CDK4 amplification

P2, N=45, Recruiting, Massachusetts General Hospital | N=30 --> 45 | Trial completion date: Sep 2025 --> Sep 2026 | Trial primary completion date: Sep 2024 --> Sep 2025

Precision medicine for rare tumors still poses challenges. In this Japanese cohort, 42.2 % of high-grade OSs had potentially actionable alterations per CKDB. Concurrent gene amplifications of KIT, KDR, and PDGFRA at 4q12, and VEGFA and CCND3 at 6p12-21, might offer promising therapeutic options for patients with recurrent/metastatic OS resistant to conventional chemotherapy.

Furthermore, it is observed that this co-delivery system can activate immune microenvironment, increasing CD8+ T cell infiltration and converting osteosarcoma from an immune-cold to an immune-hot tumor. In summary, the co-delivery system is an effective therapeutic strategy and holds promise as a novel approach for osteosarcoma treatment.

No recurrence was observed during the follow-up period of 8 months. This study aims to improve our understanding of PF by analyzing the clinicopathological characteristics of this case, including immunohistochemical (IHC) and genetic examination, and reviewing relevant literature.

This study demonstrates that immunohistochemistry for MDM2 and CDK4 can help elucidate the molecular genetic features of UA. Further studies are needed to correlate the expression of these genes with the biological behavior of UA.

Palbociclib showed limited activity in histology-agnostic CDK4- or CDK6-amplified tumors, though CNS tumors may be worthy of future investigation.

For patients whose disease progressed on a prior CDK4/6i, we demonstrated comparable median TTFs for patients rechallenged with the same CDK4/6i (4.3 months, 95%CI 3.2-5.5) and with a different CDK4/6i (4.7 months, 95%CI 3.7-6.0) when compared to the recent PACE, PALMIRA, and MAINTAIN trials. Exploratory genomic analysis suggested that the presence of mutations known to confer CDK4/6i resistance, such as TP53 mutations, CDK4 amplifications, and RB1 or FAT1 loss of function mutations may be molecular biomarkers predictive of CDK4/6i retrial failure.

Malignant transformation in fibrous dysplasia was an exceedingly rare event and with a female predominance. The overall survival rate was poor. Osteosarcoma was the most common malignant neoplasm arising in FD. MDM2 and CDK4 expression may aid in the diagnosis of secondary osteosarcoma in FD.

Additionally, we observed recurring promoter swapping events involving the regulatory regions of the FRS2, PLEKHA5, and TP53 genes. These events resulted in ectopic expression of partner genes, with the ELF1 gene being upregulated by the FRS2 and TP53 promoter regions in two distinct cases.

The CDK4/6 inhibitor palbociclib at 75 mg/m2 orally daily was tolerable in this heavily pretreated cohort. No objective responses were observed in this histology-agnostic biomarker-selected population with treatment-refractory solid tumors, demonstrating that pathway alteration alone is insufficient in pediatric cancers to generate a response to palbociclib monotherapy.

P2, N=100, Recruiting, Nationwide Children's Hospital | Not yet recruiting --> Recruiting

Clinicopathological characteristics and genetic features in young and senior EwS patients differed significantly. Targeting cell cycle dysregulation based on age subgroup may be a potential therapeutic strategy for Ewing sarcoma.

In our practice, a significant proportion of patients were prescreened with a smaller NGS panel. Despite this fact, we still found actionable alterations in 23,8% of the patients, which is in line with those reported in the literature (22-61%). Our results demonstrate that CGP can provide useful additional information and can be beneficial in the clinical management of patients with mesenchymal tumours.

No abstract available

Neither EFS nor OS were significantly different by CR status after first-line treatment. In conclusion, adding treatment with anti-GD2 mAbs at the stage of MRD helps prevent relapse that unequivocally portends poor survival.

Our findings suggest a strong correlation between HMGA2 alteration/MDM2 amplification and a peculiar nuclear atypia, advocating for their evaluation in biphasic tumours to facilitate accurate diagnosis and tailored posttumour removal monitoring. Further studies are warranted to validate these observations and elucidate their prognostic implications.

In this large-scale cohort of GLI1 co-amplified WD/DDLPS, we elucidate uniquely recurrent features including meningothelial whorls and GLI-altered morphology in dedifferentiated areas. Assessment of tumor location (retroperitoneal or mediastinal), identification of a well-differentiated liposarcoma component, and co-amplification of other spatially discrete genomic segments (1p, 6q) might aid in distinction from tumors with true driver GLI1 alterations.

This study clarified the genetic differences between OMM and NMM, and the first to report the frequent occurrence of RICTOR amplification in OMM. This analysis offers insights into the development of personalized therapeutics for OMM.

P2, N=100, Not yet recruiting, Nationwide Children's Hospital | Trial completion date: Jan 2034 --> May 2034 | Initiation date: Jan 2024 --> May 2024 | Trial primary completion date: Jan 2028 --> May 2028

P1, N=18, Not yet recruiting, University of Washington | Initiation date: Apr 2024 --> Jul 2024

P1/2, N=337, Recruiting, Pfizer | Trial completion date: Oct 2027 --> May 2028 | Trial primary completion date: Aug 2026 --> Mar 2027

P1, N=48, Active, not recruiting, Nader Sanai | Trial completion date: Jan 2024 --> Jan 2025

P1, N=50, Recruiting, Nader Sanai | Trial completion date: Feb 2024 --> Feb 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

Compared to the primary tumors of NSCLC, the genome of BMs showed an increased proportion of amplification and a decreased proportion of gene substitution/indel. Furthermore, the CDK4 amplification ratio seemed to be elevated in NSCLC patients with BM which may be associated with poor OS and RFS.

The aim of this review article is to provide a comprehensive summary of previously documented case reports and studies related to MPLs. By shedding light on the intricate details of MPLs, researchers and clinicians can gain valuable insights that may pave the way for improvements in diagnosis, treatment, and patient outcomes in the future.

Adult eGBM carried a dismal prognosis compared to GBM with IDH and H3 wild-type (typical GBM) (OS: 13.89 vs 24.30 months; P = .003) and even typical GBM without MGMT promoter methylation (OS: 13.89 vs 22.08 months; P = .036). Based on these findings, it can be concluded that adult eGBM harbors a high frequency of the 7+/10- signature and alterations in the MAPK pathway, SWI/SNF complex and cyclin-related genes and portends an extremely poor prognosis.

Overall, in our uLMS analysis, CDK4 and/or MDM2 amplification was identified in a small subset (2%) of uLMS, the majority of which are TP53/RB1-wildtype. This may suggest that CDK4/MDM2 amplification can be an alternative tumorigenic mechanism in this distinct class of uLMS, which may have therapeutic clinical implications, including possible use of specific cyclin-dependent kinase inhibitors.

Overall, in our uLMS analysis, CDK4 and/or MDM2 amplification was identified in a small subset (2%) of uLMS, the majority of which are TP53/RB1-wildtype. This may suggest that CDK4/MDM2 amplification can be an alternative tumorigenic mechanism in this distinct class of uLMS, which may have therapeutic clinical implications, including possible use of specific cyclin-dependent kinase inhibitors.

P2; Trial primary completion date: Jun 2024 --> Dec 2024

This suggests the potential use of MDM2 or CDK4 inhibitors in neoplasms where alterations in these genes do not aid the pathological diagnosis but may help identify potential therapeutic targets. In this review, we delve into the diagnosis and therapeutic implications of tumors with genetic alterations involving the chromosomal region 12q13-15, mainly MDM2, CDK4, and GLI1.

Our observations suggest that F3T3-positive GBM is a distinct molecular subgroup of the IDH-wildtype GBM. Both clinicians and pathologists should consider this rare entity in the differential diagnosis of diffuse astrocytic glioma to make an accurate diagnosis and to ensure appropriate therapeutic management.

P1, N=18, Not yet recruiting, University of Washington | Initiation date: Jan 2024 --> Apr 2024

In mice, inhibition of KIF18A leads to robust anti-cancer effects with tumor regression observed in human HGSOC and TNBC models at well-tolerated doses. Collectively, our results provide a rational therapeutic strategy for selective targeting of CIN cancers via KIF18A inhibition.

The patient underwent complete removal of the tumour without the use of radiotherapy or chemotherapy. No recurrence was observed during the follow-up period of 18 months.

P2, N=30, Not yet recruiting, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine; Shanghai Ninth People's Hospital, Shanghai Jiaotong University Scho

These findings suggest that gene alterations that activate retinoblastoma (RB) signaling pathways and PDGFR may drive tumor progression and xenograft formation in IDH2-mutant astrocytoma, which is equivalent to progressive IDH1-mutant astrocytoma. Also, our findings suggest that these genomic alterations may represent therapeutic targets in IDH2-mutant astrocytoma.

This may be related to the known molecular relationship between KDM2B and BCOR in the polycomb repressive complex 1.1. Immunohistochemical analysis of KDM2B is a potentially valuable diagnostic tool for BCOR-associated sarcomas, including those with KDM2B rearrangement.

Genomic alterations are infrequent but occur in malignant SCTs as well as a subset of benign SCTs. Molecular analysis of additional malignant SCTs is necessary to identify recurring and/or potentially actionable targets.

Collectively, we elucidated the synergistic antitumor and immunomodulatory mechanisms of the talazoparib-palbociclib combination. Further combination with PD-L1 antibody might be a promising "one-two punch" therapeutic strategy for colorectal cancer patients.

It is reasonable to believe that most sarcoma treatment centers will increase the use of massive-parallel sequencing soon. We conclude that the context in which the genetic findings are interpreted is of importance, and the interpretation of genomic findings requires considering tumor histomorphology.

This study highlights the value of integrating pharmacokinetics/pharmacodynamics and snRNA data to assess treatment effects in phase 0 surgical tissues. These findings support further development of ribociclib, but not everolimus, for the treatment of glioma patients.

In conclusion, we confirm that GLI1 IHC represents a good, quick, and cheap helpful screening tool. The inclusion of p16 may aid in pre-screening for potential GLI1-amplified neoplasms and provide insights on which tumors warrant further molecular testing.