BRAF K601

The detection of BRAF fusions and their many partners was enabled by the Afirma XA exome-enriched RNASeq panel. Although BRAF fusions occurred in only 0.2% of thyroid nodules, they were GSC-Suspicious and lacked typical BRAF/RAS mutations. Interestingly, expression signatures associated with malignancy varied by fusion partner.

Since 2016, patients with BRAFK601E-positive nodules receive less aggressive treatment. The risk of recurrence of BRAFK601E-positive tumors without other, high-risk features appears to be low, and lobectomy without radioiodine is likely sufficient treatment for these patients.

K601E-mutated neoplasms could be a unique clinicopathological entity associated with low-risk histology and reduced extrathyroidal extension, consistent with a more indolent course than V600E mutants. Although detecting K601E may potentially guide conservative management, further prospective studies are needed.

P2, N=26, Active, not recruiting, University Health Network, Toronto | Trial completion date: Mar 2024 --> Dec 2024 | Trial primary completion date: Mar 2024 --> Dec 2024

Nine patients received targeted therapy; dabrafenib/trametinib (6), pembrolizumab (2), and entrectinib (1), mostly upon tumor progression (7). Outsourcing of NGS testing was feasible; however, criteria for case selection are needed. In addition, local capacity-building in conducting the test, interpretation of the results, and access to "new drugs" continue to be a challenge in LMICs.

The BRAF mutation may represent important genetic alteration in a subset of IDC-P, highlighting the role of MAPK signaling pathway in this subtype of PCa. To the best of knowledge, this is the first description of non-V600 BRAF mutation in setting of IDC-P, which may in part explain the aggressive phenotype seen in IDC-P and could also bring more treatment options for PCa patients with IDC-P harboring such mutations.

To overcome these challenges, we conjugated a STAT3-specific decoy to thalidomide, a ligand to cereblon in E3 ubiquitin ligase complex, to generate a proteolysis-targeting chimera (STAT3DPROTAC)...Finally, local C-STAT3DPROTAC administration to human Ly3 lymphoma-bearing mice triggered tumor regression, while control C-STAT3D and C-SCR treatments had limited effects. Our results underscore the feasibility of using a PROTAC strategy for cell-selective, decoy oligonucleotide-based STAT3 targeting of and potentially other tumorigenic transcription factors for cancer therapy.

Cobimetinib plus vemurafenib showed antitumor activity in patients with advanced solid tumors with BRAF V600E mutations; additional study is warranted to confirm the antitumor activity in tumors with non-V600E BRAF mutations.

Genetic mutations were not significantly associated with clinical outcomes. However, NRAS mutations may be a prognostic predictor and CTNNB1 mutation may be a treatment effector for immune check inhibitors. A larger prospective study is required to clarify the clinical importance of genetic mutations in patients with SNMM.

Eight patients received targeted therapy; Dabrafenib/Trametinib (5), Pembrolizumab (2), Entrectinib (1), while radio-chemotherapy was used in the others. Sent abroad NGS testing was feasible, however local capacity building is necessary. In this highly selected tumor cohort, high percentage of targetable alterations were identified. NGS was helpful to characterize tumors more and to offer alternative therapies.

P2, N=26, Active, not recruiting, University Health Network, Toronto | Trial completion date: Dec 2023 --> Mar 2024 | Trial primary completion date: Dec 2023 --> Mar 2024 | Recruiting --> Active, not recruiting

Patients with NSCLCs with BRAF non-V600E, especially class III, were associated with poorer therapeutic outcomes than those with V600E. Furthermore, patients with NSCLC with class IIa had distinct clinicogenomic features, and further preclinical and clinical studies are needed to evaluate class IIa mutations as a therapeutic target.