News - AKT1 mutation - LARVOL VERI

18d

Meningioma: current updates on genetics, classification, and mouse modeling. (PubMed, Ups J Med Sci)

Most meningioma mouse models are based on patient-derived xenografts and only recently have new genetically engineered mouse models of meningioma been developed that will aid in the systematic evaluation of specific mutations found in meningioma and their impact on tumor behavior. In this article, we review recent advances in the understanding of meningioma biology and classification and highlight the most common genetic mutations, as well as discuss new genetically engineered mouse models of meningioma.

18 days ago

Preclinical • Review • Journal

AKT1 (V-akt murine thymoma viral oncogene homolog 1) • NF2 (Neurofibromin 2) • KLF4 (Kruppel-like factor 4)

AKT1 mutation

20d

The prognosis of patients treated with everolimus for advanced ER-positive, HER2-negative breast cancer is driven by molecular features. (PubMed, J Pathol Clin Res)

Overall survival was longer in patients with pS6 ≥ 3rd quartile (27.6 versus 19.3 months, p = 0.038) and in patients with any mutation in the PIK3CA/AKT/mTOR pathway (27.6 versus 19.3 months, p = 0.011). The prognosis of patients treated with everolimus for advanced ER-positive, HER2-negative breast cancer appears primarily driven by molecular features associated with the activation of the PIK3CA/AKT/mTOR pathway.

20 days ago

Journal • Metastases

HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog) • STK11 (Serine/threonine kinase 11) • INPP4B (Inositol polyphosphate-4-phosphatase type II B) • EIF4EBP1 (Eukaryotic translation initiation factor 4E binding protein 1)

ER positive • HER-2 negative • PIK3CA mutation • PTEN expression • AKT1 mutation • MTOR mutation

everolimus

23d

Capivasertib: A Novel AKT Inhibitor Approved for Hormone-Receptor-Positive, HER-2-Negative Metastatic Breast Cancer. (PubMed, Ann Pharmacother)

In the phase III CAPItello-291 trial, capivasertib in combination with fulvestrant (C+F) demonstrated improved progression-free survival (PFS) (7.3 vs 3.1 months) compared with placebo-fulvestrant (P+F) cohort in AKT-altered pathway patients who had progressed through prior aromatase inhibitor. Capivasertib is a viable treatment option for patients with PIK3CA/AKT1/PTEN activating mutations following progression on endocrine-based regimens in the metastatic setting or recurrence within 12 months of completing adjuvant therapy. Integration of capivasertib into clinical practice is ongoing; intermittent dosing and favorable toxicity are attractive for future novel combination prospective trials.

23 days ago

Review • Journal • Metastases

HER-2 (Human epidermal growth factor receptor 2) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog) • AKT2 (V-akt murine thymoma viral oncogene homolog 2)

HR positive • HER-2 negative • PIK3CA mutation • PTEN mutation • AKT1 mutation • HR positive + HER-2 negative • PTEN mutation + HR positive

fulvestrant • Truqap (capivasertib)

The frequency of NRAS mutation in stool samples of Iranian colorectal cancers compared to Finnish patients. (PubMed, J Res Med Sci)

Mutations in NRAS and FGFR3 were observed only in the Iranian cohort, while APC mutations were exclusive for the Finnish cohort. Genes involved in MAPK and PI3K-MAPK pathways showed a higher frequency of mutations in Iranian patients which may have therapeutic implications.

1 month ago

Journal

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • FGFR3 (Fibroblast growth factor receptor 3) • FGFR1 (Fibroblast growth factor receptor 1) • STK11 (Serine/threonine kinase 11) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • SMAD4 (SMAD family member 4) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • APC (APC Regulator Of WNT Signaling Pathway) • ERBB4 (erb-b2 receptor tyrosine kinase 4)

TP53 mutation • KRAS mutation • BRAF mutation • NRAS mutation • STK11 mutation • KIT mutation • APC mutation • AKT1 mutation

SYNERGY-AI: Artificial Intelligence Based Precision Oncology Clinical Trial Matching and Registry (clinicaltrials.gov)

P=N/A, N=50000, Recruiting, Massive Bio, Inc. | Trial completion date: Jun 2025 --> Jun 2027 | Trial primary completion date: Dec 2024 --> Dec 2026

1 month ago

Trial completion date • Trial primary completion date

EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ER (Estrogen receptor) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • NRAS (Neuroblastoma RAS viral oncogene homolog) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • FGFR2 (Fibroblast growth factor receptor 2) • PTEN (Phosphatase and tensin homolog) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • BCL2 (B-cell CLL/lymphoma 2) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • STK11 (Serine/threonine kinase 11) • NPM1 (Nucleophosmin 1) • HRAS (Harvey rat sarcoma viral oncogene homolog) • DNMT3A (DNA methyltransferase 1) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • RB1 (RB Transcriptional Corepressor 1) • CLDN18 (Claudin 18) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NF1 (Neurofibromin 1) • JAK2 (Janus kinase 2) • NRG1 (Neuregulin 1) • POLE (DNA Polymerase Epsilon) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • PD-1 (Programmed cell death 1) • CCND1 (Cyclin D1) • MCL1 (Myeloid cell leukemia 1) • KDR (Kinase insert domain receptor) • PBRM1 (Polybromo 1) • BAP1 (BRCA1 Associated Protein 1) • VEGFA (Vascular endothelial growth factor A) • BCL6 (B-cell CLL/lymphoma 6) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • PTCH1 (Patched 1) • FGFR4 (Fibroblast growth factor receptor 4) • MSH6 (MutS homolog 6) • CDK4 (Cyclin-dependent kinase 4) • MSH2 (MutS Homolog 2) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • MAP2K2 (Mitogen-activated protein kinase kinase 2) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • WT1 (WT1 Transcription Factor) • ATRX (ATRX Chromatin Remodeler) • BRCA (Breast cancer early onset) • RAF1 (Raf-1 Proto-Oncogene Serine/Threonine Kinase) • TSC2 (TSC complex subunit 2) • CHEK2 (Checkpoint kinase 2) • PD-L2 (Programmed Cell Death 1 Ligand 2) • ERBB4 (erb-b2 receptor tyrosine kinase 4) • JAK1 (Janus Kinase 1) • FANCA (FA Complementation Group A) • TSC1 (TSC complex subunit 1) • MDM4 (The mouse double minute 4) • POLD1 (DNA Polymerase Delta 1) • CDK6 (Cyclin-dependent kinase 6) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • PARP1 (Poly(ADP-Ribose) Polymerase 1) • AURKA (Aurora kinase A) • JAK3 (Janus Kinase 3) • RICTOR (RPTOR Independent Companion Of MTOR Complex 2) • CHEK1 (Checkpoint kinase 1) • GATA6 (GATA Binding Protein 6) • MSH3 (MutS Homolog 3) • TGFBR2 (Transforming Growth Factor Beta Receptor 2) • GNAS (GNAS Complex Locus) • MYCL (MYCL Proto-Oncogene BHLH Transcription Factor) • AKT2 (V-akt murine thymoma viral oncogene homolog 2) • CCND2 (Cyclin D2) • CCND3 (Cyclin D3) • CSF1R (Colony stimulating factor 1 receptor) • MAP3K1 (Mitogen-Activated Protein Kinase Kinase Kinase 1) • ERCC4 (ERCC Excision Repair 4, Endonuclease Catalytic Subunit) • HDAC1 (Histone Deacetylase 1) • PRDM1 (PR/SET Domain 1) • ZNF217 (Zinc Finger Protein 217) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • GATA3 (GATA binding protein 3) • PARP2 (Poly(ADP-Ribose) Polymerase 2) • PARP3 (Poly(ADP-Ribose) Polymerase Family Member 3) • SDHA (Succinate Dehydrogenase Complex Flavoprotein Subunit A) • ACVR1B (Activin A Receptor Type 1B) • ZNF703 (Zinc Finger Protein 703)

HER-2 mutation • BAP1 mutation • AKT1 mutation • FGFR3 fusion • JAK3 mutation

2ms

Comprehensive molecular and immune profiling of triple negative invasive lobular carcinoma (AACR 2024)

These data suggest that TN-ILC had higher frequency of CDH1, ERBB2, AKT1, ARID1A mutations, higher M2 macrophages and neutrophils and lower M1 macrophages and CD8 T cells infiltration and, lower T cell inflamed signature. High TMB and AR expression can translate into use of immunotherapy (ICI) and AR antagonists in these patients. Additonal analysis to determine the optimal biomarker for ICI response in TN-ILC is needed.

2 months ago

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

HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • ER (Estrogen receptor) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • BCL2 (B-cell CLL/lymphoma 2) • ARID1A (AT-rich interaction domain 1A) • CD8 (cluster of differentiation 8) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • MCL1 (Myeloid cell leukemia 1) • LAG3 (Lymphocyte Activating 3) • KMT2C (Lysine Methyltransferase 2C) • CDH1 (Cadherin 1) • BCL2A1 (BCL2 Related Protein A1) • FOXP3 (Forkhead Box P3) • PMAIP1 (Phorbol-12-Myristate-13-Acetate-Induced Protein 1) • BCL2L10 (BCL2 like 10) • BAK1 (BCL2 Antagonist/Killer 1)

PD-L1 expression • ER positive • TMB-H • MSI-H/dMMR • HER-2 mutation • ARID1A mutation • BCL2 expression • AKT1 mutation • AR expression

PD-L1 IHC 22C3 pharmDx • VENTANA PD-L1 (SP142) Assay

2ms

Genomic Variability Within Intrinsic Subtypes of Advanced Breast Cancer (USCAP 2024)

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.

2 months ago

BRCA Biomarker • Metastases

HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PGR (Progesterone receptor) • BRCA2 (Breast cancer 2, early onset) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • PTEN (Phosphatase and tensin homolog) • FGFR1 (Fibroblast growth factor receptor 1) • RB1 (RB Transcriptional Corepressor 1) • NF1 (Neurofibromin 1) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • SF3B1 (Splicing Factor 3b Subunit 1) • CCND1 (Cyclin D1) • FGF19 (Fibroblast growth factor 19) • FGF3 (Fibroblast growth factor 3)

HER-2 negative • PTEN mutation • MYC amplification • CCND1 amplification • AKT1 mutation • TP53 amplification

Prosigna™ Breast Cancer Prognostic Gene Signature Assay

2ms

BMPR1A G298D Point Mutation is a Recurrent Genomic Event in a Subset of Presumably Sex Cord-Stromal Tumors with Ambiguous Features Between Adult and Juvenile Granulosa Cell Tumors (USCAP 2024)

BMPR1A G298D mutation was exclusively identified in a subset of driverless neoplasms which were classified as granulosa cell tumors (3/27=11%). For BMPR1A-mutant tumors, the overall absence of any detectable known driver mutations supports our hypothesis that this alteration could be an alternative rare tumorigenic mechanism.

2 months ago

Clinical • Stroma

AKT1 (V-akt murine thymoma viral oncogene homolog 1) • GNAS (GNAS Complex Locus) • DICER1 (Dicer 1 Ribonuclease III) • BMPR1A (Bone Morphogenetic Protein Receptor Type 1A) • FOXL2 (Forkhead Box L2)

AKT1 mutation • GNAS mutation

FoundationOne® CDx

3ms

A gain of function mutation in AKT1 increases hexokinase 2 and diminishes oxidative stress in meningioma. (PubMed, Cytokine)

Treatment with the conventional drug of choice AZD5363 (a pan AKT inhibitor) enhanced cell death and diminished HK2 levels in AKT1 mutants...By affecting metabolism, inflammation, and redox homeostasis AKT1-E17K confers a survival advantage in meningioma cells. Our findings suggest that targeting AKT-HK2 cross-talk to induce ROS-dependent cell death could be exploited as novel therapeutic approach in meningiomas.

3 months ago

Journal

AKT1 (V-akt murine thymoma viral oncogene homolog 1) • IL6 (Interleukin 6) • CXCL8 (Chemokine (C-X-C motif) ligand 8) • TLR4 (Toll Like Receptor 4) • HK2 (Hexokinase 2) • IL1B (Interleukin 1, beta) • SOD1 (Superoxide Dismutase 1)

AKT1 E17K • AKT1 mutation

Truqap (capivasertib)

3ms

Single-cell RNA sequencing reveals the mechanism of PI3K/AKT/mTOR signaling pathway activation in lung adenocarcinoma by KRAS mutation. (PubMed, J Gene Med)

The present study provides a basic theory for the activation of the PI3K/AKT/mTOR signaling pathway as a result of KRAS mutations.

3 months ago

Journal

KRAS (KRAS proto-oncogene GTPase) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PDPK1 (3-Phosphoinositide dependent protein kinase 1)

KRAS mutation • PIK3CA mutation • KRAS wild-type • RAS wild-type • AKT1 mutation • KRAS expression

Ibrance (palbociclib)

3ms

Genetic characterization and mutational profiling of foramen magnum meningiomas: a multi-institutional study. (PubMed, J Neurosurg)

These findings provide important insights into the molecular genetics and clinicopathological characteristics of FM meningiomas. The identification of specific genetic alterations associated with tumor location, volume, calcification, histology, and sex at diagnosis may have implications for personalized treatment strategies in the future.

3 months ago

Clinical • Journal

PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • NF2 (Neurofibromin 2) • KLF4 (Kruppel-like factor 4)

PIK3CA mutation • PIK3CA H1047R • PIK3CA E545K • AKT1 E17K • NF2 mutation • AKT1 mutation • PIK3CA E545 • KLF4 K409Q

3ms

Genetic Polymorphisms and Tumoral Mutational Profiles over Survival in Advanced Colorectal Cancer Patients: An Exploratory Study. (PubMed, Curr Oncol)

Additionally, findings from the genomics of drug sensitivity (GDSC) project demonstrated that cell lines with wild-type BRAF have higher IC50 values for 5-FU compared to BRAF-mutated cell lines. In conclusion, the genetic polymorphisms DPYDrs1801265, ABCB1rs1045642, and MTHFRrs180113 may serve as useful biomarkers for predicting a poor prognosis in patients undergoing 5-fluorouracil chemotherapy, regardless of oncogene mutations.

3 months ago

Retrospective data • Journal • Metastases

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • ABCB1 (ATP Binding Cassette Subfamily B Member 1) • MTHFR (Methylenetetrahydrofolate Reductase) • DPYD (Dihydropyrimidine Dehydrogenase)

KRAS mutation • BRAF mutation • NRAS mutation • BRAF wild-type • AKT1 mutation

5-fluorouracil • leucovorin calcium

3ms

Allosteric PI3K-alpha inhibition overcomes on-target resistance to orthosteric inhibitors mediated by secondary PIK3CA mutations (YIR 2024)

Background: PIK3CA mutations occur in ~40% of HR-positive breast cancers, where alpelisib, an orthosteric PI3KÎ± inhibitor, is FDA-approved in combination with fulvestrant... To identify on-target and off-target alterations potentially mediating resistance to PI3KÎ± inhibitors, we used a targeted next-generation sequencing assay (Guardant360; Guardant Health) to analyze ctDNA in serially collected plasma samples from 32 patients with PIK3CA-mutated advanced HR-positive, HER2-negative breast cancer treated with alpelisib and inavolisib...Some mutations had differential effects on PI3Kaselective vs. pan-PI3K inhibitors, but resistance induced by all mutations could be overcome by the novel allosteric pan-mutant-selective PI3Ka-inhibitor RLY-2608... In one of the largest patient cohorts analyzed to date, this study defines the clinical landscape of acquired resistance to PI3Ka inhibitors. Genomic alterations within the PI3K pathway represent a major mode of resistance and identify a novel class of secondary PIK3CA resistance mutations that can be overcome by an allosteric PI3Ka inhibitor. Together, these findings provide insights to guide strategies to overcome resistance in PIK3CA-mutated cancers.

3 months ago

HER-2 (Human epidermal growth factor receptor 2) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog)

HR positive • HER-2 negative • PIK3CA mutation • PIK3CA H1047R • PIK3CA E545K • AKT1 mutation • PIK3CA E545 • PTEN mutation + HR positive

Guardant360® CDx

Piqray (alpelisib) • fulvestrant • RLY-2608 • inavolisib (GDC-0077)

3ms

Safety, Tolerability & Potential Anti-cancer Activity of Increasing Doses of AZD5363 in Different Treatment Schedules (clinicaltrials.gov)

P1, N=285, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2023 --> Dec 2024

3 months ago

Trial completion date • Metastases

ER positive • PIK3CA mutation • PTEN mutation • AKT1 mutation

fulvestrant • Truqap (capivasertib)

3ms

Incongruity between T cell receptor recognition of breast cancer hotspot mutations ESR1 Y537S and D538G following exogenous peptide loading versus endogenous antigen processing. (PubMed, Cytotherapy)

To investigate the basis of this lack of recognition we performed immunopeptidomics analysis of a mutant-overexpressing lymphoblastoid cell line and found that the ESR1 Y537S neopeptide was not endogenously processed, despite binding to HLA-B*40:02 when exogenously pulsed onto the target cell. These results indicate that stimulation of T cells that likely derive from the naïve repertoire with pulsed minimal peptides may lead to the expansion of clones that recognize non-processed peptides, and highlights the importance of using methods that selectively expand T cells with specificity for antigens that are efficiently processed and presented.

3 months ago

Journal • IO biomarker

ER (Estrogen receptor) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • IFNG (Interferon, gamma) • HLA-B (Major Histocompatibility Complex, Class I, B) • HLA-C (Major Histocompatibility Complex, Class I, C)

TP53 mutation • PIK3CA mutation • ER mutation • ER Y537S • ER D538G • ESR1 mutation • AKT1 mutation

4ms

p4EBP1 staining predicts outcome in ER-positive endocrine-resistant metastatic breast cancer patients treated with everolimus and exemestane. (PubMed, Br J Cancer)

This study identified a subset of patients with hormone receptor-positive endocrine-resistant metastatic breast cancer and poor outcome who would derive less benefit from everolimus and exemestane. p4EBP1 may be a useful predictive biomarker in routine clinical practice.

4 months ago

Journal • Metastases

ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog) • STK11 (Serine/threonine kinase 11) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • EIF4EBP1 (Eukaryotic translation initiation factor 4E binding protein 1)

ER positive • HR positive • PIK3CA mutation • PTEN mutation • AKT1 mutation

everolimus • exemestane

4ms

Integrated Molecular Characterization of HER2-Low Breast Cancer Using Next Generation Sequencing (NGS). (PubMed, Biomedicines)

One case of MSI was detected in a HER2-negative and ISH unamplified case. Beside IHC, NGS allows the identification of HER2-low subtype simultaneously, with the detection of multiple actionable gene mutations being helpful for molecular board treatment selection.

4 months ago

Journal • Next-generation sequencing • BRCA Biomarker

HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • AKT1 (V-akt murine thymoma viral oncogene homolog 1)

TP53 mutation • BRCA1 mutation • HER-2 amplification • HER-2 negative • PIK3CA mutation • AKT1 mutation

5ms

Colloid Pattern of Salivary Mucinous Adenocarcinomas With Recurrent BRAF V600E Mutations. (PubMed, Am J Surg Pathol)

Typical morphologic structures, CK7(+), CK20(-), CDX2(-), p63(-), p40(-), MAML2 fluorescence in situ hybridization (-), AR(-), TTF-1(-), S100(-), mammaglobin(-), or S100/mammaglobin(+) with ETV6 fluorescence in situ hybridization (-) immunophenotype, and recurrent AKT1 E17K or BRAF V600E mutations may be defined. To our knowledge, this small series represents the first genetic study on a typical colloid pattern of MA, and our study with the spectrum documentation for MA in clinicopathologic characteristics, histologic and immunophenotypes, molecular features, and clinical behavior will allow for a better understanding of these rare but distinctive tumors.

5 months ago

Journal

BRAF (B-raf proto-oncogene) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • ETV6 (ETS Variant Transcription Factor 6) • NKX2-1 (NK2 Homeobox 1) • CDX2 (Caudal Type Homeobox 2) • TP63 (Tumor protein 63) • MAML2 (Mastermind Like Transcriptional Coactivator 2)

BRAF V600E • BRAF V600 • AKT1 E17K • AKT1 mutation

5ms

Negative hyperselection of elderly patients with RAS and BRAF wild-type metastatic colorectal cancer receiving initial panitumumab plus FOLFOX or 5-FU/LV. (PubMed, Eur J Cancer)

Molecular hyperselection and comprehensive genomic profiling have a potential usefulness in elderly patients with RAS/BRAF wild-type, pMMR/MSS mCRC, eligible for upfront EGFR inhibition.

5 months ago

Journal • Metastases

HER-2 (Human epidermal growth factor receptor 2) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • MET (MET proto-oncogene, receptor tyrosine kinase) • PTEN (Phosphatase and tensin homolog) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • RAS (Rat Sarcoma Virus) • NTRK (Neurotrophic receptor tyrosine kinase)

HER-2 amplification • PIK3CA mutation • MET amplification • PTEN mutation • ALK rearrangement • BRAF wild-type • MET mutation • RET rearrangement • AKT1 mutation • PIK3CA mutation + PTEN mutation • ALK rearrangement + PIK3CA mutation

5-fluorouracil • Vectibix (panitumumab) • leucovorin calcium

5ms

Clinical and genomic landscape of FGFR3-altered urothelial carcinoma and treatment outcomes with erdafitinib: a real-world experience. (PubMed, Clin Cancer Res)

FGFR3 mutations are common in urothelial carcinoma, whereas FGFR2 alterations are rare. Discordance of FGFR3 mutational status between primary and metastatic tumors occurs frequently and raises concern over sequencing archival primary tumors to guide patient selection for erdafitinib therapy. Erdafitinib responses were typically brief and dosing was limited by toxicity. FGFR3, AKT1, and TP53 mutations detected in cfDNA represent putative mechanisms of acquired erdafitinib resistance.

5 months ago

Journal • Real-world evidence • Real-world

TP53 (Tumor protein P53) • FGFR2 (Fibroblast growth factor receptor 2) • FGFR3 (Fibroblast growth factor receptor 3) • AKT1 (V-akt murine thymoma viral oncogene homolog 1)

TP53 mutation • FGFR2 mutation • FGFR2 fusion • FGFR3 mutation • AKT1 mutation • FGFR3 fusion

Balversa (erdafitinib)

6ms

Genetic Characterization and Mutational Profiling of Foramen Magnum Meningiomas: A Multi-Institutional Study (SNO 2023)

Our findings provide important insights into the molecular genetics and clinicopathological characteristics of FM meningiomas. The identification of specific genetic alterations associated with tumor location, calcification, histology, and sex at diagnosis may have implications for personalized treatment strategies in the future.

6 months ago

Clinical

PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • NF2 (Neurofibromin 2) • KLF4 (Kruppel-like factor 4)

PIK3CA mutation • AKT1 E17K • NF2 mutation • AKT1 mutation

6ms

Allosteric PI3K-alpha inhibition overcomes on-target resistance to orthosteric inhibitors mediated by secondary PIK3CA mutations. (PubMed, Cancer Discov)

PIK3CA mutations occur in ~8% of cancers, including ~40% of HR-positive breast cancers, where the PI3K-alpha (PI3Ka)-selective inhibitor alpelisib is FDA-approved in combination with fulvestrant. Some mutations had differential effects on PI3Ka-selective vs. pan-PI3K inhibitors, but resistance induced by all mutations could be overcome by the novel allosteric pan-mutant-selective PI3Ka-inhibitor RLY-2608. Together, these findings provide insights to guide strategies to overcome resistance in PIK3CA-mutated cancers.

6 months ago

Journal

PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog)

HR positive • PIK3CA mutation • AKT1 mutation

Piqray (alpelisib) • fulvestrant • RLY-2608

6ms

Differential dynamics of fragmentomic and epigenetic circulating tumor DNA (ctDNA) features in first-line Palbociclib and Ribociclib treatment for Hormone Receptor (HR) positive, HER2 negative metastatic breast cancer (MBC) (SABCS 2023)

However, the lack of prospective cohorts comparing the distinctions among palbociclib (PAL), ribociclib (RIB) and abemaciclib (ABE) poses a significant clinical knowledge gap. Out of the 114 pts enrolled, 59 received PAL, 48 RIB, and 16 ABE. In the de novo subgroup, 51.4 % of pts were treated with PAL, 42.9% with RIB, and 5.7% with ABE. Among the pts who received PAL, 7 harbored an ESR1 mutation at BL (D538G: 2, H377R: 1, Y537N: 1, Y537S: 3).

6 months ago

Clinical • Circulating tumor DNA • Metastases

HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • CDK4 (Cyclin-dependent kinase 4)

HR positive • HER-2 negative • PIK3CA mutation • ER mutation • ER Y537S • ER D538G • ESR1 mutation • AKT1 mutation • ER Y537N • PTEN mutation + HR positive

Ibrance (palbociclib) • Verzenio (abemaciclib) • Kisqali (ribociclib)

6ms

Molecular and immunological landscape of sex-based differences in breast cancer: a distinct disease in men. (SABCS 2023)

These data indicate that MaBC has a differential mutational frequency, copy number alteration, immune gene expression and immune cell infiltration and overall survival compared to their FeBC counterparts. A better understanding of these sex-based differences with additional research may help inform disease outcomes, provide a rationale for tailored therapeutic approaches and design future treatments. Table 1.

6 months ago

Tumor mutational burden • BRCA Biomarker • MSi-H Biomarker

HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • ER (Estrogen receptor) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • STK11 (Serine/threonine kinase 11) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • ASXL1 (ASXL Transcriptional Regulator 1) • BCL6 (B-cell CLL/lymphoma 6) • KMT2D (Lysine Methyltransferase 2D) • RARA (Retinoic Acid Receptor Alpha) • WT1 (WT1 Transcription Factor) • FGF3 (Fibroblast growth factor 3) • CHEK2 (Checkpoint kinase 2) • CREBBP (CREB binding protein) • RAD51B (RAD51 Paralog B) • TSC1 (TSC complex subunit 1) • HLA-DQB1 (Major Histocompatibility Complex, Class II, DQ Beta 1) • FOXA1 (Forkhead Box A1) • MRE11A (MRE11 homolog, double strand break repair nuclease) • CHD1 (Chromodomain Helicase DNA Binding Protein 1) • PPM1D (Protein Phosphatase Mg2+/Mn2+ Dependent 1D) • FLCN (Folliculin) • IL1A (Interleukin 1, alpha) • AMER1 (APC Membrane Recruitment Protein 1) • DAXX (Death-domain associated protein) • HLA-DQB2 (Major Histocompatibility Complex, Class II, DQ Beta 2)

TP53 mutation • MSI-H/dMMR • HER-2 negative • HER-2 mutation • STK11 mutation • ASXL1 mutation • ESR1 mutation • CREBBP mutation • AKT1 mutation • TSC1 mutation • MHC-II expression • FLCN mutation • RAD51 mutation

6ms

Allosteric PI3K-alpha inhibition overcomes on-target resistance to orthosteric inhibitors mediated by secondary PIK3CA mutations (SABCS 2023)

Background: PIK3CA mutations occur in ~40% of HR-positive breast cancers, where alpelisib, an orthosteric PI3KÎ± inhibitor, is FDA-approved in combination with fulvestrant... To identify on-target and off-target alterations potentially mediating resistance to PI3KÎ± inhibitors, we used a targeted next-generation sequencing assay (Guardant360; Guardant Health) to analyze ctDNA in serially collected plasma samples from 32 patients with PIK3CA-mutated advanced HR-positive, HER2-negative breast cancer treated with alpelisib and inavolisib...Some mutations had differential effects on PI3Ka-selective vs. pan-PI3K inhibitors, but resistance induced by all mutations could be overcome by the novel allosteric pan-mutant-selective PI3Ka-inhibitor RLY-2608... In one of the largest patient cohorts analyzed to date, this study defines the clinical landscape of acquired resistance to PI3Ka inhibitors. Genomic alterations within the PI3K pathway represent a major mode of resistance and identify a novel class of secondary PIK3CA resistance mutations that can be overcome by an allosteric PI3Ka inhibitor. Together, these findings provide insights to guide strategies to overcome resistance in PIK3CA-mutated cancers.

6 months ago

HER-2 (Human epidermal growth factor receptor 2) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog)

HR positive • HER-2 negative • PIK3CA mutation • PIK3CA H1047R • PIK3CA E545K • AKT1 mutation • PIK3CA E545 • PTEN mutation + HR positive

Guardant360® CDx

Piqray (alpelisib) • fulvestrant • RLY-2608 • inavolisib (GDC-0077)

6ms

Comprehensive Genomic and Transcriptomic Analysis of Sclerosing Pneumocytoma. (PubMed, Mod Pathol)

To the best of our knowledge, this is the first comprehensive investigation of the genomic and transcriptomic characteristics of sclerosing pneumocytoma. Results of the present study provide insights on the molecular attributes of sclerosing pneumocytoma and a basis for future studies of this enigmatic tumor.

6 months ago

Journal

SOX9 (SRY-Box Transcription Factor 9)

AKT1 mutation • SOX9 expression

7ms

Meningioma (PubMed, No Shinkei Geka)

The amalgamation of molecular insights with clinical and histological parameters, alongside patient prognosis, holds significant utility in the management of patients with meningiomas. It is anticipated to pave the way for treatments founded on molecular-clinical associations.

7 months ago

Journal

CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • TERT (Telomerase Reverse Transcriptase) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • NF2 (Neurofibromin 2) • SMO (Smoothened Frizzled Class Receptor) • KLF4 (Kruppel-like factor 4)

CDKN2A deletion • NF2 mutation • AKT1 mutation • TERT mutation • SMO mutation • TERT promoter mutation

7ms

Classification and Molecular Diagnosis of Benign Brain Tumors (PubMed, No Shinkei Geka)

Thus, TERT promoter mutation and homozygous deletion of CDKN2A/B should be evaluated to define grade 2 and 3 meningiomas. In mesenchymal tumors, the term "hemangiopericytoma" has been deleted from solitary fibrous tumors.

7 months ago

Journal

CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • TERT (Telomerase Reverse Transcriptase) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • SMO (Smoothened Frizzled Class Receptor) • KLF4 (Kruppel-like factor 4) • HTRA1 (HtrA Serine Peptidase 1) • SH3PXD2A (SH3 And PX Domains 2A)

CDKN2A deletion • AKT1 mutation • TERT mutation • SMO mutation • TERT promoter mutation

8ms

Whole Exome Analysis to Select Targeted Therapies for Patients with Metastatic Breast Cancer - A Feasibility Study. (PubMed, Geburtshilfe Frauenheilkd)

Resulting treatment options were discussed in a tumor board and could be recommended in a small but relevant proportion of patients with metastatic breast cancer (7/18). Thus, this study is a valuable preliminary work for the establishment of a molecular tumor board within the German initiative "Center for Personalized Medicine" which aims to shorten time for analyses and optimize selection of targeted therapies.

8 months ago

Journal • BRCA Biomarker • MSi-H Biomarker • Metastases

HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • PTEN (Phosphatase and tensin homolog) • AKT1 (V-akt murine thymoma viral oncogene homolog 1)

MSI-H/dMMR • PIK3CA mutation • HER-2 mutation • PTEN mutation • AKT1 mutation

8ms

Study of Chemotherapy Plus Ipatasertib for People With Solid Tumors With AKT Mutations, A ComboMATCH Treatment Trial (clinicaltrials.gov)

P2, N=33, Recruiting, National Cancer Institute (NCI) | Initiation date: Sep 2023 --> Dec 2023

8 months ago

Trial initiation date • Metastases

AKT2 (V-akt murine thymoma viral oncogene homolog 2)

AKT1 mutation

paclitaxel • ipatasertib (RG7440)

8ms

DNA Methylation Identifies Epigenetic Subtypes of Triple-Negative Breast Cancers with Distinct Clinicopathologic and Molecular Features. (PubMed, Mod Pathol)

There were no differences in relation to stage, recurrence, and survival. In conclusion, DNA methylation profiling is a promising tool to classify TNBC patients into biologically relevant groups, which may result in better disease characterization and reveal potential targets for emerging therapies.

8 months ago

Journal • BRCA Biomarker • Epigenetic controller

HER-2 (Human epidermal growth factor receptor 2) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • BRCA (Breast cancer early onset)

BRCA2 mutation • BRCA1 mutation • PIK3CA mutation • HER-2 expression • AKT1 mutation • BRCA mutation

9ms

Preliminary Experimental Study on Key Technologies for Early Screening of Gastric Cancer (clinicaltrials.gov)

P=N/A, N=1100, Recruiting, Zhejiang Cancer Hospital

9 months ago

New trial

EGFR (Epidermal growth factor receptor) • 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) • FGFR2 (Fibroblast growth factor receptor 2) • PTEN (Phosphatase and tensin homolog) • HRAS (Harvey rat sarcoma viral oncogene homolog) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • TOP2A (DNA topoisomerase 2-alpha) • IL6 (Interleukin 6) • RNF43 (Ring Finger Protein 43) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • MUC16 (Mucin 16, Cell Surface Associated) • GNAS (GNAS Complex Locus) • PPP2R1A (Protein Phosphatase 2 Scaffold Subunit Aalpha)

KRAS mutation • BRAF mutation • FGFR2 mutation • RNF43 mutation • AKT1 mutation

9ms

CICLADES: CIrCuLAting Dna ESr1 Gene Mutations Analysis (clinicaltrials.gov)

P=N/A, N=146, Completed, Institut de Cancérologie de Lorraine | Active, not recruiting --> Completed

9 months ago

Trial completion • Circulating tumor DNA • Metastases

ER positive • HER-2 negative • PIK3CA mutation • ER mutation • ESR1 mutation • AKT1 mutation • ER positive + HER-2 negative

9ms

Discovering Deleterious Single Nucleotide Polymorphisms of Human AKT1 Oncogene: An In Silico Study. (PubMed, Life (Basel))

This study can be useful for pharmacogenomics, molecular diagnosis of diseases, and developing inhibitors of the AKT1 oncogene.

9 months ago

Journal

AKT1 (V-akt murine thymoma viral oncogene homolog 1)

AKT1 mutation

9ms

Ipatasertib and atezolizumab in cancers with increased PI3K-AKT pathway activity: First results from the CRAFT trial (ESMO 2023)

Conclusions Ipatasertib and atezolizumab were ineffective in this patient population with PI3K-AKT-altered tumors. More stringent molecular selection criteria and an addition trial arm were implemented (arm 5).

9 months ago

PD(L)-1 Biomarker • IO biomarker

BRAF V600E • HER-2 overexpression • HER-2 amplification • PIK3CA mutation • BRAF V600 • PTEN deletion • ALK rearrangement • BRAF V600K • AKT1 E17K • AKT1 mutation • ALK rearrangement + PIK3CA mutation

Tecentriq (atezolizumab) • ipatasertib (RG7440)

9ms

Oxidative phosphorylation is a metabolic vulnerability of endocrine therapy and palbociclib resistant metastatic breast cancers. (PubMed, Nat Commun)

Treatment by the OXPHOS inhibitor IACS-010759 strongly inhibits tumour growth in multiple endocrine and palbociclib resistant PDX. Finally, in ER + BC patients, high expression of OXPHOS associated genes predict poor prognosis. In conclusion, these results identify OXPHOS as a promising target for treatment resistant ER + BC patients.

9 months ago

Journal • Metastases

ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • AKT1 (V-akt murine thymoma viral oncogene homolog 1)

ER positive • PIK3CA mutation • AKT1 mutation

Ibrance (palbociclib) • IACS-010759

10ms

Genomic Landscape of Meningiomas. (PubMed, Adv Exp Med Biol)

In this chapter we will discuss the early cytogenetic and mutational changes uncovered in meningiomas, from the discovery of the loss of chromosome 22q and the neurofibromatosis-2 (NF2) gene to other non-NF2 driver mutations (KLF4, TRAF7, AKT1, SMO, etc.) discovered using next generation sequencing. We discuss each of these alterations in the context of their clinical significance and conclude the chapter by reviewing recent multiomic studies that have integrated our knowledge of these alterations together to develop novel molecular classifications for meningiomas.

10 months ago

Journal

AKT1 (V-akt murine thymoma viral oncogene homolog 1) • SMO (Smoothened Frizzled Class Receptor) • KLF4 (Kruppel-like factor 4)

AKT1 mutation • SMO mutation

10ms

Study of Chemotherapy Plus Ipatasertib for People With Solid Tumors With AKT Mutations, A ComboMATCH Treatment Trial (clinicaltrials.gov)

P2, N=33, Recruiting, National Cancer Institute (NCI) | Initiation date: Mar 2023 --> Sep 2023

10 months ago

Trial initiation date • Metastases

AKT2 (V-akt murine thymoma viral oncogene homolog 2)

AKT1 mutation

paclitaxel • ipatasertib (RG7440)

10ms

Integrated clinical genomic analysis reveals xenobiotic metabolic genes are downregulated in meningiomas of current smokers. (PubMed, J Neurooncol)

In this study, we conducted a comparative analysis of meningioma patients based on their smoking history, examining both their clinical trajectories and molecular changes. Meningiomas from current smokers were more likely to harbor NOTCH2 mutations, and AKT1 mutations were absent in current or past smokers. Moreover, both current and past smokers exhibited a mutational signature associated with DNA mismatch repair. Meningiomas from current smokers demonstrate downregulation of xenobiotic metabolic enzymes UGT2A1 and UGT2A2, which are downregulated in other smoking related cancers. Furthermore, current smokers exhibited downregulation xenobiotic metabolic gene sets, as well as enrichment in gene sets related to mitotic spindle, E2F targets, and G2M checkpoint, which are hallmark pathways involved in cell division and DNA replication control. In aggregate, our results demonstrate novel alterations in meningioma molecular biology in response to systemic carcinogens.

10 months ago

Journal • Tumor mutational burden

TMB (Tumor Mutational Burden) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • NOTCH2 (Notch 2) • UGT2A1 (UDP Glucuronosyltransferase Family 2 Member A1 Complex Locus) • UGT2A2 (UDP Glucuronosyltransferase Family 2 Member A2)

AKT1 mutation • NOTCH2 mutation

10ms

New information about tumours of the salivary glands : WHO classification 2022 (PubMed, Pathologie (Heidelb))

The significance of molecular findings is, however, still largely restricted to diagnostic aspects. Newly included entities include microsecretory carcinoma (defined by an SS18::MEF2C fusion), sclerosing microcystic adenocarcinoma (similar to skin adnexal tumours of the same name) and mucinous adenocarcinoma (characterized by AKT1 mutations with heterogeneous morphology).

10 months ago

Review • Journal

AKT1 (V-akt murine thymoma viral oncogene homolog 1) • MEF2C (Myocyte Enhancer Factor 2C) • SS18 (SS18 Subunit Of BAF Chromatin Remodeling Complex)

AKT1 mutation

10ms

Uncovering the molecular landscape of meningiomas and the impact of perioperative steroids on patient survival. (PubMed, Acta Neurochir (Wien))

The combination of clinical, pathomorphological, and genetic data allows us to characterize the tumor better and assess its prognosis. Corticosteroids perioperatively and peri-meningioma edema were associated with shorter OS, according to our study. Glucocorticoids should be used judiciously for the shortest time required to achieve symptomatic relief.

10 months ago

Retrospective data • Journal

AKT1 (V-akt murine thymoma viral oncogene homolog 1)

NF2 mutation • AKT1 mutation