New Routes to Targeted Therapy of Intrahepatic Cholangiocarcinomas Revealed by Next-Generation Sequencing

TLDR

Intrahepatic cholangiocarcinoma is a primary liver cancer subtype that is rarely curable by surgery, its incidence is rising, and relapsed disease carries a poor prognosis with current systemic therapies largely extrapolated from other gastrointestinal malignancies. The study aimed to determine whether genomic profiling of clinical ICC samples could uncover alterations linked to targeted therapies and enable personalized treatment, so the authors performed high‑coverage DNA sequencing of 28 FFPE specimens covering 3,320 exons of 182 cancer‑related genes and 36 introns of 14 frequently rearranged genes. Sequencing revealed frequent alterations in ARID1A, IDH1/2, and TP53 (each 36%) and MCL1 amplification (21%) among the 28 ICC samples. Seventy‑one percent of cases harbored at least one potentially actionable alteration—including FGFR2, KRAS, PTEN, and others—and 14% displayed novel FGFR2 or N.

Abstract

Intrahepatic cholangiocarcinoma (ICC) is a subtype of primary liver cancer that is rarely curable by surgery and is rapidly increasing in incidence. Relapsed ICC has a poor prognosis, and current systemic nontargeted therapies are commonly extrapolated from those used in other gastrointestinal malignancies. We hypothesized that genomic profiling of clinical ICC samples would identify genomic alterations that are linked to targeted therapies and that could facilitate a personalized approach to therapy.DNA sequencing of hybridization-captured libraries was performed for 3,320 exons of 182 cancer-related genes and 36 introns of 14 genes frequently rearranged in cancer. Sample DNA was isolated from 40 μm of 28 formalin-fixed paraffin-embedded ICC specimens and sequenced to high coverage.The most commonly observed alterations were within ARID1A (36%), IDH1/2 (36%), and TP53 (36%) as well as amplification of MCL1 (21%). Twenty cases (71%) harbored at least one potentially actionable alteration, including FGFR2 (14%), KRAS (11%), PTEN (11%), CDKN2A (7%), CDK6 (7%), ERBB3 (7%), MET (7%), NRAS (7%), BRCA1 (4%), BRCA2 (4%), NF1 (4%), PIK3CA (4%), PTCH1 (4%), and TSC1 (4%). Four (14%) of the ICC cases featured novel gene fusions involving the tyrosine kinases FGFR2 and NTRK1 (FGFR2-KIAA1598, FGFR2-BICC1, FGFR2-TACC3, and RABGAP1L-NTRK1).Two thirds of patients in this study harbored genomic alterations that are associated with targeted therapies and that have the potential to personalize therapy selection for to individual patients.