A French prospective real-life cohort confirmed the favorable prognosis of nonmetastatic microsatellite instability (MSI) colorectal cancers. These cancers nevertheless entailed a high risk for recurrence in stage III, especially when not treated with adjuvant chemotherapy. The initial follow-up results of the cohort were presented at the French-speaking Days of Hepato-Gastroenterology and Digestive Oncology.
According to the study, more than a quarter of patients with stage III colorectal cancer did not receive neoadjuvant chemotherapy. "Rather than a disregard for recommendations, I believe it is mainly about patients who were not fit to receive treatment. At least I hope so. This will need to be verified," lead author David Tougeron, MD, PhD, gastroenterologist and digestive oncologist at Poitiers University Hospital in Poitiers, France, told Medscape French edition.
"There is a tendency to think that stage III MSI cancers have a better prognosis, compared with other colorectal cancers, like stage II, but this is not true. They also have a poor prognosis and should be treated with chemotherapy if the patient is fit to receive it," said Tougeron.
DNA Repair Deficiency
The real-life cohort reported a similar 3-year recurrence-free survival (RFS) among patients with stage II colorectal cancer with or without chemotherapy (79.3% and 84.7%, respectively). In stage III, however, the 3-year RFS is 69.3% with adjuvant chemotherapy compared with 40.7% without adjuvant chemotherapy.
Colorectal cancers with a DNA mismatch repair deficiency (dMMR) leading to MSI represent 15% of colorectal cancers. The multiple mutations induced during DNA replication in these repeated sequences of the genome, known as microsatellites, contribute to carcinogenesis.
The dMMR-MSI nonmetastatic colorectal cancers are associated with a better prognosis but resistance to adjuvant 5-fluorouracil-based treatment in stage II. However, in metastatic situations, the dMMR-MSI status is associated with a poor prognosis but major effectiveness with checkpoint inhibitor immunotherapy.
In colorectal cancer, "determining MSI is a major issue regardless of the stage," said Tougeron. Two techniques are used: Molecular biology through circulating tumor DNA analysis (MSI status) and immunohistochemistry by evaluating the expression level of MMR system proteins (dMMR status).
Lynch Syndrome
All colorectal cancers must be analyzed. According to the recommendations of the National Cancer Institute, both tests are to be performed to confirm satellite instability in case of suspicion of Lynch syndrome, a genetic disease affecting MMR genes responsible for DNA repair, or when treatment with checkpoint inhibitors is considered.
Initiated in 2016, before the arrival of immunotherapies in this indication, the French COLOMIN2 cohort aimed to evaluate the therapeutic management and real-life prognosis of patients with MSI colorectal cancer.
Between 2016 and 2021, 637 patients treated in 37 centers were included. Stage II tumors were the plurality (40.9%). Then came stage III (29.3%), metastatic stage IV (18.7%), and stage I (11.1%). In three quarters of cases, MSI was determined by immunohistochemistry.
The average age of included patients was around 70 years. Women are in the majority (60%), which is expected for this type of cancer, said Tougeron. In 41% of cases, Lynch syndrome was confirmed. Patients with the syndrome were younger, while sporadic forms were more common in older patients.
Among metastatic patients, 86.4% had synchronous metastases, which were discovered at the initial diagnosis. The majority had a single metastatic site (76.6%), mainly hepatic (45.1%), peritoneal (37.2%), and nodal (19.5%). Pulmonary metastases remain rare (less than 10%).
Prognostic Factors
In the case of stage II, most patients did not receive adjuvant chemotherapy (82%), "which is logical, since these patients generally have a good prognosis," said Tougeron. After a median follow-up of 40.7 months, the recurrence rate was 6% compared with 13% in patients who received chemotherapy. "Rates that remain very low," Tougeron added.
For stage III, the situation was different. The recurrence rate was 23% in patients treated with chemotherapy compared with 29% in those who did not receive treatment. While treatment is recommended in stage III, "patients may have refused or may not have been able to be treated because of their age or the presence of comorbidities," said Tougeron.
In patients with metastatic stage IV, the results were more difficult to interpret because immunotherapy did not benefit all patients. The median progression-free survival was 28 months with immunotherapy compared with 11 months with the previous standard treatment combining chemotherapy and targeted therapy.
The cohort follow-up continued with the aim of evaluating the long-term recurrence rate. The team was also working on researching and identifying clinical and biological prognostic factors, particularly from tumor samples from nearly 500 patients.
Such a collection of biological samples from MSI colorectal cancer had never been carried out before. Among the avenues to explore are "understanding the absence of immune infiltrate in certain tumors, which have poor prognosis," said Tougeron.
This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.