PIK3CA C420R

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

Patients had received a median number of 4 (range: 1-16) prior systemic treatments for ABC, including CDK4/6 inhibitor, chemotherapy, fulvestrant and everolimus in 227 (97.4%), 180 (77.3%), 175 (75.1%) and 131 (56.2%) patients, respectively. To our knowledge, this is the largest real-life assessment of alpelisib efficacy. Despite heavy pre-treatments, patients derived a clinically relevant benefit from alpelisib and fulvestrant.

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.

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.

For HR+/HER2- advanced breast cancer patients with disease progression following endocrine-based therapy, the NCCN guideline recommends testing for PIK3CA mutations with tumour or liquid biopsy to identify suitable patients for targeted therapy with alpelisib, an oral α-specific PI3K inhibitor in combination with fulvestrant. The prevalence of PIK3CA mutations and the presence of most common hotspot mutations in exons 20 and 9 was consistent with prior published studies. The clinical relevance of PIK3CA mutations in HER2 +ve BC patients needs further assessment.

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

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

Sixty-eight patients (32%) had at least one PIK3CA mutation detectable in their plasma, and we obtained 83.1% agreement between the cfDNA analysis and the corresponding tumors. The high sensitivity and robustness of these new dPCR assays make them well-suited for rapid and cost-effective detection of PIK3CA mutations in the plasma of MBC patients.

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

Our study reveals the heterogeneity in PI3K-AKT-mTOR pathway among the breast cancer molecular subtypes in our cohort. Moreover, the number and specific sites of PIK3CA mutations have distinct prognostic impact.

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.

Moreover, efficacy evaluation showed significant tumor-regression activity in the BID group of animals compared to the QD (79% versus 43% respectively). Although further studies are needed to evaluate time-dependent drug exposure in tumor and plasma samples, these preliminary findings support the BID clinical schedule of MEN1611 in the B-PRECISE-01 clinical trial (NCT03767335).

We demonstrated that ddPCR offers a highly sensitive and purely quantitative method to measure low MAF with minimal sample input requirements, which highlights the potential use of ddPCR for MRD monitoring. As one possible MRD monitoring approach, NGS panel-based assays may identify all variants at baseline screening, followed by ddPCR as a complementary solution for MRD monitoring of single variants. Currently, there are ongoing efforts in examining longitudinal ctDNA variant changes in CRC patients receiving treatment to further confirm which variants could be used for MRD monitoring in CRC.

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.

Background: Alpelisib (a PI3Kα-specific inhibitor) has demonstrated clinical benefit in combination with fulvestrant and is approved for PIK3CA-mutated, ER +,HER- metastatic breast cancer (MBC) patients who relapsed after aromatase inhibitor (Andre F et al, NEJM, 2019). The ddPCR assay is a very sensitive, rapid, and cost-effective technique for the selection of alpelisib treatment in routine clinical practice. We plan to compare these results to those obtained from matched tumour biopsies.Legal entity responsible for the study: The authors. Funding: La Vannetaise.

Background: Alpelisib (a PI3Kα-specific inhibitor) has demonstrated clinical benefit in combination with fulvestrant and is approved for PIK3CA-mutated, ER +,HER- metastatic breast cancer (MBC) patients who relapsed after aromatase inhibitor (Andre F et al, NEJM, 2019). The ddPCR assay is a very sensitive, rapid, and cost-effective technique for the selection of alpelisib treatment in routine clinical practice. We plan to compare these results to those obtained from matched tumour biopsies.Legal entity responsible for the study: The authors. Funding: La Vannetaise.