RAS mutation

This exploratory analysis from a randomized phase II study shows a non-significant improvement in TTR from the addition of neoadjuvant panitumumab to peri-operative FOLFOX in RAS/BRAF-wt LACC. Hyperselection with EREG/AREG status was associated with increased efficacy. A dedicated prospective trial within a biomarker selected population is under development.

P1/2, N=27, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed

Mutation of DICER1 gene is a non-negligible molecular event and it may represent an aggressive subset of FDTCs. DICER1 has RAS-like clinical characteristics and DICER1-mutant tumors exhibit more aggressive clinical behaviors compared with those with BRAFV600E and RET fusions.

Our data suggested that FOLFIRI plus ramucirumab was effective and tolerable for CRC refractory to fluoropyrimidine and oxaliplatin without anti-angiogenesis. Serum VEGF-D levels may not be predictive but TSP-2 may be a potential prognostic biomarker for ramucirumab's efficacy.

BRAFV600E tend to display florid nuclear features, whereas the RAS- mutation is associated with subtle nuclear features. These findings emphasize the distinct cytological profiles of BL and RL PTC, reinforcing the need for precise subtyping to guide tailored management.

Notably, in the RAS-p110α complex structures, RAS interaction with p110α is limited to the RAS-binding domain and does not involve the kinase domain. This study underscores the pivotal role of the RAS-PI3Kα interaction in PI3Kα activation and provides a blueprint for designing PI3Kα isoform-specific inhibitors to disrupt this interaction.

A 1.2 Å crystal structure of the S89D mutant revealed substantial local conformational changes, as well as alterations propagating to the nucleotide-binding pocket, providing a structural basis for the observed biochemical properties. Collectively, these findings established that the S89D mutation activated Ras by enhancing intrinsic nucleotide exchange, offering new insights into Ras allostery.

despite s-CPM being associated with impaired OS after CRS-HIPEC, the onset of PM was not found to be an independent determinant for survival. High-risk molecular and histological features strongly influence oncological outcomes after CRS-HIPEC. This is valuable data that could aid in preoperative patient selection process for CRS-HIPEC.

Many differentially expressed genes are drawn from immune response and regulation pathways. These findings highlight the value of further investigations into the contributions of 22qDEL events to PTC, perhaps mediated through immune perturbations.

P2, N=23, Completed, Cardiff Oncology | Active, not recruiting --> Completed | Trial completion date: Apr 2026 --> Dec 2024 | Trial primary completion date: Nov 2025 --> Dec 2024

P2, N=78, Recruiting, Canadian Cancer Trials Group | Trial completion date: Jun 2025 --> May 2026 | Trial primary completion date: Dec 2024 --> Dec 2025

Early dynamics of ctDNA during first-line oxaliplatin-based chemotherapy hold prognostic value, supporting the idea of prospectively validating a ctDNA-RECIST framework in the early care pathway of mCRC patients.

The discovery in 2013 by Shokat and colleagues of a druggable pocket in KRAS paved the way to FDA approval of the first covalently binding KRASG12C inhibitors, sotorasib and adagrasib, in 2021 and 2022, respectively. However, rather than marking the end of a successful assault on the Mount Everest of cancer research, this landmark only revealed new challenges in RAS drug discovery. In this review, we highlight the progress on defining resistance mechanisms and developing combination treatment strategies to improve patient responses to KRAS therapies.

Our study demonstrates that pMLH1 hypermethylation, MMRd, BRAFmut and CIMP phenotype do not completely overlap in CRC. These findings further refine the knowledge on the molecular landscape of CRC and may have critical implications also for the clinical management of the disease.

Furthermore, mutation sites of TP53 were different between EMD versus non-EMD patients, with gain-of-function mutations enriched in patients with EMD. Our data highlights distinct molecular abnormalities in patients with EMD and provides potential mechanistic insights for novel therapeutic targets for the future.

For most people, FOLFOX + Bevacizumab may be the best second-line systemic treatment regimen for mCRC. For RAS-mutant populations, FOLFIRI + Bevacizumab + Panitumumab is recommended. However, the therapeutic effect may be affected by the patient's physiological state, and clinicians should apply it based on actual conditions.

While RAS mutations are prevalent in thyroid cancer, they do not significantly impact most clinical and pathological features. However, the presence of RAS mutations is associated with a significantly higher risk of distant metastasis and mortality, suggesting their potential role as a prognostic marker in thyroid cancer. These findings underscore the importance of RAS mutation testing in risk stratification and treatment planning for thyroid cancer patients.

P1, N=9, Terminated, Taipei Medical University Shuang Ho Hospital | Trial completion date: Dec 2024 --> Mar 2024 | Recruiting --> Terminated | Trial primary completion date: Dec 2024 --> Mar 2024; The overall profile does not support development for metastatic colorectal cancer

Oral administration of ADT-007 prodrug also inhibited tumor growth. Thus, ADT-007 has the potential to address the complex RAS mutational landscape of many human cancers and to improve treatment of RAS-driven tumors.

These data suggest EREG is a promising target for the development of ADCs for treating CRC and other cancer types that express high levels of EREG. While the efficacy of clinically approved anti-EGFR mAbs are largely limited by RAS mutational status, EREG ADCs may show promise for both RAS mutant and wildtype patients, thus improving existing treatment options.

During a limited 1.5-year follow-up period, neither a confirmed local recurrence nor a distant organ metastasis occurred in this case. We propose that BRAF fusion variations can occur in metastatic EOCC.

These proteins could serve as readily accessible markers in morphologically borderline cases showing RAS mutations. Additionally, our findings may provide insights into the distinct pathogenic pathways through which RAS-mut and RAS-wt NIFTPs arise, highlighting the pivotal role of constitutive RAS-mitogen-activated protein kinase (MAPK) pathway activation in the development and progression of RAS-mut tumors.

At the end, we briefly speculate on the potential strategies for targeting RAS mutated lung cancers, considering various approaches targeting DNA replication, DNA repair and the cGAS-STING pro-inflammatory pathway. These new lines of therapy, especially when used in combinations, may enhance treatment efficacy and overcome the challenges associated with these mutations.

Our data show that baseline serum levels of hepcidin are an independent risk factor for OS in MSS mCRC patients undergoing standard first-line treatment. Further prospective and extensive studies are needed to confirm and validate our findings.

The management of metastatic colorectal cancer in patients harboring RAS mutations primarily involves chemotherapy, often combined with bevacizumab, as a standard first-line treatment...Further research is needed to validate these mechanisms and understand the impact of the neo-RAS wt phenomenon on long-term outcomes, such as overall survival and progression-free survival. This review provides a comprehensive overview of the current understanding of the neo-RAS wt phenomenon, including its incidence, potential mechanisms, and clinical implications.

Triplet induction chemotherapy is a treatment of choice in selected patients with SMRC, allowing to adapt the therapeutic strategy to the response and invasiveness of the various sites.

RAS mutation was an independent predictor of LTP and OS after RFA for patients with CRLM. RAS-mutant tumors require wider safety margins.

Despite being in early stages, research on KRAS silent mutations holds promise for uncovering novel insights that could inform personalized cancer treatments. In conclusion, this review underscores the evolving landscape of KRAS silent mutations, advocating for further exploration to bridge fundamental biology with clinical applications in oncology.

Bethesda III-VI thyroid nodules with isolated RAS mutations have a low rate of aggressive histopathologic features and are unlikely to recur. Thyroid lobectomy may be sufficient treatment for these tumors.

While our study showed no significant difference in three-year RFS, adjuvant chemotherapy intensification with HAI-FUDR is feasible and may offer early benefits in RFS and long-term OS. Nonetheless, a larger sample size is needed for validation and identifying which patient subgroup might benefit from this regimen.

Our results highlight the prognostic significance of TMB in MSS metastatic colon cancer patients, suggesting its potential role in patient stratification and treatment decision-making.

The randomized FIRE-4.5 (AIO KRK0116) trial compared first-line therapy with FOLFOXIRI (folinic acid, fluorouracil, oxaliplatin, and irinotecan) plus either cetuximab or bevacizumab in B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E-mutant metastatic colorectal cancer (mCRC) patients. Those patients also achieved a significantly greater disease control rate (89% vs 20%; P = 0.008). In conclusion, LB evaluating ctDNA is informative and may help to guide treatment in patients with BRAF V600E-mutated mCRC.

Moreover, the role of PIK3CA mutations in vascular overgrowth syndromes is explored, alongside emerging targeted therapies, such as PI3K and MEK inhibitors, that promise improved outcomes for patients with these challenging conditions. The integration of histology, molecular diagnostics, and multidisciplinary care remains critical for the accurate diagnosis and optimal treatment of vascular anomalies in the era of precision medicine.

We aimed to compare FOLFIRI and bevacizumab with FOLFIRI and aflibercept in terms of overall survival (OS), progression-free survival (PFS) and safety in patients with RAS-mutant metastatic colon cancer who progressed after first-line FOLFOX or XELOX and bevacizumab treatment...As a result of our study, in patients with metastatic RAS-mutant colon cancer who progressed after first-line oxaliplatin-based doublet chemotherapy and bevacizumab, better OS and PFS results were obtained in patients receiving bevacizumab with FOLFIRI compared to patients receiving aflibercept with FOLFIRI. In addition, the side effect profile was more tolerable in the bevacizumab arm.

We report a new RIT1 M90I -mutant autochthonous lung tumor model The most common oncogenic variant of RIT1, RIT1 M90I , weakly promotes lung tumor development RIT1 M90I drives the formation of lethal lung tumors in cooperation with p53 and Nf2 tumor suppressor gene loss RIT1 M90I and YAP cooperatively regulate cJUN expression Therapeutic MEK and TEAD targeting suppresses RIT1 M90I -driven tumorigenesis.

While the efficacy of clinically approved anti-EGFR mAbs are largely limited by RAS mutational status, EREG ADCs may show promise for both RAS mutant and wildtype patients, thus improving existing treatment options. Significance: EREG-targeting antibody-drug conjugates demonstrate acceptable safety and robust therapeutic efficacy in RAS mutant and wildtype colorectal cancer, suggesting their potential as an alternative to EGFR-targeted therapy to benefit a broader patient population.

Findings indicate a general worse prognosis for patients with early-onset colorectal cancer compared to late-onset patients. Interestingly this seems to occur regardless of the molecular status. These observations might have a considerable impact on clinical practice and research.

Hits were identified using tandem mass spectrometry, and orthogonal validation showed effective inhibition of KRASG12D with IC50 values as low as 25 nM, and excellent selectivity over the wild type form. These findings have the potential to lead to new drugs that target mutant RAS-driven cancers, and provide proof-of-principle for the phosphoestamer chemical platform against PPIs in general - opening up new possibilities in neurodegenerative disease, viral infection, and many more conditions.

Nodules with RAS mutations (NRAS, KRAS, HRAS) and TP53 inactivating mutations were considered to be in the intermediate-risk group, while those with non-pathogenic mutations (negative and variants of uncertain significance) were placed in the low-risk group. When combined with cytopathology, NGS increases the sensitivity of diagnosing benign and malignant thyroid nodules, and the reference is useful for patient risk stratification.

Overall, more than half of the UCs had potentially druggable genetic alterations. The proposed NGS panel permits comprehensive and cost-efficient analysis of UC-specific molecular targets and may be considered in clinical routine.

Microfollicles were infrequently seen in nodules with oncocytic predominance; however, those that had microfollicles had high incidence of positive molecular findings. Oncocytic nuclear atypia was present in all the resected neoplastic cases. NRAS and KRAS mutations were the most common molecular abnormalities detected.

regorafenib is a multi-kinase inhibitor, and gastrointestinal perforation has been reported as a serious adverse event, although it is rare. We report a case of upper gastrointestinal perforation during regorafenib administration, with some discussion of the literature.