Tumor genomic profiling of resected cholangiocarcinomas may reveal mutations targetable with agents currently being used for other cancers, according to the results of a study presented at the Society of Surgical Oncology (SSO) 2021 International Conference on Surgical Cancer Care.1 Among patients with resected cholangiocarcinoma who underwent tumor genomic profiling, “significant mutations were common, a median of two per patient,” stated the study’s lead author, Lucas W. Thornblade, MD, MPH, Fellow, City of Hope National Medical Center, Duarte, California. “We found that approximately 9 of 10 patients in this population will have at least one drug associated with mutations in their specific tumor,” he added.
“Cholangiocarcinoma has a poor prognosis, with 5-year survival rates between 8% and 10%,” and adjuvant therapies “have limited effects on survival,” Dr. Thornblade said. “Given that postoperative recurrence rates are as high as 70%, the burden is now on us to bring these potentially course-altering personalized data to the bedside for our patients.”
The burden is now on us to bring these potentially course-altering personalized data to the bedside for our patients [with resected cholangiocarcinoma].— Lucas W. Thornblade, MD, MPH
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One-Third Underwent Tumor Genetic Sequencing
A retrospective review identified 114 patients with cholangiocarcinoma who underwent surgical resection at City of Hope between 2010 and 2020. The mean age of patients was 64.5 years, and 44.7% were women. The most common surgical procedure was standard liver resection, performed for 54% of patients with intrahepatic tumors (46% of the tumors were poorly differentiated). However, according to Dr. Thornblade, “28.5% required a Whipple, and 18% underwent liver resection with biliary reconstruction.” Negative margins were achieved in 75%.
“The majority of patients received some chemotherapy,” mostly gemcitabine or cisplatin, he added. Radiation therapy was administered to 38.4% of patients, and immunotherapy was given to 9.6%.
Almost one-third of patients, 36 of 114, underwent some type of tumor genetic sequence testing, and about one-third of these patients underwent whole-exome sequencing. Patients who had genetic sequence testing were on average about 6 years younger than those who did not undergo sequencing, emphasized Dr. Thornblade. “Otherwise, we found no other differences in clinical or treatment features between patients who underwent sequencing and those who did not,” he added.
Dr. Thornblade continued: “We didn’t observe any differences in the rates of mutations among the cancers sequenced via whole-exome methods vs the ones sequenced via hotspot technology. Rates of tumor genetic sequence testing were higher in the middle and later years of the decade, reflecting the increasing availability and familiarity of this testing.”
Three Alterations Stood Out
A mutation was identified in 89% of those tested in the study. Mutations aligned with a median of one drug per patient, but the number “was as high as 11 candidate drugs in one patient. An average of seven clinical trials were identified per patient,” Dr. Thornblade reported.
“We found 41 unique gene alterations, and 3 clinically significant alterations stood out. They were BRAF V600E mutations, which occurred in 8%; FGFR alterations, in 8%; and IDH1/2 mutations, in 14%,” Dr. Thornblade reported. “I highlight these three mutations because of emerging evidence for targeted therapy,” he added.
“In the recent phase II ROAR trial, patients with BRAF V600E–mutated cholangiocarcinoma experienced a remarkable 51% response rate to BRAF and MEK inhibition,”2 Dr. Thornblade stated. Another phase II trial is “among several to highlight clear response of patients with FGFR mutations and fusions to targeted therapies for this growth factor.”3 In addition, “a recent trial showed a clear benefit in progression-free survival for patients receiving ivosidenib, which blocks IDH.”4
Nearly 25% Received Targeted Agent
About 23% of the study patients eligible for a targeted therapy received one. “Median follow-up for our cohort was 22 months, and median overall survival was estimated at 59 months,” Dr. Thornblade commented. “In this small sample, we did not perceive any differential survival advantage for those treated with targeted therapies.”
“Moving forward, I think it will become standard of care for some assay to be part of the workup for these cancers,” Dr. Thornblade predicted. He acknowledged that cost may be a barrier, noting “these tests run $5,000 or $6,000 on the open market.”
DISCLOSURE: Dr. Thornblade reported no conflicts of interest.
1. Thornblade LW: Patterns of whole genome sequencing and actionable mutations in resected cholangiocarcinoma. SSO 2021 International Conference on Surgical Care. Abstract 37. Presented March 18, 2021.
2. Subbiah V, Lassen U, Élez E, et al: Dabrafenib plus trametinib in patients with BRAF V600E-mutated biliary tract cancer: A phase 2, open-label, single-arm, multicentre basket trial. Lancet Oncol 21:1234-1243, 2020.
3. Javle M, Lowery M, Shroff RT, et al: Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J Clin Oncol 36:276-282, 2018.
4. Abou-Alfa GK, Macarulla T, Javle MM, et al: Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): A multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 21:796-807, 2020.