key role in the development of certain forms of colorectal cancer.

Mismatch repair deficiency is found in 15% to 20% of sporadic (noninherited) colorectal cancers and in nearly all colorectal cancers associated with Lynch syndrome, which constitute up to 5% of all colorectal cancers. Mismatch repair deficiency is also found in other tumor types including stomach, small bowel, endometrial, prostate, and ovarian cancer. Testing for mismatch repair deficiency is widely available and could enable identification of a larger population of patients who might benefit from pembrolizumab and other PD-1 drugs.

That discovery has led to the ability to identify individuals who have inherited misspellings in these mismatch repair genes and are at high risk for colorectal cancer, providing an opportunity to personalize screening by starting colonoscopy at a very early age and, thereby, saving many lives. But now a new consequence of this work has appeared. Vogelstein and his colleagues report that mismatch repair research may help fight cancer in a way that few would have foreseen two decades ago: predicting which cancer patients are most likely to respond to a new class of immunotherapy drugs, called anti-programmed death 1 (PD-1) inhibitors.

In a small, proof-of-principle study recently published in The New England Journal of Medicine and presented at the American Society of Clinical Oncology’s annual meeting, the Johns Hopkins researchers reported that they could predict the benefit of an anti-PD-1 inhibitor called pembrolizumab (Keytruda®) by scanning patients’ tumor samples for defects in mismatch repair. Regardless of their type of cancer, patients whose tumors were mismatch repair deficient were more likely to respond to the immune-boosting, anti-PD-1 drug than those with tumors proficient in mismatch repair. In fact, the worse the tumor cells were at repairing DNA, the better the patients fared on anti-PD-1 therapy!

This may all sound counterintuitive. However, researchers say it supports the hypothesis that immunotherapy may be most effective against tumors with many mutations. (In the new study, the tumor cells deficient in mismatch repair contained more than 20 times as many mutations, on average, than tumor cells proficient in mismatch repair.) The idea is that the greater the number of DNA glitches in a tumor cell, the more abnormal proteins it will produce—and the more abnormal proteins that are generated, the greater the odds that the body’s immune cells will regard the tumor cells as “foreign” and target them for destruction.

To test this hypothesis, Vogelstein, Luis Diaz, Jr., and their colleagues initiated a phase II clinical trial to evaluate pembrolizumab, which is already approved by the Food and Drug Administration for treating certain patients with melanoma, in 32 patients with advanced colorectal cancer. Some of the patients had tumors that were mismatch repair deficient; others had tumors proficient in mismatch repair. The researchers also enrolled nine people with cancers of the pancreas/bile duct, uterus, small bowel, and stomach that tested positive for mismatch repair defects. The patients, all of whom had not responded to at least one previous cancer treatment, were administered the anti-PD-1 drug intravenously every two weeks.

After at least 20 weeks of anti-PD-1 therapy, the researchers found that colorectal tumors shrank in about 40 percent of patients in the mismatch repair deficient group, compared to none in the mismatch repair proficient group. Furthermore, 78 percent of the mismatch repair deficient group was free of tumor progression at 20 weeks, compared to 11 percent of the mismatch repair proficient group.

According to the researchers, the average overall survival time for colorectal patients in the mismatch repair deficient group has not yet been reached because some are still responding well to anti-PD-1 therapy, more than a year after the study started. In contrast, average overall survival among patients in the mismatch proficient group was reported to be only 5 months.

As for the patients with other types of mismatch repair deficient cancer, their tumors shrank at rates similar to those seen in mismatch repair deficient colorectal cancer. However, such patients tended to respond faster to anti-PD-1 therapy than the colorectal cancer patients. And, unlike the colorectal group, a complete remission of cancer was observed in one patient—a woman with uterine cancer. No treatment-related deaths occurred in the study, with the most serious adverse reaction being pneumonitis (inflammation of the lung) in one patient.

The team will continue to follow these patients and enroll more volunteers to see if their findings hold up in a larger study. They also hope to start similar trials for some of the many other types of cancer, such as prostate and ovarian, known to contain mismatch repair deficiencies in a small percentage of tumors. Another area of scientific exploration is whether patients whose tumors contain other types of DNA repair deficiencies, such as those caused by POLD, POLE, and MYH mutations, might also benefit from anti-PD-1 therapy.

This research is just one of many outstanding examples of how decades of research by NIH-supported basic, translational, and clinical scientists continue to move us towards the era of precision medicine. NIH’s National Cancer Institute recently took a major step in that direction by announcing the Molecular Analysis for Therapy Choice, or NCI-MATCH trial. This pioneering clinical study will precisely match patients from as many as 2,400 sites across the country to one of more than 20 targeted drugs or drug combinations based on the particular molecular abnormalities of their individual tumors [5]. With this and many other new efforts envisioned by the Precision Medicine Initiative, it seems as though a future of more precise, individualized approaches to the diagnosis, treatment, and prevention of cancer and many other diseases is now within sight.

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About kjmonahan

Service lead for Family History of Bowel Cancer Clinic

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