Molecular and clinical characterization of BRAF mutations in pancreatic ductal adenocarcinomas (PDACs).

Abstract

214 Background: The activation of the RAS/RAF/MEK/ERK pathway is critical for the proliferation, survival, and tumorigenesis of PDACs. Oncogenic mutations in KRAS (90%) or BRAF (3%) are recurrent genomic alterations, but their co-occurrence is not well described. We reviewed BRAF alterations and clinical outcomes in consecutive PDAC patients (pts). Methods: Perthera, Inc. deploys an IRB-approved registry that was utilized in partnership with PanCAN’s “Know Your Tumor” program. Perthera uses CAP/CLIA accredited multi-Omic profiling, including next generation DNA sequencing (NGS, Foundation Medicine) and proteomics/immunohistochemistry (Neogenomics Inc. and Caris Life Sciences, Inc.). We used a Fisher's exact test with multiple testing correction to compare frequencies of mutations and protein over-/under-expression between BRAF-mutated (n = 21) and BRAF wild type pts (n = 745). Results: Of 766 pancreatic cancer pts, 21 pts were identified with BRAF mutations. 18 pts were diagnosed with PDAC, 1 pancreatoblastoma, 1 pancreatic acinar cell carcinoma, and 1 mixed acinar neuroendocrine carcinoma. Amongst the 18 PDAC pts with BRAF mutations, nine variations were found: V600E (5/18), BRAF fusion (4/18), N486_P490del (3/18), T310I (1/18), K601N (1/18), G596R (1/18), exon 2-10 deletions & S467L (1/18), equivocal amplification of BRAF (1/18), and a BRAF inframe deletion (1/18). KRAS was mutated in 6% of BRAF mutated PDACs, compared to 94% in BRAF wild type PDACs (p < 0.001). Amongst KRAS wild type PDACs, 53% of CDKN2A mutated pts had BRAF mutations vs. only 15% of CDKN2A wild type cases (p < 0.05). Two BRAF mutated pts from the database were given BRAF inhibitors. A sustained response to the combination dabrafenib and trametinib was observed in a BRAF V600E mutated PDAC pt, while no response was seen in a pt with concurrent KRAS G12A & BRAF K601N mutations who received trametinib. Conclusions: BRAF mutations are significantly and inversely correlated with KRAS alterations. The most common BRAF alteration, V600E mutation, was found to be mutually exclusive with the KRAS mutation. Clinical trials targeting BRAF alterations in KRAS wild type pancreatic cancer appears warranted.

Identification of targetable BRAF ΔN486_P490 variant by whole-genome sequencing leading to dabrafenib-induced remission of a BRAF-mutant pancreatic adenocarcinoma

“…A second liver biopsy to better understand the potential mechanism of escape post–dabrafenib treatment was not possible because of the patient's deteriorating clinical condition. Somatic BRAF mutations occur in 3% of pancreatic cancers and are often inversely correlated with KRAS variants (Cancer Genome Atlas Research Network 2017; Guan et al 2018). The ΔNVTAP BRAF has been observed in <0.5% pancreatic cases (Guan et al 2018).…”

“…Somatic BRAF mutations occur in 3% of pancreatic cancers and are often inversely correlated with KRAS variants (Cancer Genome Atlas Research Network 2017; Guan et al 2018). The ΔNVTAP BRAF has been observed in <0.5% pancreatic cases (Guan et al 2018). Here, we show evidence of partial response and direct targetability of dabrafenib in a patient with an identified BRAF in-frame pathogenic deletion that had previously only been described in preclinical studies.…”

Systemic therapy in metastatic pancreatic adenocarcinoma: current practice and perspectives

“…These include the fusion in the neurotrophin receptor tyrosine kinase (NRTK) and ROS1 fusions, NRG1 fusions, ALK rearrangement and BRAF mutations, have been found to be more prevalent than in KRAS mutated PDAC. [86][87][88][89] Fusions in the NRTK gene family leads to a chimeric tropomyosin receptor kinase (TRK) fusion protein and is an oncogenic driver in various types of tumors. Larotrectinib, a TRK inhibitor, has shown efficacy in a phase I-II trial including 1 PDAC, with an ORR of 75%, 90 and is approved by the FDA for any tumor harboring an NTRK gene fusion.…”

Successful BRAF/MEK inhibition in a patient with BRAFV600E-mutated extrapancreatic acinar cell carcinoma

“…Schreck et al report on two patients with high-grade glioma who were successfully treated with BRAF/MEK inhibition (Schreck et al 2018). In BRAF V600E -mutated pancreatic cancer, within early basket trials, one patient with PDAC responded to vemurafenib (Hyman et al 2015) and another PDAC patient showed prolonged survival under dabrafenib/trametinib combination treatment (Guan et al 2018). In contrast to PDAC, to our knowledge, there have been no reports of BRAF-targeted treatments in PAC patients until today.…”