Colorectal cancer: Tracking down subtypes

“MSI and TIL are established biomarkers in colorectal cancer. The question is: is it possible to make even more differentiated predictions by combining the two markers? We investigated this question by combining all available studies and evaluating them together. The result of this meta-analysis suggests that a classification system that records MSI and TIL together is suitable for optimizing the prognostic assessment of early-stage colorectal cancer,” says DKFZ researcher Michael Hoffmeister, last author of the meta-analysis.

Microsatellite instability – what does that mean? Microsatellites are short DNA sequences in the genome that are repeated hundreds of times and are particularly susceptible to errors when copying genetic information. The cells can repair such mismatch errors. However, if the repair system does not function properly, mismatch errors accumulate and the length of the microsatellites changes. This is known as microsatellite instability (MSI).

In colorectal cancer, testing the tumor tissue for MSI is informative because tumors in early stages (without metastases) with high microsatellite instability (MSI-H) have a better prognosis than colorectal cancer with microsatellite stability (MSS). This is important for therapy planning. In particular, MSI-H tumors can be treated well with modern immunotherapeutics – so-called checkpoint inhibitors – while MSS tumors respond less well to these drugs. On the other hand, there are also therapies that have been shown to have little effect on MSI tumors. Testing for MSI is therefore now routinely used in colorectal cancer in order to find the best possible therapy for the individual patient.

According to first author Durgesh Wankhede, the meta-analysis now presented argues in favor of further differentiating the MSI subtype depending on whether lymphocytes have migrated into the tumor tissue or not. Lymphocytes are immune cells that play a central role in the defense against cancer. The presence of immune cells in tumor tissue has – as expected – proven to be prognostically favorable.

“We now wanted to know whether we would gain additional information by combining MSI and TIL. There are already a number of studies that have investigated this question, but the significance of these trials was limited, mainly due to the small number of cases. We therefore combined 21 studies with a total of around 14,000 patients and were able to differentiate between four subtypes with different prognoses based on this extensive data material,” explains Michael Hoffmeister.

Colorectal cancer patients whose tumors had a high microsatellite instability and a high number of infiltrating lymphocytes (MSI/TIL-H) had the best prognosis. Patients with this marker combination lived longer overall, and they lived longer disease-free. Microsatellite stability plus lymphocyte infiltration (MSS/TIL-H) proved to be the second most favorable constellation. In contrast, patients with little or no immune cells found in the tumor tissue had a comparatively poor prognosis, although the prognosis was largely independent of microsatellite status. This means that the MSI/TIL-L and MSS/TIL-L subtypes had a similarly poor treatment outcome.

“The meta-analysis suggests that combined MSI/TIL testing could be superior to isolated testing for MSI in routine diagnostics,” summarizes Michael Hoffmeister and Durgesh Wankhede adds: “At the same time, long-term studies should be initiated to evaluate the significance of this marker combination with regard to the chances of success of adjuvant chemotherapy in early colorectal cancer stages.” A commentary on the meta-analysis in the journal Lancet Gastroenterology & Hepatology states: “The integration of MSI-TIL assessment could represent a step forward in personalized treatment strategies.”

Wankhede et al: Clinical significance of combined tumour-infiltrating lymphocytes and microsatellite instability status in colorectal cancer: a systematic review and network meta-analysis. Lancet Gastroenterol Hepatol 2024;

With more than 3,000 employees, the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) is Germany’s largest biomedical research institute. DKFZ scientists identify cancer risk factors, investigate how cancer progresses and develop new cancer prevention strategies. They are also developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ’s Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to questions relating to cancer.

To transfer promising approaches from cancer research to the clinic and thus improve the prognosis of cancer patients, the DKFZ cooperates with excellent research institutions and university hospitals throughout Germany:

National Center for Tumor Diseases (NCT, 6 sites)

German Cancer Consortium (DKTK, 8 sites)

Hopp Children’s Cancer Center (KiTZ) Heidelberg

Helmholtz Institute for Translational Oncology (HI-TRON Mainz) – A Helmholtz Institute of the DKFZ

DKFZ-Hector Cancer Institute at the University Medical Center Mannheim

National Cancer Prevention Center (jointly with German Cancer Aid)

The DKFZ is 90 percent financed by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg. The DKFZ is a member of the Helmholtz Association of German Research Centers.

Contact:

Dr. Sibylle Kohlstädt

Strategic Communication and Public Relations

German Cancer Research Center

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Email: presse@dkfz.de