BRAF V600

Targeted therapies against RAF kinases have achieved substantial success, especially in BRAF-V600E-mutant melanomas, where inhibitors like vemurafenib and dabrafenib have demonstrated remarkable efficacy, leading to improved patient outcomes. This review discusses the clinical advancements in RAF-targeted therapies, with a focus on ongoing efforts to overcome therapeutic resistance and enhance outcomes for cancer patients. It also underscores the persistent challenges in effectively targeting RAF kinase in oncology.

As a result, PROTAV and ICB combination enhances melanoma complete regression rates and eradicated 100% large Braf V600E melanoma without recurrence in syngeneic mice. PROTAVs hold the potential for robust tumor combination immunotherapy.

In summary, our research showed that PDE4D drives rewiring of the MAPK pathway in BRAF-mutated melanoma resistant to MAPK inhibitors and suggests that PDE4 inhibition is a novel therapeutic option for treatment of BRAF-mutated melanoma patients.

Preoperative FDG-PET non-invasively identifies lesions with residual high-risk pathologies following neoadjuvant BRAF-directed targeted therapy and immunotherapy for BRAF-mutated ATC. FDG-PET avidity may serve as an early prognostic marker which correlates with residual high-risk pathology in BRAF-mutated ATC following neoadjuvant therapy.

This study provides data on the molecular epidemiology of lung adenocarcinoma in Brazil, confirming high prevalence of EGFR mutations, ALK fusions, and MET exon 14 skipping alteration. Biomarker detection is largely affected by biospecimen collection and processing, with one third of the patients eligible for non-NGS testing only, which presents reduced coverage and sensitivity for actionable drivers.

Although the morphological findings and the presence of fusion indicated that the tumor was a cerebellar AG, the DNA methylome profile did not match that of AG. An accumulation of more cases is needed to determine the precise nature of the tumor, which may lead to an expansion of the tumor concept.

The LR model developed using the backward stepwise regression, outperformed ML models in predicting malignancy in AUS thyroid nodules. The corresponding nomogram based on this model provides a valuable and practical tool for personalized risk assessment, potentially reducing unnecessary surgeries and enhancing clinical decision-making.

P2, N=59, Active, not recruiting, Mayo Clinic | Recruiting --> Active, not recruiting | N=30 --> 59

This study highlights distinct genetic abnormalities and actionable alterations in Japanese melanoma patients. This suggests a lower tumor mutational burden in East Asian cutaneous melanoma, which may affect the efficacy of immune checkpoint inhibitors. The heterogeneity of driver mutations across and within individuals highlights the need for personalized treatment approaches.

Furthermore, the performance of our new classifier showed a strong correlation with the expert-curated classifier (Spearman rho = 0.726, p = 5.28 e-08), and correlated with the molecular expression-based classifier, BRS (BRAF-RAS scores) (Spearman rho = 0.418, p = 1.92e-13). Utilizing WSIs, we implemented an automated workflow with deep CNN model that accurately classifies driver mutations in PTCs.

Over 80% of patients remained relapse- and metastasis-free at 12 months after 2L dab/tram initiation, with only 2 deaths observed. Dab/tram appears to have activity in the 2L adjuvant setting, although more follow-up is required.

P1, N=325, Active, not recruiting, Exelixis | Trial completion date: Nov 2024 --> May 2027 | Trial primary completion date: Nov 2024 --> Aug 2026

Previously reported associations of dMMR were observed. The higher-than-expected proportion of patients with dMMR is likely driven by the inclusion of older patients in this real-world study. Many patients were able to access immunotherapy prior to PBS listing, potentially through trials or access programs. Early uptake of pembrolizumab following PBS listing has been high, and this effective and well-tolerated option has increased the proportion of elderly patients receiving active therapy.

Ultrasound indicators, C-TIRADS score combined with BRAF gene status, Tg and clinical indicators of patients have important value in predicting cervical CLNM and LLNM in PTC. The Nomogram prediction models constructed based on the above indicators can effectively predict the risk of LNM in PTC.

This study shows that the incorporation of molecular testing can considerably improve brain tumor diagnoses in Nigeria. Furthermore, this study highlights the diagnostic challenges in resource-limited settings and what is at stake in the global disparities of brain tumor diagnosis.

Skin metastasis of PTC should be suspected in patients who develop an upper body skin lesion with a history of PTC, even without evidence of disease metastasis. For high-risk patients with skin metastasis of PTC with BRAF and TERT gene mutations, long-term surveillance for recurrence should be recommended in cases with a poor prognosis, and further research of these cases should be conducted in the future to optimize surgical and medical care.

Importantly, inhibition of the lysine demethylase LSD1 with a clinically relevant inhibitor attenuated targeted therapy-induced EEC enrichment through blocking the interaction of LSD1, CoREST2 and STAT3. Our findings that BRAF plus EGFR inhibition induces lineage plasticity in BRAF V600E CRC represents a new paradigm for how resistance to BRAF plus EGFR inhibition occurs and our finding that LSD1 inhibition blocks lineage plasticity has the potential to improve responses to BRAF plus EGFR inhibitor therapy in patients.

By using the novel PDX platform, the results presented in this study demonstrate that the treatments with Palbociclib or Dabrafenib/Trametinib significantly reduced tumor size. In conclusion, PDX models offer a deeper understanding of eGBM at the genomic level and facilitate the identification of potential therapeutic targets. Further translational studies of this novel PDX model hold promise for advancing the diagnosis and treatment of this specific subtype of glioblastoma.

Patients diagnosed with PTC harboring RET fusion presented with distinctive clinical characteristics and sonographic patterns, underscoring the unique diagnostic value of ultrasound examination. It can provide a preoperative non-invasive primary screening method for RET-fusion diagnosis, thus facilitating targeted patients with purposeful molecular sequencing to improve treatment outcomes.

We also discuss the challenges and opportunities originating from recent clinical trials evaluating targeted treatments and our own institutional experience at UCLH that have aimed to address some of these biological complexities and have translated into improved patient outcomes via effective molecularly driven patient selection strategies. We also provide perspectives on emerging novel, next generation targeted inhibitors overcoming treatment resistance to previous targeted agents with demonstrated clinical value in a challenging patient population.

In summary, the majority of the targeted NIFTPs had "suspicious" Afirma testing results (85 %), TIRADS 4 scores (60 %) and either AUS/FLUS (53.7 %) or FN (31.5 %) FNA results. The sensitivity and specificity of cytology for diagnosing NIFTP were 90 % and 57 %, respectively, with a positive predictive value (PPV) of 16 % and negative predictive value of 98 %.

NGS technology can comprehensively analyze the genetic mutations in PTC patients, which provides important prompts for the occurrence, development, diagnosis and treatment of PTC. In addition, BRAF V600E mutation, RET fusion and TERT mutation are associated with a number of high-risk clinicopathological features. Detection of genetic mutations in PTC patients by NGS is of great significance.

P2, N=24, Active, not recruiting, Providence Health & Services | Trial completion date: Oct 2026 --> Oct 2027 | Trial primary completion date: Oct 2024 --> Oct 2025

Successful downstream delivery of clinical services, however, requires appropriate subsequent management, in a resource-limited environment. Our institutional experience demonstrates the feasibility, efficiency, and effectiveness of an ANP-led mainstreaming model of care for hereditary colorectal cancer.

CNN-based classifiers achieved an AUROC of 86.1, 95% CI (85.0, 87.3), while the tumour-location-guided CNNs outperformed the other classifiers with an average AUROC of 88.64, 95% CI (87.6, 89.7), which was statistically significant (P-value .0018). Incorporating tumour location probability maps into CNN models led to significant improvements for molecular subtype identification of pLGG.

Squamous cells in thyroid FNAs carry a broad differential diagnosis with variable prognoses. It is crucial to interpret squamous cells in the context of clinical and radiographic findings for optimal patient care.

Blood-based LB performed by NGS is a non-invasive viable alternative tool for molecular genotyping and identifiy tumor-derived somatic alterations to increase the number of pts elegible to target therapy and guide personalized medicine.

Our study provides an example of implementation of molecular profiling in an academic pre-screening program. Further analysis will investigate treatment matching rates, drug access schemes, and their impact on treatment efficacy and survival.

TRIPLETE is a phase III trial where 435 pts with RAS/BRAF wt – per local assessment – mCRC were randomized to receive first-line FOLFOX/ panitumumab (pan) or mFOLFOXIRI/pan... In contrast to previous data, negative hyperselection both through tissue and plasma analysis failed to demonstrate a prognostic role among pMMR RAS/BRAF wt mCRC pts treated with first-line chemotherapy plus pan. The confounding effect of the associated chemotherapy is a potential explanation for this finding. Tissue and plasma analyses at baseline failed to provide fully concordant results.

The LIBImAb Study is a phase III, randomized, openlabel, comparative, multi-center trial to assess the superiority in terms of efficacy of bevacizumab versus cetuximab in combination with FOLFIRI in mCRC pts, RAS/BRAFwt on tumor tissue and RAS/BRAF mutant (RAS/BRAFmut) at liquid biopsy... These data indicate the feasibility of cfDNA-based prospective enrolment in an interventional trial using a test with a rapid TAT for screening of RAS/ BRAF status in plasma. Our preliminary findings also suggest that ctDNA testing might better recapitulate the tumor heterogeneity of mCRC pts thus complementing tissue genomic profiling.

Materials and The phase II CAPRI 2-GOIM trial investigates the efficacy and safety of biomarkerdriven, cetuximab-based, sequence of three treatment lines in mCRC... Baseline plasma-based comprehensive genomic profiling is feasible with high concordance with tissue-based analysis. Liquid biopsy allows identification of misdiagnosed RAS/BRAF alterations and the ultra-selection of pts, which could benefit from anti-EGFR therapies. Finally, potentially actionable gene alterations were found in half of the pts.

Higher AF was associated with gross ETE and increased recurrence risk. This may inform initial management in patients with PTC harboring an isolated BRAF V600E mutation.

The overall prognosis of BRAF V600E mutant mCRC patients is poor. Poor differentiation and liver metastases were negative independent prognostic factors for OS. First-line triplet-drug therapy was associated with better OS, especially in patients with good physical condition and high tumor burden.

A detail estimation of KRASG12D mut mCRC patients' characteristics and expected outcomes may be useful when planning future studies in this subgroup. The high prevalence of PI3K/PTEN/Akt pathway activating alterations may affect the efficacy of targeted strategies.

Despite the rarity of NTRK fusions in pancreatic cancer, larotrectinib and entrectinib have exhibited effectiveness in NTRK fusion-positive pancreatic cancers. Additionally, repotrectinib, a next-generation NTRK inhibitor, has shown promising activity in NTRK positive pancreatic cancer patients who have developed acquired resistance to previous NTRK inhibitors. Immune checkpoint inhibitors, such as pembrolizumab and dostarlimab, have proven to be effective in dMMR/MSI-H pancreatic cancers...It is crucial to continue implementing comprehensive screening strategies that encompass the ability to detect all these tumor-agnostic biomarkers. This will be essential in identifying pancreatic cancer patients who may benefit from these therapies.

A BRAF V600E mutation detected was deemed pathogenic following discussion at a molecular tumour board, and recommendation of further investigations led to the diagnosis of an occult haematological malignancy. We report the importance of molecular tumour board discussion and recommendations in the identification of incidental, pathogenic findings on circulating tumour DNA.

P4, N=110, Active, not recruiting, Rennes University Hospital | Trial primary completion date: Sep 2024 --> Jun 2025

P1/2, N=75, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

IF-PTC from the isthmus is molecularly different compared with IF-PTC from the lobes. More data are needed to know if a change in surgical therapy is warranted in isthmic thyroid cancers relative to lobar cancers and if this molecular data should influence isthmic thyroid cancer management and monitoring.

Interestingly, C2 was less effective in suppressing A375 and B16-F10 cell lines (LD50 C2 < LD50 Dabrafenib/control), with its LD50 value nearly matching that of the Trametinib control in B16-F10 cell lines. Consequently, GSCRE, especially C2 or Caulersin, shows promise as a new molecule for developing functional foods to combat aging and human melanoma. However, further in vivo studies and clinical trials are necessary to confirm these findings.

Dabrafenib plus trametinib, as the first tumor-agnostic therapy, has been approved by the US Food and Drug Administration for the treatment of adult and pediatric patients aged 6 years and older harboring a BRAF V600E mutation with unresectable or metastatic solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. Therefore, we have established a universal and systematic strategy for diagnosing and treating solid tumors with BRAF mutations. In this expert consensus, we (1) summarize the epidemiology and clinical characteristics of BRAF mutations in different solid tumors, (2) provide recommendations for the selection of genetic testing methods and platforms, and (3) establish a universal strategy for the diagnosis and treatment of patients with solid tumors harboring BRAF mutations.

Early-stage CRC patients can have distinct genomic profiles and CGP in this population can help expand access to targeted therapies.