PIK3CA H1047L

The developed novel multi-marker liquid bead array assay for the simultaneous detection of PIK3CA and ESR1 hotspot mutations in single CTCs is highly specific, highly sensitive, high-throughput, and sample-, cost-, and time-saving. This multi-marker liquid bead array assay can be extended to detect up to 100 mutations in many genes at once and can be applied for bulk CTC and ctDNA analysis.

Background: The VOYAGER-trial compared avapritinib (ava) with regorafenib (rego) in patients (pts) with advanced gastrointestinal stromal tumors (GIST) in a 3rd-line setting. In a 3rd-line setting, pathogenic PIK3CA mutations represent the most common genomic event in an oncogenic KIT signaling intermediate but were found in only 4.7% of pts using ctDNA sequencing. The presence of PIK3CA mutations in plasma did not preclude prolonged disease control to ava or rego. Limitations of this analysis are the small sample size and the possibility of clonal hematopoiesis of indeterminate potential (CHIP) as PIK3CA mutations were not confirmed in tumor samples.

These results demonstrate that the TCR repertoire is associated with characteristics, genetic alterations, and clinical outcomes. Monitoring changes in the TCR repertoire may serve as a prognostic biomarker for breast cancer patients.

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.

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.

P2, N=66, Recruiting, Breast Cancer Trials | N=140 --> 66

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 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.

In 10% of cases, an increase in the number of copies of the EGFR and KRAS genes was found, and in 10% of cases, a fusion gene (RNA) MET- MET.M13M15, TMPRSS2-ERG.The identified genome changes were processed by the server through the FDA, NCCN, EMA, ESMO registries to search for the most appropriate therapy options that exist in world practice for a specific type and localization of the established mutation.ConclusionConclusion. For personalized prescription of targeted drugs, it is more efficient to use multigene diagnostics for a comprehensive study of the mutational status of a tumor.

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.

With the FDA approval of alpelisib, the evaluation of PIK3CA for activating mutations is becoming routinely...Besides, p. H1047R mutation detected by dPCR showed a significant association with breast cancer phenotype (p = 0.019) and lymphatic nodes infiltration (p = 0.046). Digital PCR showed a high sensitivity to detect mutations in tumor samples and it might be capable to detect low-rate mutations and tumor subpopulations not detected by Sanger sequencing.

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.

PIK3CA mutations could be used as an indicator of clinical outcome or targeted therapy for multiple breast cancer subgroups in Northwest China.

The ddPCR results revealed that 32.8% (n=22) of the ctDNA samples contained our target mutation alleles. CTCs were found in 77.2% (17/22) of these mutated samples and NGS results showed 87.5% concordance in analyzed CTCs for our targeted hot spot mutations with ctDNA results from ddPCR. The presence of PIK3CA hot spot mutations detected in both CTCs and ctDNA (n=29) was 86.2% concordant.

Updated analysis of the FAKTION trial data show a significant improvement in OS in the ITT population. Enhanced subgroup analysis suggests that the benefit of capivasertib in both PFS and OS may be predominantly in patients with PIK3CA/AKT1/PTEN pathway altered tumours, but further elucidation will be forthcoming from the ongoing Phase 3 CAPItello-291 study in which participants with PA and PNA tumours have been recruited.

Overall, PIK3CA gene mutations are present in a large number of patients and may help define patient subsets who can benefit from therapies targeting the PI3K pathway. The systematic assessment of PIK3CA gene mutations in HNSCC patients will require further methodological standardisation.

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

A targetable somatic PIK3CA mutation is reported in 30% of IBC, allowing for treatment by PI3Kα-specific inhibitors, such as alpelisib...Our results revealed no prognostic or predictive value of PIK3CA mutations at the diagnosis of non-metastatic IBC but highlighted the prognostic value of the cfDNA rate at diagnosis. Our study showed that a corresponding circulating PIK3CA mutation was identified in 55% of LAIBC patients with PIK3CA-mutated tumours, while no circulating mutation was found among patients with PI3KCA wild-type tumours.

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

CNSide may be a viable platform to detect CSF-TCs, with potential use as a diagnostic tool for LM in patients with metastatic breast cancer. Additional, larger studies are warranted.

These two PIK3CA hotspot mutations therefore not only contribute to tumor progression in patients with MBC but may also serve as targets for the development of novel small molecule therapeutic strategies.

Whole exome sequencing (WES) identified three missense mutations FLT1 [p.R1016G], PIK3CA [p.H1047L], and C11orf42 [p.A304P] and a mitochondrial frameshift insertion MT-ND4 [c.1107_1108insC; p.P370fs]. These WES results suggest that FLT1 and/or PIK3CA variants may contribute to tumor growth/transformation while the MT-ND4 variant may relate to proliferation, angiogenesis and/or inhibition of apoptosis.

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.

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.

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

The median survival on EGFR inhibitors was 24.84m (22.48m including Poziotinib), 27.3m on Alectinib and 10.64m on Immunotherapy. Stage I (n:2) Stage II (n:2) Stage IIIA (n:3) Stage IIIB (n:5) Stage IIIC (n:1) Stage IVA (n:4) Stage IVB (n:8) Curative Intent 1 2 2 3 Surgery/Adjuvant Chemotherapy +/- RT 1 1 Radical RT 1 1 2 Concurrent ChemoRT +/- Durvalumab 2 Recurrence/Progression No Yes Yes Yes Total (n) 1 1 3 Palliative Setting 1 1 2 2 1 4 8 Declined/No further Tx 1 1 2 1 Palliative RT (1st L) 1 1 1 2 Chemotherapy (1st L) 1 1 Chemo + Pembrolizumab (1st L) 1 TKI (1st L) 1 1 1 1 3 Gefitinib 1 1 1 Afatinib 1 1 1 1 Alectinib 1 Immunotherapy (1st L) 1 Nivolumab 1 Pembrolizumab Progression to 1st L No No Yes Yes Yes Yes 2nd Line Tx (n) 2 1 1 2 TKI (2nd L) 1 2 Immunotherapy (2nd L) 1 1 Chemotherapy (2nd L) 1 1 Progression to 2nd L Yes 3rd Line Tx (n) 1 Alive (n:9 - 36%) 1 (50%) 2 (100%) 2 (66%) 0 1 (100%) 0 3 (37.5%) Conclusion PIK3CA mutations did not follow a specific pattern and, despite being associated with other mutations in almost half the cases, they do not seem to influence treatment response or median survival either with TKI or checkpoint inhibitors. Infrequent mutations need to be further assessed to determine their impact while future research should focus on defining the subgroup where inhibitors of the AKT pathway may prove beneficial.

CFS was also longer for abemaciclib + fulvestrant versus placebo + fulvestrant both in PIK3CA mutant (HR: 0.63; 95% CI: 0.39, 1.03) and PIK3CA wild-type (HR: 0.53; 95% CI: 0.35, 0.80). Summary In this exploratory analysis of MONARCH 2, abemaciclib + fulvestant demonstrated benefit in OS, TTC and CFS in patients with and without PIK3CA mutations.

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.

PIK3CA mutations can be detected using liquid biopsy even in patients with no PIK3CA mutations in their primary tumors; thus, combination analysis using tissue and liquid biopsies can provide clinically useful information for patients with breast cancer.

In this phase 2 pilot study, Trastuzumab biosimilar plus Gedatolisib presented 45.5% of response rate with manageable toxicity in patients with HER-2 positive MBC with PIK3CA aberration. Clinical trial information: NCT03698383. This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health &Welfare, Republic of Korea (Grant number: HI17C2206).