TP53 amplification

P1, N=35, Active, not recruiting, M.D. Anderson Cancer Center | Phase classification: P1b --> P1

EGFR p.T790M is not only the major resistance mechanism to afatinib but also related to favourable survival outcomes. MET amplification and TP53 mutations were associated with poorer overall survival.

P1, N=140, Recruiting, Boehringer Ingelheim | Phase classification: P1a/1b --> P1

There is a great genomic variability in each intrinsic subtype of advanced BC, with apparently no genomic pattern correlating with each phenotype. Although a transcriptomic test (Prosigna) can help in the classification of the tumors, NGS sequencing with an extended panel allows identifying genetic variants that might benefit the patient with a targeted therapy i a significant percentage of cases.

One patient received Capmatinib and one patient Pembrolizumab. This study showed that NSCLC with METex14 are poorly differenciated tumors with necrotic background,multinucleation,atypical mitoses,and pleomorphic/sarcomatoid features. Larger studies are needed to confirm our preliminary findings. Routine NGS testing on cytological specimens is feasible and essential for METex14 testing and select patients with advanced lung NSCLC for targeted therapies.

Recent evidence also shows that inhibition of Cyclin-dependent kinases (CDKs), such as CDK4/6, CDK2, CDK8/19 and CDK12/13 can contribute to RS through disruption of DNA repair and replication control. Here, we review the main causes of RS in cancers as well as main therapeutic targets-ATR, CHK1, PARP and their inhibitors.

Whole-exome sequencing analysis revealed that CZH1 cells had typical genomic features of HNSCC, including mutations of TP53 and amplifications of multiple transcripts. Therefore, our newly developed CZH1 cell line could serve as an efficient tool for the in vitro investigation of the etiology, pathogenesis, and preclinical treatment of HPSCC.

As our understanding of biology evolves, there has been increased morphologic recognition and characterization of tumor phenotypes that are present in this advanced post-treatment setting. New and promising biomarkers (delta-like ligand 3 and others) have been discovered, which opens up novel therapeutic avenues including immunotherapy and antibody-drug conjugates for this lethal disease with currently limited treatment options.

Brigimadlin (BI 907828) is a highly potent MDM2-p53 antagonist that has shown promising activity in preclinical and early-phase clinical studies. This manuscript describes the rationale and design of an ongoing phase IIa/IIb Brightline-2 trial evaluating brigimadlin as second-line treatment for patients with advanced/metastatic BTC, PDAC, lung adenocarcinoma, or bladder cancer.

The most common genetic alterations that give rise to distinct androgen different differentiation states are gene fusion of TMPRSS2 with ETS family genes, deletion, or mutation of tumor suppressor PTEN and TP53 gene, amplification or splicing of AR, altered DNA repair genes. In this review, we describe key genes and genetic changes that have been recognized to contribute to altered prostate environment.

Our targeted analysis of MDM2 in a well-characterized cohort of GC patients showed that MDM2 amplification is rare, of no specific histological phenotype, and may not be always mutually exclusive with TP53 mutations. Given the low number of cases, currently, no diagnostic or therapeutic recommendation related to MDM2 amplification can be given for GC of Western origin.

HER2 amplifications were found in 10% of advanced BTC and did not represent an independent predictive factor for OS. Of clinical significance, patients with HER2-amplified BTC derive a significant benefit from anti-HER2 therapy.

We conclude that the morphologic spectrum of EWSR1::PATZ1 is broader than has been previously appreciated. Although more long-term follow-up is needed, the prognosis of these very rare sarcomas may be more favorable than previously reported.

Single-cell RNA sequencing revealed a high intratumoral heterogeneity with neuronal and oligodendroglial lineage signatures. High-throughput drug screening using both mouse and human tumor cells finally indicated high efficacy of Doxorubicin, Irinotecan, and Etoposide as possible therapy options that children with HGG-MYCN might benefit from.

P2, N=155, Recruiting, Boehringer Ingelheim | Phase classification: P2a/2b --> P2

P1, N=269, Recruiting, Boehringer Ingelheim | Phase classification: P1a/1b --> P1 | N=204 --> 269

Furthermore, we examined the interplay between p53R172H and NF-kB and found that the p53R172H physically interacts with the NF-kB subunit RelA and facilitates its nuclear translocation. Conclusions Overall, we characterize how a common p53 mutation in PDAC co-opts non-coding regulatory DNA to augment the expression of selective chemokine genes and establishes an immunosuppressive TME to shield the therapeutic benefits of ICIs.

P2, N=40, Terminated, Rain Oncology Inc | N=65 --> 40 | Trial completion date: Aug 2024 --> Oct 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Aug 2024 --> Oct 2023; Sponsor Decision

P1b, N=35, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jul 2023 --> Apr 2025 | Trial primary completion date: Jul 2023 --> Apr 2025

Genomic analysis in circulating MCL cells using the EC-NDC assay provides comprehensive information on genetic alterations in MCL leading to better disease characterization and risk assessment. Implementing routine genomic profiling in MCL may be useful in the era of precision medicine and individualized patient management

Cellular migratory properties are associated with cellular ultrastructure, epithelial-to-mesenchymal transition status and the status of TP53 mutation in the genome.

Prior to treatment, his lambda light chain was 4547.5 mg/L and an IgG 1930 mg/dL with the following high risk features: 8 prior lines of therapy including belantamab; high risk genomics (loss of TP53, amplification 1q, 13q deletion); extramedullary disease. Severe manufacturing shortages of BCMA directed CAR-T therapy (idecel and ciltacel) are daunting with no clear solution in sight. Thus an efficacious bispecific antibody targeting BCMA is sorely needed. Cytopenias and CKD/ESRD would have made both of our patients above ineligible for the MajesTEC-1 trial.

Genetic alterations in the p53 pathway may be critical in Asian patients with melanoma undergoing ICI treatment. Further investigation is required to explore this mechanism and validate these findings.

Acquired TP53 mutations were detected in sequential liquid biopsies as a novel exploratory resistance mechanism to milademetan. These results suggest that milademetan could be a potential therapeutic strategy for intimal sarcoma.

P2, N=65, Active, not recruiting, Rain Oncology Inc | Recruiting --> Active, not recruiting

Furthermore, patients with T790M mutation showed a trend towards improved PFS (P=0.052). Conclusions Lung surgery following targeted therapies is safe and can be used to predict the prognosis of patients with initially unresectable NSCLC.

Patient received erlotinib 150 mg daily as frontline treatment in December 2018. We present the case of a patient with advanced stage NSCLC, with EGFR mutation, Secondary T790M positive and MET amplification, received osimertinib and capmatinib as third-line treatment. The efficacy was different from previous report (1), using both combination in EGFR mutation, T790M negative, MET-amplified patient, emphasizing the marginal effect in this subgroup.

The current case report shows that next-generation sequencing can explain why osimertinib is ineffective in EGFR-mutated SCC. The therapeutic strategy for patients with EGFR mutant-positive SCC should include an analysis of coexisting genetic abnormalities by next-generation sequencing. Therapy with EGFR tyrosine kinase inhibitor might be recommended if no additional gene associated with resistance to tyrosine kinase inhibitor is detected.

In addition, EGFR-TKIs combined with bevacizumab can further improve the efficacy, as reported in study JO25567 and NEJ026. Aumolertinib plus anlotinib showed preliminary efficacy as first-line therapy in EGFR-mutant NSCLC patients with brain metastases. The initial subgroup results may demonstrated superior activity of aumolertinib plus anlotinib in patients with multiple intracranial metastases or EGFR 19Del positive. And although with comutations, NSCLC patients with brain metastasis can still benefit from aumolertinib plus anlotinib.

A phylogenetic analysis is still ongoing at our center. This more comprehensive evaluation may pave the way toward a more precise understanding of the genetics underneath the development of BM, potentially revealing novel molecular targets and leading to prospective future studies and more personalized treatment.

Thus, glycometabolism self-amplifies via a glucose-induced post-translational modification cascade culminating in CRL4-mediated p53 degradation. Such mutation-independent p53 checkpoint bypass may represent the carcinogenic origin and targetable vulnerability of hyperglycemia-driven cancer.

The Archer panel presented high performance and good coverage in GC-rich regions as CEBPA gene being a promising test in accuracy of somatic analysis and was validated in our laboratory.

We highlight how MYC directly and indirectly, with cooperation with KRAS, affect epigenetic reprogramming and metastasis. Additionally, we summarize the recent findings from single cell genomic approaches that highlight heterogeneity in PDAC and tumor microenvironment, and provide molecular avenues for PDAC treatment in the future.

We present a case of a 55-year-old male diagnosed with AML-MRC with a pathogenic variant in TP53 and amplification of KMT2A (MLL) without rearrangement. We discuss presentation, importance of diagnostic testing through multiple modalities, and the changes in classification and diagnostic criteria between the 2017 World Health Organization (WHO) revised 4th edition and the WHO 5th edition and International Consensus Classification (ICC).

1. Immunohistochemical panel of markers helps to differentiate the EJGA and might influence on treatment strategy; 2. Siewert III tumors represent a distinct biological entity and should be treated differently; 3.

Currently, ten patients with BTC had received BI 907828 ± ezabenlimab (an immune checkpoint inhibitor). The final primary analysis will be performed after all treated patients have been followed for ≥12 weeks, or until study discontinuation. As of February 2023, 16 patients have been enrolled.Clinical trial identification: NCT05512377.Editorial acknowledgement: Medical writing assistance, funded by Boehringer Ingelheim, was provided by Jim Sinclair, PhD, of Ashfield MedComms, an Inizio Company, during the preparation of this abstract.Legal entity responsible for the study: Boehringer Ingelheim.

P2a/2b, N=155, Recruiting, Boehringer Ingelheim | Trial completion date: Nov 2026 --> Mar 2027

P1b, N=35, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

The patient started on ACNS 0334 chemotherapy receiving one dose of vincristine and high dose methotrexate...Treatment was recommended with focal proton radiation to the tumor bed to avoid toxicity of craniospinal radiation in patient with Fanconi anemia followed by adjuvant bevacizumab, everolimus and posaconazole to avoid toxicities from conventional chemotherapy... Germline testing and tumor sequencing is essential in all patients diagnosed with medulloblastoma. This may prompt the early diagnosis of patients with genetic predisposition syndromes that may affect the clinical course and genetic counseling of the patients and families. Moreover, different mutations can affect long term survival rates and relate to a poor prognosis.

PTEN and TP53 mutations show mutually exclusive behavior between subtypes and display a difference in survival. This work identifies metabolic subtypes with distinct characteristics at the transcriptome and genome levels, highlighting the metabolic heterogeneity within EC.