By Jeff Mitchell on Mar 22, 2019 12:13:41 PM
March is Colorectal Cancer Awareness Month and the Colorectal Cancer Alliance has implemented the charmingly named “Don’t Assume” campaign to raise awareness for the third most common form of cancer.1 In the era of precision medicine, there have been advancements in the way CRC can be treated, including via the anti-EGFR monoclonal antibodies Erbitux® (Cetuximab) and Vectibix® (Panitumumab). Unfortunately, variants within the genes downstream of EGFR in the protein signaling cascade can have a negative impact on these therapies. The National Comprehensive Cancer Network (NCCN) recommends determining tumor gene status of KRAS, NRAS, and BRAF in CRC tumors for this very reason; both the use of a Next Generation Sequencing (NGS) panel or traditional tumor profiling methods are mentioned.2 To the detriment of patients, tumor biopsies are invasive, often painful, and can be dangerous.1 However, there is another newer tool available, the analysis of circulating tumor DNA (ctDNA) via liquid biopsy.
ctDNA is fragmented DNA shed off from tumor cells that can be found in the plasma of cancer patients. Similarly, to the DNA from a tissue sample, analysis of ctDNA can be used for targeted therapy selection; however, a challenge of detecting ctDNA molecules is that they are usually found in a large background of wild-type (normal) cell free DNA (cfDNA) molecules. The fraction of ctDNA to cfDNA found in blood can be less than 1%. Admera Health has developed a patent pending enrichment technology for both NGS and qPCR that allows for the detection of ctDNA molecules at frequencies of 0.1% and 0.01%, respectively. This technology is ideal for providing targeted therapies when tumor tissue is not available. However, there are other potential uses too.
It is common for tumors being treated with targeted therapy to eventually develop therapeutic resistance; this can happen a couple of ways. Treatment with targeted therapy can provide selective pressure by eliminating cancer cells with targeted biomarkers, allowing cancer cells with mutations associated with resistance to freely divide. Stubborn cancer cells can also spontaneously acquire mutations associated with resistance during targeted therapy treatment. Within CRC tumors, mutations in the previously mentioned KRAS and NRAS genes as well as MET amplification are known to result in anti‑EGFR treatment resistance.3 By sampling at different time points, Admera Health’s LiquidGx™ allows for monitoring of these mutations. This could potentially result in an early change in treatment at the first sign of disease progression.
With the recent developments in immunotherapy, there are additional options to treat CRC, specifically the anti-PD-1 monoclonal antibodies OPDIVO® (nivolumab) and Keytruda® (pembrolizumab). When profiling a tissue biopsy, PD-L1 status and Tumor Mutation Burden can predict the likely response to immunotherapy. However, neither of these approaches are viable with a focused liquid biopsy test like LiquidGx™. By including Microsatellite Instability (MSI) in LiquidGx™, an immunotherapy recommendation can be made by analyzing five well characterized MSI sites that can signal a deficient mismatch repair (MMR) system. The MMR system corrects errors that occur during DNA replication. A deficient mismatch repair (dMMR) can result in an accumulation of mutations and ultimately cancer, including CRC. Both OPDIVO® and Keytruda® have MSI as a biomarker on their drug labels indicating they may be efficacious treatment options.
By combining the utility of a gene panel of actionable biomarkers, including MSI, with rapid turnaround time and the flexibility of a non-invasive sample, LiquidGx™ is a unique service offering. This uniqueness only intensifies when coupling this assay with PGxOnco™ for supportive care and chemotherapeutic selection.
1) Wills et al. “Role of Liquid Biopsies in Colorectal Cancer”. Current Problems in Cancer, vol 42, Issue 6, Nov 18, Pp 593-600
2) NCCN Clinical Practice Guideline in Oncology (NCCN Guidelines® Colon Cancer, Version 1.2019, March 15, 2019
3) Zhao et al. “Mechanisms of Resistance to Anti-EGFR Therapy in Colorectal Cancer”. Oncotarget, vol 8, 2017, Pp 3980-4000