Abstract P1-05-06: The frequency of somatic mutations in the PIK3CA gene in Kazakhstani patients with metastatic HR+ HER2-negative breast cancer

Abstract Relevance: Up to 40% of HR+ HER2-negative breast cancer (BC) cases contain mutations in the PIK3CA gene and are a major cause of the development of hormone resistance. Activation of the PI3K protein (phosphatidylinositol-3-kinase) regulates proliferation and apoptosis, and somatic mutations in the PIK3CA gene can activate these processes. Information on the frequency and spectrum of PIK3CA mutations is important for determining the strategy of drug treatment. A combination of the selective PI3K inhibitor alpelisib and the estrogen receptor antagonist fulvestrant may be used as therapy for such tumors. Objective of the study: To determine the frequency and spectrum of mutations in the PIK3CA gene in patients with “luminal HER2 (-) metastatic breast cancer in the Kazakh population.” Materials and Methods: The presence of mutations in exons 7, 9, and 20 of the PIK3CA gene was determined in a sample of 320 tumor specimens from patients diagnosed with “luminal HER2 (-) metastatic breast cancer” who received antitumor therapy during the period of 2017-2023 at the Kazakh Institute of Oncology and Radiology. The age of patients ranged from 25 to 86 years, with a mean age of 65.6 years; all patients were women. Of the 320 patients, 183 (57.2%) were of menopausal age, 81 (25.3%) were perimenopausal, and 56 (17.5%) were premenopausal. Patients with the luminal subtype “A” accounted for 134 (41.9±2.75)%, and those with the luminal subtype “B” accounted for 186 (58.1±2.75)%. Her2neu - 1+ was observed in 128 (40%) patients, and Her2neu – 0 in 192 (60%) patients. For patients with the luminal subtype “A”, 55 had Her2neu - 1+ and 79 had Her2neu – 0; for the luminal subtype “B”, 73 had Her2neu - 1+ and 113 had Her2neu – 0. DNA extraction was performed using the GeneJET FFPE DNA Purification Kit from paraffin blocks. Amplification and detection of results were conducted using the PIK3CA Mutation Analysis Kit for Real-Time PCR (Entrogen), which includes the mutation spectra E542K, E545K, E545Q, H1047R, and H1047L. Results: Among the 320 patients, 75 (23.4%) had various mutations in the PIK3CA gene, which is somewhat lower than global data. For example, according to cBioPortal, the mutation frequency of PIK3CA in breast cancer is 37% (1888/5129). The three most frequent missense mutations in the PIK3CA gene were p.H1047R - 36 (48%), mutation p.E542K - 22 (29.3%), and mutation p.E545K - 15 (20%). Another mutation, p.H1047L, was found in 2 (2.7%) cases, while the p.E545Q mutation was not detected in our sample. PIK3CA mutations in the luminal subtype “A” were found in 33 (44%) cases, with Her2neu - 1+ status identified in 14 (42.4%) cases and Her2neu - 0 in 19 (57.6%) cases. In the luminal subtype “B” (n=42), Her2neu - 1+ was found in 18 (42.9%) cases, and Her2neu - 0 in 24 (57.1%) cases. PIK3CA mutations were more frequently found in women of perimenopausal age - 43 (57.3%) cases, and in menopausal age - 32 (42.7%) cases. Among Kazakh nationality patients (179 in total), 35 (19.6±2.96%) were found to have the PIK3CA mutation. Conclusions: The prevalence of PIK3CA mutations in the Kazakh population sample (n=320) was 23.4%, and the spectrum of PIK3CA mutations generally aligns with data from large international studies. PIK3CA mutations were somewhat more frequently found in patients of menopausal age (57.2%±2.76%), as well as in patients with the luminal subtype “B” Her2neu – 0. Among Kazakh women, the frequency of PIK3CA mutations was lower at 35 (19.6±2.96%) compared to women of other nationalities (28.4%). Bibliography: Martínez-Sáez O., Chic N., Pascual T., Adamo B. et al. Frequency and spectrum of PIK3CA somatic mutations in breast cancer // Breast Cancer Res. 2020. Vol. 22 (1). Р. 45. DOI: 10.1186/s13058-020-01284-9. Mosele F., Stefanovska B., Lusque A., et al. Outcome and molecular landscape of patients with PIK3CA-mutated metastatic breast cancer. Ann Oncol. 2020;31(3):377-386. https://doi.org/10.1016/j.annonc.2019.11.006 Citation Format: Mariya Dmitrenko, Dilyara Kaidar, Kaldygul Smagulova, Samat Kaldarbekov, Madina Orazalieva. The frequency of somatic mutations in the PIK3CA gene in Kazakhstani patients with metastatic HR+ HER2-negative 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 P1-05-06.