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

Abstract

The tumor genome of a patient with advanced pancreatic cancer was sequenced to identify potential therapeutic targetable mutations after standard of care failed to produce any significant overall response. Matched tumor-normal whole-genome sequencing revealed somatic mutations in BRAF, TP53, CDKN2A, and a focal deletion of SMAD4. The BRAF variant was an in-frame deletion mutation (ΔN486_P490), which had been previously demonstrated to be a kinase-activating alteration in the BRAF kinase domain. Working with the Novartis patient assistance program allowed us to treat the patient with the BRAF inhibitor, dabrafenib. The patient's overall clinical condition improved dramatically with dabrafenib. Levels of serum tumor marker dropped immediately after treatment, and a subsequent CT scan revealed a significant decrease in the size of both primary and metastatic lesions. The dabrafenib-induced remission lasted for 6 mo. Preclinical studies published concurrently with the patient's treatment showed that the BRAF in-frame mutation (ΔNVTAP) induces oncogenic activation by a mechanism distinct from that induced by V600E, and that this difference dictates the responsiveness to different BRAF inhibitors. This study describes a dramatic instance of how high-level genomic technology and analysis was necessary and sufficient to identify a clinically logical treatment option that was then utilized and shown to be of clinical value for this individual.

Metastatic Pancreatic Cancer with BRAF and P53 Mutations: Case Report of Therapeutic Response to Doublet Targeted Therapy

“…In another case report, a patient was found to have BRAF, P53, and CDKN2A mutations, and a SMAD4 deletion found on deep sequencing. The patient received single-agent dabrafenib with a good response but relapsed in 4 months and did not respond to the addition of trametinib [13].…”

Personalizing Medicine With Germline and Somatic Sequencing in Advanced Pancreatic Cancer: Current Treatments and Novel Opportunities

“…A case report of a patient with BRAF ΔNVTAPmutated pancreatic cancer described a partial response and clinical improvement with dabrafenib therapy. 87 Clinical trials are enrolling patients with both atypical non-V600E mutations and other aberrations (including activating deletions) in BRAF, including trials of the ERK inhibitor ulixertinib (NCT04488003 and NCT02465060).…”

Retrospective Case Series Analysis of RAF Family Alterations in Pancreatic Cancer: Real-World Outcomes From Targeted and Standard Therapies

“…Importantly, BRAF ΔNVTAP does not confer sensitivity to the BRAF inhibitor vemurafenib despite an increase in RAS -independent dimerization-dependent kinase activity for cells with this in-frame deletion. 13 , 51 However, there are clinical case reports of significant activity with dabrafenib in patients with BRAF ΔNVTAP deletions, 52 which aligns with the observation that dabrafenib fits better than vemurafenib inside the BRAF pocket at the conformational binding-level. Interestingly, there is an important structural paralogy between BRAF and EGFR where BRAF V600E mutations in Exon 15 and BRAF ΔNVTAP deletions in Exon 11 conceptually mirror EGFR L858R mutations in Exon 21 and various EGFR deletions in Exon 19, which have represented the core actionable subset of activating EGFR variants in non–small-cell lung cancer.…”