Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA Cancer J Clin. 2025;75(1):10–45. https://doi.org/10.3322/caac.21871.

Article  PubMed  PubMed Central  Google Scholar 

Giaquinto AN, Sung H, Newman LA, et al. Breast cancer statistics 2024. CA Cancer J Clin. 2024;74(6):477–95. https://doi.org/10.3322/caac.21863.

Article  PubMed  Google Scholar 

Cristofanilli M, Rugo HS, Im SA, et al. Overall survival with palbociclib and fulvestrant in women with HR+/HER2- ABC: updated exploratory analyses of PALOMA-3, a double-blind, phase III randomized study. Clin Cancer Res. 2022;28(16):3433–42. https://doi.org/10.1158/1078-0432.Ccr-22-0305.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Sledge GW Jr, Toi M, Neven P, et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35(25):2875–84. https://doi.org/10.1200/jco.2017.73.7585.

Article  PubMed  CAS  Google Scholar 

Slamon DJ, Neven P, Chia S, et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N Engl J Med. 2020;382(6):514–24. https://doi.org/10.1056/NEJMoa1911149.

Article  PubMed  CAS  Google Scholar 

Neven P, Petrakova K, Val Bianchi G, et al. Abstract PD2-05: biomarker analysis by baseline circulating tumor DNA alterations in the MONALEESA-3 study. Cancer Res. 2019;79(4_Suppl.):PD2-05. https://doi.org/10.1158/1538-7445.Sabcs18-pd2-05.

Article  Google Scholar 

Tolaney SM, Toi M, Neven P, et al. Clinical significance of PIK3CA and ESR1 mutations in circulating tumor DNA: analysis from the MONARCH 2 study of abemaciclib plus fulvestrant. Clin Cancer Res. 2022;28(8):1500–6. https://doi.org/10.1158/1078-0432.Ccr-21-3276.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Im S-A, Lu Y-S, Bardia A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019;381(4):307–16. https://doi.org/10.1056/NEJMoa1903765.

Article  PubMed  CAS  Google Scholar 

Turner NC, Im S-A, Saura C, et al. Inavolisib-based therapy in PIK3CA-mutated advanced breast cancer. N Engl J Med. 2024;391(17):1584–96. https://doi.org/10.1056/NEJMoa2404625.

Article  PubMed  CAS  Google Scholar 

Browne IM, André F, Chandarlapaty S, Carey LA, Turner NC. Optimal targeting of PI3K-AKT and mTOR in advanced oestrogen receptor-positive breast cancer. Lancet Oncol. 2024;25(4):e139–51. https://doi.org/10.1016/s1470-2045(23)00676-9.

Article  PubMed  CAS  Google Scholar 

Millis SZ, Ikeda S, Reddy S, Gatalica Z, Kurzrock R. Landscape of phosphatidylinositol-3-kinase pathway alterations across 19 784 diverse solid tumors. JAMA Oncol. 2016;2(12):1565–73. https://doi.org/10.1001/jamaoncol.2016.0891.

Article  PubMed  Google Scholar 

Fritsch C, Huang A, Chatenay-Rivauday C, et al. Characterization of the novel and specific PI3Kα inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials. Mol Cancer Ther. 2014;13(5):1117–29.

Article  PubMed  CAS  Google Scholar 

Hao C, Wei Y, Meng W, Zhang J, Yang X. PI3K/AKT/mTOR inhibitors for hormone receptor-positive advanced breast cancer. Cancer Treat Rev. 2025;132:102861. https://doi.org/10.1016/j.ctrv.2024.102861.

Article  PubMed  CAS  Google Scholar 

Andre F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019;380(20):1929–40. https://doi.org/10.1056/NEJMoa1813904.

Article  PubMed  CAS  Google Scholar 

Huang CH, Mandelker D, Schmidt-Kittler O, et al. The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science. 2007;318(5857):1744–8. https://doi.org/10.1126/science.1150799.

Article  PubMed  CAS  Google Scholar 

Glaviano A, Foo ASC, Lam HY, et al. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol Cancer. 2023;22(1):138. https://doi.org/10.1186/s12943-023-01827-6.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Herrera-Abreu MT, Palafox M, Asghar U, et al. Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer. Cancer Res. 2016;76(8):2301–13. https://doi.org/10.1158/0008-5472.Can-15-0728.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Miller TW, Balko JM, Fox EM, et al. ERα-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. Cancer Discov. 2011;1(4):338–51. https://doi.org/10.1158/2159-8290.Cd-11-0101.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Wander SA, Cohen O, Gong X, et al. The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor-positive metastatic breast cancer. Cancer Discov. 2020;10(8):1174–93. https://doi.org/10.1158/2159-8290.Cd-19-1390.

Article  PubMed  PubMed Central  CAS  Google Scholar 

O’Leary B, Cutts RJ, Liu Y, et al. The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial. Cancer Discov. 2018;8(11):1390–403. https://doi.org/10.1158/2159-8290.Cd-18-0264.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Park L, Thompson SL, Roose J, et al. Testing patterns and prevalence of PIK3CA, AKT1, and PTEN alterations among patients (pts) with HR+/HER2- metastatic breast cancer (mBC) in the US. J Clin Oncol. 2024;42(16_Suppl.):1041. https://doi.org/10.1200/JCO.2024.42.16_suppl.1041.

Article  Google Scholar 

Vitale SR, Martorana F, Stella S, et al. PI3K inhibition in breast cancer: identifying and overcoming different flavors of resistance. Crit Rev Oncol Hematol. 2021;162:103334. https://doi.org/10.1016/j.critrevonc.2021.103334.

Article  PubMed  Google Scholar 

Browne IM, Okines AFC. Resistance to targeted inhibitors of the PI3K/AKT/mTOR pathway in advanced oestrogen-receptor-positive breast cancer. Cancers (Basel). 2024;16(12):2259. https://doi.org/10.3390/cancers16122259.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Varkaris A, Fece de la Cruz F, Martin EE, et al. Allosteric PI3Kα inhibition overcomes on-target resistance to orthosteric inhibitors mediated by secondary PIK3CA mutations. Cancer Discov. 2024;14(2):227–39. https://doi.org/10.1158/2159-8290.Cd-23-0704.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Juric D, Castel P, Griffith M, et al. Convergent loss of PTEN leads to clinical resistance to a PI(3)Kα inhibitor. Nature. 2015;518(7538):240–4. https://doi.org/10.1038/nature13948.

Article  PubMed  CAS  Google Scholar 

Jia S, Liu Z, Zhang S, et al. Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature. 2008;454(7205):776–9. https://doi.org/10.1038/nature07091.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Kumari N, Wright SC, Witham CM, et al. USP10/GSK3β-mediated inhibition of PTEN drives resistance to PI3K inhibitors in breast cancer. J Clin Invest. 2025;135(22):e180927. https://doi.org/10.1172/jci180927.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Razav