Microsatellite Stable Colorectal Cancer (MSS CRC) is a common subtype of colorectal cancer, a disease that begins in the large intestine. This article clarifies what MSS CRC means, how it is identified, and what treatment strategies are employed.
Understanding Microsatellite Stability
Microsatellites are short, repetitive segments of DNA found throughout the human genome. These sequences consist of repeating units of one to six DNA building blocks. In microsatellite stability, “stable” signifies that the length of these repetitive DNA sequences remains consistent within tumor cells compared to normal cells. This consistent length indicates that the cell’s DNA mismatch repair (MMR) system is functioning correctly, accurately fixing errors that occur during DNA replication.
The mismatch repair system acts as a proofreader for DNA, correcting mispaired bases or small insertions and deletions that can arise as DNA copies itself. Identifying a tumor as microsatellite stable suggests that its DNA repair mechanisms are intact, preventing the accumulation of specific types of genetic mutations.
Distinguishing MSS from MSI
The distinction between Microsatellite Stable (MSS) and Microsatellite Instability (MSI) in colorectal cancer is crucial for diagnosis. Microsatellite instability occurs when the lengths of these repetitive DNA sequences change within tumor cells, either becoming longer or shorter. This instability points to a deficient mismatch repair (dMMR) system, meaning the cell’s ability to correct DNA replication errors is impaired.
The difference in mismatch repair status profoundly influences how colorectal cancer is managed and its likely progression. MSI-H tumors often exhibit more mutations, making them more recognizable by the immune system and particularly responsive to certain immunotherapies, such as immune checkpoint inhibitors. In contrast, MSS tumors, which possess a functional mismatch repair system, display fewer mutations and are less likely to respond to these immunotherapies.
How MSS Status is Determined
Determining the microsatellite status of a colorectal cancer tumor involves laboratory tests performed on a tissue sample obtained during a biopsy or surgery. One primary screening method is immunohistochemistry (IHC). This test uses antibodies to detect the presence or absence of four main mismatch repair proteins: MLH1, MSH2, MSH6, and PMS2. The presence of all four proteins suggests a functional mismatch repair system and, consequently, MSS status.
Another common method is polymerase chain reaction (PCR)-based testing for microsatellite instability. This technique directly analyzes the length of specific microsatellite markers in the tumor DNA compared to normal DNA. If the lengths of these markers are consistent between the tumor and normal tissue, the tumor is classified as MSS. PCR testing can also be used to confirm results from IHC or when IHC results are inconclusive.
Treatment Approaches for MSS Colorectal Cancer
Treatment strategies for Microsatellite Stable Colorectal Cancer are tailored to the individual patient, considering the stage of the disease and overall health. Surgery often serves as the initial treatment for localized disease, aiming to remove the tumor and affected lymph nodes. Following surgery, chemotherapy is administered to eliminate any remaining cancer cells and reduce the risk of recurrence. Common chemotherapy regimens include FOLFOX (a combination of folinic acid, fluorouracil, and oxaliplatin) and FOLFIRI (folinic acid, fluorouracil, and irinotecan), which are systemic treatments.
Targeted therapies represent another important component of treatment for advanced MSS CRC, focusing on specific molecular pathways that promote cancer growth. These agents include anti-VEGF (vascular endothelial growth factor) inhibitors, which block new blood vessel formation, and anti-EGFR (epidermal growth factor receptor) agents, which target a protein involved in cell growth. The use of these therapies depends on the presence of specific genetic mutations within the tumor, such as the absence of KRAS or NRAS mutations for anti-EGFR agents. Immunotherapy, particularly immune checkpoint inhibitors like PD-1/PD-L1 inhibitors, shows limited effectiveness in MSS tumors due to their lower mutational burden compared to MSI-H tumors. However, ongoing research explores combination therapies and novel strategies to enhance the immune response in MSS CRC.
Prognosis and Patient Outlook
The prognosis for Microsatellite Stable Colorectal Cancer differs from that of MSI-H CRC, particularly concerning responsiveness to immunotherapy. While MSI-H tumors show a more favorable prognosis, especially when treated with checkpoint inhibitors, MSS CRC requires conventional therapies. Nevertheless, advancements in surgical techniques, chemotherapy regimens, and targeted therapies have improved outcomes for patients with MSS CRC over recent decades.
Early detection of colorectal cancer plays an important role in improving the prognosis for MSS CRC, as treatment is more effective when the disease is caught at an earlier stage. Personalized treatment plans, which consider the tumor’s specific characteristics and the patient’s overall health, further contribute to optimizing outcomes. Research continues to explore new therapeutic avenues, including novel drug combinations and approaches to overcome resistance to existing treatments.