Haystack MRD® served as a real-time method to track how patients respond to treatment, identifying response to therapy earlier than traditional imaging methods
In a landmark study, many patients with mismatch repair–deficient (dMMR, also known as MMRd) cancers were effectively treated with immunotherapy alone, without surgery, chemotherapy, or radiation. 100% of patients with dMMR rectal cancer, and around 2/3 of patients with other dMMR cancers, had no sign of cancer after immunotherapy—without having to undergo life-altering surgery.1 These results not only show that immunotherapy alone can be effective in dMMR cancers, but also highlight the role of circulating tumor DNA (ctDNA) as a promising biomarker to track how cancers respond to treatment.
“This is very exciting and shows that a broad range of tumors with this genetic mutation, called MMRd, can be treated with immunotherapy, replacing surgery and radiation, giving patients better quality of life,” said Dr Andrea Cercek, lead author of the study and co-director of the Center for Young Onset Colorectal and Gastrointestinal Cancer at Memorial Sloan-Kettering Cancer Center (MSK). Due to Cercek’s groundbreaking immunotherapy work, she was included in Time Magazine’s annual list of the 100 most influential individuals in health, TIME100 Health 2025.
Dr Luis Diaz Jr, senior author of the study and a pioneer in immunotherapy, added: “We’re using the biology of the tumor to direct therapy—not just its location in the body. And with ctDNA, we can monitor treatment effectiveness without invasive procedures.”
Helping the body’s immune system target and destroy cancer cells
The typical approach for patients with early-stage cancer is surgery, often combined with chemotherapy and radiation. While these treatments often work to eliminate the tumor, they may come with significant and, in cases like rectal cancer, life-changing effects.
“Current treatments like surgery, radiation, and chemotherapy can seriously affect quality of life,” Diaz said. “For example, treating rectal cancer this way can lead to infertility and problems with bowel, bladder, and sexual function as well as other daily challenges.”
Immunotherapy is a different type of treatment that helps the body’s own immune system find and destroy cancer cells. A group of immunotherapy drugs called immune checkpoint inhibitors work by blocking proteins that mask or hide cancer cells. These drugs “release the brakes” on the immune system to help immune cells find and eliminate the cancer. The drug used in the study, dostarlimab (Jemperli®), works in this way.
Mismatch repair–deficient (dMMR) cancers have a unique biology that makes them highly sensitive to immunotherapy. These cancers are unable to repair some types of mistakes that occur when DNA is copied. This leads to a high rate of mutations, making them easier for the immune system to recognize with immunotherapy.
Cercek and Diaz wanted to find out whether immunotherapy alone can successfully treat patients with dMMR cancers and allow them to avoid chemotherapy, radiation, and even surgery. They designed a study where they treated dMMR rectal cancer patients with dostarlimab for 6 months.
Early data from the study showed groundbreaking results for patients with dMMR rectal cancer: for all participants, the cancer disappeared with immunotherapy alone, allowing them to forgo surgery. These promising results led the investigators to ask whether this approach could be extended beyond rectal cancer to all early-stage dMMR tumors, regardless of tumor site.
In a phase 2 trial, Cercek’s team studied whether dostarlimab could be used to treat early-stage dMMR cancers found at any location in the body. The results were shared at the 2025 American Association of Cancer Research (AACR) annual meeting and published in the New England Journal of Medicine.
In the study, 103 patients completed treatment. These patients included 2 groups: 49 patients with dMMR rectal cancer and an exploratory group of 54 patients with dMMR cancers at other sites (eg, esophagus, colon, stomach, urothelial tissue, small bowel, endometrium). Dostarlimab treatments were given by infusion every 3 weeks for 6 months.
Immunotherapy effective without need for surgery in most study participants
As with the early results, the outcomes were remarkable. Most patients with dMMR cancers who were treated with immunotherapy achieved clinical complete response—that is, the cancer disappeared—with immunotherapy alone. Patients whose cancer was eliminated included:
- 100% of patients with dMMR rectal cancer (49/49 patients; 95% confidence interval [CI], 92.7%-100%)
- 65% of patients with other, nonrectal dMMR cancers (35/54 patients; 95% CI, 50.6%-77.3%)
- 82% of patients overall (84/103 patients; 95% CI, 72.7%-88.5%)
As a result, 80% of patients (82 out of 103) avoided surgery. “This is a very significant response, and the results were even better than we had hoped,” said Cercek. “We found that some cancer types responded extremely well to the immunotherapy, including colon and stomach cancer.”2
80% of patients avoided surgery
Treatment with dostarlimab has proved to be long-lasting. Two years after treatment, 92% of patients were still free of cancer. At the latest follow-up time (a median of 21.5 months), 100% of patients in the study survived.
Patients whose cancer did not completely disappear were still able to have surgery, meaning that treating them with dostarlimab first did not cause them to miss the opportunity for surgery. For these patients, Cercek noted, “we often saw that the immunotherapy shrunk the tumor and sometimes even lowered the staging assigned to the cancer. We also saw lower rates of cancer recurrence, suggesting that even if the effect wasn’t a home run, it helped most patients.”2
100% of patients survived
Circulating tumor DNA as a real-time indicator of treatment response
A challenge in applying this new approach is tracking the cancer’s response to treatment. The current standard is to monitor treatment response with imaging and endoscopy, when possible.
To help see how patients responded to treatment in a minimally invasive way, Cercek’s team also measured ctDNA with Haystack MRD by Quest Diagnostics®—a highly sensitive blood test that is personalized based on each patient’s tumor.
Tumors continually release small amounts of ctDNA into the bloodstream. Advanced DNA sequencing, such as that used by Haystack MRD, can identify tiny amounts of ctDNA in the blood. Testing for ctDNA can detect cancer in amounts too small to be seen with traditional methods (imaging and endoscopy).
Monitoring for ctDNA served as a sensitive and accurate way to measure the dMMR cancer’s response to treatment:
- ctDNA testing showed which patients had a complete response a median of 1.4 months into treatment, sooner than traditional methods
- Levels of ctDNA correlated with biopsies (positive biopsies were also positive for ctDNA), meaning that ctDNA testing might be useful as a “liquid biopsy”
- In 100% of patients (84/84 patients, 95% CI, 95.7%-100%) whose tumors disappeared, ctDNA had cleared by the end of treatment, indicating that the ctDNA testing was highly specific—there were no false-positive results
- In patients whose cancer did not disappear completely or recurred, ctDNA stayed present throughout treatment
These results supported ctDNA as a reliable, minimally invasive way to measure treatment response. The authors said ctDNA provided “a unique window” into the dynamic response to immunotherapy, allowing them to reliably monitor how patients responded to treatment in real time.1
Preserving organs, fertility, and quality of life
Traditional treatments for rectal and other gastrointestinal cancers often involve life-altering surgeries, including colostomies and fertility loss. In this study, 3 patients with dMMR rectal cancer were able to conceive and give birth after treatment—an outcome that may not have been possible with standard care.3
“Preserving a patient’s quality of life while also successfully achieving positive results in eliminating their cancer is the best possible outcome,” Cercek said. “They can return to their daily routines and maintain their independence.”4
Looking ahead
Patients from the study will be followed to determine longer-term outcomes. For example, Cercek wants to find out whether patients treated with immunotherapy might live longer than those who are treated with surgery instead.5
For patients with dMMR cancers, which represent 2% to 3% of early-stage solid tumors, this approach could fundamentally shift the treatment paradigm. Surgery, chemotherapy, and radiation may no longer be the default options when lasting responses can be achieved with immunotherapy alone.
Next, Cercek plans to study why some patients did not respond to the therapy and to explore using immunotherapy for additional types of cancer.2
This study marks a significant shift in how dMMR cancers can be managed—offering many patients a path to cure without the potentially life-altering side effects of major surgery, radiation, and chemotherapy.
The study results also support ctDNA detection as a valuable tool for assessing treatment response in real time. Haystack MRD provided a minimally invasive, real-time method to track therapeutic response that can be used even when imaging or biopsies are challenging.
“The bottom line is that everyone did benefit. No one was harmed. It takes home the message that therapy like this can lead to significant clinical complete responses, tumor downstaging, and significant improvement in the quality of life of patients,” said Cercek.5 She added, “I see this as… an incredibly effective approach in early-stage disease where we can use immunotherapy and, with the majority of these tumors, replace standard of care and surgery.”5
The study authors also stated that, “Testing for circulating tumor DNA may become an important addition to the response assessment performed after neoadjuvant therapy, especially when endoscopy and biopsy of the tumor are not feasible.”1
Download the clinical trial study summary or read the full study publication [link to NEJM article].
References
- Cercek A, Foote MB, Rousseau B, et al. Nonoperative management of mismatch repair–deficient tumors. N Engl J Med. Published online April 27, 2025. doi:10.1056/NEJMoa2404512
- Immunotherapy could replace surgery enabling patients to retain their organs and enhance their quality of life. April 27, 2025. https://www.mskcc.org/news-releases/immunotherapy-could-replace-surgery-enabling-patients-to-retain-their-organs-and-enhance-their-quality-of-life
- Piersol, William. December 16, 2024. https://www.mskcc.org/news/rectal-cancer-disappears-after-experimental-use-immunotherapy1
- Swim Across America grant funding of Memorial Sloan-Kettering Cancer Center clinical trial shows that immunotherapy alone could replace surgery enabling patients to retain their organs and enhance their quality of life. April 27, 2025. https://saaswim.com/tag/immune-system/
- TIME100 health 2025. Time. Accessed August 4, 2025. https://time.com/collections/time100-health-2025/
