PIK3CA E545A

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).

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.

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

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

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

KEY POINTS: Brain metastasis from endometrial primary is rare, and histopathological features may be augmented with molecular analysis to aid in diagnosis. Comparison of the molecular makeup of the primary endometrial lesion with the metastatic lesion may reveal high-risk molecular features that may be indicative of metastatic potential.

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.

The findings of this pilot study suggest that the presence of a PI3K mutation in liquid biopsy correlates with a worse PFS in patients with ABC receiving CDK4/6i, and that liquid biopsy is a useful tool to suggests a better tailored pharmacological intervention.

Recently, alpelisib, a PI3Kα inhibitor, combined with hormonotherapy has improved progression-free survival in mutated advanced luminal BC... In our cohort, a wide spectrum of PIK3CA mutations was found in patients with metastatic breast cancer, suggesting the clinical relevance of molecular screening. Double PIK3CA mutations were identified in 15.8% of mutant tumors and maybe related to higher sensitivity to PI3K inhibitors. E545D mutation was always associated with a second mutation suggesting a different biological behavior.

The presence of phosphatidylInositol-4,5-bisphosphate 3-Kinase catalytic subunit alpha p.E545A mutation was detected in plasma. This approach may suggest the use of liquid biopsy and the development of specific targeted therapy for precision personalized medicine even in rare carcinosarcomas.