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Genetics-guided therapy in neuroendocrine carcinoma: response to BRAF- and MEK-inhibitors
Lovisa Falkman1, Anders Sundin2, Britt Skogseid1
1Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Background:
Metastatic neuroendocrine carcinoma (NEC) is associated with short survival. Other than platinum-based chemotherapy, there is no clear standard regimen. Current guidelines suggest that combination treatment with BRAF-inhibitors should be considered for patients with BRAF V600E-mutated NEC. However, since only eight such patients have been reported in the literature, our object was to confirm the validity of this recommendation.
Methods:
This was a single-center retrospective cohort study conducted at Uppsala University Hospital. The included patients 1) had a histopathologically confirmed diagnosis of NEC, 2) were diagnosed between January 1st, 2018 and December 31st, 2023, 3) had tumor tissue genetically screened by a broad next-generation sequencing (NGS) panel, and 4) showed a tumor mutation for which there is a currently available targeted therapy.
Results:
We screened 48 patients diagnosed with NEC between January 1st, 2018 and December 31st, 2023. Twelve had been analyzed with a broad NGS-panel, and two had a targetable mutation. Both these patients harbored a BRAF V600E-mutated colon-NEC and were treated with BRAF- and MEK-inhibitors dabrafenib and trametinib in second-line. At first radiological evaluation (RECIST 1.1), both patients had a reduction of tumor size, which decreased by 31 and 40%. Both had short response periods, and their overall survival was 12 and 9 months.
Conclusions:
BRAF-mutated NEC is sensitive to treatment with BRAF- and MEK-inhibitor combination. These results further support that DNA sequencing should be considered as standard of care in NECs to screen for potential treatment targets.
Insights
BRAF V600E-mutated neuroendocrine carcinoma (NEC) shows sensitivity to BRAF and MEK inhibitors. This supports using DNA sequencing to identify treatment targets in NEC patients.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Metastatic neuroendocrine carcinoma (NEC) has a poor prognosis with limited standard treatment options beyond platinum-based chemotherapy.
- Current guidelines recommend considering BRAF-inhibitor combinations for NEC with BRAF V600E mutations, but evidence is scarce.
- Limited case reports necessitate further investigation into the efficacy of targeted therapies for BRAF-mutated NEC.
Purpose of the Study:
- To evaluate the effectiveness of BRAF-inhibitor combination therapy in patients with BRAF V600E-mutated metastatic neuroendocrine carcinoma.
- To confirm the clinical validity of current guidelines recommending targeted therapy for this specific NEC subtype.
- To assess the response and survival outcomes in a small cohort of patients with BRAF-mutated NEC treated with BRAF and MEK inhibitors.
Main Methods:
- A single-center retrospective cohort study was conducted at Uppsala University Hospital.
- Patients with histopathologically confirmed NEC diagnosed between 2018 and 2023 were included.
- Tumor tissue underwent broad next-generation sequencing (NGS) to identify targetable mutations.
Main Results:
- Two out of 48 NEC patients analyzed had a targetable mutation, both harboring BRAF V600E in colon-NEC.
- Both patients received second-line treatment with dabrafenib and trametinib, showing tumor size reductions of 31% and 40%.
- Response durations were short, with overall survival of 12 and 9 months, respectively.
Conclusions:
- BRAF V600E-mutated NEC demonstrates sensitivity to combination therapy with BRAF and MEK inhibitors.
- These findings support the routine use of DNA sequencing in NEC diagnostics to identify actionable targets.
- Targeted therapy may offer a treatment avenue for select patients with BRAF-mutated NEC.
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