PIK3CA N345K

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

PIK3CA is among the most frequently mutated genes in BC (approximately 40% of cases) and its mutations portend sensitivity to PI3K inhibitors, such as alpelisib, in combination with hormonal treatment in HR+/HER2- cases... In our analysis PIK3CA was confirmed to be the most frequently mutated gene (51% of cases); however, due to the specific European regulatory constraints, it was deemed to be actionable in a minority of cases, suggesting that NGS profiling should be performed early on after the diagnosis of metastatic disease, in order to inform the overall therapeutic strategy. Other potentially actionable alterations (FGFR1/2, AKT, HER2 ex 20 mutations) emerged from extended NGS profiling, suggesting its potential utility in selected HR+/HER2- mBC pts.

However, intriguingly, ResolveOME™ uncovered cells of stem-like identity harboring PIK3CA missense mutations as well as uncovered cells still formally identified as epithelial and harboring mutant PIK3CA but with differential expression profiles—indicative of cells morphing cell state. Finally, the TotalSeq™ antibody panel unveiled intercellular heterogeneity and interpatient heterogeneity both in cell-surface protein phenotype of immune cells and in epithelial identity and signaling.This ongoing study continues to catalog the three omic layers in increasing numbers of single cells and significantly expanding targeted surface-protein analysis harnessing the power of the single-cell united data to determine the “penetrance” of genomic changes in the context of cognate transcript and protein information, with the ultimate goals of defining DCIS to IDC transition factors as well as novel biomarker identification that may be exploited therapeutically.

We identified pts with EGFR mutations or ALK rearrangements who developed PIK3CA/PTEN alterations in tissue biopsy and/or circulating tumor DNA upon progression to first-line osimertinib/alectinib. Activating PI3KCA mutations and molecular events leading to PTEN loss are frequent events at resistance to first-line EGFR/ALK TKIs, and can be detected concomitantly. Functional assays confirmed that these alterations act as resistance mechanisms. These observations are of interest as PI3KCA/mTOR inhibitors may have a role in overcoming resistance.

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.

For germline BRCA1-mutated breast cancer, TP53 R175H was unanimously the most frequent mutation among the three germline cohorts. Our study provides lists of potential shared neoantigens among BRCA1-related breast cancer, which may be used in developing off-the-shelf neoantigen-based vaccines.

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

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.

Background: Alpelisib (PIQRAY®) in combination with fulvestrant was approved by the US- FDA in May of 2019 for patients with hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) PIK3CA mutant advanced or metastatic breast cancer (aBC or mBC) following progression on aromatase inhibitors. This retrospective study demonstrates that 38% of mBC patients’ cancers across all sub-types harbored a PIK3CA mutation where multiple testing platforms were utilized in the community setting. Approximately 30% of patients with HR+/HER2-/ PIK3CA mutant status did receive alpelisib. Co-morbidities and other clinically relevant factors between PIK3CA mutant patients who did and did not receive alpelisib, such as those on oral diabetes medication, insulin or had elevated HgbA1c, should be studied further.

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.

Taken together, 17% (20/118) of ESCC patients harbored mutations in the NFE2L2/KEAP1/CUL3 pathway, which may be eligible for clinical trials of glutaminase inhibitor telaglenastat...Furthermore, 11.9% (14/118) patients carried activating PIK3CA mutations including N345K, E542K, E545K, M1043I and H1047R which may be targeted by PIK3CA inhibitor alpelisib... Our findings indicated that amplification of the 11q13 amplicon and dysfunction of the KEAP1-NRF2-CUL3 axis are the major driving events of ESCC . The results of genomic profiling can guide physicians to enroll a significant portion of ESCC patients into genomically matched clinical trials.

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 .