Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Clin Cancer Res. 2023 Dec 1;29(23):4853-4862. doi: 10.1158/1078-0432.CCR-23-1926.
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.
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 II+III BRAF mutants and 1,042 WT).
In the entire BTC clinical cohort, the median PFS was shorter for class I [HR, 2.11 (P < 0.001)] and class II+III [HR, 1.72 (P = 0.007)] as compared with BRAF WT. OS was also shorter in class I [HR, 2.04 (P = 0.011)] and class II+III [HR, 1.86 (P = 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 II+III mutations appear to be mutually exclusive with FGFR2 and KRAS.
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.
BRAF 突变在胆管癌（BTC）中较为罕见，但鉴于 BTC 靶向治疗的最新进展，此类突变具有重要意义。我们调查了接受一线化疗治疗的 BRAF 突变型晚期 BTC 患者的临床结局。此外，我们还研究了 BTC 中肝内胆管癌（iCCA）亚组中 BRAF Ⅰ型、Ⅱ型和Ⅲ型突变的基因组图谱。
我们分析了两个不重叠的队列。我们在“基因组队列”中检查了 BRAF 突变型 iCCA 的基因组图谱[187 个 I 型、82 个 II 型、113 个 III 型 BRAF 突变体和 8026 个野生型（WT）]。我们还在另一个多机构的 BTC 患者的“临床队列”中分析了一线化疗中位无进展生存期（PFS）和总生存期（OS），该队列包括 iCCA、肝外胆管癌（eCCA）和胆囊癌；41 个 I 型、32 个 II+III BRAF 突变体和 1042 个 WT）。
在整个 BTC 临床队列中，I 型和 II+III 型 BRAF 突变的中位 PFS 更短[I 型 HR，2.11（P < 0.001）和 II+III 型 HR，1.72（P = 0.007）]。与 BRAF WT 相比，I 型和 II+III 型 BRAF 的 OS 也更短[I 型 HR，2.04（P = 0.011）和 II+III 型 HR，1.86（P = 0.002）]。在 iCCA 亚组中，I 型改变与 FGFR2、IDH1/2、ERBB2 和 KRAS 突变互斥。II+III 型突变似乎与 FGFR2 和 KRAS 互斥。
在 BTC 中，所有类型的 BRAF 突变均与预后较差相关。BRAF 突变发生在 5%的 iCCA 亚组中，可能与其他可靶向突变互斥。
