PIK3CA E545

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.

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.

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.

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.

We observed concordance and heterogeneity in the status of actionable mutations between the CSF, peripheral blood, and systemic metastatic tumor tissue. Larger studies are needed to assess the clinical utility of these observations, particularly with the development of several novel targeted agents that are CNS-penetrant.

Patients with ER+/HER2- advanced or mBC who previously had 1-2 lines of endocrine therapy, and prior CDK4/6i, were randomized 1:1 to receive elacestrant or SOC (aromatase inhibitor or fulvestrant). Elacestrant showed significantly greater PFS when prior treatment duration with CDK4/6i was at least 12 months, suggesting prior exposure to CDK4/6i is a surrogate marker for endocrine sensitivity. In this population, elacestrant demonstrated superior efficacy, compared to SOC, even in patients with concomitant PIK3CA or TP53 mutations, expression of HER2 low, or presence of liver and/or lung metastases. These results suggest an active ER-driven pathway for this group despite the presence of other resistance mechanisms, where single-agent oral elacestrant could be an attractive option compared to combination therapies or intravenous HER2 low-targeted ADCs.

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 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.

We developed a comprehensive multiplex mutant detection method with high sensitivity and specificity. This study demonstrates the strong potential of Absolute Q dPCR as a powerful multiplex platform for early mutation detection and monitoring in liquid biopsy samples.

Here, we report a case that continuous pembrolizumab monotherapy treatment induced complete remission of a recurrent cervical cancer patient with systemic metastasis and PIK3CA-E545K mutation, implying that PIK3CA mutation is potentially a biomarker for pembrolizumab treatment in cervical cancer...PIK3CA mutations may predict the response of cervical cancer to PD-1 blockade. The efficacy of PI3Kα inhibitors combined with PD-1 antibodies is promising in cervical cancer and warrants additional clinical and mechanistic investigations.

At the same time, the PIK3CAE545 mutation occurred with the same frequency between the two groups of RV patients. Conclusions Thus, this study showed that the presence or absence of human papillomavirus dramatically affects tumor differentiation.

BKPyV tumor positivity in the NMIBC subset with FGFR3- or PIK3CA-mutated tumors was also associated with a higher risk of progression to MIBC (p=0.019). In conclusion, our results support smoking and BKPyV infection as risk factors contributing to bladder tumorigenesis in the general patient population through distinct molecular mechanisms.

Our data show that an MS approach can be used to demonstrate which shared oncogene-derived neoepitopes are processed and presented by common HLA alleles, and those MS data can rapidly be used to develop TCRs against these common tumor-specific antigens. Although further characterization of these neoepitope-specific murine TCRs is required, ultimately, they have the potential to be used clinically for adoptive cell therapy.

Although additional basic researches and clinical trials are necessary, various inhibitors may be effective therapeutics for PIK3CA mutation-positive cSCC. Our study revealed the prevalence of PIK3CA mutations in cSCC.

In patient-derived models, erdafitinib was synergistic with pictilisib in the presence of PIK3CA E545K, whereas erdafitinib-gefitinib combination was able to overcome bypass resistance mediated by EGFR activation. Eleven (52%) patients harbored alterations in the PI3K-mTOR pathway (n = 5 TSC1/2, n = 5 PIK3CA, n = 1 NF2, n = 1 PTEN). In patient-derived models, erdafitinib was synergic with pictilisib in the presence of PIK3CA E545K, while erdafitinib-gefitinib combination was able to overcome bypass resistance mediated by EGFR activation.

The secondary endpoints were to decipher the mutation types across breast cancer subtype, menopausal status, and time to treatment failure after everolimus (an mTOR inhibitor) or cyclin-dependent kinase 4/6 (CDK4/6) inhibitor treatment...A high frequency of PIK3CA mutations was detected in Taiwanese patients with breast cancer, which was consistent with previous studies. Early detection of PIK3CA mutations might influence therapeutic decisions, leading to better treatment outcomes.

Statistically significant increase in the frequency of exon 9 mutations of the PIK3CA gene is specific for the group of patients with Her2-low BC. Our results supported the concept of Her2-low BCs as the unique entity and pointed out the need of their further study.

Multifactorial analysis showed that TP53 mutation (HR 2.198, 95% CI 1.006-4.803; P = 0.048) and RB1 mutation (HR 8.798, 95% CI 1.604-48.269; P = 0.012) were independent risk factors for PFS with first-line targeted therapy. Conclusions This research added to the evidence that co-alterations such as TP53, MET, and RB1 are prospective prognostic biomarkers in NSCLC patients treated with EGFR-TKI.

Table: 439P PIK3CA mutation results of HeSMO's program Conclusions In our series, 40.94% of the patients tested, were detected with mutations in PIK3CA gene, in accordance with published data. Apart from the significant implications for treatment possibilities in a substantial patients' population, these results provide valuable epidemiological data and strengthen our efforts for reimbursement of PIK3CA mutation testing in Greece.

Table: 495P Conclusions Our results support the determination of PIK3CA in tissue as the diagnostic method of choice, although further studies are needed to assess the role of liquid biopsy in the detection of PIK3CAm. In our population, the presence of PIK3CAm confers worse prognosis in luminal BC, being significantly worse in mutation carriers in exon 9 regardless visceral involvement.

Methods We studied a unicentre cohort of 262 patients with steroid hormone receptor-positive, HER2-negative eBC, who were planed to be treated with endocrine therapy only: aromatase inhibitor (AI, n=183) or Tamoxifen (TAM, n=69), AI and TAM (n=9), Fulvestrant (n=1) and tested the three most common somatic PIK3CA gene mutations (H1047R, E545K, E542K) by qPCR. Conclusions Although we observed a trend that AIs are less effective in patients with PIK3CA mutated tumours, formal validation is still lacking. Further data including prospective studies are required.