PIK3CA amplification

Using integrative analysis, we also detected recurrent alterations in the WNT, TGFB, TP53, IGF2/PI3K, and RTK/RAS pathways. Our study thus advances the molecular profiling of CRC in Hispanics and Latinos; suggests precision medicine therapeutics can be tailored to an underrepresented community; and demonstrates genetic similarity can be an important component in understanding colorectal carcinogenesis.

Importantly, co-targeting N-cadherin and p110α/AKT caused additive reduction in cell migration in vitro and metastases formation in vivo. Together, this study reveals the molecular pathways driven by the PIK3CA aberrations and the exploitable vulnerabilities in PIK3CA-aberrated serous ovarian cancer cells.

Among patients with advanced BTC, ctDNA-based genotyping showed acceptable concordance with tissue genomic profiling. Liquid biopsy using ctDNA could be a valuable complement to tissue-based genomic analysis in BTC.

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

This study underscores the potential of ctDNA as a predictive and prognostic biomarker for patients with HER2-mutated advanced-stage solid tumors treated with neratinib and trastuzumab. The presence of HER2 mutations in ctDNA generally matched those in tumor tissues, and elevated ctDNA fractions were linked to poorer outcomes. Further research is necessary to validate the role of ctDNA in optimizing anti-HER2 therapy for HER2-mutated tumors.

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

PIK3CA is also prevalent in MpBC and potentially targetable. Our findings may inform the development of novel targeted therapeutic regimens and improve outcomes for this rare but aggressive breast cancer subtype.

Remarkably, PIK3CA amplification was found to be an independent cancer predictor. Furthermore, combined PIK3CA and SOX2 amplification is emerging as a valuable and easy-to-implement tool for cancer risk assessment in patients with laryngeal precancerous lesions beyond current WHO histological grading.

P2, N=100, Not yet recruiting, Nationwide Children's Hospital | Trial completion date: Aug 2033 --> Jan 2034 | Initiation date: Aug 2023 --> Jan 2024 | Trial primary completion date: Aug 2027 --> Jan 2028

We observed enrichment of genetic aberrations of DNA damage response pathway (TP53 and CDKN2A/B), and a significant increase in MCL heterogeneity. We identified LRP1B inactivation as a new potential driver of MCL relapse.

However, PI3K exhibits opposing effects on Wnt/β-catenin signaling in distinct tumor subsets, whereby PI3K promotes Wnt/β-catenin activation in ER+ cancers, but paradoxically suppresses this pathway in ER- breast cancers. This review discusses the molecular mechanisms for PI3K-Wnt crosstalk in breast cancer, and how Wnt-targeted therapies have the potential to contribute to treatment regimens for breast cancers with PI3K dysregulation.

Tumor genomic profiling can facilitate the selection of targeted/immunotherapies, as well as clinical trial enrollment, for patients with cervical cancer.

The combination of anlotinib and osimertinib might be an efficacy and safety treatment option for patients with EGFR T790M mutation who have failed prior EGFR-TKI. Dynamic changes of ctDNA could be used to monitor treatment response and to explore mechanisms of acquired resistance to therapy.

Potency of HMBD-001 to inhibit tumor growth as monotherapy or in combination with cetuximab and/or docetaxel was evaluated using murine CDX and PDX models. An analysis of copy number variations and expression of genes in Chr3q, Chr3p and Chr7p confirms that genes involved in HER3 signaling are frequently amplified and have higher expression in squamous compared to non-squamous NSCLC. Several genetic alterations in sqNSCLC lead to HER3 and EGFR pathway activation. HMBD-001, a potent anti-HER3 mAb, in combination with EGFR inhibition and chemotherapy, has the potential to greatly improve clinical outcomes following immune-chemotherapy. Hummingbird Bioscience plans to initiate Phase Ib clinical trials in biomarker selected populations of sqNSCLC in H2, 2023.

Based on NGS and PD-L1 IHC, gene mutation, TMB and PD-L1 expression are analyzed. Cox single factor and PFS are used to verify that these molecular markers are independent of TMB and PD-L1 for targeted therapy of lung cancer.

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.

In the present paper, we describe two clinical cases in which patients harboring PIK3CA-amplified TNBC received a targeted treatment with the mTOR-inhibitor everolimus and the PI3K-inhibitor alpelisib, respectively, with evidence of disease response on 18F-FDG positron-emission tomography (PET) imaging. Hence, we discuss the evidence presently available regarding a possible predictive value of PIK3CA amplification for response to targeted treatment strategies, suggesting that this molecular alteration might represent an intriguing biomarker in this sense. Considering that few of the currently active clinical trials assessing agents targeting the PI3K/AKT/mTOR pathway in TNBC select patients based on tumor molecular characterization, and none of these based on PIK3CA copy number status, we urge for the introduction of PIK3CA amplification as a criterion for patient selection in future clinical trials in this setting.

P2, N=100, Not yet recruiting, Nationwide Children's Hospital

PI3K/mTOR dual inhibition, PI3Kalpha inhibitor, AKT inhibitor, FGFR inhibitor, ALK/IGF1R inhibitor, CDK4/6 inhibitor, BCl2 inhibitor, WEE1 inhibitor, ATR inhibitor, DNA-PK inhibitor, AT2AR inhibitor, Mcl-1 inhibitor, MEK1/2 inhibitor, EZH2 inhibitor, HDAC inhibitor, CDK9 inhibitor, DNMT3 inhibitor, BRD4/BET inhibitor, JAK2 inhibitor, CXCR4 inhibitor, FAK inhibitor, BTK inhibitor, eribulin, & VEGFR2/ PDGFR/FGFR or VEGFR2/c-MET/Axl triple blockage might be effective on TW2.6 and reverse treatment refractoriness, maybe through the inhibition of mesenchymal transformation, pRB, & PI3K/AKT /mTOR signaling and the modulation of stemness & PD1/PDL1 pathway...All cell lines will be tried to be categorized as TCGA subtypes for the reference of future drug combinations.Cell linesSCC25KBSASCAL27FaDuSCC15SCC9SCC4TW2.6Differ- entiationWellPoorPoorPoorPoorWellWellWellWell, but rapidly replicated, with high hyper-diploidy & complex rearrangementsHPV statusHPV 16/18HPV18--HPV 16/18--HPV 6/11-EGFR statusMediumLowHighHighMediumHighLowMedium to highUnknownDocetaxel sensitivity+++++++++++++ to +++++-+Cisplatin sensitivity+++++++++++++- to +-- to +5-FU sensitivity+++++++++++-+ to ++-- to +Afatinib sensitivity+++- to +-+++++ to +++++++++-Polo-like kinase Inhibitor sensitivity+++++++++++++ to +++- to +-- to +VEGFR2 Inhibitor sensitivity----+++++--++PI3K/ mTOR inhibitorAll cell lines sensitiveCDK4/6 Inhibitor response+++- to ++++++ to +++++++++++++ to +++Western blotsWeak p-AKT & VEGF-A, mild PDL1 and BMI-1, Gli-1(+)Weak p-AKT, mild PDL1 and strong VEGF-A & BMI-1, p16(+)Moderate p-AKT & BMI-1, high PDL1, mild VEGF-AHigh p-AKT & VEGF-A, mild PDL1 & BMI-1High VEGF-A, moderate p-AKT & PDL1, weak BMI-1, Gli-1(+)Weak p-AKT & VEGF-A, mild PDL1 & BMI-1Weak p-AKT, VEGF-A, & BMI-1, moderate PDL1Moderate p-AKT & VEGF-A, strong BMI-1, mild PDL1, Gli-1(+)High p-AKT, PDL1, & VEGF-A and moderate BMI-1NGSCCND1 gain, CDKN2A deletion, FRG1 mutation, HGF mutation, p53 mutation, ATR mutation, SMO mutation, RUNX1T1 mutationSTK11 mutation, PDGFRA mutation, IGF1 mutation, BCOR mutation, EGFR mutation, NOTCH1 mutation, MET mutation, IKZF1 mutation, NFKB1 mutation, DPYD mutation, FGFR4 mutation, BRCA1 mutation, MSH2 mutation, DNMT3A mutationKRAS mutation, MDM2 mutation, TMB-H, AXIN1 loss, RAD51D mutation, NOTCH1/2 mutation, ERBB4 mutation, PALB2 mutation, p53 mutation, POLE mutation, CASP8 mutation, BRCA2 mutation, RNF43 mutation, LRP1B mutation, MET mutationCDKN2A deletion, EGFR amplification, SMAD4 mutation, TMB-H, LRP1B mutation, APC mutation, CASP8 mutation, CREBBP mutation, PIK3CG mutation, NRAS mutation, ABL1 mutation, FGF23 mutation, HGF mutation, ATRX mutation, p53 mutation, ERBB2 mutation, ROS1 mutation, EP300 mutation, NRAS mutation, CDKN1A mutation, KDM6A mutation, FLT4 mutationCCND1 gain, CDKN2A deletion, FLCN mutation, TMB-H, LRP1B mutation, SMAD4 loss, SF3B1 mutation, FAT1 mutation, VHL mutation, NOTCH3 mutation, EPHA5 mutation, p53 mutation, ERCC2 mutationCCND1 gain, EGFR amplification, SMO mutation, ATR mutation, FAT1 loss, NTRK1 mutation, KMT2D mutation, p53 mutation, NOTCH3 mutationCDKN2A deletion, AXIN2 amplification, SMAD3 loss, HRAS mutation, ATR mutation, NF1 mutation. IGF1R mutation, FLCN mutation, KEAP1 mutation, ASXL1 mutation, PMS2 mutationCCND1 gain, NF1 loss, LRP1B mutation, NSD1 mutation, KMT2D mutation, p53 mutation, EPHA2 mutationFAT1 loss, CCND3/FGF10 amplification, PIK3CA H1047R mutation, STK11 mutation, RICTOR/FLCN amplification, VEGF-A amplification , TSC2 mutation, EPHB1 mutation, MAP2K4 mutation, KDM5A mutation, PDGFRB mutation, SETD2 mutation, RPTOR mutation, APC mutation, DDR2 mutation, ATM mutation, MDM2 mutation, p53 mutation, CDK12 mutation, HRAS mutation, MYC mutation, CDK8 mutation, ARID1B lossOutcomesBest; like TCGA CL (HPV+) subtypeLike TCGA basal subtype, but responded to particular treatments eachBasalBasalLike TCGA mesen-chymal subtype (HPV+)Like TCGA CL(HPV-) subtype, different characters between these 3 cell linesCL(HPV-) subtypeCL(HPV-) subtypeWorse; like TCGA EMT subtype (HPV-)Potential treatmentsAll sensitive maybe; Hedgehog inhibitor , HGF/c-MET inhibitor, and I/O could be tried(1) Taxane, cisplatin, PLKi (2) mTORi (3) IGF1Ri, METi, PDGFRi, FGFRi (4) Epigenetics (5) I/O(1) Taxane, cisplatin, 5-FU, PLKi (2) CDK4/6i (3) I/O (4) DDRi (5) KRASi, METi, HERi (6) p53 reactivator and MDM2/Mcl-1 inhibitor(1) Taxane, cisplatin, 5-FU, PLKi (2) CDK4/6i (3) Mild EGFRi response (4) I/O (5) NRASi, FGFRi, HGF/c-METi/ROS1i/HERi (6) p53 reactivator/DDRi/Epigenetics(1) Cisplatin, 5-FU (2) EGFRi and VEGFR2i (3) Weak to PLKi & CDK4/6i (4) I/O (5) mTORi (6) Ephi (7) DDR/Epigenetics (8) p53 reactivator (9) HIFi(1) Taxane and PLKi (2) EGFRi, VEGFR2i, CDK4/6i (3) NTRKi (4) Hedgehog inhibitor (5) DDRi, epigenetics,& p53 reactivator(1) Taxane &5-FU (2) EGFRi (3) HRASi (4) DDRi/Epigenetics (5) I/O (6) IGF1Ri (7) mTORi(1) EGFRi (2) CDK4/6i (3) I/O (4) Epigenetics (5) Ephi (6) p53 reactivator(1) CDK4/6 inhibitor (2) Multi-targeted VEGFR TKI (3) PI3K/AKT/mTOR inhibitor (4) ICIs combination (5) p53 reactivator/ DDR interventions/Epigenetics (6) Dasatinib, HRASi, EphB1/B4 interventions Further NGS analysis may translate these HNSCC cell lines to represent TCGA subtypes for the reference of future drug combinations, esp... Further NGS analysis may translate these HNSCC cell lines to represent TCGA subtypes for the reference of future drug combinations, esp. immunotherapy, basic/translational research, and animal models. LRP1B will be a potential ICIs efficacy biomarker in HNSCC.

Here, we present the course of diagnosis and treatment of a patient with advanced SqCLC, harboring not only CDKN2A mutation but also PIK3CA amplification, Tumor Mutational Burden-High (>10 mutations/megabase), and a Tumor Proportion Score of 80%. After disease progression on multiple lines of chemotherapy and immunotherapy, he responded favorably to treatment with the CDK4/6i Abemaciclib and later achieved a durable partial response to immunotherapy rechallenge with a combination of anti-PD-1 and anti-CTLA-4, nivolumab, and ipilimumab.

To validate the conformational change of PIK3CA and TP53, 80% mutation of H1047R in the kinase domain of p110α expressed ubiquitously in PIK3CA protein that alters PI3K pathway, while R282W mutation in DNA binding helix (H2) region of P53 protein inhibits the transcription factor in P53 pathway causing MBC. According to our findings, the extrinsic (hypoxia, oxidative stress, and acidosis); intrinsic factors (MYC amplification) in PIK3CA and TP53 mutations will provide potential insights for developing novel therapeutic methods for MBC therapy.

Activating driver mutations were identified in invasive cancers only. High mutational load correlated with metastases, which in turn represented clonal disease.

T-DM1 appears to overcome HER2 resistance. T-DM1 benefit does not appear dependent on immune activation, but these results do not rule out an influence of the tumor immune microenvironment on degree of response.

These results were obtained from a TCGA cohort mainly composed of Caucasians (69.7%) and patients with early-stage LUSC (98.7%). We are evaluating the prognostic and predictive value of MCR AMP in a diverse patient population of advanced LUSC patients.

The genomic profiling of Brazilian NSCLC indicated actionable mutations and remarkable genomic amplifications and deletions. Our results may contribute to improve the knowledge about the molecular profile of admixed patients.

As we previously reported, incidence of RAS and BRAF heterogeneity were 10% and 4%, respectively. Heterogeneity of RAS and BRAF mutations had no effect on the response rate of EGFR blockade as first line chemotherapy. Other possible causes of resistance could be MET or HER-2 amplification, PIK3CA mutation, or ALK fusion.

Targetable alterations and oncogenic rearrangements are enriched in KRAS wt PDAC compared to KRAS mut. These analyses provide additional therapeutic options and may improve outcomes for KRAS wt patients, warranting blood-based ctDNA genomic profiling in PDAC, especially when a tissue biopsy is not feasible or sufficient for comprehensive genomic profiling.

PIK3CA amplifications were more common in diffuse-type GC with early recurrence, while ARID1A mutations were more common in patients with single-site recurrence. Targeted therapy and immunotherapy might be helpful for these patients.

" WES and RNA-Seq were performed on 54 tumor samples from 49 patients with R/R DLBCL receiving CART19, either axicabtagene ciloleucel (n = 30), tisagenlecleucel (n = 18), or lisocabtagene maraleucel (n = 1). Integrated molecular analysis of the LME and genomic alterations provides valuable information about correlative biomarkers for response to CART19 immunotherapy in DLBCL patients. With this cohort, PIK3CA amplification corresponded to improved PFS in DLBCL. We observed increased MHCII expression and centrocyte-like cells in GCB DLBCL CART19 responders, while SMAD1 was higher in ABC responders."

The present study elucidated the differential benefits of afatinib within different mutation genotypes and first revealed the spectrum of potential resistance mechanisms in patients with EGFR G719X/L861Q/S768I. The results of this study may provide practical clinical information that can guide optimal treatment in this setting.

Testing with in vivo models of each drug combination has thus far confirmed that each is synergistic per CDI metrics. Those combinations are currently being tested for efficacy in the metastatic setting with a set of basal-like PDXs.

P4, N=6, Completed, Samsung Medical Center | Unknown status --> Completed | N=25 --> 6

Mucinous histology is associated with diminished benefits from anti-EGFR therapy in patients with left-sided RAS/BRAF wild-type colorectal cancer. These patients should be considered for bevacizumab-based therapy in the first- and second-line settings.

This study provides insights into the systematic combinatory effect associated with CDK4/6 inhibition and supports further initiation of clinical trials using the palbociclib plus alpelisib combination in HPV HNSCC with PIK3CA alterations.

PIK3CA exon 20 mutational signatures in Egyptian BC patients could suggest a disease etiology involving homologous recombination deficiency (HRD) and polymerase eta (Pol η). Nucleotide substitution patterns could indicate the role of exposure to oxidative stress and some carcinogens such as 4-aminobiphenyl and Aristolochic acid.

Activating PIK3CA mutations occur frequently across cancer types and could be considered for tissue-agnostic drug development. PIK3CA fusion and amplification events are extremely rare. Most PIK3CA missense mutation variants are described as oncogenic, while fusions are described as VUS, which may limit the impact of precision oncology for patients with this alteration.

No abstract available

In our large cohort study, we present the landscape of EGFR+ dual drivers and their associated clinical and genomic features and survival outcomes, which could aid in therapeutic decisions and facilitate the development of combination therapies.

All observed/available data among each cohort will be evaluated before choosing the combination dose for a subsequent cohort. The trial opened for enrollment in October 2021.