PIK3CA E545

The top 10 mutations that most commonly accompanied PIK3CA variations were KRAS, NF1, TP53, EGFR, PTEN, BRAF, KIT, CDKN2A, SMARCA4, and ATM mutations, respectively. PIK3CA variations, along with other gene variations, may influence cancer progression and thus may play a crucial role in the determination of targeted treatment strategies.

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.

The frequent alterations of the PI3K pathway in gynecological cancers could emerge as new treatment target. Our data confirm the high frequency of PIK3CA mutations establishing EC as an ideal candidate for testing of PI3K inhibitors regardless of the TCGA classification. Moreover, these data confirm that other targetable mutations are present also in MSS EC group thus suggesting that new target agents should be explored.

Mutational hotspots are a recurrent feature in both genes which, due to positive selection during tumorigenesis, can be potentially exploited by targeted treatments, as has been demonstrated by the US Food and Drug Administration (FDA)-approved PI3K inhibitor alpelisib in advanced hormone-receptor positive (HR+) breast cancer... The AGENA ClearSEEK PIK3CA and TP53 Panels combine low hands-on time requirements with accurate data assessment, and provide a reliable tool for clinical trial evaluation of known actionable PIK3CA mutations and response to PI3K inhibitors in breast cancer, as well as for investigating the oncogenic activities of TP53 hotspot mutations and patient selection e.g., for cell cycle targeting therapies.

Characterization of the two different approaches in terms of sensitivity results in comparable detection limits (229 copies μL-1 and 224 copies μL-1, respectively), though RPA followed by lambda exonuclease digestion yields significantly higher currents. Finally, this method, together with a designed wild-type blocking oligo that inhibits binding of the wild-type target DNA during probe-target hybridization, allows for detecting the PIK3CA point mutations H1047R, E545K, and E542K in the presence of wild-type target DNA when the proportion of mutant target DNA is >20%.

Background The AKT inhibitor capivasertib was recently approved in the 2L+ setting for patients (pts) with hormone receptor-positive metastatic breast cancer with alterations in PIK3CA, AKT1, and/or PTEN...However, one-third of patients have variants beyond E542, E545, and H1047 with less certainty about targetability. The preponderance of rare PIK3CA mutations and co-occurrences between PIK3CA, AKT1, and PTEN with genes outside the PI3K pathway merits functional investigation.

However, clinical trials have been predominantly carried out with selected populations and single drugs (Palbociclib, Ribociclib or Abemaciclib). At baseline, and considering the pre-defined criteria, ctDNA analysis detected PIK3CA mutations in 32.25% and 44.44% of patients by AVENIO and ddPCR, respectively. ESR1 mutations were detected in 3.22% and 9.37% by AVENIO and ddPCR, respectively. For PIK3CA mutations, the Kappa value was 0.62 (p-value: 0.0004) and 0.47 for ESR1 mutations (p-value: 0.0039).

This study explores the prognostic and predictive role of PIK3CA hotspot mutations in low-risk postmenopausal breast cancer patients randomized to receive tamoxifen or no systemic treatment, followed for over 25 years with extensive clinical records...In conclusion, PIK3CA mutations predominate within the ER+/HER2- subtype, are associated with good clinical markers, and longer DRFI in all patients, especially among highly proliferative and high-risk tumors, but not within ultralow risk patients. Ongoing investigation aims to decipher other factors associated with PIK3CA mutations in patients with indolent tumors who present long-term relapses and may take advantage of new treatment strategies.

Therapies targeting mutations in this pathway approved in conjunction with endocrine therapy include alpelisib, everolimus and capivasertib...She received nab-paclitaxel/atezolizumab for 4 months, letrozole and abemaciclib for 2 months, letrozole alone for 6 months, and letrozole and ribociclib for 6 weeks. Given presence of PIK3CA mutation, 4th line treatment with fulvestrant and alpelisib was planned...After progressing on capecitabine after 2 months, alpelisib with exemestane was initiated...Due to a low ejection fraction despite work with cardiooncology, she was not a candidate for trastuzumab deruxtecan. She progressed on oral cyclophosphamide and methotrexate after 2 months and Sacituzumab govitecan after 3 months...Comprehensive biomarker assessment is needed to identify patients who may benefit from sequential therapies. There is a need for trials comparing therapies that target the PI3K pathway at distinct points, potential sequencing of these therapies, and the optimal sequence strategy.

72 of 84 patients were treated with traditional neoadjuvant chemotherapy plus trastuzumab meanwhile 12 of 84 received neoadjuvant chemotherapy plus trastuzumab and pertuzumab. We would like to acknowledge the contribution of Multispecialistic Biobank Research Core Facilty G-STeP, Fondazione Policlinico Universitario "A. Gemelli" IRCCS (Biobank-FPG) who provided the bioresources.

Additionally, Cas9n improves the specificity of the sensor, accurately distinguishing a pair of base-mismatched sequences, and reducing the occurrence of false positives. Overall, the sensor exhibits excellent selectivity, reproducibility, and potential for early diagnosis of breast cancer.

Multi-hit mutations in PIK3CA are seen in 1.7% of advanced CRC, a meaningful prevalence given the high burden of CRC worldwide, and may represent a subset of patients that have enhanced sensitivity to PI3K inhibition. Future investigation regarding the clinical utility of PI3K inhibitors is warranted in multi-hit PIK3CA CRC.

The developed novel multi-marker liquid bead array assay for the simultaneous detection of PIK3CA and ESR1 hotspot mutations in single CTCs is highly specific, highly sensitive, high-throughput, and sample-, cost-, and time-saving. This multi-marker liquid bead array assay can be extended to detect up to 100 mutations in many genes at once and can be applied for bulk CTC and ctDNA analysis.

PIK3CA co-occurring mutations in other genes may represent distinct subsets of NSCLC. Further elucidation of the roles of PIK3CA hotspot mutations combined with other driver mutations, including EGFR and KRAS, is needed to guide effective treatment in patients with advanced NSCLC.

Considering the recent approval of capivasertib for HR+/HER2- metastatic breast cancer (MBC) harboring PI3K-AKT pathway alts based on tissue NGS, we assessed the concordance of tissue and ctDNA NGS for PIK3CA, AKT1, PTEN as well as ESR1. We identified 367 HR+/HER2- MBC pts treated at MSK with tissue NGS by MSK-IMPACT within 60 days of ctDNA NGS by either Guardant360 or MSK-ACCESS, without intervening therapy... Tissue-ctDNA concordance for the detection of any oncogenic alteration was high for PIK3CA, AKT1, moderate for ESR1, and low for PTEN. More alts were detected in ctDNA for ESR1 and in tissue for PTEN, reflecting acquired ESR1 alts after estrogen deprivation and the current lack of ctDNA assay PTEN copy number loss detection. Additional correlative analyses (e.g.

However, the role of mutated PIK3CA in adenocarcinoma has not been discussed. In addition, mutations occurring in other main members of the PI3K-AKT-mTOR signaling pathway other than PIK3CA were also excluded.

Alpelisib represents an active treatment option in patients with recurrent gynecological cancers harboring a PIK3CA mutation. These findings support the need of biomarker-driven randomized trials of PI3K inhibitors in gynecological cancers.

Conclusions To our knowledge, this is the first AME-specific dataset illustrating that ctDNA NGS can identify PIK3CAm, PTENm, AKT1m, and co-alterations that may inform therapeutic decisions for patients with ABC. Our results indicate a similar prevalence of these mutations in AME and other regions.

The genomic profiling performed using biopsies from young colorectal cancer patients provides a unique ability to identify the potential 'Å“genomic triggers' for the development and progression of cancer in these patients. In this study in addition to known colorectal cancer associated gene mutations we identified recurrent missense mutations in DDR oncogene. This information can be further used to develop not only targeted treatment options for these patients but also to design new screening protocols for identifying high risk patients for optimal surveillance.

When dosed in the HCC1954 tumor model in mice, 17 provided tumor regressions and a clear pharmacodynamic response. X-ray cocrystal structures from several PI3Kα inhibitors were obtained, revealing three distinct binding modes within PI3KαH1047R including a previously reported cryptic pocket in the C-terminus of the kinase domain wherein we observe a ligand-induced interaction with Arg1047.

Our data demonstrate that Nucleic Acid BCT maintains mutant allele frequencies and the plasma transcriptome profile of blood samples during ambient temperature storage. This provides precious sample integrity during whole blood storage and transport, offering laboratories and assay developers reduced preanalytical variability for NGS-based analysis of gene mutations, fusions, indels, and the plasma transcriptome. Nucleic Acid BCT is for Research Use Only.

This study offers insights into the genomic landscape of advanced breast cancer subtypes through liquid biopsy. The observed prevalence of PIK3CA mutations supports the potential efficacy of PI3K inhibitors across these diverse types of breast cancer, laying the groundwork for personalized therapeutic strategies and biomarker identification for prognosis and targeted therapies.

The commercially available Oncolipsy PIK3CA CE-IVD kit is highly sensitive and specific for the detection of four PIK3CA hotspot mutations in primary tumors and plasma-cfDNA.

P2, N=51, Recruiting, GOG Foundation | Not yet recruiting --> Recruiting

Intensive ctDNA quantification improves metastatic breast cancer surveillance and enables individualized risk-based scheduling of clinical care.

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.

Background: PIK3CA mutations occur in ~40% of HR-positive breast cancers, where alpelisib, an orthosteric PI3Kα inhibitor, is FDA-approved in combination with fulvestrant... To identify on-target and off-target alterations potentially mediating resistance to PI3Kα 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.

This study reveals a novel role for the XBS formula in impeding autophagy initiation and demonstrates its potential as a candidate drug to counteract autophagy-induced treatment resistance in NSCLC.

PIK3CA-E542K, ErbB2 amplification, and SMAD4 mutations could be potential biomarkers for PD-1 inhibitors, but a single instance is insufficient to validate the hypotheses. A larger number of patients or more clinical data will be necessary to determine whether these gene mutations are appropriate biomarkers for patients when treatment with PD-1 inhibitors.

P1/2, N=102, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=108, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2024 --> Dec 2024 | Trial primary completion date: Jun 2024 --> Dec 2024

P1, N=108, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

Participants received neoadjuvant paclitaxel with trastuzumab, lapatinib, or both. In ERBB2/HER2-positive EBC, PIK3CA mutations were associated with lower pCR rates and independently associated with worse long-term EFS. These findings appear to be associated with PIK3CA mutations in HR-positive and luminal EBC.

Our study shows the frequency of PIK3CAm and distribution of exons 9 and 20 are similar to those found previously in the literature by Tan (Xie) et al., 2022. Our results demonstrate PIK3CA having a low frequency of MSI-H co-occurrence, higher TMB scores, and increased co-occurring alterations with notable increased in APC, BRAF, EGFR, ERBB2 and KRAS, which may suggest higher genomic instability. Our findings underscore the clinical significance of PIK3CAm in the context of CRC, emphasizing their role as key drivers of oncogenesis, and supports the development of tailored therapeutic strategies such as combining PIK3CAi with immunotherapy or other targeted therapies.

P2, N=66, Recruiting, Breast Cancer Trials | N=140 --> 66

P1, N=108, Recruiting, National Cancer Institute (NCI) | Phase classification: P1b --> P1

Patients with symptomatic residual tumors (N=6, 46%) were treated with targeted therapies (Erdafitinib=3, Trametinib=1, Ponatinib / Everolimus=1, Dasatinib=1) and two patients received Radiation therapy. In summary, cortical tumors bearing FGFR alterations present with refractory seizures and are eminently treatable with surgical resection. Targeted therapy with FGFR specific inhibitors is tolerated well and updated response assessment of our patients will be presented in the meeting.

For patients on genomically-driven targeted therapy and RT combination trials, alterations detected using plasma ctDNA, especially PIK3CA, may be used to rapidly assess eligibility. Serial ctDNA collection may serve as a potential response biomarker with further validation.

These findings strongly encourage further investigation into TCRs targeting driver mutations in MBC, with the aim of advancing neoantigen-targeted TCR-T therapies into clinical trials. Additionally, the PIK3CA_H1047L neoantigen holds great promise as a potential candidate for the development of effective cancer vaccines.

Our results support the PIK3CA determination in tissue as the diagnostic method of choice, although further studies could better define the role of liquid biopsy in the detection of PIK3CAm. In our population, the presence of PIK3CAm confers poorer prognosis in luminal BC, being significantly worse in mutation carriers in exon 9 regardless visceral involvement and plasma mutation detection. Table.

73 of 84 patients were treated with traditional neoadjuvant chemotherapy plus trastuzumab meanwhile 13 of 84 received neoadjuvant chemotherapy plus trastuzumab and pertuzumab. We would like to acknowledge the contribution of Multi-specialistic Biobank Research Core Facility G-STeP, Fondazione Policlinico Universitario "A. Gemelli" IRCCS (Biobank-FPG) who provided the bio-resources.