{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T23:56:14Z","timestamp":1770508574104,"version":"3.49.0"},"reference-count":44,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T00:00:00Z","timestamp":1769731200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Evidence on the efficacy of alpelisib in combination with fulvestrant after progression on CKD4\/6 inhibitors (CDK4\/6i) is derived from a single non-comparative prospective study. Conversely, the effectiveness of everolimus plus exemestane on PIK3CA-mutant metastatic breast cancer (BC) after CDK4\/6i failure has never been investigated in a prospective study. In this retrospective study, we compared alpelisib plus endocrine therapy (ET) with everolimus plus exemestane in patients with PIK3CA-mutant metastatic BC post-CDK4\/6i progression. Methods: We tracked 40 patients treated with alpelisib plus ET and 22 treated with everolimus plus exemestane. We further identified 42 patients who did not harbor PIK3CA mutations (PIK3CA-wild-type group) and received everolimus as a subsequent treatment after progression on CDK4\/6i. The timeframe spanned from 1st March 2020 to 30th November 2024. Results: The median progression-free survival (PFS) for the alpelisib group was 4.9 months compared to 4.5 months for the everolimus group [Hazard ratio (HR), 1.22; 95% CI, 0.65\u20132.28; p-value = 0.53]. The median overall survival (OS) was 9.6 months and 18.3 months for alpelisib and everolimus, respectively (HR, 0.67; 95% CI, 0.25\u20131.76; p-value = 0.47). Median PFS in the PIK3CA-mutant everolimus plus ET group was 4.5 months (95% CI, 2.8\u20136.7) compared to 5 months (95% CI, 3.5\u20136.9) for the PIK3CA-wild-type everolimus plus ET group (HR, 0.77; 95% CI, 0.46\u20131.29; p-value = 0.32). The most common side effects in the alpelisib group were hyperglycemia (57.5%), rash (27.5%), and anorexia (22.5%), while the most common side effects in the everolimus group were fatigue (40.9%) and stomatitis (27.3%). Conclusions: Our results regarding the efficacy of alpelisib plus ET were inferior to those reported in the current literature. Conversely, outcomes of everolimus plus exemestane were consistent with the current literature, denoting that the combination is an acceptable treatment option for patients with PIK3CA-mutant metastatic BC.<\/jats:p>","DOI":"10.3390\/cancers18030468","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T17:38:34Z","timestamp":1769794714000},"page":"468","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comparison Between Alpelisib Plus Endocrine Therapy and Everolimus Plus Endocrine Therapy After CDK4\/6 Inhibitors Progression in Patients with PIK3CA-Mutant Metastatic Breast Cancer: A Single-Center Retrospective Study"],"prefix":"10.3390","volume":"18","author":[{"given":"Sotiris","family":"Loizidis","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Bank of Cyprus Oncology Center, 32 Acropoleos Avenue, Nicosia 2006, Cyprus"},{"name":"Department of Medical Oncology, German Medical Institute, 1 Nikis Avenue, Limassol 4108, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Damianos","family":"Michaelides","sequence":"additional","affiliation":[{"name":"Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, Nicosia 2371, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiola","family":"Marcou","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Bank of Cyprus Oncology Center, 32 Acropoleos Avenue, Nicosia 2006, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleni","family":"Kakouri","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Bank of Cyprus Oncology Center, 32 Acropoleos Avenue, Nicosia 2006, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ifigenia","family":"Konstantinou","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Bank of Cyprus Oncology Center, 32 Acropoleos Avenue, Nicosia 2006, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anastasia","family":"Constantinidou","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Bank of Cyprus Oncology Center, 32 Acropoleos Avenue, Nicosia 2006, Cyprus"},{"name":"School of Medicine, University of Cyprus, Panepistimiou 1, Nicosia 2408, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stavroula","family":"Theophanous-Kitiri","sequence":"additional","affiliation":[{"name":"Pharmacy Department, Bank of Cyprus Oncology Center, 32 Acropoleos Avenue, Nicosia 2006, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0487-3418","authenticated-orcid":false,"given":"Elisavet","family":"Papageorgiou","sequence":"additional","affiliation":[{"name":"A.G. Leventis Clinical Trials Unit, Bank of Cyprus Oncology Center, 32 Acropoleos Avenue, Nicosia 2006, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7065-1237","authenticated-orcid":false,"given":"Kyriaki","family":"Michailidou","sequence":"additional","affiliation":[{"name":"Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, 6 Iroon Avenue, Nicosia 2371, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Myria","family":"Galazi","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Bank of Cyprus Oncology Center, 32 Acropoleos Avenue, Nicosia 2006, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1186\/s12943-023-01827-6","article-title":"PI3K\/AKT\/mTOR signaling transduction pathway and targeted therapies in cancer","volume":"22","author":"Glaviano","year":"2023","journal-title":"Mol. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1242\/jcs.093773","article-title":"Classes of phosphoinositide 3-kinases at a glance","volume":"127","author":"Jean","year":"2014","journal-title":"J. Cell Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1186\/bcr3605","article-title":"PIK3CA mutations in breast cancer: Reconciling findings from preclinical and clinical data","volume":"16","author":"Zardavas","year":"2014","journal-title":"Breast Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"(2012). Comprehensive molecular portraits of human breast tumours. Nature, 490, 61\u201370.","DOI":"10.1038\/nature11412"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1126\/science.aaw9032","article-title":"Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3K\u03b1 inhibitors","volume":"366","author":"Vasan","year":"2019","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.annonc.2019.11.006","article-title":"Outcome and molecular landscape of patients with PIK3CA-mutated metastatic breast cancer","volume":"31","author":"Mosele","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.gde.2009.11.002","article-title":"Targeting the PI3K signaling pathway in cancer","volume":"20","author":"Wong","year":"2010","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_8","unstructured":"(2026, January 08). U.S Food & Drug Administration, Available online: https:\/\/www.fda.gov\/drugs\/resources-information-approved-drugs\/fda-approves-alpelisib-metastatic-breast-cancer."},{"key":"ref_9","unstructured":"(2026, January 08). European Medicines Agency. Available online: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/piqray#authorisation-details."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1056\/NEJMoa1813904","article-title":"Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer","volume":"380","author":"Ciruelos","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.annonc.2020.11.011","article-title":"Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: Final overall survival results from SOLAR-1","volume":"32","author":"Ciruelos","year":"2021","journal-title":"Ann. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e629","DOI":"10.1016\/S1470-2045(24)00673-9","article-title":"Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4\/6 inhibitor (BYLieve): One cohort of a phase 2, multicentre, open-label, non-comparative study","volume":"25","author":"Rugo","year":"2024","journal-title":"Lancet Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1056\/NEJMoa1109653","article-title":"Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer","volume":"366","author":"Baselga","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1200\/JCO.2014.60.1971","article-title":"Correlative Analysis of Genetic Alterations and Everolimus Benefit in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From BOLERO-2","volume":"34","author":"Hortobagyi","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1038\/s41388-024-02986-6","article-title":"Fulvestrant and everolimus efficacy after CDK4\/6 inhibitor: A prospective study with circulating tumor DNA analysis","volume":"43","author":"Vasseur","year":"2024","journal-title":"Oncogene"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"TPS1109","DOI":"10.1200\/JCO.2022.40.16_suppl.TPS1109","article-title":"EPIK-B5: A phase III, randomized study of alpelisib (ALP) plus fulvestrant (FUL) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2\u2212), PIK3CA-mutated advanced breast cancer (ABC) progressing on\/after an aromatase inhibitor (AI) with a cyclin-dependent kinase 4\/6 inhibitor (CDK4\/6i)","volume":"40","author":"Laurentiis","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_17","unstructured":"(2026, January 08). Australian New Zealand Clinical Trials Registry. Available online: https:\/\/www.anzctr.org.au\/Trial\/Registration\/TrialReview.aspx?ACTRN=12619001117101."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1038\/s41388-023-02615-8","article-title":"Correction: Alpelisib and fulvestrant in PIK3CA-mutated hormone receptor-positive HER2-negative advanced breast cancer included in the French early access program","volume":"42","author":"Akla","year":"2023","journal-title":"Oncogene"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e1133","DOI":"10.1002\/onco.13804","article-title":"Effectiveness of Alpelisib + Fulvestrant Compared with Real-World Standard Treatment Among Patients with HR+, HER2\u2212, PIK3CA-Mutated Breast Cancer","volume":"26","author":"Turner","year":"2021","journal-title":"Oncologist"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Alaklabi, S., Roy, A.M., Attwood, K., George, A., O\u2019Connor, T., Early, A., Levine, E.J., and Gandhi, S. (2022). Real-world outcomes with alpelisib in metastatic hormone receptor-positive breast cancer patients: A single institution experience. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.1012391"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1177\/10781552221096413","article-title":"The efficacy and safety of alpelisib in breast cancer: A real-world analysis","volume":"28","author":"Miller","year":"2022","journal-title":"J. Oncol. Pharm. Pract."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Raphael, A., Salmon-Divon, M., Epstein, J., Zahavi, T., Sonnenblick, A., and Shachar, S.S. (2022). Alpelisib Efficacy in Hormone Receptor-Positive HER2-Negative PIK3CA-Mutant Advanced Breast Cancer Post-Everolimus Treatment. Genes, 13.","DOI":"10.3390\/genes13101763"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"103708","DOI":"10.1016\/j.clon.2024.103708","article-title":"Alpelisib in advanced breast cancer\u2014A real world report of toxicity and efficacy, a multi-centre analysis","volume":"38","author":"Morrison","year":"2025","journal-title":"Clin. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1016\/j.annonc.2020.05.001","article-title":"Time course and management of key adverse events during the randomized phase III SOLAR-1 study of PI3K inhibitor alpelisib plus fulvestrant in patients with HR-positive advanced breast cancer","volume":"31","author":"Rugo","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.1111\/bcp.15143","article-title":"Adverse events of alpelisib: A postmarketing study of the World Health Organization pharmacovigilance database","volume":"88","author":"Chen","year":"2022","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3854","DOI":"10.1002\/cncr.34928","article-title":"Incidence, risk factors, and management of alpelisib-associated hyperglycemia in metastatic breast cancer","volume":"129","author":"Shen","year":"2023","journal-title":"Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2052","DOI":"10.1056\/NEJMra1704560","article-title":"Phosphatidylinositol 3-Kinase, Growth Disorders, and Cancer","volume":"379","author":"Goncalves","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"102520","DOI":"10.1016\/j.eclinm.2024.102520","article-title":"Preventing alpelisib-related hyperglycaemia in HR+\/HER2\u2212\/PIK3CA-mutated advanced breast cancer using metformin (METALLICA): A multicentre, open-label, single-arm, phase 2 trial","volume":"71","author":"Tolosa","year":"2024","journal-title":"eClinicalMedicine"},{"key":"ref_29","unstructured":"(2026, January 08). Alpelisib (Piqray): CADTH Reimbursement Recommendation: Indication: In combination with Fulvestrant for the Treatment of Postmenopausal Women, and Men, with Hormone Receptor\u2013Positive, Human Epidermal Growth Factor Receptor 2 (HER2)-Negative, PIK3CA-Mutated Advanced or Metastatic Breast Cancer After Disease Progression Following an endocrine-Based Regimen with a Cyclin-Dependent Kinase 4 and 6 (CDK4\/6) Inhibitor, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK595392\/."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.clbc.2021.10.002","article-title":"Real-World Outcomes of Everolimus and Exemestane for the Treatment of Metastatic Hormone Receptor-Positive Breast Cancer in Patients Previously Treated With CDK4\/6 Inhibitors","volume":"22","author":"Mo","year":"2022","journal-title":"Clin. Breast Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"141","DOI":"10.6004\/jnccn.2018.7094","article-title":"Retrospective Analysis of Treatment Patterns and Effectiveness of Palbociclib and Subsequent Regimens in Metastatic Breast Cancer","volume":"17","author":"Xi","year":"2019","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_32","first-page":"1178223420944864","article-title":"Outcome of Everolimus-Based Therapy in Hormone-Receptor-Positive Metastatic Breast Cancer Patients After Progression on Palbociclib","volume":"14","author":"Dhakal","year":"2020","journal-title":"Breast Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1097\/00000421-199008000-00005","article-title":"Bone-only versus visceral-only metastatic pattern in breast cancer: Analysis of 150 patients. A GOCS study","volume":"13","author":"Perez","year":"1990","journal-title":"Am. J. Clin. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1038\/s41571-020-00457-x","article-title":"Liquid biopsy enters the clinic\u2013implementation issues and future challenges","volume":"18","author":"Ignatiadis","year":"2021","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/s10549-023-07010-1","article-title":"Discordance of PIK3CA mutational status between primary and metastatic breast cancer: A systematic review and meta-analysis","volume":"201","author":"Rosin","year":"2023","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Tankova, T., Senkus, E., Beloyartseva, M., Bor\u0161tnar, S., Catrinoiu, D., Frolova, M., Hegmane, A., Jane\u017e, A., Krni\u0107, M., and Lengyel, Z. (2022). Management Strategies for Hyperglycemia Associated with the \u03b1-Selective PI3K Inhibitor Alpelisib for the Treatment of Breast Cancer. Cancers, 14.","DOI":"10.3390\/cancers14071598"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1007\/s10549-021-06476-1","article-title":"Factors leading to alpelisib discontinuation in patients with hormone receptor positive, human epidermal growth factor receptor-2 negative breast cancer","volume":"192","author":"Cheung","year":"2022","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/s41523-024-00626-6","article-title":"Circulating tumor DNA validity and potential uses in metastatic breast cancer","volume":"10","author":"Amato","year":"2024","journal-title":"npj Breast Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1097\/CCO.0000000000001168","article-title":"Liquid biopsy in breast cancer: Promises and challenges","volume":"37","author":"Loizidis","year":"2025","journal-title":"Curr. Opin. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s13058-020-01284-9","article-title":"Frequency and spectrum of PIK3CA somatic mutations in breast cancer","volume":"22","author":"Chic","year":"2020","journal-title":"Breast Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1016\/j.annonc.2022.05.520","article-title":"ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: A report from the ESMO Precision Medicine Working Group","volume":"33","author":"Pascual","year":"2022","journal-title":"Ann. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3246","DOI":"10.1200\/JCO.22.00338","article-title":"Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial","volume":"40","author":"Bidard","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1056\/NEJMoa2404625","article-title":"Inavolisib-Based Therapy in PIK3CA-Mutated Advanced Breast Cancer","volume":"391","author":"Turner","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2058","DOI":"10.1056\/NEJMoa2214131","article-title":"Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer","volume":"388","author":"Turner","year":"2023","journal-title":"N. Engl. J. Med."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/3\/468\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T09:06:58Z","timestamp":1770196018000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/3\/468"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,30]]},"references-count":44,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["cancers18030468"],"URL":"https:\/\/doi.org\/10.3390\/cancers18030468","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,30]]}}}