Dynamics of MSI and Genomic Profile of Colorectal Cancer In the Course of Immune Checkpoint Inhibitor Therapy

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Microsatellite instability or mismatch repair deficiency occurs in 20% of CRC, and is predominantly found in non-metastatic tumors. The success of the CheckMate 142 and KEYNOTE-177 clinical trials has shifted the treatment paradigm of the MSI/dMMR CRC, which has led to the adoption of immune checkpoint inhibitors (ICI) by international treatment standards. However, despite the encouraging effects of ICI, up to 30% of patients are resistant to treatment and exhibit rapid disease progression shortly after starting ICI. On the other hand, around 30% of patients treated with ICI demonstrate prolonged responses to the treatment with a duration of response of over 40 months. Furthermore, for \~10% of patients, treatment with ICI results in pseudo-progression - a phenomenon of a short-term increase followed by the decrease of the tumor volume. Currently, the mechanisms and biomarkers associated with the response or resistance to ICI in MSI-positive CRC are largely unknown. Select studies suggest that BRAF mutations (specifically, BRAF p.V600E) might negatively affect the patients' progression-free survival following ICI, however, these data are premature. The primary hypothesis is that the clonal heterogeneity and the evolution of MSI status of MSI-positive CRC will play a role in the development of ICI treatment resistance. The primary objective of the study is to investigate the dynamics of MSI status in serial liquid biopsy samples from patients with MSI-positive tumors receiving ICI.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

* Male/female participants must be at least 18 years of age on the day of signing informed consent and have a histologically confirmed diagnosis of colorectal cancer.
* Verified MSI/dMMR positivity as measured by 5-loci PCR or 4-antibody IHC.
* The patient is scheduled to start treatment with any of the immune checkpoint inhibitors 2-4 weeks after the inclusion in the study.
* Have provided an archival tumor tissue sample obtained prior to the start of treatment with immune checkpoint inhibitor(s). Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides.
* Patient has to be able to provide serial blood samples during the course of treatment, as well as on every follow-up tumor scan.
* The participant (or legally acceptable representative if applicable) provides written informed consent to participate in the trial.
* Have measurable disease based on RECIST 1.1.
* Have adequate organ function.

Exclusion Criteria:

* Prior treatment with immune checkpoint inhibitors.
* For female participants: pregnancy or planned pregnancy.
* The unavailability of the tumor or serial liquid biopsy samples.