Managing microsatellite instability (MSI-H) High colorectal cancer with Precision Oncology

Avishek Roy

Scientific Liaison Manager
4baseCare

In the era of precision medicine, it’s essential to have a thorough understanding of molecular profiles and altered signaling pathways in order to identify individuals who could benefit from targeted therapies. The ultimate goal of cancer genome profiling (CGP) is to enable precision oncology medicine or treatment tailoring based on each specific genetic alteration of each patient’s tumor. Several medications for the treatment of colorectal cancer (CRC) have been approved, and pharmacogenetic testing using biomarkers have been accepted to aid in patient selection. Throughout the last decade, targeting molecular pathways of tumor growth/proliferation has become a primary focus of anti-cancer therapy in the development of novel and innovative therapies for CRC. The underlying processes of significant genetic abnormalities such as the finding of cancer driver genes and their frequency in advanced-stage CRC patients, have been revealed through preclinical and translational research. Mismatch repair deficiency (MMR-D), BRAF V600E mutant, and human epidermal growth factor receptor 2 (HER2) have all been studied extensively in the quest to develop therapies for advanced-stage CRC patients.

According to the current NCCN Clinical Practice Guidelines for Colon Cancer, all patients with metastatic CRC should have their tumor tissue genotyped for TP53, APC, KRAS, NRAS, and BRAF mutations. Each of these biomarkers’ prognostic value is critical in offering individualized therapy. Patients with known KRAS (exon 2, 3, 4) or NRAS (exon 2, 3, 4) mutations should not be treated with cetuximab or panitumumab. Unless taken alongside a BRAF inhibitor, patients with the BRAF V600E mutation are unlikely to respond to panitumumab or cetuximab. For hypermutated cancers that are responsive to immune checkpoint suppression, microsatellite instability status is a common and reliable biomarker. After fluoropyrimidine, oxaliplatin, and irinotecan, checkpoint blockade treatment exhibits remarkable response rates and durability in mismatch repair-deficient CRC, and is currently approved by the FDA for microsatellite instability-High (MSI-H) CRC.

Microsatellite instability (MSI) has been found in a variety of cancers, the most prevalent of which are colorectal, endometrial, and gastric adenocarcinomas. The presence or absence of MSI has been found as a potential biomarker with potential clinical and therapeutic significance as a result of large-scale cancer genome sequencing initiatives.   The mismatch repair (MMR) system, one of several cellular DNA repair systems, checks and maintains the repeat count of microsatellites throughout cell division in normal cells. MSI occurs when the MMR system is disrupted, resulting in cells being unable to control the lengths of their microsatellites during cell division. Cells with a defective MMR system will produce microsatellite sequences of variable lengths after numerous division cycles. Microsatellite instability is associated with a significantly higher risk of CRC with distinct clinical and pathological characteristics, such as a larger tumor mutational burden and a higher number of tumor-infiltrating lymphocytes (TILs).

Colorectal cancer with MSI can be categorized into three distinct phenotypes: MSI-high (MSI-H), MSS (Microsatellite Stable) and MSI-low (MSI-L). Instability in more than 30% of the markers is defined as MSI-H and alteration in 10–30% of the markers is considered as MSI-L. The MSI-H phenotype is frequently associated with downstream frame shift mutations that create a high mutational burden in DNA. The clinical significance of MSI has been well described in colorectal cancer, as patients with MSI-H (MSI-high) colorectal cancers having a better prognosis than those with MSS (microsatellite stable) tumors.

The most notable advance in precision oncology therapeutics for advanced CRC has been the use of immune checkpoint inhibitor therapy for treatment of refractory MSI-H CRC. MSI-H colorectal cancers have been proven to be more vulnerable to immune-enhancing therapies. Within the last few years, three immunotherapy drugs were approved to treat metastatic MSI-high colon cancers.  The USFDA granted nivolumab expedited approval in 2017, Ipilimumab received accelerated approval a year later, and in 2020 pembrolizumab received approval. These Programmed death 1 (PD-1) inhibitors have emerged as a highly effective therapy for patients with MSI-H metastatic colorectal cancer that is refractory to standard chemotherapy combinations. Pembrolizumab is first-line immunotherapy for metastatic colon cancer with a high MSI score. That means you won’t need to start with chemotherapy. Researchers compared pembrolizumab to chemotherapy as a first-line treatment for MSI-high metastatic colon cancer in a clinical trial (randomized, phase 3, open-label KEYNOTE-177 trial). Pembrolizumab resulted in a substantial increase in progression-free survival. Pembrolizumab-treated trial participants also reported fewer adverse events than those who received chemotherapy. On the contrary MSS colorectal cancer is considered as Immunotherapy refractory.