BRAF Variants and Therapeutic Direction in Intrahepatic Cholangiocarcinoma

By: Celeste L. Dixon
Posted: Friday, March 17, 2023

BRAF variant subtypes are likely to affect responses to targeted therapy—BRAF inhibitors and MEK inhibitors—in patients with intrahepatic cholangiocarcinoma, according to cohort study results involving 1,175 individuals who underwent curative resection between 2009 and 2017. The subtypes also seem to influence disease characteristics and prognosis. The findings, using the largest known cohort of patients with intrahepatic cholangiocarcinoma ever analyzed, suggest that identifying and classifying BRAF variants may help to guide treatment decision-making, Shao-Lai Zhou, MD, PhD, of Fudan University, Shanghai, and colleagues in JAMA Network Open.

Of the 1,175 patients, 49 had 20 different subtypes of BRAF somatic variance: 13 with BRAF V600E variants and 36 with non–BRAF V600E variants. The team selected eight drugs either approved for clinical use or in current clinical trials; then they “assessed their association with the viability of six patient-derived organoid lines harboring wild-type BRAF or endogenous BRAF variants: ICC-1 (wild-type), ICC-2 (V600E), ICC-3 (K601E), ICC-4 (D594G), ICC-5 (N581S), and ICC-6 (L597P).”

Pharmacologic screens in the ICC-1 organoids revealed a slight sensitivity to lenvatinib but resistance to the other seven drugs, the investigators continued. “The ICC-2 organoids were sensitive to BRAF inhibition (dabrafenib, vemurafenib) as well as MEK inhibition (trametinib). The ICC-3, ICC-4, and ICC-5 organoids were not sensitive to BRAF inhibition; however, they all showed sensitivity to MEK inhibition, especially by trametinib in the ICC-4 and ICC-5 organoids, which both harbored class 3 BRAF variants,” they wrote. ICC-6 organoids exhibited broad resistance to most drugs, with only slight sensitivity to trametinib and cobimetinib.

BRAF V600E variants, but not overall BRAF variants or non–BRAF V600E variants, were associated with worse overall survival (P =  .03) and increased risk of recurrence (lower disease-free survival; P = .04). Additionally, compared with patients with non–BRAF V600E variants, patients with BRAF V600E variants were more likely to have large tumor size (P = .007), multiple tumors (P = .04), and more vascular/bile duct invasion (P = .04).

Disclosure: The study authors reported no conflicts of interest.

JAMA Network Open

---