PIK3CA Q546

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.

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).

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

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.

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.

Taken together, our work provided a comprehensive analysis of driver and targetable alterations in SBA, which can facilitate the practice of precision oncology in this challenging disease.

In this group of HR/HER2 breast cancer patients, common PIK3CA gene mutations account for the vast majority of the mutations. New rare variants in PIK3CA are also identified while their clinical significance needs to be further studied in a large cohort and/or multi-center study.

A smaller fraction of H1047R in blood compared to a tumor indicates its low copy number in circulation. Thus H1047R mutation can be used as a predictive pCR and the development of a specific inhibitor against this mutation may be useful in the fight against this breast cancer subtype.

PIK3CA mutation assays are intended for use as a companion diagnostic test, to aid clinicians in the identification of breast cancer patients who may be eligible for treatment with alpelisib, an alpha-specific PIK3CA inhibitor, based on a PIK3CA mutation detected result... Screening for PIK3CA mutations highlighted the highly diverse mutational status of this gene among breast cancer patients. As the mutational profile of a patient renders them eligible for targeted therapy, an urgent need arises to perform comprehensive next-generation sequencing assays to detect additional hotspot and non-hotspot mutations.

P1/2, N=6, Terminated, David VanderWeele | Trial completion date: Dec 2024 --> Aug 2022 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2023 --> Aug 2022; Funder Decision

P2, N=51, Not yet recruiting, GOG Foundation | Trial completion date: Apr 2025 --> Apr 2026 | Initiation date: Apr 2022 --> Jan 2023 | Trial primary completion date: Aug 2024 --> Apr 2025

P1/2, N=6, Active, not recruiting, David VanderWeele | Recruiting --> Active, not recruiting | N=38 --> 6

The reliability of the experimental results was verified by the qRT-PCR test. The constructed SERS-based analytical micro-platform has great potential in dynamic monitoring of cancer staging and could be used as a clinical tool for early cancer screening.

P1/2, N=38, Recruiting, David VanderWeele | Trial primary completion date: Feb 2022 --> Dec 2023

Somatic hotspot mutations KRAS p.G12C and PIK3CA p.Q546K are associated with colorectal cancers from biallelic MUTYH carriers compared with non-carriers (p = 2 × 10 and p = 6 × 10, respectively). Here, we demonstrate the potential application of mutational signatures to tumor sequencing workflows to improve the identification of biallelic MUTYH carriers.

Detection of these mutations in voided urine samples showed a high specificity (100%) for both genes and a moderate sensitivity: 100% for AKT1 and 66.7% for PIK3CA genes. this study shows clearly that mutations in AKT1 and PIK3CA are rare events and could not be considered as valuable biomarkers for bladder cancer management.

P2, N=11, Completed, NRG Oncology | Active, not recruiting --> Completed

P=N/A, N=200, Recruiting, Novartis Pharmaceuticals | Not yet recruiting --> Recruiting

P2, N=51, Not yet recruiting, GOG Foundation

Alpelisib, an α-selective PI3K inhibitor and degrader, demonstrated efficacy in combination with fulvestrant in the Phase III SOLAR-1 trial in pts with PIK3CA -mut HR+, HER2- ABC. In this study, PIK3CA mut rates, 43.0% in Asia, 44.0% in Europe, 40.9% in LA, and 30.7% in ME, were consistent across regions and closely followed previous reports, supporting the prevalence of this mut outside the trial setting and in a more diverse real-world pt population. The most common PIK3CA muts found in this study were H1047R, E545K, and E542K, consistent with SOLAR-1. PIK3CA mut rates were comparable in primary vs metastatic samples, supporting the existing body of evidence that PIK3CA mut are truncal and can be tested on any available tissue.

56 patients received therapy of inhibitors of cycline-dependent kinase CDK4/6 in combination with Letrosol or Fulvestrant.21 patients received therapy of inhibitors of cycline-dependent kinase CDK4/6 as a first line treatment, 19 patients as a second line treatment, 13 patients as a third line treatment and 3 patients as a forth and more line treatment...Median time of remission in patients who received treatment in an adjuvant setting with standard hormonal therapy - Tamoxifen or aromatase inhibitors Anastrazol or Letrozol is 41 months against 50 months in groups of with mutations and without respectively...Age of onset didn’t influence the detection of mutations in PIK3CA gene. Patients with mutation in Exon9 had less PFS compared to patients without any mutations but the difference is not statistically significant.

P, N=200, Not yet recruiting, Novartis Pharmaceuticals

All the patients received therapy of inhibitors of cycline- dependent kinase CDK4/6 in combination with aromatase inhibitors or Fulvestrant; in all cases they have received prior anticancer therapy and showed progression...Conclusion A mutation in the PIK3CA gene as a part of tumor genesis is a response predictor to treatment of metastatic breast cancer. Patients with a mutation in the PIK3CA gene in comparison with a control group presented worse results of progression free survival.

All the patients received therapy of inhibitors of cycline- dependent kinase CDK4/6 in combination with aromatase inhibitors or Fulvestrant; in all cases they have received prior anticancer therapy and showed progression...Conclusion A mutation in the PIK3CA gene as a part of tumor genesis is a response predictor to treatment of metastatic breast cancer. Patients with a mutation in the PIK3CA gene in comparison with a control group presented worse results of progression free survival.

All the patients received therapy of inhibitors of cycline- dependent kinase CDK4/6 in combination with aromatase inhibitors or Fulvestrant; in all cases they have received prior anticancer therapy and showed progression...Conclusion A mutation in the PIK3CA gene as a part of tumor genesis is a response predictor to treatment of metastatic breast cancer. Patients with a mutation in the PIK3CA gene in comparison with a control group presented worse results of progression free survival.

All the patients received therapy of inhibitors of cycline- dependent kinase CDK4/6 in combination with aromatase inhibitors or Fulvestrant; in all cases they have received prior anticancer therapy and showed progression...Conclusion A mutation in the PIK3CA gene as a part of tumor genesis is a response predictor to treatment of metastatic breast cancer. Patients with a mutation in the PIK3CA gene in comparison with a control group presented worse results of progression free survival.

Cohort A: HR+/HER2- pts receiving fulvestrant (FUL) alone (n = 124) or ALP/FUL (n = 111) in treatment line ≥2L were considered in survival analysis . This study validates the activity of ALP among a diverse real world population, showing pts with PIK3CA mutations have longer rwPFS on ALP/FUL than FUL alone . Pts with SOLAR1m were more likely to be treated with ALP- and tended to be treated in earlier line setting- than pts with OTHERm . No consistent effect in a small subset of pts with OTHERm treated with ALP was observed, but there is evidence that OTHERm may differ in their degree of PI3K activation, oncogenicity, and ALP sensitivity .

Further validation of these mutations using PIK3CA reporter assays led to the identification of several significant hypo-morphic signals in TP53 mutant samples. We defined this phenomenon as mutational mimicry (i.e. mutations in proteins mimicking those in established oncogenes) and we propose it as a tool for predicting tumor sensitivity/resistance to drugs.