TP53 mutation

Based on preclinical studies showing synergism with simultaneous inhibition of the estrogen receptor (ER), CDK4/6 and PI3K pathways and based on window of opportunity studies showing that metformin suppresses PI3K/mTOR signaling in endometrial cancer (EC), we conduct a non-randomized phase 2 study of letrozole/abemaciclib/metformin in ER positive endometrioid EC (NCT03675893). There are no objective responses among TP53 mutated ECs and among NSMP (no specific molecular profile) tumors with RB1 or CCNE1 alterations; CTNNB1 mutations correlate with clinical benefit. Pharmacokinetic analyses demonstrate that administration of letrozole and abemaciclib with metformin result in a more than 3-fold increase in metformin exposure.

P2, N=160, Active, not recruiting, French Innovative Leukemia Organisation | Recruiting --> Active, not recruiting | Trial primary completion date: Jan 2026 --> Aug 2025

This novel combination of ATR inhibitor berzosertib with irinotecan did not lead to objective responses in patients with TP53-mutated, advanced gastroesophageal adenocarcinoma. The combination regimen was well tolerated without unexpected adverse events. This trial was registered with ClinicalTrials.gov (NCT03641313).

Patients ≥60 years with Ph-negative B-cell ALL and TP53 VAF ≥45% had poor outcomes, with 4-year event-free survival (EFS) and overall survival (OS) of 28%, driven primarily by increased relapse risk, even among patients treated with frontline inotuzumab ozogamicin (INO) and/or blinatumomab. TP53 persistence at remission occurred in 44% of tested patients and was associated with increased ALL relapse risk. These results demonstrate that TP53 VAF is prognostic in older patients with Ph-negative B-cell ALL; high VAF may increase relapse risk but is not independently associated with survival in younger patients.

It may be prudent to maintain increased vigilance for persistent vulvar lesions, particularly in HPV-negative and histologically ambiguous settings. Comprehensive assessment (including immunohistochemistry) may facilitate earlier detection and more accurate diagnosis, thereby potentially improving treatment outcomes.

Moreover, MutAnt prediction scores of deleteriousness improved somatic variant calling from RNA sequencing data compared to standard approaches. MutAnt's high performance in distinguishing neutral and protein-disrupting mutations highlights its potential clinical utility in variant classification.

The CSC-defective traits in DDB1-deficient CRC cells were rescued by p53 deficiency but not by its overexpression, indicating that the CUL4A-DDB1-mediated regulation of p53 stability may control cancer stem-like properties in CRC. In summary, our findings emphasize DDB1 as a key regulator of colorectal cancer stemness and p53 stability through its O-GlcNAcylation at Ser-764, which enhances the E3 ligase activity of the CUL4-DDB1 complex.

Likewise, a combination of selective inhibitors of KRAS (RMC-6236/daraxonrasib), EGFR family (afatinib), and STAT3 (SD36) induced the complete regression of orthotopic PDAC tumors with no evidence of tumor resistance for over 200 d posttreatment...Of importance, this combination therapy was well tolerated. In sum, these results should guide the development of new clinical trials that may benefit PDAC patients.

Aumolertinib plus anlotinib was effective and well-tolerated as first-line therapy in EGFR-mutant NSCLC patients with BMs. Trial Registration: ClinicalTrials.gov(identifier NCT04978753, registered July 20, 2021).

This study identified intratumoral microbial signatures as independent prognostic biomarkers and validated their reproducibility in an external cohort. Our findings support a microbiota-immune axis contributing to immune evasion in OSCC, offering novel avenues for prognostic stratification and therapeutic intervention.

A plasma sample serves as a supplement for identifying GPS when a tissue sample is unavailable. Moreover, the integration of FISH, NGS, and ddPCR provided a comprehensive assessment of MET amplification.