Cholangiocarcinoma News

Expert Perspective on the Evolving Standard of Care in Biliary Tract Cancers

December 2021, Vol 2, No 4

Mitesh J. Borad, MD, Mayo Clinic College of Medicine and Science, Phoenix, AZ, delivered an expert Keynote Perspective at the 3rd Annual Summit, highlighting genomic profiling as the standard of care in the management of patients with intrahepatic cholangiocarcinoma (CCA), with liquid biopsy becoming the tool of choice for genomic profiling in biliary tract cancers.

Dr Borad discussed current global approaches to CCA from a personalized medicine point of view. “The human model system is truly maybe the best place to start and end, and this would be considered bedside-to-bench research,” he said.

Integrated sequencing allows for the investigation of several aspects of disease at once and a comprehensive view of the disease, including germline analysis, therapy selection, pharmacogenomics, clonal evolution, disease prognosis, and monitoring response to therapy.

Identifying the disease driver may be done through multiplatform concordance, mutation transcript specific expression, heuristic knowledge, ranking of events, and target hyperselection. The prevalence of FGFR2 fusions in CCA is approximately 10%, almost exclusively in intrahepatic CCA. The patient-derived xenograft model can be used to identify the potential benefits and the relative efficacy of drugs, he explained.

“Working with colleagues in the radiation department, we have been trying to identify mutation signatures, using Fourier transform–based methods, what we would call radiomics, machine learning, or artificial intelligence, to see if we could identify those patients, or at least enrich very quickly, so we know if we have a patient with an FGFR2 fusion on our hands or not,” said Dr Borad. “And you can apply the same understanding to other mutations, such as IDH1/2 or KRAS.”

When we manage driver mutations with drugs such as pemigatinib, tumor shrinkage has been seen in up to 80% of cases. These responses have been semidurable, so the current unmet need is how to keep these responses durable, or how to overcome resistance, Dr Borad said.

He explained that tumor evolution is clearly common, and oncologists have to analyze it comprehensively and often to stay on top of the treatment. Whole-genome sequencing and other “omics” assessment should also be done; however, cost is a limitation. The analysis should be done at every decision point. As an initial step toward adopting this approach, comprehensive analysis may be completed at the initial diagnosis, but the compromise may be somewhere in the middle.

The ERRFI1 gene (or MIG-6) is a regulator of multiple pathways, such as EGFR or MET. Treating patients with erlotinib led to reduced tumor volume at 3 months.

Microsatellite instability-high is a targetable biomarker, with highly durable response rates after treatment in solid tumors. Mutational burden is variable across biliary tract cancers. Very deep and durable responses have been seen in patients with mismatch repair-deficient (dMMR) who received PD-1 blockade therapy. However, some patients do not respond to this therapy. “Studying these heterogeneities will be key to our understanding of how we approach these problems,” said Dr Borad.

Liquid biopsy may be used for target (or biomarker) identification, prognostication, dMMR detection, and response assessment in the next year or two. The benefits of liquid biopsy include speed, minimal invasiveness, ability to complete serial analysis without harm, possible improved representation of tumor heterogeneity, and it may be used to detect early resistance to therapy.

How can we select therapy better to increase the likelihood of response? Dr Borad suggested that tumor organoids and ex vivo therapy models may be incorporated for clinical decision enhancement as predictive tools.

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