On May 25th, These Biomarkers Became Famous…(and They’ve Been on CGI’s Test Menu for Over 5 Years)

Written by: AndrewLincoln

Published on:
October 10th, 2017


FDA’s approval of Keytruda (pembrolizumab) on May 25th was an important first for the cancer community – the first time the agency had approved a drug to be given based on biomarkers of patients’ tumors, rather than the location in the body or the tumor type. Merck’s checkpoint inhibitor was approved for patients with solid tumors identified as being microsatellite instability (MSI)-high or mismatch repair (MMR)-deficient. The approval was based on data from 149 patients with MSI-high or MMR-deficient tumors, 90 of whom had colorectal cancer. Fourteen other cancer types constituted the remaining cases. Genetic instability status of the patients was determined by either an investigational polymerase chain reaction test for MSI or by immunohistochemistry tests for expression of MMR proteins.

Keytruda’s landmark approval has urged labs in the precision diagnostics space to expand their offerings by adding MSI/MMR profiling to their testing menu for various solid tumor indications.

Based on the association with hereditary colorectal cancer [including familial adenomatous polyposis (FAP) and Lynch syndrome (LS; also known as Hereditary Non-Polyposis Colon Cancer (HNPCC)] and the use in prognostic and therapeutic decision-making for sporadic colorectal cancer, CGI has been offering MSI and MMR testing for a number of years as part of its comprehensive testing services for solid tumors. We would like to explain these tests today as they have become increasingly important for various cancer indications, specifically for identification of patients more likely to respond to immuno-oncology (IO) therapies.

MSI-high or MMR-deficient tumors are most commonly found in endometrial cancer, colorectal cancer (up to 5% of metastatic patients), and other gastrointestinal cancer patients. These molecular features have also been identified in patients with genitourinary, breast, thyroid, and other cancers.

CGI now offers an upfront MSI/MMR testing not only for colorectal cancer but also for additional cancer indications, including melanoma, breast, upper gastrointestinal, ovarian, thyroid, cervical, endometrial, and bladder.


A short refresher on MSI and MMR

Microsatellites are repeated DNA sequences which are present throughout the human genome. They are polymorphic among individuals but are unique and uniform in length in every tissue in each person. Microsatellites are prone to errors during DNA replication, particularly in the setting of abnormal DNA mismatch repair (MMR). DNA from tumor cells with defective MMR function exhibits an inconsistent number of microsatellite nucleotide repeats when compared to germline DNA, a finding referred to as “microsatellite instability.” MSI is the hallmark of a defective MMR system.

What actually causes tumors to be seen as immunogenic is quite complex, but in a general sense it was noticed fairly early on that cancers with high mutational burdens were more likely to be immunogenic. MSI-high and MMR-deficient tumors have an extremely high mutational load, even compared to tumors with other types of DNA repair defects, such as BRCA-mutated tumors.

The possible mechanism behind this correlation may be that the genomic instability of the tumor leads to higher mutational load which then leads to formation of neoantigens, recruitment of immune cells, and release of proinflammatory factors in the microenvironment.

The overall response rate in the 149 patients in the Keytruda trial was about 40 percent. In 80 percent of those patients who responded at all, the responses lasted for more than six months, once again confirming the outstanding durability of responses to IO therapy.MSI and MMR are suitable and reliable tests easily adoptable in clinical practice to identify patients for such therapy.

CGI’s MSI test is a fluorescent PCR-based assay that involves comparing allelic profiles of microsatellite markers generated by amplification of DNA from matching normal and tumor samples, which are suspected to be MMR deficient. Alleles that are present in the tumor sample but not in corresponding normal samples indicate MSI. PCR product is separated by capillary electrophoresis, and data are analyzed (fragment analysis).

CGI’s MMR analysis comprises of a comprehensive panel of IHC assays to determine and quantitate the expression of the four most common MMR proteins – MLH-1, MSH2, MSH6, and PMS2.

CGI leads the way in IO testing with a full suite of tests that include:

  • All 4 FDA-approved PD-L1 tests
  • NGS on both Illumina and Thermo Fisher platforms
  • Nanostring
  • Complete::IO unique and comprehensive flow cytometry panel
  • Tumor mutation burden (TMB) – launching soon

Our expertise, quick TATs, as well as our flexibility in testing options make us a preferred partner to meet your clinical trial and drug development needs. Drop me an email to schedule a conversation to learn more about the tests or about integrating our IO offerings into your clinical trial biomarker strategy!