Recent Advances and New Methodologies in Cholangiocarcinoma

Day 1 of the Annual Cholangiocarcinoma Foundation Conference, now in its 15th year, saw a patient-focused agenda featuring experts from around the world. Topics ranged from COVID-19 and the advances made despite the pandemic to clinical conversations and perspectives from both patients and caregivers.

At the start of the conference, things were kicked off by co-chairs John Bridgewater, MD, PhD, of the University of Central London Cancer Institute; and Funda Meric-Bernstam, MD, of The University of Texas MD Anderson Cancer Center.

Bridgewater discussed the impact that the COVID-19 pandemic has had on research and on patients with cholangiocarcinoma. Although some cancer patients, including those with hematologic malignancies and lung cancer, fared worse when infected with COVID-19, cholangiocarcinoma patients on chemotherapy did not seem to be disproportionately susceptible to serious COVID-19 infection.

In the long term, there is not yet ample data to determine the long-term effects of the pandemic on patients with cholangiocarcinoma. “It will be probably years before we’re able to fully assess the impact of COVID on health services and, consequently, the ability to diagnose cholangiocarcinoma during the pandemic,” he said. Even so, there was a definite drop in diagnosis and services during the first lockdown.

Another change that occurred during the pandemic was the boom in telemedicine, which swept oncology and other facets of health care by storm as it became the safest way to engage with patients.

Huge downsides of the lockdowns in the UK were a pause in clinical trials during the first lockdown, which have since commenced; and that research funding, largely coming from charity in normal times, virtually disappeared during the first lockdown and has yet to return, Bridgewater said.

Despite the challenges, progress was still made over the past year, as Meric-Bernstam emphasized in her part of the discussion, which focused on advances in cholangiocarcinoma that have largely involved genomics and precision medicine.

She provided a brief overview of the genetic code, genomic alterations, oncogenes, mutations, and gene fusions before digging in to one gene fusion in particular that has been

“We talk a lot about genomically informed targeted therapy, talking about using this information about mutating genes, copy-number changes, and fusions to better identify therapies. This is all very relevant, especially for biliary tract tumors, because we’ve really discovered that there are several genes that we think drive the growth of cancers,” Meric-Bernstam said.

In intrahepatic cholangiocarcinoma, those include FGFR2 fusions, IDH1 ontogenetic mutation, and BRAF V600 mutation, she noted. Gallbladder cancer and extrahepatic carcinomas, she pointed out HER2 and KRAS gene alterations.

It was an exciting year thanks to the FDA approval of pemigatinib, an FGFR inhibitor indicated for cholangiocarcinoma, Meric-Bernstam explained. It is the first targeted treatment in this cancer type, and the research supporting the approval showed 35.5% of patients with FGFR2 fusions of rearrangements had an objective response.

“This is the first approval for a genomically informed therapy for cholangiocarcinoma. FGFR is clearly proven to be a target of cholangiocarcinoma. And interestingly, there are several other FGFR- targeted therapies in development,” she said. The success of this trail, she added, shows that even in a disease as rare as cholangiocarcinoma, there can be successful, international trials and rapid accrual to move research along.

Genomic testing should be the standard of care in this cancer type, she said, as emerging data adds to discussions of potential targets. Liquid biopsies are also an emerging technology in cancer that may be able to help determine mechanisms of drug resistance. Meric-Bernstam also highlighted the potential importance of repeat biopsies throughout treatment, both liquid and from tumor tissue.

Overall, the expansion of precision oncology is a key aspect of the past year and where Meric-Bernstam sees cholangiocarcinoma treatment going in the future.

Mark Ghobrial, MD, PhD, director of the Houston Methodist J.C. Walter Jr. Transplant Center, picked up the discussion with topics in liver transplantation for intrahepatic cholangiocarcinoma.

Traditionally, resection. of part of the liver has been the strategy when this cancer presents in the liver, but less than 30% of patients present with resectable tumors, he said. Chemotherapy has seen many advances and can also be an effective approach, particularly gemcitabine and cisplatin, but progress has not been rapid in that area, either.

More recent research in transplantation, which was first met with some resistance, has shown success compared to resection, he said. One study showed that transplantation led to more success than resection, and also examined where chemotherapy fits into the picture. Compared with patients who received only chemotherapy or who received chemotherapy after transplant, those who received chemotherapy before the transplant did much better.

Tumor size also mattered in the success rate of transplant, with recurrence rates much lower with tumors less than 2 centimeters versus those greater than 2 centimeters, according to other research, Ghobrial said. The difference in 5-year survival was significant, with about 70% of patients with tumors less than 2 centimeters surviving in 5 years compared with about 40% in the larger tumor group.

“Let's look at the lessons from the previous literature that neoadjuvant therapy or chemotherapy given before transplantation is very effective when combined with a liver transplant,” Ghobrial said. “Liver transplant for selected patients can be successful. The question is: Who are the patients that should be selected for transplant?”

He and his team conducted research on transplantation, considering patients with unresectable disease eligible after 6 months of neoadjuvant therapy, which they used as a surrogate marker that the tumor was amenable to treatment. Presenting scans, he showed that transplantation led to better outcomes, although the study was very small.

Still, based on the results of the case series, which first included 7 transplants but now numbers about 17, liver transplant has potential in cholangiocarcinoma.

“Twenty years ago, the first results were very poor. Today, liver transplantation has become the preferred methodology for hepatocellular cancer or hepatoma,” Ghobrial said. “So liver transplantation can be performed successfully in patients with unresectable intrahepatic cholangiocarcinoma with excellent outcomes—within 60% or 80% survival 5 years out after this after this diagnosis is very good compared to any other modality. Liver transplant exhibits survival advantage compared with resection at any stage.”