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Whitepaper
Precision Medicine Comes of Age
Cancer treatment based on tumor signature instead of tumor type
May 09, 2019
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The U.S. Food and Drug Administration (FDA) recently granted accelerated approval in a new indication for three immune checkpoint inhibitors (ICIs), pembrolizumab (Keytruda®, Merck & Co), nivolumab (Opdivo®, Bristol-Myers Squibb), ipilimumab (Yervoy®, Bristol-Myers Squibb) and one protein kinase inhibitor, larotrectinib (Vitrakvi®, Bayer and Loxo Oncology). These approvals are noteworthy because they are based on a common biomarker rather than a tumor type. They reflect a new therapeutic approach in precision medicine and a major potential shift in the approach to cancer treatment, in which physicians’ treatment decisions are based on a tumor signature rather than tumor tissue type. Based on the success of microsatellite-instability-high (MSI-high) genetic testing of colorectal, gastric/ gastroesophageal and hepatocellular carcinoma and of neurotropic receptor tyrosine kinase (NRTK), the approvals show that the FDA is willing to accept novel – and potentially more agile – therapeutic/diagnostic development approaches.

Recently, PD-L1 expression has been extensively studied as a prognostic and predictive biomarker in various tumor types treated with ICIs in clinical trials. However, questions remain. These include the cut-off percentage of expression that can be considered as positive; whether PD-L1 testing can be performed only on fresh or archival tissues; and whether patients with no expression of PD-L1 can have a clinical response to anti–PD-1 and anti–PD-L1 antibodies. The trials that evaluated PD-L1 as a prognostic biomarker yielded inconclusive results. Some of them showed that patients with PD-L1 or PD-1 positive expression have significantly shorter overall survival, while in others, no correlation was seen between biomarker expression and outcomes. Therefore, there is a need for refinement of predictive biomarkers to determine their value as prognostic biomarkers, and to identify more potential responders to ICIs.


INTRODUCTION TO MICROSATELLITE INSTABILITY (MSI) AND MICROSATELLITE STABLE (MSS)

Mutations in one or more of several hundred cancer driver genes are sufficient to initiate tumor formation. Many such driver genes have been used in the development of targeted therapies, which are often tied to specific molecular defects in particular indications. For example, crizotinib is approved for patients with locally advanced or metastatic non-small cell lung cancer that is ALK positive, while vemurafenib is approved for patients with unresectable or metastatic melanoma with BRAF V600E mutations. And yet, exploratory analyses have demonstrated that the average tumor harbors thousands of mutations, often due to DNA mismatch repair deficiency (dMMR). Many of these mutations occur in protein-coding genes, and thus contribute to the overall mutational load of the tumor, but do not confer a cancer phenotype and are thus termed “passenger” mutations. Still other mutations occur in regions of repetitive DNA known as microsatellites,1 which exist as di-, tri- and tetra-nucleotide tandem repeats. The number of repeats in a given microsatellite varies within populations and by allele in an individual; when defects in mismatch repair occur in a tumor, the number of repeats can change, a condition known as microsatellite instability (MSI). These tumors are referred to as being MSI-high, or MSI-H. It is now well established that two distinct immunologic subtypes exist, according to the dMMR status, namely, MSI-H and microsatellite stable (MSS) subtypes, which are mutually exclusive. For instance, in colorectal cancer (CRC) 15% of the tumors are MSI-H and 85% are MSS.2,3 The MSI-H type is a common phenomenon across a significant fraction of tumors, reaching a frequency of 10% to 50%.

MMR is an important repair mechanism that ensures genomic integrity and is mediated by key proteins that form heterodimers to recognize and remove DNA errors. Loss of MMR protein function leads to an accumulation of DNA replication errors, which can manifest as MSI. These replication errors can also lead to mutated proteins, some of which are immunogenic – they are no longer recognized as “self” by the immune system – and can thus lead to immune cell infiltration and improved sensitivity to ICIs.


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