News - FBXW7 mutation

2ms

Targeting Protein Kinase, Membrane-Associated Tyrosine/Threonine 1 (PKMYT1) for Precision Cancer Therapy: From Discovery to Clinical Trial. (PubMed, J Med Chem)

This perspective summarizes, for the first time, the PKMYT1 structure, function, and inhibitors in both the literature and patent applications reported to date. Compounds are described focusing on their design and optimization process, structural features, and biological activity with the aim to promoting further drug discovery efforts targeting PKMYT1 as a potential precision therapy.

2 months ago

Review • Journal

KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • CCNE1 (Cyclin E1) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • PKMYT1 (Protein Kinase Membrane Associated Tyrosine/Threonine 1) • PPP2R1A (Protein Phosphatase 2 Scaffold Subunit Aalpha)

TP53 mutation • KRAS mutation • CCNE1 amplification • FBXW7 mutation

8ms

Genetic analysis of cervical cancer with lymph node metastasis. (PubMed, J Gynecol Oncol)

The somatic SNV/Indels of EP300 and FBXW7, SBS3 homologous recombination-mediated DNA repair defect were enriched in lymph node-positive patients. For lymph node-positive patients, EP300 or FBXW7 mutations predicted poor prognosis. No matter lymph node-positive or negative, more co-occurring mutation number predicted poor prognosis. PIK3CA mutation may account for the higher TMB and help identify patients who benefit from immunotherapy.

8 months ago

Journal • Tumor mutational burden • IO biomarker

PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • EP300 (E1A binding protein p300)

TMB-H • PIK3CA mutation • FBXW7 mutation

8ms

Clinical characteristics, proteins, and genes related to interstitial pneumonia-associated squamous cell carcinoma of the lungs. (PubMed, Pathol Res Pract)

ERBB4 and KDR mutations were observed in both with or without IP, and these genes may be tumor-related genes in SCC. These molecular markers may help determine the prognoses of patients with SCC with IP and direct the development of treatment approaches.

8 months ago

Journal

KDR (Kinase insert domain receptor) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • ERBB4 (erb-b2 receptor tyrosine kinase 4) • STAT3 (Signal Transducer And Activator Of Transcription 3) • STAT5A (Signal Transducer And Activator Of Transcription 5A)

FBXW7 mutation • STAT3 expression • KDR mutation

9ms

Recurrent mutations in tumor suppressor FBXW7 bypass Wnt/β-catenin addiction in cancer. (PubMed, Sci Adv)

These FBXW7-mutant Wnt/β-catenin-independent tumors are susceptible to multi-cyclin-dependent kinase inhibition. An in-depth understanding of primary resistance to anti-Wnt/β-catenin therapies allows for more appropriate patient selection and use of alternative mechanism-based therapies.

9 months ago

Journal

RNF43 (Ring Finger Protein 43) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • FBXW7 (F-Box And WD Repeat Domain Containing 7)

FBXW7 mutation • RNF43 mutation

9ms

Epidermal growth factor receptor (EGFR) is a target of the tumor-suppressor E3 ligase FBXW7. (PubMed, Proc Natl Acad Sci U S A)

These observations were further strengthened in CRC-derived organoid lines and validated in a cohort of patients treated with panitumumab. Our data imply that FBXW7 mutations reduce EGF dependency by disabling EGFR turnover.

9 months ago

Journal

EGFR (Epidermal growth factor receptor) • FBXW7 (F-Box And WD Repeat Domain Containing 7)

EGFR mutation • FBXW7 mutation

Vectibix (panitumumab)

1year

Correlation between TP53, KRAS, SMAD4 and other mutations profile and neoadjuvant therapy efficacy and prognosis in locally advanced rectal cancer. (ASCO-GI 2024)

Co-mutations in TP53, KRAS, and SMAD4 may serve as factors for predicting the effectiveness of preoperative treatment and prognosis in locally advanced rectal cancer.

1 year ago

Clinical • Metastases

KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • NRAS (Neuroblastoma RAS viral oncogene homolog) • SMAD4 (SMAD family member 4) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • APC (APC Regulator Of WNT Signaling Pathway)

TP53 mutation • KRAS mutation • NRAS mutation • PIK3CA mutation • APC mutation • FBXW7 mutation • SMAD4 mutation

1year

Histological transformation into SCLC: An important resistance mechanism of NSCLC upon immunotherapy. (PubMed, Front Immunol)

However, the exact mechanisms underlying this conversion remain unclear. Currently, there is a lack of guidelines for the management of transformed SCLC from NSCLC following immunotherapy, with chemotherapy being the most commonly employed treatment approach.

1 year ago

Review • Journal • IO biomarker

ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • RB1 (RB Transcriptional Corepressor 1) • FBXW7 (F-Box And WD Repeat Domain Containing 7)

TP53 mutation • ALK mutation • FBXW7 mutation

1year

A New t(7; 9)(p12; q34) Involving NOTCH1 and IKZF1 in Pediatric T-Cell Lymphoblastic Lymphoma (ASH 2023)

Summary/perspectivesThis new t(7; 9)(p12; q34) involving ICN1 illustrates the importance to look for ICN1 more extensively in parallel to NOTCH1/FBXW7 mutations in the screening of Notch1 activation pathway in T-ALL/LL specially in the event of a stratification on Notch1 status for treatment. As both NOTCH1 and IKZF1 are major actors of normal T-cell differentiation/proliferation, the oncogenic role of the fusion NOTCH1: : IKZF1 in T-ALL/LL deserves a better understanding in a larger population and will be further explored.

1 year ago

Clinical

NOTCH1 (Notch 1) • CD8 (cluster of differentiation 8) • IKZF1 (IKAROS Family Zinc Finger 1) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • CD4 (CD4 Molecule) • CD7 (CD7 Molecule)

NOTCH1 mutation • FBXW7 mutation

1year

FBXW7-loss sensitizes cells to ATR inhibition through induced mitotic catastrophe. (PubMed, Cancer Res Commun)

ATR-inhibition induces an accelerated S-phase, leading to mitotic catastrophe and cell death caused by the high replication stress present in FBXW7-/- cells. In addition, we provide evidence in cell and organoid studies, and mining of publicly available high throughput drug screening efforts, that this genotype-specific vulnerability extends to multiple types of cancer, providing a rational means of identifying responsive patients for targeted therapy.

1 year ago

Journal

FBXW7 (F-Box And WD Repeat Domain Containing 7)

FBXW7 mutation

1year

Population-specific mutation patterns in breast tumors from African American, European American, and Kenyan patients. (PubMed, Cancer Res Commun)

To conclude, we found mutational profiles that were different between these patient groups. The differences concentrated among genes with low mutation frequencies in breast cancer.

1 year ago

Journal • Tumor mutational burden

TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • ARID1A (AT-rich interaction domain 1A) • FBXW7 (F-Box And WD Repeat Domain Containing 7)

TP53 mutation • PIK3CA mutation • ARID1A mutation • FBXW7 mutation

1year

Frontline Consolidation with Nelarabine for Adults with High-Risk T-Cell Acute Lymphoblastic Leukemia. Results of the Graall-2014/T Atriall Phase 2 Study (ASH 2023)

NELA was given at 1,500 mg/sqm/day at day 1,3 and 5 in combination with etoposide and cyclophosphamide for a maximum of 5 courses during consolidation (2 cycles) and maintenance (3 cycles). While NELA did not yield an overall improved outcome in the study population, benefits were observed in favorable MRD responders and non-ETP patients. Additional prospective studies are needed to further delineate the specific patient subgroups that might benefit from NELA.

1 year ago

Clinical • P2 data

PTEN (Phosphatase and tensin homolog) • NOTCH1 (Notch 1) • FBXW7 (F-Box And WD Repeat Domain Containing 7)

PTEN mutation • NOTCH1 mutation • FBXW7 mutation

cyclophosphamide • etoposide IV • nelarabine

1year

NGS-Based Stratification Refines the Risk Stratification in T-ALL and Identifies a Very High-Risk Subgroup of Patients (ASH 2023)

This model identifies 3 subgroups at CR1: a large favorable Risk (CR1-FAV) group (231/332, 70%) with CIR at 5 years estimated at 19% (95%CI:14%-24%) (Figure B), a subgroup of Adverse risk (CR1-ADV) patients (30/332, 9%) with a 5-year CIR of 68% (95%CI:46%-82%) and an Intermediate risk (CR1-INT) group (71/332, 21%) with a 5-year CIR of 37% (95%CI:26%-48%). Conclusion T-ALL NGS-based stratification combined with WBC and MRD evaluation sharpens the prognostic classification in T-ALL and identifies a new subgroup of adverse risk patients who should benefit from innovative therapeutic approaches.

1 year ago

Clinical • Next-generation sequencing

KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • DNMT3A (DNA methyltransferase 1) • NOTCH1 (Notch 1) • IKZF1 (IKAROS Family Zinc Finger 1) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • PIK3R1 (Phosphoinositide-3-Kinase Regulatory Subunit 1) • EP300 (E1A binding protein p300) • PHF6 (PHD Finger Protein 6)

TP53 mutation • PTEN mutation • DNMT3A mutation • FBXW7 mutation • PHF6 mutation • EP300 mutation

1year

A rare case of endometrial carcinoma with an FGFR3::TACC3 fusion and an institutional review of FGFR3::TACC3 fusions (AMP 2023)

Fusions are overall uncommon events in endometrial carcinoma. We present a rare case of an FGFR3::TACC3 fusion in a case of endometrial carcinoma. In our institutional cohort, we demonstrated that FGFR3::TACC3 fusions are most frequently identified in high-grade gliomas, but can be seen in other tumor types as well.

1 year ago

Review • Clinical

HER-2 (Human epidermal growth factor receptor 2) • TP53 (Tumor protein P53) • FGFR3 (Fibroblast growth factor receptor 3) • TACC3 (Transforming acidic coiled-coil containing protein 3) • FBXW7 (F-Box And WD Repeat Domain Containing 7)

TP53 mutation • FBXW7 mutation • FGFR3 fusion

Oncomine™ Comprehensive Assay v3M

1year

Exploration of Multiomic Profiles and Biomarkers as Predictors of Neoadjuvant Chemoradiotherapy Responsiveness in Esophageal Squamous Cell Carcinoma. (PubMed, Int J Radiat Oncol Biol Phys)

Through a multiomics approach, we described the biological characteristics of ESCC with distinct responses to neoadjuvant chemoradiotherapy and proposed a panel of 12 proteins as predictive biomarkers for non-pCR patients.

1 year ago

Journal • Tumor mutational burden • PARP Biomarker

TMB (Tumor Mutational Burden) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • HLA-B (Major Histocompatibility Complex, Class I, B) • STAT1 (Signal Transducer And Activator Of Transcription 1) • GBP1 (Guanylate Binding Protein 1) • ISG15 (ISG15 Ubiquitin Like Modifier) • MX1 (MX Dynamin Like GTPase 1) • TRIM21 (Tripartite Motif Containing 21)

FBXW7 mutation

over1year

Genomic signatures and prognosis of advanced stage Chinese pediatric T cell lymphoblastic lymphoma by whole exome sequencing. (PubMed, Front Pediatr)

Although T-ALL and T-LBL both originate from precursor T-cells and are considered different manifestations of the same disease and the outcome of T-LBL is favorable when using T-ALL-based chemotherapy, there are differences in the gene distribution between T-LBL and T-ALL. It seems that the PI3K-Akt signaling pathway and the USP34 gene play important roles in T-LBL, but medicines targeting the USP34 gene or the PI3K-Akt pathway may be invalid.

over 1 year ago

Journal • Metastases

NOTCH1 (Notch 1) • MAP2K2 (Mitogen-activated protein kinase kinase 2) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • JAK3 (Janus Kinase 3) • PHF6 (PHD Finger Protein 6) • USP34 (Ubiquitin Specific Peptidase 34)

NOTCH1 mutation • FBXW7 mutation • JAK3 mutation • PHF6 mutation

over1year

Exploration of Multiomic Profiles and Biomarkers as Predictors of Neoadjuvant Chemoradiotherapy Responsiveness in Esophageal Squamous Cell Carcinoma (ASTRO 2023)

over 1 year ago

Clinical • Tumor mutational burden • PARP Biomarker

FBXW7 mutation

over1year

Functional analysis reveals driver cooperativity and novel mechanisms in endometrial carcinogenesis. (PubMed, EMBO Mol Med)

By transcriptomic analysis, we identify LEF1 signalling as upregulated in Fbxw7/FBXW7-mutant mouse and human endometrial cancers, and in human isogenic cell lines carrying FBXW7 mutation, and validate LEF1 and the additional Wnt pathway effector TCF7L2 as novel FBXW7 substrates. Our study provides new insights into the biology of high-risk endometrial cancer and suggests that targeting LEF1 may be worthy of investigation in this treatment-resistant cancer subgroup.

over 1 year ago

Journal

TP53 (Tumor protein P53) • PTEN (Phosphatase and tensin homolog) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • TCF7L2 (Transcription Factor 7 Like 2)

TP53 mutation • TP53 deletion • FBXW7 mutation

over1year

Biallelic FBXW7 knockout induces AKAP8-mediated DNA damage in neighbouring wildtype cells. (PubMed, Cell Death Discov)

Here, we describe a hitherto unknown phenomenon of AKAP8-mediated DNA damage from FBXW7 mutant to neighbouring wildtype cells. Our findings demonstrate the importance of elucidating the local effect of cancer driver mutations between subclonal populations.

over 1 year ago

Journal

FBXW7 (F-Box And WD Repeat Domain Containing 7)

FBXW7 mutation

over1year

Different Mutational Landscape in HPV-induced and HPV-independent Invasive Penile Squamous Cell Cancers. (PubMed, Mod Pathol)

While genetic mutations in tumor suppressor genes drive HPV-independent penile carcinogenesis, oncogenic action of E6 and E7 substitute for mutations in HPV-induced SCC. A subgroup of patients with advanced SCC may be candidates for targeted therapy and clinical trials, although the majority of advanced penile SCC remain a therapeutic challenge.

over 1 year ago

Journal

TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • FGFR3 (Fibroblast growth factor receptor 3) • HRAS (Harvey rat sarcoma viral oncogene homolog) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • FBXW7 (F-Box And WD Repeat Domain Containing 7)

TP53 mutation • PIK3CA mutation • FGFR3 mutation • CDKN2A mutation • FBXW7 mutation

over1year

Comprehensive genomic and immunohistochemical profiles and outcomes of immunotherapy in patients with recurrent or advanced cervical cancer. (PubMed, Front Oncol)

During this timeframe, 73 patients received pembrolizumab monotherapy, among whom a small portion showed a durable response. Comprehensive genomic and IHC profiling may help identify potential candidates for targeted immunotherapy in patients with cervical cancer.

over 1 year ago

Journal • Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker • Metastases

HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • STK11 (Serine/threonine kinase 11) • HRD (Homologous Recombination Deficiency) • CCNE1 (Cyclin E1) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • FAT1 (FAT atypical cadherin 1)

TP53 mutation • PIK3CA mutation • HER-2 expression • STK11 mutation • CCNE1 amplification • FBXW7 mutation • PD-L1 expression + HER-2 overexpression

TruSight Oncology 500 Assay

Keytruda (pembrolizumab)

over1year

Pathobionts in the tumour microbiota predict survival following resection for colorectal cancer. (PubMed, Microbiome)

Networks of pathobionts in the tumour mucosal niche are associated with tumour mutation and metabolic subtypes and predict favourable outcome following CRC resection. Video Abstract.

over 1 year ago

Observational data • Journal

FBXW7 (F-Box And WD Repeat Domain Containing 7)

FBXW7 mutation

over1year

Comprehensive characterization of FBXW7 mutational and clinicopathological profiles in human colorectal cancers. (PubMed, Front Oncol)

Moreover, in MSI patients, the FBXW7 mutated group showed higher M1 macrophage, CD8+ T cell, and regulatory T cell (Tregs) infiltration rates, and significant enrichment of multiple immune-related gene sets, including interferon-gamma response, interferon-alpha response, IL6 JAK STAT3 signaling, p53 pathway. This analysis comprehensively identified FBXW7 alterations in colorectal cancer patients and uncovered the molecular, clinicopathological, and immune-related patterns of FBXW7-altered CRC patients.

over 1 year ago

Journal • Tumor mutational burden

TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma) • IL6 (Interleukin 6) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • JUN (Jun proto-oncogene)

FBXW7 mutation

over1year

Different miRNAs Related to FBXW7 Mutations or High Mitotic Indices Contribute to Rectal Neuroendocrine Tumors: A Pilot Study. (PubMed, Int J Mol Sci)

No change in miRNA expression was associated with a tumor size >1 cm, lymphovascular invasion, or Ki-67 index. In summary, we identified different miRNA signatures involved in FBXW7 mutations or high mitotic indices in rectal NETs, which may play a critical role in tumor behavior.

over 1 year ago

Journal

FBXW7 (F-Box And WD Repeat Domain Containing 7) • MIR34A (MicroRNA 34a-5p) • MIR221 (MicroRNA 221) • MIR324 (MicroRNA 324) • MIR1246 (MicroRNA 1246) • MIR361 (MicroRNA 361) • MIR769 (MicroRNA 769) • MIR181C (MicroRNA 181c)

FBXW7 mutation

almost2years

Onco-microbial community profiling identifies clinico-molecular and prognostic subtypes of colorectal cancer. (PubMed, Gastroenterology)

OCS classification stratified CRCs into three distinct subgroups with different clinico-molecular features and outcomes. Our findings provide a framework for a microbiota-based stratification of CRC to refine prognostication and to inform the development of microbiota-targeted interventions.

almost 2 years ago

Journal • MSi-H Biomarker

TP53 mutation • BRAF V600E • MSI-H/dMMR • PIK3CA mutation • BRAF V600 • FBXW7 mutation

almost2years

Whole-Exome Sequencing and cfDNA Analysis Uncover Genetic Determinants of Melanoma Therapy Response in a Real-World Setting. (PubMed, Int J Mol Sci)

In immunotherapy-treated patients, samples from responders showed higher TMB and lower LOH and were more frequently diploid compared to non-responders. Secondary germline testing and cfDNA analysis proved their efficacy in finding germline predisposing variants carriers (8.3%) and following dynamic changes during treatment as a surrogate of tissue biopsy, respectively.

almost 2 years ago

Journal • Real-world evidence • Tumor mutational burden • IO biomarker • Real-world

BRAF (B-raf proto-oncogene) • TMB (Tumor Mutational Burden) • PTEN (Phosphatase and tensin homolog) • GNAQ (G Protein Subunit Alpha Q) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • RAC1 (Rac Family Small GTPase 1)

TMB-H • BRAF mutation • BRAF V600 • PTEN mutation • GNAQ mutation • FBXW7 mutation

almost2years

Comprehensive characterization of FBXW7 mutational and clinicopathological profiles in human colorectal cancers (AACR 2023)

Comprehensive profiling of FBXW7 in colorectal patients revealed that FBXW7 mutations were associated with better OS, except the FBXW7 R465C mutation was identified as an indicator for worse OS.

almost 2 years ago

Clinical • Tumor mutational burden

TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma) • FBXW7 (F-Box And WD Repeat Domain Containing 7)

TMB-H • FBXW7 mutation • FBXW7 R505C

almost2years

Genomic features, evolutionary patterns, and minimal residual disease at surgical margins as novel prognostic/predictive biomarkers in locally advanced rectal cancer (AACR 2023)

Comprehensive genomic profiling helps identify multiple molecular prognostic and/or predictive biomarkers that could predict patients’ clinical outcomes to nCRT and TME and direct nCRT treatment regimen, thus facilitating more accurate prognostic estimation, a better balance between treatment efficacy and quality of life, and timely adjusted treatment decisions.

almost 2 years ago

Minimal residual disease • Metastases

KRAS (KRAS proto-oncogene GTPase) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • FBXW7 (F-Box And WD Repeat Domain Containing 7)

KRAS mutation • MYC amplification • FBXW7 mutation • MYC positive

almost2years

Loss of CDKN2A/B is a Molecular Marker of High-grade Histology and is Associated with Aggressive Behavior in Acinic Cell Carcinoma. (PubMed, Mod Pathol)

AciCC with ATM mutations may be amenable to targeted therapy. Immunotherapy can be considered as a treatment option for a subset of AciCC patients.

almost 2 years ago

Journal • Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker

TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • PTEN (Phosphatase and tensin homolog) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • MTAP (Methylthioadenosine Phosphorylase) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • BIRC3 (Baculoviral IAP repeat containing 3) • FAT1 (FAT atypical cadherin 1) • ARID2 (AT-Rich Interaction Domain 2)

PD-L1 expression • TP53 mutation • ATM mutation • PTEN mutation • CDKN2A deletion • CDKN2A mutation • FBXW7 mutation

MSK-IMPACT

almost2years

CircFBXW7 in patients with T-cell ALL: depletion sustains MYC and NOTCH activation and leukemia cell viability. (PubMed, Exp Hematol Oncol)

Plus, low circFBXW7 levels were associated with a particular gene expression profile in T-ALL patients, which was remarkably mirrored by the effects of circFBXW7 loss-of-function in vitro. CircFBXW7 depletion notably emerges as a new factor enhancing a proliferative phenotype and the activation of the MYC signaling pathway, key players in this aggressive malignancy.

almost 2 years ago

Journal

NOTCH1 (Notch 1) • FBXW7 (F-Box And WD Repeat Domain Containing 7)

MYC expression • FBXW7 mutation • NOTCH1 expression

2years

Real-world clinicopathological and molecular characteristics, treatment patterns, and outcomes in patients with KRAS G12C–mutated metastatic colorectal cancer in AACR Project GENIE. (ASCO-GI 2023)

Most patients received oxaliplatin- or irinotecan-based regimens in the first two LOTs. In this select patient cohort with KRAS G12C mutated mCRC from US academic centers, outcomes, particularly rwPFS, were poor in later lines of therapy. Frontline OS and rwPFS were longer than in other similar studies, which may be attributable to the young median age and high proportion of surgical resection in the metastatic setting observed in this cohort.

2 years ago

Clinical • Real-world evidence • Tumor mutational burden • MSi-H Biomarker • Real-world • Metastases

KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • FBXW7 (F-Box And WD Repeat Domain Containing 7)

KRAS mutation • TMB-H • MSI-H/dMMR • KRAS G12C • PIK3CA mutation • KRAS wild-type • RAS wild-type • KRAS G12 • FBXW7 mutation

oxaliplatin • irinotecan

2years

A phase II study to explore biomarkers for the use of mFOLFOX6/XELOX plus bevacizumab as a first-line chemotherapy in patients with metastatic colorectal cancer (WJOG7612GTR). (PubMed, ESMO Open)

The addition of BV was unable to compensate for the poor PFS associated with a high pVEGF-Asi level, suggesting that pVEGF-Asi is unlikely to be a good predictive biomarker of the efficacy of mFOLFOX6/XELOX + BV therapy. The clinical significance of circulating ICAM-1, mutant RAS, and mutant FBXW7 levels should be studied further.

2 years ago

P2 data • Journal

FBXW7 (F-Box And WD Repeat Domain Containing 7) • ICAM1 (Intercellular adhesion molecule 1)

RAS mutation • FBXW7 mutation

Avastin (bevacizumab) • 5-fluorouracil • capecitabine • oxaliplatin • leucovorin calcium

2years

Mutational Status of SMAD4 and FBXW7 Affects Clinical Outcome in TP53-Mutated Metastatic Colorectal Cancer. (PubMed, Cancers (Basel))

Gene set enrichment analysis revealed specific molecular pathways associated with SMAD4 and FBXW7 mutations in TP53-defficient tumors. Conclusively, SMAD4 and FBXW7 mutations in TP53-altered tumors were predictive of a negative prognostic outcome in mCRC patients treated with first-line regimens.

2 years ago

Journal • Clinical data

TP53 mutation • KRAS mutation • BRAF mutation • NRAS mutation • PIK3CA mutation • FBXW7 mutation • SMAD4 mutation

MSK-IMPACT

2years

Multi-omics inference of differential breast cancer-related transcriptional regulatory network gene hubs between young Black and White patients. (PubMed, Cancer Genet)

The results point to several driver genes as being involved in the observed differences between the cohorts. The findings here form the basis for further mechanistic exploration.

2 years ago

Journal • BRCA Biomarker

PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • BRCA (Breast cancer early onset) • CDH1 (Cadherin 1) • EP300 (E1A binding protein p300) • HUWE1 (HECT UBA And WWE Domain Containing E3 Ubiquitin Protein Ligase 1) • MIR93 (MicroRNA 93) • TRAF6 (TNF Receptor Associated Factor 6)

PIK3CA mutation • FBXW7 mutation • BRCA mutation

2years

Genomic Characterization of Patients in a Phase 2 Study of Zanubrutinib in BTK Inhibitor–Intolerant Patients with Relapsed/Refractory B-Cell Malignancies (ASH 2022)

However, some patients (pts) have experienced toxicities to BTK inhibitors ibrutinib (ibr) and acalabrutinib (acala), which lead to dose reduction or treatment discontinuation. Exploratory analysis results confirmed that cell cycle, DNA damage, and NOTCH1 pathway genes were frequently mutated in pts with B-cell malignancies on study BGB-3111-215 (pts intolerant to ibr and/or acala). Pts with mutations associated with poor prognosis at baseline were more likely to develop PD.

2 years ago

P2 data • Clinical

KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • RB1 (RB Transcriptional Corepressor 1) • NOTCH1 (Notch 1) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • SF3B1 (Splicing Factor 3b Subunit 1) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • CHEK2 (Checkpoint kinase 2) • BIRC3 (Baculoviral IAP repeat containing 3) • SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase) • PLCG2 (Phospholipase C Gamma 2) • CCND2 (Cyclin D2)

TP53 mutation • ATM mutation • NOTCH1 mutation • MYD88 mutation • SF3B1 mutation • MYD88 L265P • ATM deletion • RB1 deletion • CHEK2 mutation • CXCR4 mutation • FBXW7 mutation • PLCG2 mutation • KRAS deletion • MYD88 wild-type

PredicineHEME™

Imbruvica (ibrutinib) • Brukinsa (zanubrutinib) • Calquence (acalabrutinib)

2years

Molecular Landscape of Chronic Lymphocytic Leukemia Using Targeted Gene Panel Sequencing (ASH 2022)

FBXW7 and NOTCH1 pathogenic variants have the same biological consequences in CLL, therefore presence of FBXW7 mutations may have clinical relevance regarding anti-CD20 therapy. Taken together, these NGS results complemented with the study of IGHV mutational status and cytogenetic data can contribute to better prognostic workup and management of our CLL patients.

2 years ago

IO biomarker

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • NRAS (Neuroblastoma RAS viral oncogene homolog) • PTEN (Phosphatase and tensin homolog) • BCL2 (B-cell CLL/lymphoma 2) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • NOTCH1 (Notch 1) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • SF3B1 (Splicing Factor 3b Subunit 1) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • IGH (Immunoglobulin Heavy Locus) • CD79B (CD79b Molecule) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • BIRC3 (Baculoviral IAP repeat containing 3) • STAT3 (Signal Transducer And Activator Of Transcription 3) • CARD11 (Caspase Recruitment Domain Family Member 11) • PIK3CD (Phosphatidylinositol-4 5-Bisphosphate 3-Kinase Catalytic Subunit Delta) • PLCG2 (Phospholipase C Gamma 2) • MAPK1 (Mitogen-activated protein kinase 1) • STAT5B (Signal Transducer And Activator Of Transcription 5B) • TCF3 (Transcription Factor 3) • POT1 (Protection of telomeres 1) • DDX3X (DEAD-Box Helicase 3 X-Linked)

TP53 mutation • PIK3CA mutation • NOTCH1 mutation • Chr del(11q) • SF3B1 mutation • IGH mutation • BIRC3 mutation • FBXW7 mutation • TS 12

2years

Cytogenetic and molecular characteristics and outcomes of adult patients with early T-cell precursor acute lymphoblastic leukemia. (PubMed, Eur J Haematol)

In a subgroup analysis of patients treated with allo-HCT in CR1 (n=29), 5-year OS was 53.8% for ETP-ALL and 55.4% for non-ETP-ALL. Our data showed molecular characteristics of ETP-ALL and non-ETP-ALL and revealed that intensive chemotherapy followed by allo-HCT for post-remission therapy can contribute to preserved survival outcome of adult patients with ETP-ALL.

2 years ago

Journal

CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • DNMT3A (DNA methyltransferase 1) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • FBXW7 (F-Box And WD Repeat Domain Containing 7)

DNMT3A mutation • CDKN2A deletion • CDKN2A mutation • FBXW7 mutation

over2years

A Study of LY2606368 (Prexasertib) in Patients With Solid Tumors With Replicative Stress or Homologous Repair Deficiency (clinicaltrials.gov)

P2; Active, not recruiting --> Completed

over 2 years ago

Trial completion

BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • CCNE1 (Cyclin E1) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • CHEK2 (Checkpoint kinase 2) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D)

BRCA2 mutation • BRCA1 mutation • ATM mutation • MYC amplification • PALB2 mutation • CCNE1 amplification • FBXW7 mutation • RAD51C mutation • RAD51D mutation • RAD51 mutation

OncoPanel™ Assay

prexasertib (ACR-368)