TY - JOUR
T1 - Comparative Genomic Analysis and Clinical Outcomes of BRAF-mutated Advanced Biliary Tract Cancers
AU - Tang, Tin Yun
AU - Nichetti, Federico
AU - Kaplan, Ben
AU - Lonardi, Sara
AU - Pietrantonio, Filippo
AU - Salvatore, Lisa
AU - Vivaldi, Caterina
AU - Rimassa, Lorenza
AU - de Braud, Filippo
AU - Rizzato, Mario Domenico
AU - Pavlick, Dean
AU - Chu, Randy
AU - De Armas, Anaemy Danner
AU - Sharaf, Radwa
AU - Sokol, Ethan
AU - Ahnert, Jordi Rodon
AU - Ross, Jeffrey S.
AU - Javle, Milind
AU - Niger, Monica
N1 - Publisher Copyright:
©2023 American Association for Cancer Research.
PY - 2023
Y1 - 2023
N2 - Purpose: BRAF mutations are rare in biliary tract cancers (BTC), but are of interest given the recent developments in targeted therapy for BTC. We investigated the clinical outcomes in a cohort of BRAF-mutant advanced BTC treated with first-line chemotherapy. Furthermore, we investigated the genomic landscape of BRAF class I, II, and III mutations in the intrahepatic cholangiocarcinoma (iCCA) subgroup of BTC. Experimental Design: We analyzed two nonoverlapping cohorts. We examined the genomic landscape of BRAF-mutated iCCA in a “genomic cohort” [187 class I, 82 class II, 113 class III BRAF mutants and 8,026 wildtype (WT)]. We also analyzed median progression-free survival (PFS) and overall survival (OS) on first-line chemotherapy in a separate multi-institutional “clinical cohort” of patients with BTC (including iCCA and extrahepatic cholangiocarcinoma (eCCA) and gallbladder cancer; 41 class I, 32 class IIþIII BRAF mutants and 1,042 WT). Results: In the entire BTC clinical cohort, the median PFS was shorter for class I [HR, 2.11 (P < 0.001)] and class IIþIII [HR, 1.72 (P ¼ 0.007)] as compared with BRAF WT. OS was also shorter in class I [HR, 2.04 (P ¼ 0.011)] and class IIþIII [HR, 1.86 (P ¼ 0.002)] as compared with BRAF WT. In the iCCA subgroup, class I alterations were mutually exclusive with FGFR2, IDH1/2, ERBB2, and KRAS mutations. Class IIþIII mutations appear to be mutually exclusive with FGFR2 and KRAS. Conclusions: In BTC, all classes of BRAF mutations are associated with a worse prognosis. BRAF mutations occur in 5% of iCCA subgroup and may be mutually exclusive with other targetable mutations.
AB - Purpose: BRAF mutations are rare in biliary tract cancers (BTC), but are of interest given the recent developments in targeted therapy for BTC. We investigated the clinical outcomes in a cohort of BRAF-mutant advanced BTC treated with first-line chemotherapy. Furthermore, we investigated the genomic landscape of BRAF class I, II, and III mutations in the intrahepatic cholangiocarcinoma (iCCA) subgroup of BTC. Experimental Design: We analyzed two nonoverlapping cohorts. We examined the genomic landscape of BRAF-mutated iCCA in a “genomic cohort” [187 class I, 82 class II, 113 class III BRAF mutants and 8,026 wildtype (WT)]. We also analyzed median progression-free survival (PFS) and overall survival (OS) on first-line chemotherapy in a separate multi-institutional “clinical cohort” of patients with BTC (including iCCA and extrahepatic cholangiocarcinoma (eCCA) and gallbladder cancer; 41 class I, 32 class IIþIII BRAF mutants and 1,042 WT). Results: In the entire BTC clinical cohort, the median PFS was shorter for class I [HR, 2.11 (P < 0.001)] and class IIþIII [HR, 1.72 (P ¼ 0.007)] as compared with BRAF WT. OS was also shorter in class I [HR, 2.04 (P ¼ 0.011)] and class IIþIII [HR, 1.86 (P ¼ 0.002)] as compared with BRAF WT. In the iCCA subgroup, class I alterations were mutually exclusive with FGFR2, IDH1/2, ERBB2, and KRAS mutations. Class IIþIII mutations appear to be mutually exclusive with FGFR2 and KRAS. Conclusions: In BTC, all classes of BRAF mutations are associated with a worse prognosis. BRAF mutations occur in 5% of iCCA subgroup and may be mutually exclusive with other targetable mutations.
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U2 - 10.1158/1078-0432.CCR-23-1926
DO - 10.1158/1078-0432.CCR-23-1926
M3 - Article
C2 - 37773629
AN - SCOPUS:85178649620
SN - 1078-0432
VL - 29
SP - 4853
EP - 4862
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 23
ER -