Immunotherapy in rectal cancer: who it works for
You have probably heard about the study in which every patient was cured without surgery. It is real, and the result genuinely is exceptional. But the press coverage left out the most important part: who it applies to.
The short answer: a minority. Only 5-10% of rectal cancers have the molecular profile that responds to this approach. For the other 90-95%, immunotherapy alone does not work.
This article tries to state “for whom yes” and “for whom no” with equal emphasis.
What dMMR and MSI-H mean
Cells have a system for repairing the errors that arise when DNA is copied — the mismatch repair system. When that system fails, errors accumulate and the tumour ends up carrying a very large number of mutations.
- dMMR (deficient mismatch repair) describes the faulty repair system, determined by immunohistochemistry on the biopsy
- MSI-H (high microsatellite instability) is the measurable consequence of that fault, determined by molecular testing
In practice the two overlap heavily and designate the same group of tumours.
Why it matters: a tumour with very many mutations produces very many abnormal proteins, which the immune system can recognise as foreign. Immunotherapy does not attack the tumour directly — it releases the brakes on the immune system, which then does the work itself. And that mechanism only functions if the immune system has something to recognise.
Tumours without this defect — pMMR or MSS, the great majority — carry few mutations, are immunologically “invisible”, and do not respond to immunotherapy given alone.
What the dostarlimab study showed
The results that travelled around the world come from a phase 2 study in patients with locally advanced dMMR rectal cancer.
All 42 patients who completed dostarlimab treatment had a complete clinical response — the tumour could no longer be detected clinically, endoscopically or on imaging. None needed surgery or radiotherapy. At a median follow-up of 17.9 months there was no evidence of disease, and in a subgroup followed longer, at a median of 26.3 months, responses had been maintained for at least a year.
The registrational AZUR-1 trial met its primary objective, opening the way to approval of this approach as the first immunotherapy able to eliminate or delay the need for chemotherapy, radiotherapy and surgery in this group of patients.
For a patient with a low rectal cancer who would otherwise have faced pelvic radiotherapy and an operation carrying the risk of a stoma and of LARS syndrome, the difference is enormous.
Who it does not work for
This section matters as much as the previous one.
If your tumour is pMMR / MSS — the situation for 90-95% of patients — immunotherapy given alone is not the right treatment, and the results above do not apply. Standard treatment remains based on radiotherapy or chemoradiotherapy, surgery and, where indicated, chemotherapy.
There is intensive research into combinations that might make MSS tumours respond to immunotherapy, but these are not standard of care.
It matters that you know this, because hope placed in the wrong direction costs time, and in rectal cancer time has direct consequences for stage.
How to find out which group you are in
Testing is done on the biopsy fragment obtained at colonoscopy, so it requires no additional procedure. Immunohistochemistry can be performed for the four MMR proteins (MLH1, MSH2, MSH6, PMS2), or molecular testing for MSI.
Guidelines recommend testing all newly diagnosed colorectal cancers. In practice this is not always done automatically.
Ask explicitly whether MMR/MSI testing was done on your biopsy. It is a simple question, and the answer can change the whole treatment plan. If it was not done, it can be done retrospectively on the existing paraffin block.
Testing has a second use: a dMMR result can be the first clue to Lynch syndrome, which has consequences for the whole family.
In metastatic disease
Here the situation has been established for longer. In patients with metastatic dMMR/MSI-H colorectal cancer, immunotherapy is an accepted treatment and has substantially changed the prognosis of this subgroup.
This is another reason why molecular testing has to be requested from the outset in metastatic disease, not after other treatment lines have failed.
What remains to be learned
Honesty requires this part too:
Follow-up is still relatively short. The results are spectacular, but the question “how durable are these responses at 5 and 10 years” does not yet have a complete answer.
A complete clinical response does not automatically mean cure. Patients enter a strict surveillance programme, similar to that in the watch and wait strategy, with repeated endoscopy and MRI. If disease returns, surgery remains available.
Availability differs. Access to these drugs outside clinical trials depends on approvals and reimbursement, which do not move at the same pace everywhere.
What to ask
- Was MMR or MSI testing done on my biopsy? What was the result?
- If it was not done, can it be done on the existing material?
- If I am dMMR, am I eligible for immunotherapy, in standard treatment or in a clinical trial?
- If I am pMMR, what is the standard plan for me?
The difference between asking and not asking the first question can be, for a minority of patients, the difference between treatment with a drug and an operation with a stoma.
The information in this article is educational. Eligibility for immunotherapy is determined by the oncologist, on the basis of molecular testing.