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Several Biomarkers Offer Potential in Predicting Immunotherapy Response in Digestive Cancers


Potential biomarkers include tumor mutational burden, microsatellite instability, and circulating tumor DNA.

Research and real-world experience have shown that programmed death-ligand 1 (PDL1) alone cannot predict which patients with digestive system cancers will respond to immune checkpoint inhibitors, resulting in a need for other biomarkers. While there are still no well-established biomarkers for these patients, several have been touted as potential options, say researchers of a new study.

Potential biomarkers include tumor mutational burden (TMB), microsatellite instability (MSI), and circulating tumor DNA (ctDNA).

“Recently, TMB has evolved as an emerging biomarker in immunotherapy, especially in terms of drug-response and prognosis prediction,” commented the researchers. “In fact, in several cancer types, such as [non-small cell lung cancer], melanoma and urothelial cancer (UC), the level of TMB has been noted to be related with the clinical outcomes; for example, the higher expression of TMB after anti-PD-1/PD-L1 or anti-CTLA-4 treatment, perhaps present better clinical performance in terms of [overall survival rates], than lower levels of TMB.”

A 2018 study was the first to suggest a potential correlation between TMB level and clinical outcomes in gastric cancer (GC) after showing, among 55 patients receiving pembrolizumab, that overall survival rates (88.9%) were significantly higher among TMB-high patients than among TMB-moderate and TMB-low patients (20% and 11.1%, respectively). Last year, a study presented at the American Society of Clinical Oncology meeting suggested that TMB should be a PD-L1 independent biomarker.

Data has also supported the use of TMB in esophageal cancer (EC) and colorectal cancer (CRC). For example, a study including 110 patients with EC and CRC found that higher TMB was always associated with improved outcomes.

“How to standardize the detection procedures of existing biomarkers (such as PD-L1 and TMB) and how to search the new biomarkers to join the prediction team is a critical part,” wrote the researchers of the study. “And the combination of multiple biomarkers, rather than a single molecule, will provide stronger value for immunotherapy-based precision treatment.”

The researchers also point out that MSI is a widely used biomarker in CRC treatments and in GC, research has suggested that patients with the MSI subtype have a favorable response to immunotherapy. The researchers note that MSI may not be a good fit for most tumor types of the digestive system, as the incidence of MSI-H in hepatocellular carcinoma (HSS) is just 2% and data has shown no superior survival with pembrolizumab.

ctDNA measured by liquid biopsy has also showed promise as a complement to tissue biopsy, according to the researchers, highlighting its success in early diagnosis, efficacy assessment, and prognosis evaluation in CRC, GC, and HCC.

“Indeed, ctDNA is promising in cancer treatments (mostly as a pre-chemotherapy or post-chemotherapy marker) and is not yet sufficiently credible in immunotherapy,” wrote the researchers. “The emergence of liquid biopsy could make up for the lack of tissue biopsy and better meet the demands of precision medicine, but its clinical popularization in the future urgently requires more large sample and well-designed trials. Meanwhile, standardization and optimization of ctDNA testing appears to be equally meaningful.”


Zeng Z, Yang B, Liao Z. Biomarkers in immunotherapy-based precision treatments of digestive system tumors. Front Oncol. Published online March 11, 2021. doi:10.3389/fonc.2021.650481

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