Perspectives on Cancer Genome Profiling


Genomic Predictors of Immunotherapy Response

One of the most cutting-edge pan-cancer biomarkers for response to cancer therapeutics is microsatellite instability (MSI). Resulting from deficient mismatch-repair (MMR), MSI is a clinically relevant condition characterized by the progressive shortening of mononucleotide genomic tracts. With recent advances in precision medicine, our ability to detect MMR deficiency in patients has taken the oncology community by storm.

By using MSI as a biomarker, the oncologist can now identify patients who have higher levels of mutational burden due to MMR deficiency and therefore better define their treatment strategies. A higher tumor mutational burden has been proven to be the key factor for neoantigen production and subsequently the application of immunotherapeutics. MMR-deficient tumors have recently been shown to respond strikingly well to checkpoint blockade therapies, such as pembrolizumab (Le et al 2015).

On Tuesday, April 11th, Dr. Michael Overman of the MD Anderson Cancer Center in Houston gave a webinar with our very own Dr. Donna Nichol, discussing the clinical utility of noninvasive detection of MSI in patients across varied solid tumor indications. Dr. Overman summarized the details of a recent phase 2 study he led in which 74 patients with MSI-high colorectal cancer were treated with the PD-1 inhibitor nivolumab. This was the largest ever sample size of MMR-deficient tumors, and he reported that nivolumab monotherapy led to a 73.8% overall survival rate at 12 months, and an increase in overall quality of life (EQ-5D Index), which rose to the population norm.

As a result of his study, Dr. Overman recommends that all metastatic colorectal cancer patients be tested for MSI status, declaring, “MSI is the best predictive marker that we have!” He also made the point that gastric and endometrial patients also have relatively high MSI prevalence rates (22% and 28% of patients respectively).

Addressing the need for MSI detection, Dr. Nichol presented our highly specific and extremely sensitive PlasmaSELECTTM 64 liquid biopsy assay, the first liquid biopsy assay to offer MSI detection. The NCCN guidelines argue that although tissue is the gold standard, plasma biopsy should be used in cases where tissue biopsy is not feasible. Utilizing digital genomic approaches, PlasmaSELECT 64 achieves high sensitivity and specificity in 64 well-established cancer genes that were carefully identified for clinical actionability.

Of these 64 genes, 56 are the basis of targeted therapies in current clinical trials, and 11 already have approved targeted therapies. In addition to the evaluation of exons in genes that are frequently mutated in cancer, PlasmaSELECT 64 also performs a comprehensive genomic analysis of translocations in 18 genes and copy number analyses in 19 genes. PlasmaSELECT 64 can detect sequence mutations with a lower limit of detection of >0.5%, a specificity of 99.9997%, and a sensitivity of 99.4%. With the advancement of liquid biopsies that can profile a tumor population and detect MSI status, our goal of attaining a high level of precise care is within reach.