Who This Is For
MSI-high colorectal cancer immunotherapy is becoming an important topic for patients diagnosed with colon cancer or rectal cancer.
“I have been diagnosed with colon cancer or rectal cancer. My doctor told me the cancer is MSI-high or dMMR. I have heard immunotherapy can work very well in some cancers. Could immunotherapy work for me?”
This article is for people with:
- Colon cancer
- Rectal cancer
- MSI-high or dMMR colorectal cancer
- Lynch syndrome-associated bowel cancer
- Patients considering treatment before or after surgery
- Patients seeking a colorectal cancer second opinion
A Clinical Observation From My Practice
As both a medical oncologist and cancer genetics physician, I regularly see patients with Lynch syndrome and other hereditary cancer syndromes.
One of the biggest changes I have seen is that genetic testing is no longer only about identifying cancer risk.
It is increasingly helping us choose treatment.
Approximately 3–4% of colorectal cancers are caused by Lynch syndrome.
When I discover that a patient has an MSI-High (MSI-H) or mismatch repair deficient (dMMR) cancer, my thinking immediately changes.
The question is no longer simply:
“What stage is the cancer?”
The question becomes:
“Could this cancer respond exceptionally well to immunotherapy?”
For many years, chemotherapy, radiation and surgery were the main treatments for colon and rectal cancer.
Today, emerging research suggests that some MSI-High colorectal cancers may respond so well to immunotherapy that it could fundamentally change how we treat these patients.
MSI-High Colorectal Cancer Immunotherapy: Why MSI Testing Matters
Not all colon cancers are the same.
Similarly, not all rectal cancers are the same.
Some cancers have a weakness in their DNA repair system. These cancers are called MSI-High or mismatch repair deficient cancers.
Because of this weakness, they may be more visible to the immune system.
For this reason, immunotherapy may be one of the most important advances in colorectal cancer treatment for selected patients.
The emerging message is simple:
The biology of the cancer may be just as important as the stage of the cancer.
Clinical Trial 1: NICHE-2 Colon Cancer Study
What Was The Question?
Can immunotherapy work before surgery in patients with locally advanced MSI-High colon cancer?
How Was The Study Performed?
Patients with locally advanced MSI-High colon cancer received immunotherapy before surgery.
Researchers then examined the tumour after surgery to see how much cancer remained.
Results
- 98% had a pathological response.
- 95% had a major pathological response.
- 68% had a complete pathological response.
- Early recurrence rates were extremely low.
Why This Matters
This study showed that some MSI-High colon cancers are extraordinarily sensitive to immunotherapy.
Clinical Trial 2: Dostarlimab in Rectal Cancer
What Was The Question?
Can immunotherapy eliminate rectal cancer without chemotherapy, radiation or surgery?
How Was The Study Performed?
Patients with locally advanced MSI-High rectal cancer received dostarlimab immunotherapy.
Researchers monitored whether the cancer completely disappeared.
Results
- Early studies reported very high complete response rates in carefully selected patients.
- Many patients avoided surgery.
- Many patients avoided permanent stomas.
Why This Matters
These results are among the most remarkable ever reported in colorectal cancer.
It has also raised an interesting question.
Is MSI-High rectal cancer biologically different from MSI-High colon cancer?
We do not yet know the answer.
However, the responses seen in rectal cancer have been extraordinary.
Clinical Trial 3: ctDNA Clearance After Immunotherapy
What Was The Question?
Can immunotherapy eliminate microscopic cancer that cannot be seen on scans?
How Was The Study Performed?
Researchers studied patients who remained ctDNA-positive after surgery.
These patients received immunotherapy.
Results
- Most patients cleared their ctDNA at 6 months.
- Recurrence rates appeared lower than expected.
- Survival outcomes were encouraging.
Why This Matters
This provides biological evidence that immunotherapy may be eliminating microscopic residual disease.
In other words, immunotherapy may be doing far more than simply shrinking a tumour on a scan.
Key Results
- In the NICHE-2 colon cancer study, almost all patients responded to immunotherapy.
98% of patients had a pathological response, meaning the cancer showed a major effect from treatment when the tumour was examined after surgery. - Many patients had very little cancer left after treatment.
95% had a major pathological response, meaning only a very small amount of cancer remained. - Some patients had no cancer seen in the surgical specimen.
68% had a complete pathological response, meaning no remaining cancer was found when the tumour was examined after surgery. - In MSI-high rectal cancer, immunotherapy results have been remarkable.
Studies of dostarlimab reported very high complete response rates, allowing many patients to avoid chemotherapy, radiation and surgery during follow-up. - ctDNA studies suggest immunotherapy may also help clear microscopic disease.
In some patients who still had tumour DNA detectable in the blood after surgery, immunotherapy helped clear ctDNA, which may suggest a lower risk of recurrence.
What Do These Results Mean for Patients?
These results do not mean that every patient with colon cancer or rectal cancer should receive immunotherapy.
However, they show that MSI-high and dMMR cancers behave differently from many other bowel cancers.
Because these cancers may be more visible to the immune system, immunotherapy may work particularly well in this group.
For some patients, immunotherapy may change the treatment conversation completely.
Instead of only asking whether surgery, chemotherapy or radiation is needed, doctors may increasingly ask:
“Is this cancer MSI-high or dMMR?”
Importantly, this result can influence treatment options, genetic counselling, family risk, and sometimes even the possibility of avoiding more intensive treatment.
However, these decisions are complex.
They should always be discussed with a specialist oncologist who understands colorectal cancer, immunotherapy and cancer genetics.
Overall, MSI-high colorectal cancer immunotherapy is changing how oncologists think about selected colon and rectal cancers.
Three Key Takeaways
- MSI testing should be performed in every patient with colorectal cancer.
- Some MSI-High cancers may respond better to immunotherapy than conventional chemotherapy.
- Genetic testing can influence treatment decisions, not just cancer risk assessment.
References
- Chalabi M, Verschoor YL, Tan PB, et al. Neoadjuvant immunotherapy in locally advanced mismatch repair-deficient colon cancer. N Engl J Med. 2024;390(21):1949-1958. doi:10.1056/NEJMoa2400634.
- Cercek A, Lumish M, Sinopoli J, et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med. 2022;386(25):2363-2376. doi:10.1056/NEJMoa2201445.
- Cercek A, Foote MB, Rousseau B, et al. Nonoperative management of mismatch repair-deficient tumors. N Engl J Med. 2025;392(23):2297-2308. doi:10.1056/NEJMoa2404512.
- Janjigian YY, Foote MB, Lumish M, et al. Abstract CT002: Circulating tumor DNA status to direct adjuvant immunotherapy for mismatch repair deficient tumors. Cancer Res. 2025;85(8_Suppl_2):Abstract CT002.
- Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med. 2003;348(10):919-932. doi:10.1056/NEJMra012242.
Frequently Asked Questions (FAQs)
- What is MSI-High?
MSI-High means the cancer has defects in its DNA repair system.
- Does MSI-High mean I have Lynch syndrome?
Not always.
Further testing is usually required.
- Should every colorectal cancer patient have MSI testing?
Yes. It is now considered an essential biomarker.
- Is immunotherapy available in Australia?
In some situations yes.
Access depends on the stage of disease, PBS criteria, private insurance and clinical trial availability.
Dr Dilanka De Silva
MBBS, MRCP(UK), FRACP, PhD
Medical Oncologist & Cancer Genetics Physician
Melbourne, Australia