What the acronyms mean
Cells have a system that corrects the errors made when DNA is copied: the MMR (mismatch repair) system, made up of the proteins MLH1, MSH2, MSH6 and PMS2. When it fails, the tumour is dMMR (deficient) and accumulates errors in repetitive stretches of DNA called microsatellites: that is high microsatellite instability, MSI-H. dMMR and MSI-H are two ways of measuring the same thing (by immunohistochemistry or by PCR/NGS).
The opposite is pMMR / MSS (stable), which is the most common.
How many patients it affects
- Around 15 % of early-stage colon cancers (I-III).
- Only 4-5 % of metastatic cases, because MSI-H tumours tend to relapse less.
- It is more frequent in the right colon and in older people (through MLH1 methylation) or young people (through Lynch syndrome).
Why it changes treatment
A tumour with thousands of mutations produces many "foreign" proteins that the immune system can recognise. Immunotherapy (anti-PD-1 antibodies such as pembrolizumab or nivolumab, alone or with ipilimumab) releases the brake on the immune system and in MSI-H achieves frequent and, most importantly, durable responses.
- Metastatic disease: first-line pembrolizumab doubled the time without progression compared with chemotherapy (KEYNOTE-177 study) and is the standard option in Europe. Nivolumab + ipilimumab is also approved.
- Localised dMMR rectal cancer: in small studies, immunotherapy alone (dostarlimab) achieved complete responses in almost all patients, avoiding surgery and radiotherapy. It is still considered experimental and is done within trials or specific protocols.
- Stage II-III: fluoropyrimidine-only chemotherapy (capecitabine or 5-FU without oxaliplatin) adds little or nothing in dMMR. There are trials of immunotherapy before surgery with very promising results.
Lynch syndrome
A dMMR tumour raises the question of whether the cause is hereditary. Lynch syndrome explains roughly 1 in 4-5 dMMR tumours. It is tested with a blood test (genetic counselling clinic). If confirmed, your first-degree relatives can be tested and, if they carry it, have colonoscopies every 1-2 years from age 20-25: that prevents cancers.
What to ask at your appointment
- Is my tumour dMMR/MSI-H? Has the test been done? (It should be done in every case.)
- Have I been referred to genetic counselling to rule out Lynch syndrome?
- If I have metastases: is immunotherapy my first option?
- If I am stage II-III or have rectal cancer: is there a trial of immunotherapy before surgery?