Abstract P1-05-27: Analytical comparison of tissue-based next-generation sequencing assays for the detection of PIK3CA, AKT1, and PTEN tumor alterations in breast cancer

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Abstract Background: Next-generation sequencing (NGS) testing in patients with advanced breast cancer (ABC) enables genomic biomarker interrogation, potentially guiding clinical management. Results from the CAPItello-291 Phase 3 randomized trial led to the approval of the first-in-class pan-AKT inhibitor capivasertib in combination with fulvestrant as a treatment option in patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative ABC, with one or more PIK3CA/AKT1/PTEN tumor alterations following disease progression on/after prior aromatase inhibitor therapy. PIK3CA/AKT1/PTEN alterations are present in approximately 50% of all HR-positive/HER2-negative breast cancers and also in around 30% of all triple-negative breast cancers (TNBC). This study aimed to analytically compare the ability of commercially available tissue-based NGS assays to detect PIK3CA/AKT1/PTEN tumor genomic alterations in breast cancer samples. Methods: Formalin-fixed, paraffin-embedded tumor samples collected from patients with TNBC were analyzed at three different sites using the following commercial NGS assays in accordance with the manufacturers’ instructions: AVENIO Tumor Tissue CGP (Roche), TruSight Oncology 500 (Illumina), oncoReveal Core LBx (Pillar Biosciences), Oncomine Comprehensive Assay v3 (ThermoFisher Scientific), AmoyDx HANDLE Classic (Amoy Diagnostics), and SOPHiA ExtHRS (SOPHiA GENETICS). Detection of single nucleotide variants, insertions/deletions, and copy number variants in PIK3CA, AKT1, and PTEN approved by the FDA as genomic alterations which determine eligibility for treatment with capivasertib in combination with fulvestrant in patients with HR-positive/HER2-negative ABC was recorded and compared. Positive percent agreement (PPA), negative percent agreement (NPA), and overall percent agreement (OPA) were calculated for all assays. AVENIO Tumor Tissue CGP was used as the reference assay, as the content is broadly comparable to the FDA-approved FoundationOne CDx assay. Results: Overall, 45 samples were processed, and all samples were included in the final analysis. PPA, NPA, and OPA for any alteration(s) (PIK3CA, AKT1 or PTEN) versus AVENIO (reference) were: TruSight: 86.0%, 100.0%, and 86.7%; oncoReveal: 81.4%, 100.0%, and 82.2%; Oncomine: 81.4%, 100.0%, and 82.2%; AmoyDx: 86.0%, 100.0%, and 86.7%; SOPHiA: 88.4%, 100.0%, and 88.9%. There was 100.0% PPA, NPA, and OPA for both PIK3CA and AKT1 between TruSight, Oncomine, AmoyDx, SOPHiA and AVENIO. For oncoReveal, PPA, NPA, and OPA were 100.0%, 94.1%, and 97.8% for PIK3CA and 100.0%, 100.0%, and 100.0% for AKT1 alterations, respectively. For PTEN alterations, PPA, NPA, and OPA per assay versus reference were: TruSight: 58.8%, 96.4%, and 82.2%; oncoReveal: 17.6%, 100.0%, and 68.9%; Oncomine: 35.3%, 100.0%, and 75.6%; AmoyDx: 47.1%, 100.0%, and 80.0%; SOPHiA: 58.8%, 100.0%, and 84.4%. Lower agreement for PTEN alterations was due to differences in gene coverage and ability of some assays to detect complex PTEN genomic alterations, such as large rearrangements and copy number variations. Conclusions: All assays evaluated demonstrated good concordance with the AVENIO Tumor Tissue CGP test, especially for detecting capivasertib treatment eligible alterations in AKT1 and PIK3CA. Further improvement on detection of PTEN structural and copy number alterations is needed for some assays in order to maximise patient identification for capivasertib in combination with fulvestrant. These data can help clinicians make informed decisions regarding suitable diagnostic tests to determine patient eligibility for breast cancer therapies. Citation Format: Xiaodun Li, Alexander Yarunin, Benjamin Chaffey, Manisha Maurya, Peter Stewart, Fionn Corr, Efstratios Efstratiou, Kirsty Trewellard, David Gonzalez. Analytical comparison of tissue-based next-generation sequencing assays for the detection of PIK3CA, AKT1, and PTEN tumor alterations in breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-05-27.

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