by Dr. C.H. Weaver M.D. 7/2019
Microsatellite instability (MSI) is a biomarker for response to PD-1 immune checkpoint inhibitors. PD-1 inhibitors in metastatic colorectal carcinoma (mCRC) with MSI-high (MSI-H) have demonstrated a high disease control rate and favorable progression-free survival (PFS); however, reported response rates to Keytruda (pembrolizumab) and Opdivo (nivolumab) are variable suggesting that additional predictive biomarkers could be helpful.(1,2)
Microsatellite instability (MSI) is the condition of genetic hypermutability or a predisposition to mutations in cells that results from impaired DNA mismatch repair (MMR). DNA MMR corrects errors that spontaneously occur during DNA replication such as single base mismatches or short insertions and deletions. The proteins involved in MMR correct polymerase errors by forming a complex that binds to the mismatched section of DNA, excises the error, and inserts the correct sequence in its place.(1) Cells with abnormally functioning MMR are unable to correct errors that occur during DNA replication and consequently accumulate errors. This causes the creation of novel microsatellite fragments. The presence of MSI represents phenotypic evidence that MMR is not functioning normally, and specific tests can be used to detect for the presence of MSI. (3-6)
High levels of microsatellite instability (MSI-high) occur in about 10% to 15% of colorectal cancers as well as non-colorectal cancers, and research has demonstrated that ~ 50% of MSI-high patients with mCRC respond to treatment with Keytruda resulting in a one-year survival rate of about 50%, which is significantly better than chemotherapy.(9)
Not all patients with MSI-high cancer however respond to treatment. Research suggests that the tumor mutational burden (TMB) may help further predict which patients with MSI-high disease can be optimally treated with immune checkpoint inhibitors.
Tumor mutational burden is a measurement of the mutations carried by tumor cells and is a predictive biomarker being studied to evaluate its association with response to immunotherapy. TMB is measured using DNA sequencing, such as Whole Exome Sequencing (WES) to determine the number of acquired mutations in the tumor. Tumor cells with high TMB may have more novel antigens (targets) which are associated with an increase in cancer-fighting T cells to direct an anti-cancer response. (6-11)
The presence of MSI-high is associated with higher TMB, however TMB does not guarantee the presence of MSI-high. Testing for MSI-high is recommended for all colorectal cancers and it may be beneficial to measure most patients for MSI-high using a next-generation sequencing test because of the potential implications on treatment response.
Doctors have evaluated TMB in a small sample of mCRC patients and found a very strong association between TMB and response to treatment. In their study all patients with high TMB responded to therapy. Among the nine patients with low tumor mutational burden however, three exhibited disease control and six experienced disease progression. After a median follow-up of more than 18 months, the average duration of survival without cancer progression had not been reached for patients with high TMB but was only 2 months for those with low TMB.
The researchers estimated the optimal predictive cut point for TMB to be between 37 mutations/megabyte and 41 mutations/megabyte. They then used the Foundation Medicine database to analyze a larger group of patients with mCRC to confirm the optimal TMB cut point of 37 mutations/megabyte they identified.
Patients who fall outside the cut-point range may be less likely to benefit from anti-PD-1/PD-L1 therapy but the best approach to these patients is still being determined.
“These data offer a potential explanation for the heterogeneity in responses described with PD-1 inhibitors in recent prospective clinical trials in microsatellite instability-high colorectal cancer and support the integration of tumor mutational burden score as a potential decision tool in the sequencing of checkpoint inhibition and chemotherapy.
- Ramalingam S. Abstract CT078. Presented at American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago.
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- Gibney GT et al. Lancet Oncol. 2016; 6;17: e542-e551.
- Mandal R, Samstein RM, Lee KW, et al. Genetic diversity of tumors with mismatch repair deficiency influences anti–PD-1 immunotheray response. Science. 2019;364(6439):485-491.
- Samstein RM, Lee CH, Shoushtari AN, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 2019;51(2):202-206.
- Le DT, Uram JN, Wang H. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509-2520.
- Janjigian YY, Sanchez-Vega F, Jonsson P, et al. Genetic predictors of response to systemic therapy in esophagogastric cancer. Cancer Discov. 2018;8(1):49-58.
- Yaeger R, Chatila WK, Lipsyc MD, et al. [Clinical sequencing defines the genomic landscape of metastatic colorectal cancer](https://www.cell.com/cancer-cell/fulltext/S1535-6108(17%2930556-1). Cancer Cell. 2018;33(1):125-136.