For decades, the go-to approach for treating many cancers has involved a difficult trio: surgery, chemotherapy, and radiation. However, new research is pointing to a potentially life-changing alternative for some patients that could eliminate the need for these traditional treatments entirely.

At the American Association for Cancer Research’s annual meeting in Chicago, researchers presented new findings suggesting immunotherapy may be powerful enough for cancer treatment but typically isn’t used as a first-line treatment. Instead, they’re brought in if approaches like chemotherapy and radiation don’t work or if cancer returns or has already spread.

Dr. Andrea Cercek of Memorial Sloan Kettering Cancer Center, who led the Phase 2 clinical trial, shared that these aggressive tumours may also be uniquely vulnerable to immunotherapy. The study results were published simultaneously in The New England Journal of Medicine.

Immunotherapy drugs help train the body’s immune system to identify and destroy cancer cells. These treatments are especially effective against tumours with mismatch repair deficiencies, as the high number of mutations in these tumours creates more opportunities for immune cells to detect and attack them.

What Is Mismatch Repair Deficiency?

Mismatch repair deficiency is a mutation that hampers a cell’s ability to fix errors when DNA is copied. This causes an accumulation of genetic errors and results in a tumour with many mutations. Interestingly, this same weakness also makes the tumour a better target for immunotherapy. That’s because the more mutations a tumour has, the more foreign it appears to the immune system, allowing immunotherapy drugs to detect and destroy cancer cells more easily.

This mutation isn’t equally common across all cancer types. It occurs more frequently in some cancers than in others. It occurs in 10–20% of colorectal cancers, 16% of ovarian cancers, Up to 30% of endometrial cancers, and Between 8–22% of non-metastatic gastroesophageal cancers.

A Closer Look at the Study

This new trial builds on an earlier smaller study involving 12 rectal cancer patients who used the immunotherapy drug dostarlimab as the first treatment. These 12 rectal cancers were advanced but had not spread elsewhere in the body. All the 12 patients had MMRd. By the end of the treatment period, all 12 patients showed a complete response — meaning their tumours had entirely disappeared with no signs of cancer remaining. As a result, none of them needed to undergo additional standard cancer treatments like surgery, chemotherapy, or radiation.

The researchers began their study with rectal cancer patients because the standard treatments, especially surgery, can significantly affect a person’s life. In many cases, rectal cancer surgery involves removing the rectum, which is the final section of the large intestine. When this happens, patients often need a colostomy, a procedure that redirects the intestine to an opening in the abdomen, allowing waste to exit the body into an external pouch called an ostomy bag. As Dr. Diaz explained, this kind of surgery can have a profound and lasting impact on a patient’s quality of life.

The second part of the trial expanded the treatment to more people, including those whose cancers had mismatch repair deficiency and were still at an early stage, meaning the tumours hadn’t spread beyond the original spot, including cancers of the oesophagus, endometrium, kidneys, ureters, liver, gallbladder, and bile ducts.

The latest study broadened the scope, enrolling 103 patients with different types of early-stage cancers and dividing them into two groups.

In the first group, it has 49 with colorectal cancers (mostly rectal). All the 49 patients completed six months of immunotherapy, every single one responded to the treatment, and none required follow-up surgery, chemo, or radiation. Around 75% remained cancer-free one year after completing treatment.

In the second group (with other MMRd cancers), 54 patients completed six months of immunotherapy, and 35 (around 61%) had complete responses. These patients also avoided further treatment, although long-term data has not yet been published.

Dr. Suneel Kamath, a gastrointestinal medical oncologist at the Cleveland Clinic, emphasized that cancers with mismatch repair deficiencies are relatively rare, making up only 1% to 2% of all cancer cases. He cautioned that the findings are promising but do not represent a universal cure. “Unfortunately, this is not going to be something that is a cure-all,” he noted.

The new findings bring a sense of hope for individuals diagnosed with cancers involving mismatch repair deficiencies. As Dr. Suneel Kamath, a gastrointestinal medical oncologist at the Cleveland Clinic, noted, cancer surgery can often be life-altering. “A huge number might not need surgery and can be cured from the immunotherapy alone,” he said.

Dr. Luis Diaz added that for patients with mismatch repair deficiency, avoiding up to 80% of surgeries may be possible. This could make a remarkable difference in patient care. Preserving organs by avoiding surgery can significantly improve the quality of life. Many cancer-related operations come with serious side effects, including sexual dysfunction, loss of bowel control, acid reflux, and infertility. Similarly, chemotherapy and radiation are known to affect fertility. These considerations are critical now, as cancer diagnoses are rising among younger individuals, according to Dr. Andrea Cercek.

The study suggests that immunotherapy might serve as a first-line treatment for early-stage cancers with mismatch repair deficiencies. Traditionally, immunotherapy has been used only when other treatments have failed or the cancer has spread. However, these results indicate that it could sometimes replace surgery, chemotherapy, or radiation.

“Immune therapies have a ton of potential. This shows we might be able to start with that,” said Dr. Heather Yeo, a surgical oncologist at Weill Cornell Medicine in New York City.

Although further, larger-scale studies are necessary to validate these findings, Dr. Diaz believes that integrating immunotherapy as a standard treatment instead of more invasive methods may be closer than ever for patients with the right cancer profile.