Decades of cancer research have opened the door for us to better understand the genetic abnormalities underpinning certain cancers. In the early years of cancer research, the focus was on identifying the various types of cancers and their growth pattern. In the last few decades, medical researchers have begun to identify the pathways and triggers that cause cancer to develop and grow. 

In the genetic age, the quest now is to identify cancer-related genomic alterations and formulate actionable steps that can change the course of the disease.

Such is the case with cholangiocarcinomas (CCAs), cancers that are currently defined by their anatomical location—intrahepatic or extrahepatic. The incidence of CCA is around 1 per 100,000 person-years in the United States and in various European countries, such as France, Germany, Ireland, and the Netherlands.

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Accelerated Genomic Research

CCA is known to be an aggressive type of cancer that has a high mortality rate. In the United States, about 7 to 9 individuals out of 10 will die within 5 years of their diagnosis. Part of the reason for this is that CCA is notoriously insidious and tends to be discovered only in later stages, when associated signs and symptoms become more prominent. 

Read more about CCA epidemiology

Histologically, CCAs can be classified according to how poorly differentiated they appear. However, histological data about CCA does not sufficiently impact treatment decisions and hence only has a marginal impact on clinical outcomes. Medical researchers have found that molecular profiling reveals much more nuanced and useful information regarding CCA. 

In Annals of Oncology, Bekaii-Saab and colleagues wrote, “Recent advances in comprehensive and integrative molecular profiling have revealed substantial molecular heterogeneity of CCA, even within anatomically or histologically defined subtypes, with important implications for diagnosis and disease classification, prognosis, and treatment.” 

Increasing global partnership has accelerated genomic research into CCA and other types of cancers; as of February 2020, more than 2600 genomes of 38 types of tumors have been analyzed, involving the collaboration of scientists from 37 different countries. 

Because the prognosis of CCA is poor and early diagnosis of the disease is difficult to obtain through conventional means, physicians are looking to advancements in genomic profiling in the hopes of making a difference. Bekaii-Saab et al wrote, “Molecular diagnosis at the individual patient level may provide useful information for treatment planning and selection of appropriate therapies, especially targeted therapy.” 

However, when considering the implementation of genomic profiling for CCA, there are many practical considerations to take into account. 

Barriers to Widespread Genomic Profiling 

Scientists have proposed greater access to genomic profiling for patients suspected of having cancer. In Swiss Medical Weekly, Nik-Zainal and colleagues wrote, “It is quite possible, or even likely, that having a [whole genome sequencing] for every (relevant) solid cancer will become a routine part of the diagnostic process for every patient within the next 10-20 years, if not sooner.” 

The case for this is compelling. We now possess the technology to sequence a whole human genome in a single day; in other words, the speed at which we are able to carry out genome profiling is significant, provided that the facilities to do so are available. While sequencing costs remain relatively high, the increasing use of cancer genome profiling is expected to bring down costs in the years ahead. 

At present, the main factors limiting access to genome profiling are a lack of infrastructure and skilled personnel, as well as bureaucratic resistance. For genome profiling to be conducted in all corners of the globe, we need to ensure there are pathologists, geneticists, and scientists in place who are able to read and interpret a whole cancer genome. In addition, genomic data should be handled professionally and stored in a manner that enables machine learning to glean further insights into the disease.

Genome profiling for solid tumors generally requires tissue samples obtained via tumor biopsy. However, in the case of CCAs (and other biliary tract tumors), tissue biopsies can be more difficult to obtain. Among the challenges of obtaining a CCA tissue sample are inadequate tumor content in the tissue sample and a higher risk of morbidity associated with repeated biopsy attempts. 

Read more about CCA treatment

Scientists are going around this problem by developing genome profiling assays using blood samples. “However, although liquid biopsies are minimally invasive, circulating tumor DNA (ctDNA) constitutes only a fraction of cfDNA, and limited quantities of ctDNA retrieved from blood samples pose challenges to the sensitivity of liquid biopsy-based assays for solid tumors,” Bekaii-Saab et al wrote.

Making Genomic Data Actionable

Another practical barrier to the wider implementation of genome profiling in CCA is the slow pace of therapy development based on genomic data. For genome profiling in CCA to truly impact the course of the disease, we need to have therapies that are tailored toward the information that genome profiling can yield. This means we need to invest in clinical trials studying chemotherapeutic agents that incorporate genomic profiling data. 

Nik-Zainal and colleagues explained, “This is not a trivial exercise and years of work are ahead of us before we will be in a position to match therapies to genomic status more effectively in the future.” 

We can build toward a future in which genome profiling is as easily accessible as getting an X-ray or other imaging scan. However, we also need to ensure that we know how to use the information yielded wisely and effectively. The work pointed at building the systems and infrastructure to make this a reality must begin in earnest now. 


Bekaii-Saab TS, Bridgewater J, Normanno N. Practical considerations in screening for genetic alterations in cholangiocarcinomaAnn Oncol. 2021;32(9):1111-1126. doi:10.1016/j.annonc.2021.04.012

Nik-Zainal S, Memari Y, Davies HR. Holistic cancer genome profiling for every patientSwiss Med Wkly. 2020;150:w20158. doi:10.4414/smw.2020.20158