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ASCO Presentation Points to Clinically Relevant Mutations in Subset of Biliary Tract Tumors

CHICAGO (GenomeWeb) – A study presented at this week's American Society of Clinical Oncology annual meeting may have uncovered clinically actionable mutations in a significant subset of difficult-to-treat, advanced biliary cancers tested by targeted sequencing. 

Milind Javle, a gastrointestinal medical oncology researcher with the University of Texas MD Anderson Cancer Center, presented the work and shared vignettes about biliary tract cancer cases in which treatment was targeted based on the mutations identified. 

He and his colleagues from MD Anderson, the University of Chicago, Albany Medical College, and Foundation Medicine did FoundationOne testing on tumor samples from more than 550 individuals with biliary tract cancer, sequencing the protein-coding exons of 315 cancer-related genes as well as the introns of genes that are commonly rearranged in cancer. 

The results provided a look at some of the recurrently mutated genes found across and within each of the three main biliary tract cancer subtypes — intrahepatic cholangiocarcinoma (IHCCA), extrahepatic cholangiocarcinoma (EHCCA), and gallbladder carcinomas (GBCA) — which can vary in frequency depending on geography, environmental exposures, and more. 

The sequence data also revealed mutations in the tumors that opened up new treatment possibilities for individual patients, Javle explained. 

Within the set of 412 IHCCA tumors, 57 EHCCA tumors, and 85 GBCA tumors they considered, he and his colleagues saw comparable mutation frequencies across the biliary cancer subtypes. 

But the types of recurrent mutations detected differed somewhat depending on the subtype considered. Many of the alterations identified in all of the subtypes seemed to impact genes from cell cycle regulation or chromatin remodeling pathways, for example. 

But a slightly higher proportion of IHCCA tumors contained certain alterations, including BRAF mutations, FGR1 fusions, or IDH1/2 substitutions. On the other hand, a subset of the other two tumor types contained mutations such as ERBB2 amplification. 

Many of the targetable mutations in the tumors turned up at low frequency, Javle noted. Still, he and his team suspect that at least some of these genetic glitches may be relevant to patient care. 

The data also offered some anecdotal clues about the potential of applying targeted treatments in cases where relevant mutations do turn up. 

In a 67-year-old man with IHCCA that had metastasized to the liver, for example, Javle and his colleagues reportedly saw a decrease in the metastatic mass after eight weeks of treatment targeting a BRAF V600E mutation in the tumor. 

Javle also pointed to examples of GBCA patients whose metastatic or recurrent tumors were treated with agents targeting FGFR fusions, HER2 amplifications, EGFR amplifications, or other mutation combinations. 

Beyond targeted mutations, he and his team are also exploring the possibility of gleaning prognostic insights from the alterations identified in the biliary tract cancer subtypes, such as KRAS mutations that seem to coincide with aggressive forms of disease. 

In an oral discussion of the abstract, Melanie Thomas, a medical oncologist and member of the Gibbs Cancer Center and Research Institute's gastrointestinal cancer team, praised the group for bringing together such a large group of biliary tumor samples, noting that just a few dozen EHCCA cases were included in the Cancer Genome Atlas effort, for example, due to the relative rarity of the biliary tract cancers.