Successful BRAF/MEK inhibition in a patient with BRAF^V600E-mutated extrapancreatic acinar cell carcinoma

Abstract

Pancreatic acinar cell carcinoma (PAC) is a rare disease with a poor prognosis. Treatment options for metastatic PAC are limited and often follow chemotherapeutic regimens for pancreatic ductal adenocarcinoma. Although recurrent genomic alterations, such as BRAF fusions and defects in genes involved in homologous recombination DNA repair, have been described in PAC, data on the clinical efficacy of molecularly guided, targeted treatment are scarce. Here we describe the case of a 27-yr-old patient with BRAF V600E-mutated PAC who was successfully treated with a combination of BRAF and MEK inhibitors. The patient presented to our clinic with abdominal pain and weight loss. Imaging showed extensive retroperitoneal disease as well as mediastinal lymphadenopathy. Because of elevated α-fetoprotein (AFP) levels and inconclusive histologic findings, a germ cell tumor was suspected; however, PEI chemotherapy was unsuccessful. A repeat biopsy yielded the diagnosis of PAC and treatment with FOLFIRINOX was initiated. Comprehensive molecular profiling within the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) precision oncology program revealed a somatic BRAF V600E mutation and a germline PALB2 stop-gain mutation. Therapy was therefore switched to BRAF/MEK inhibition, resulting in almost complete remission and disease control for 12 mo and a remarkable improvement in the patient's general condition. These results indicate that BRAF alterations are a valid therapeutic target in PAC that should be routinely assessed in this patient population.

Vemurafenib Combined With Trametinib Significantly Benefits the Survival of a Patient With Stage IV Pancreatic Ductal Adenocarcinoma With BRAF V600E Mutation: A Case Report

“…In view of the fact that the patient has received combined targeted therapy and other treatments, it is difficult to attribute the benefit of the patient entirely to targeted therapy. A recent case also showed a positive response to combined targeted therapy in patients with pancreatic acinar cell carcinoma with BRAF V600E mutations, who achieved almost complete remission for 12 months (32). Considering that acinar cell carcinoma of the pancreas is a rare pancreatic exocrine tumor with more favorable prognosis than PDAC (33), the significance of combined targeted therapy for this tumor is less exciting than PDAC.…”

AGAP3: A novel BRAF fusion partner in pediatric pancreatic‐type acinar cell carcinoma

“…Whether the BRAF ‐fusion gene partner has an impact on sensitivity or resistance to those targeted drugs is not known yet 24 . The use of BRAF and/or MEK inhibitors has been reported in two patients with metastatic BRAF V600E‐mutated PACC, showing at least a transient complete response 14,25 . Moreover, pre‐clinical studies demonstrated sensitivity to MEK inhibitors in SND1::BRAF ‐transformed cells 7 …”

“…24 The use of BRAF and/or MEK inhibitors has been reported in two patients with metastatic BRAF V600E-mutated PACC, showing at least a transient complete response. 14,25 Moreover, pre-clinical studies demonstrated sensitivity to MEK inhibitors in SND1::BRAF-transformed cells. 7 Several methods are currently available to detect gene rearrangements or fusion genes.…”

Two rare cancers of the exocrine pancreas: to treat or not to treat like ductal adenocarcinoma?

“…Several groups of investigators have analyzed retrospective case series to identify the most beneficial regimens for advanced PACC patients [169,[177][178][179] . Overall, the objective response rate to FOLFIRINOX appears to be higher than for any other regimen, with 16 of 21 patients receiving this regimen in the first-line setting achieving objective responses [169,178,180,181] . All studies also agree that gemcitabine monotherapy has poor efficacy in PACC, with no responses reported in 10 patients described in 2 studies.…”