BRAF V600

Preoperative BRAF V600E testing provides excellent detection for classical PTC (sensitivity 90.2%, specificity 100%) but exhibits limited sensitivity for FVPTC (40%). Based on the 3rd edition TBSRTC and 5th edition WHO classification, our risk-stratified algorithm could reduce unnecessary surgeries by 25-30% in indeterminate nodules while maintaining perfect specificity for classical PTC, achieving optimal clinical decision-making.

P1/2, N=50, Recruiting, St. Justine's Hospital | Not yet recruiting --> Recruiting

Using high-throughput screening, we established that combining p38 inhibitors with the BRAF inhibitor dabrafenib showed strong synergy in vitro, including in cells resistant to dabrafenib and trametinib that had acquired a secondary TP53 mutation. Overall, our findings suggest an oncogenic link between the MAPK and p38/MAPK14 pathways and that combining p38 pathway inhibitors with dabrafenib-targeted therapy could improve treatment outcomes for aggressive thyroid cancers. However, more specific and effective p38 inhibitors are required to fully harness this potential.

BRAF-mut PTC is associated with a pro-inflammatory TME milieu compared to BRAF-wt PTC. However, in this limited data set, treatment choice was not associated with differences in OS in BRAF-mut PTC.

As CFT1946 progresses through clinical development, the field of oncoprotein-specific degradation will mature. See related article by Kreger et al., p. 438.

Multigene testing is underutilized in this population. While many targeted therapies carry a high risk of pneumonitis, sotorasib appeared relatively safe. Despite the risks, identifying and treating actionable oncogenic drivers may improve survival.

The greatest benefits of encorafenib plus binimetinib were observed in patients with evidence of high TMB and/or tumor immune infiltration, suggesting potential immune contributions to efficacy, which were not observed with vemurafenib. BRAF V600 detectability in ctDNA appears to have utility as a marker of prognosis and response in this population.

P1/2, N=75, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2025 --> Dec 2027 | Trial primary completion date: Dec 2025 --> Dec 2027

The data are in line with current literature that targeted treatment is being applied for selected LC patients in CZ. It can be expected that LC patients benefit from therapeutic and other clinical improvements, which however do not reduce the primary importance of anti-smoking campaigns.

However, SOX2 is uniquely upregulated in progenitor-derived tumours and is expressed in 20% of human cSCC, indicating it might mark tumours arising from committed progenitors. Here, we show that SOX2 overexpression, along with MAPK activation, in progenitors induces a stem-like state and renders this otherwise resistant population permissive to rapid transformation.

P2, N=1, Active, not recruiting, Genmab | N=90 --> 1

To our knowledge, this is the first report of dual TERTp mutations detected in the preoperative setting in thyroid carcinoma. Clinical correlation with future cases will be of interest, particularly if cases with monoallelic dual TERTp mutations are discovered.