The Critical Role of Molecular Profiling in Cholangiocarcinoma

Dr. Mitesh Borad, Oncologist, Associate Professor of Medicine at Mayo Clinic College of Medicine and Science

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Cholangiocarcinoma (CCA) is a rare and often overlooked cancer that forms in the bile duct. Rare in that it affects fewer than 10,000 people in the U.S.,^[i] but overlooked likely because of its non-specific symptoms — including abdominal pain, night sweats, fatigue, jaundice, general discomfort and weakness – which can make it difficult for physicians to identify.^[ii] Too often, CCA becomes a diagnosis of exclusion, only determined after physicians undergo rigorous processes to rule out other potential explanations to reach a diagnosis. As such, CCA is often diagnosed at an advanced stage when curative modalities such as surgery are not feasible and the prognosis is poor.^{[ii], [iii]}

Given the non-specific nature of symptoms associated with the diagnosis of CCA, other than jaundice, early detection is uncommon. In my own practice, I have found that a growing number of patients are being incidentally diagnosed by the presence of lesions, which are identified through imaging in the absence of other typical CCA symptoms.

Historically, the only potentially curative treatment for CCA has been surgery, but even after surgery, relapse rates are high, and patients have a median survival of only about 12 months.^[iv] More recently, technological interventions are making it possible to more efficiently evaluate CCA by allowing researchers to look closely inside each person’s tumors to see exactly which mutations are present.

This type of testing, called molecular profiling, pinpoints driver mutations, or genomic abnormalities.^[v] Molecular profiling can help detect these abnormalities earlier on in disease progression.^[vi]

For example, FGFR2 fusion or rearrangement is observed in 10 — 15% of patients whose CCA originates in the bile ducts within the liver, known as intrahepatic CCA.^[vi],[vii]

While a variety of molecular profiling methods are now available, next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) are among the most common. NGS allows us to analyze a tissue sample for multiple alterations at the same time, while FISH tests are conducted to identify one specific, predetermined alteration at a time.^[viii],[ix]

Molecular profiling isn’t consistently conducted, and it often isn’t even considered until after first-line chemotherapy has failed. Knowing that, I encourage patients within my practice to undergo molecular profiling early on in a patient’s CCA diagnosis, and I urge my hepatology and gastroenterology colleagues to do the same.

It is critical that physicians understand the importance of early molecular profiling when it comes to treating patients with CCA. More broadly, molecular profiling has helped scientists and physicians better understand how cancer can start, grow and spread in the body.

For more information on FGFR2 fusions and next generation sequencing in cholangiocarcinoma, visit https://www.fgfrscience.com/.

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_{[i] Key Statistics for Bile Duct Cancer. American Cancer Society. https://www.cancer.org/cancer/bile-duct-cancer/about/key-statistics.html. Accessed February 2020.}

_{[ii] Banales JM, et al. Nat Rev Gastroenterol Hepatol. 2016;13:261‒280.}

_{[iii] Uhlig J, et al. Ann Surg Oncol. 2019;26:1993—2000.}

_{[iv] Bridgewater J, et al. J Hepatol. 2014;60(6):1268-1289.}

_{[v] Lowery M, et al. Clin Cancer Res. 2018;24(17):4154-4161.}

_{[vi] Graham RP, et al. Hum Pathol. 2014;45:1630‒1638.}

_{[vii] Farshidfar F, et al. Cell Rep. 2017;18(11):2780—2794.}

_{[viii] Damodaran S, Berger MF, Roychowdhury S. Am Soc Clin Oncol Educ Book. 2015;e175-e182.}

_{[ix] Hu L, Ru K, Zhang L, et al. Biomark Res. 2014;2(1):3.}

Disclosures: Dr. Borad reports financial ties to Incyte, ADC Therapeutics, Exelixis Pharmaceuticals, G1 Therapeutics, Immunovative Therapies, Inspyr Therapeutics, Lynx Group, OncBioMune Pharmaceuticals, Western Oncolytics