Alpelisib is an α-selective phosphatidylinositol 3-kinase inhibitor used for treating hormone receptor-positive (HR+), human epidermal growth receptor 2-negative (HER2-), PIK3CA-mutated locally advanced or metastatic breast cancer following disease progression on or after endocrine therapy. Hyperglycemia is an on-target effect of alpelisib affecting approximately 60% of treated patients, and sometimes necessitating dose reductions, treatment interruptions, or discontinuation of alpelisib. Early detection of hyperglycemia and timely intervention have a key role in achieving optimal glycemic control and maintaining alpelisib dose intensity to optimize the benefit of this drug. A glycemic support program implemented by an endocrinology-oncology collaborative team may be very useful in this regard. Lifestyle modifications, mainly comprising a reduced-carbohydrate diet, and a designated stepwise, personalized antihyperglycemic regimen, based on metformin, sodium-glucose co-transporter 2 inhibitors, and pioglitazone, are the main tools required to address the insulin-resistant hyperglycemia induced by alpelisib. In this report, based on the consensus of 14 oncologists and seven endocrinologists, we provide guidance for hyperglycemia management strategies before, during, and after alpelisib therapy for HR+, HER2-, PIK3CA-mutated breast cancer, with a focus on a proactive, multidisciplinary approach.

1st Department of Oncology Comenius University Faculty of Medicine Bratislava Heydukova 10 812 50 Bratislava Slovakia

Department of Diabetology Clinical Emergency Hospital of Constanta Romania Tomis Bvd No 145 900591 Constanta Romania

Department of Endocrinology Clinical Hospital Center Split School of Medicine University of Split Šoltanska 1 21000 Split Croatia

Department of Endocrinology Diabetes and Metabolic Disease University Medical Center Zaloska 7 1000 Ljubljana Slovenia

Department of Endocrinology Medical University of Sofia 2 Zdrave Str 1431 Sofia Bulgaria

Department of Oncology and Radiotherapy Medical University of Gdańsk Smoluchowskiego 17 80 214 Gdańsk Poland

Department of Oncology Clinical Hospital Center Split School of Medicine University of Split Spinčićeva 1 21000 Split Croatia

Division of Endocrinology Diabetes and Metabolism Sheba Medical Center Tel Hashomer Ramat Gan 52621 Israel

Division of Medical Oncology Institute of Oncology Ljubljana Zaloska 2 1000 Ljubljana Slovenia

Faculty of Medicine Ovidius University of Constanta University Alley No 1 900470 Constanta Romania

Institution N N Blokhin National Medical Research Center of Oncology of the Ministry of Health of the Russian Federation 23 Kashirskoye Avenue 115478 Moscow Russia

Masaryk Memorial Cancer Institute Žlutý kopec 543 7 Brno Střed Staré 602 00 Brno Czech Republic

Medical Oncology Department The Bank of Cyprus Oncology Centre 32 Acropoleos Avenue Strovolos Nicosia 2006 Cyprus

National Institute of Oncology Rath Gy Str 7 9 1122 Budapest Hungary

Out Patient Department of Medical Oncology Riga East University Hospital Oncology Center of Latvia 4 Hipokrata Str LV1079 Riga Latvia

Sackler Faculty of Medicine Tel Aviv University P O Box 39040 Ramat Aviv Tel Aviv 69978 Israel

Slovak Republic Department of Medical Oncology St Elisabeth Cancer Institute Heydukova 10 812 50 Bratislava Slovakia

Szent János Hospital Diós árok 1 3 1125 Budapest Hungary

The Legacy Heritage Oncology Center and Dr Larry Norton Institute SorokaMedical Center Yitzhack 1 Rager Blvd 151 Be'er Sheva Israel

See more in PubMed

Cardoso F., Paluch-Shimon S., Senkus E., Curigliano G., Aapro M.S., Andre F., Barrios C.H., Bergh J., Bhattacharyya G.S., Biganzoli L., et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5) Ann. Oncol. 2020;31:1623–1649. doi: 10.1016/j.annonc.2020.09.010. PubMed DOI PMC

National Comprehensive Cancer Network NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. V2.2019. [(accessed on 15 April 2020)]. Available online: https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf.

Hartkopf A.D., Grischke E.M., Brucker S.Y. Endocrine-resistant breast cancer: Mechanisms and treatment. Breast. Care. 2020;15:347–354. doi: 10.1159/000508675. PubMed DOI PMC

O’Leary B., Cutts R.J., Liu Y., Hrebien S., Huang X., Fenwick K., Andre F., Loibl S., Loi S., Garcia-Murillas I., et al. The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial. Cancer Discov. 2018;8:1390–1403. doi: 10.1158/2159-8290.CD-18-0264. PubMed DOI PMC

Turner N.C., Neven P., Loibl S., Andre F. Advances in the treatment of advanced oestrogen-receptor-positive breast cancer. Lancet. 2017;389:2403–2414. doi: 10.1016/S0140-6736(16)32419-9. PubMed DOI

Goncalves M.D., Hopkins B.D., Cantley L.C. Phosphatidylinositol 3-kinase, growth disorders, and cancer. N. Engl. J. Med. 2018;379:2052–2062. doi: 10.1056/NEJMra1704560. PubMed DOI

Martinez-Saez O., Chic N., Pascual T., Adamo B., Vidal M., Gonzalez-Farre B., Sanfeliu E., Schettini F., Conte B., Braso-Maristany F., et al. Frequency and spectrum of PIK3CA somatic mutations in breast cancer. Breast Cancer Res. 2020;22:45. doi: 10.1186/s13058-020-01284-9. PubMed DOI PMC

Cancer Genome Atlas Network Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61–70. doi: 10.1038/nature11412. PubMed DOI PMC

Andre F., Ciruelos E., Rubovszky G., Campone M., Loibl S., Rugo H.S., Iwata H., Conte P., Mayer I.A., Kaufman B., et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N. Engl. J. Med. 2019;380:1929–1940. doi: 10.1056/NEJMoa1813904. PubMed DOI

Miller T.W., Balko J.M., Arteaga C.L. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J. Clin. Oncol. 2011;29:4452–4461. doi: 10.1200/JCO.2010.34.4879. PubMed DOI PMC

Mosele F., Stefanovska B., Lusque A., Tran Dien A., Garberis I., Droin N., Le Tourneau C., Sablin M.P., Lacroix L., Enrico D., et al. Outcome and molecular landscape of patients with PIK3CA-mutated metastatic breast cancer. Ann. Oncol. 2020;31:377–386. doi: 10.1016/j.annonc.2019.11.006. PubMed DOI

Sobhani N., Roviello G., Corona S.P., Scaltriti M., Ianza A., Bortul M., Zanconati F., Generali D. The prognostic value of PI3K mutational status in breast cancer: A meta-analysis. J. Cell. Biochem. 2018;119:4287–4292. doi: 10.1002/jcb.26687. PubMed DOI PMC

Andre F., Ciruelos E.M., Juric D., Loibl S., Campone M., Mayer I.A., Rubovszky G., Yamashita T., Kaufman B., Lu Y.S., et al. 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. Ann. Oncol. 2021;32:208–217. doi: 10.1016/j.annonc.2020.11.011. PubMed DOI

Fritsch C., Huang A., Chatenay-Rivauday C., Schnell C., Reddy A., Liu M., Kauffmann A., Guthy D., Erdmann D., De Pover A., et al. Characterization of the novel and specific PI3Kalpha inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials. Mol. Cancer Ther. 2014;13:1117–1129. doi: 10.1158/1535-7163.MCT-13-0865. PubMed DOI

O’Brien N.A., McDermott M.S.J., Conklin D., Luo T., Ayala R., Salgar S., Chau K., DiTomaso E., Babbar N., Su F., et al. Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer. Breast Cancer Res. 2020;22:89. doi: 10.1186/s13058-020-01320-8. PubMed DOI PMC

Rugo H.S., Lerebours F., Ciruelos E., Drullinsky P., Ruiz M., Borrego M.R., Neven P., Park Y.H., Prat A., Bachelot T., et al. Alpelisib + fulvestrant in patients with PIK3CA5 mutated hormone-receptor positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDKi) + aromatase inhibitor (AI): BYLieve study results. J. Clin. Oncol. 2020;38((Suppl. 15)):1006. doi: 10.1200/JCO.2020.38.15_suppl.1006. PubMed DOI

Rugo H.S., Andre F., Yamashita T., Cerda H., Toledano I., Stemmer S.M., Jurado J.C., Juric D., Mayer I., Ciruelos E.M., et al. 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. Ann. Oncol. 2020;31:1001–1010. doi: 10.1016/j.annonc.2020.05.001. PubMed DOI

Rugo H.S., Lerebours F., Juric D., Turner N.C., Chia S.K.L., Drullinsky P., Prat A., Villanueva Vazquez R., Akdere M., Arce C., et al. Alpelisib + letrozole in patients with PIK3CA5 mutated hormone-receptor positive (HR+), human epidermal growth factor receptor-2-negative (HER2–) advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDKi) + fluvestrant: BYLieve study results. Cancer Res. 2021;81:PD2-07

Baselga J., Im S.A., Iwata H., Cortes J., De Laurentiis M., Jiang Z., Arteaga C.L., Jonat W., Clemons M., Ito Y., et al. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:904–916. doi: 10.1016/S1470-2045(17)30376-5. PubMed DOI PMC

Di Leo A., Johnston S., Lee K.S., Ciruelos E., Lonning P.E., Janni W., O’Regan R., Mouret-Reynier M.A., Kalev D., Egle D., et al. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018;19:87–100. doi: 10.1016/S1470-2045(17)30688-5. PubMed DOI

Janku F., Yap T.A., Meric-Bernstam F. Targeting the PI3K pathway in cancer: Are we making headway? Nat. Rev. Clin. Oncol. 2018;15:273–291. doi: 10.1038/nrclinonc.2018.28. PubMed DOI

Shields M., Mo Q., Armitage M., Sharpe S.C., Costa R.L.B. A systematic review and meta-analysis of selected toxicity endpoints of alpelisib. Oncotarget. 2020;11:3793–3799. doi: 10.18632/oncotarget.27770. PubMed DOI PMC

Nunnery S.E., Mayer I.A. Management of toxicity to isoform alpha-specific PI3K inhibitors. Ann. Oncol. 2019;30((Suppl. 10)):x21–x26. doi: 10.1093/annonc/mdz440. PubMed DOI

Anders C.K., LeBoeuf N.R., Bashoura L., Faiz S.A., Shariff A.I., Thomas A. What’s the price? Toxicities of targeted therapies in breast cancer care. Am. Soc. Clin. Oncol. Educ. Book. 2020;40:55–70. doi: 10.1200/EDBK_279465. PubMed DOI

Fruman D.A., Chiu H., Hopkins B.D., Bagrodia S., Cantley L.C., Abraham R.T. The PI3K pathway in human disease. Cell. 2017;170:605–635. doi: 10.1016/j.cell.2017.07.029. PubMed DOI PMC

Katso R., Okkenhaug K., Ahmadi K., White S., Timms J., Waterfield M.D. Cellular function of phosphoinositide 3-kinases: Implications for development, homeostasis, and cancer. Annu. Rev. Cell Dev. Biol. 2001;17:615–675. doi: 10.1146/annurev.cellbio.17.1.615. PubMed DOI

Knight Z.A., Gonzalez B., Feldman M.E., Zunder E.R., Goldenberg D.D., Williams O., Loewith R., Stokoe D., Balla A., Toth B., et al. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell. 2006;125:733–747. doi: 10.1016/j.cell.2006.03.035. PubMed DOI PMC

Hopkins B.D., Pauli C., Du X., Wang D.G., Li X., Wu D., Amadiume S.C., Goncalves M.D., Hodakoski C., Lundquist M.R., et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature. 2018;560:499–503. doi: 10.1038/s41586-018-0343-4. PubMed DOI PMC

Qiu J., Zheng Q., Meng X. Hyperglycemia and chemoresistance in breast cancer: From cellular mechanisms to treatment response. Front. Oncol. 2021;11:628359. doi: 10.3389/fonc.2021.628359. PubMed DOI PMC

European Medicines Agency Piqray (Alpelisib) [Summary of Product Characteristics] [(accessed on 15 April 2020)]. Available online: https://www.ema.europa.eu/en/documents/product-information/piqray-epar-product-information_en.pdf.

US Food and Drug Administration Piqray® (Alpelisib) Tablets, for Oral Use [Prescribing Information] [(accessed on 15 April 2019)]; Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212526s000lbl.pdf.

American Diabetes Association 3. Prevention or delay of type 2 diabetes: Standards of Medical Care in Diabetes–2019. Diabetes Care. 2019;42:S29–S33. doi: 10.2337/dc19-S003. PubMed DOI

American Diabetes Association 5. Lifestyle management: Standards of Medical Care in Diabetes–2019. Diabetes Care. 2019;42:S46–S60. doi: 10.2337/dc19-S005. PubMed DOI

Noch E., Yin I., Cantley L. EXTH-36. PI3K inhibition in conjunction with the ketogenic diet reduces growth and neuroinflammation in pediatric high-grade glioma. Neuro-Oncology. 2019;21:vi89. doi: 10.1093/neuonc/noz175.368. DOI

Zou Y., Fineberg S., Pearlman A., Feinman R.D., Fine E.J. The effect of a ketogenic diet and synergy with rapamycin in a mouse model of breast cancer. PLoS ONE. 2020;15:e0233662. doi: 10.1371/journal.pone.0233662. PubMed DOI PMC

Pollak M. Diet boosts the effectiveness of a cancer drug. Nature. 2018;560:439–440. doi: 10.1038/d41586-018-05871-x. PubMed DOI

Grandl G., Straub L., Rudigier C., Arnold M., Wueest S., Konrad D., Wolfrum C. Short-term feeding of a ketogenic diet induces more severe hepatic insulin resistance than an obesogenic high-fat diet. J. Physiol. 2018;596:4597–4609. doi: 10.1113/JP275173. PubMed DOI PMC

American Diabetes Association 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes–2019. Diabetes Care. 2019;42:S90–S102. doi: 10.2337/dc19-S009. PubMed DOI

Davies M.J., D’Alessio D.A., Fradkin J., Kernan W.N., Mathieu C., Mingrone G., Rossing P., Tsapas A., Wexler D.J., Buse J.B. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) Diabetologia. 2018;61:2461–2498. doi: 10.1007/s00125-018-4729-5. PubMed DOI

Moin T., Schmittdiel J.A., Flory J.H., Yeh J., Karter A.J., Kruge L.E., Schillinger D., Mangione C.M., Herman W.H., Walker E.A. Review of metformin use for type 2 diabetes prevention. Am. J. Prev. Med. 2018;55:565–574. doi: 10.1016/j.amepre.2018.04.038. PubMed DOI PMC

Knowler W.C., Barrett-Connor E., Fowler S.E., Hamman R.F., Lachin J.M., Walker E.A., Nathan D.M., Diabetes Prevention Program Research Group Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 2002;346:393–403. PubMed PMC

American Diabetes Association Standards of medical care in diabetes—2014. Diabetes Care. 2015;38:S31–S33. PubMed

Aljofan M., Riethmacher D. Anticancer activity of metformin: A systematic review of the literature. Future Sci. OA. 2019;5:FSO410. doi: 10.2144/fsoa-2019-0053. PubMed DOI PMC

Burnette S., Poehlein E., Lee H.-J., Force J., Westbrook K., Moore H. Risk factor (RF) identification (ID) and hyperglycemia (HG) prevention with alpelisib (ALP) + fulvestrant (FLV) in PIK3CA-mutated, hormone-receptor positive (HR+), human epidermal growth factor-2 negative (HER2−) advanced breast cancer (ABC) Ann. Oncol. 2021;32:S470. doi: 10.1016/j.annonc.2021.08.536. DOI

Busaidy N.L., Farooki A., Dowlati A., Perentesis J.P., Dancey J.E., Doyle L.A., Brell J.M., Siu L.L. Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt-mTOR pathway. J. Clin. Oncol. 2012;30:2919–2928. doi: 10.1200/JCO.2011.39.7356. PubMed DOI PMC

Perry R.J., Shulman G.I. Sodium-glucose cotransporter-2 inhibitors: Understanding the mechanisms for therapeutic promise and persisting risks. J. Biol. Chem. 2020;295:14379–14390. doi: 10.1074/jbc.REV120.008387. PubMed DOI PMC

Park J., Shin S.W. Alpelisib for PIK3CA-mutated advanced breast cancer. N. Engl. J. Med. 2019;381:686 PubMed

Flory J., Lipska K. Metformin in 2019. JAMA. 2019;321:1926–1927. doi: 10.1001/jama.2019.3805. PubMed DOI PMC

Bonnet F., Scheen A. Understanding and overcoming metformin gastrointestinal intolerance. Diabetes Obes. Metab. 2017;19:473–481. doi: 10.1111/dom.12854. PubMed DOI

Olgun A. “Metformin-resistant” folic acid producing probiotics or folic acid against metformin’s adverse effects like diarrhea. Med. Hypotheses. 2017;106:33–34. doi: 10.1016/j.mehy.2017.07.009. PubMed DOI

Staels B. Metformin and pioglitazone: Effectively treating insulin resistance. Curr. Med. Res. Opin. 2006;22((Suppl. 2)):S27–S37. doi: 10.1185/030079906X112732. PubMed DOI

Alam F., Islam M.A., Mohamed M., Ahmad I., Kamal M.A., Donnelly R., Idris I., Gan S.H. Efficacy and safety of pioglitazone monotherapy in type 2 diabetes mellitus: A systematic review and meta-analysis of randomised controlled trials. Sci. Rep. 2019;9:5389. doi: 10.1038/s41598-019-41854-2. PubMed DOI PMC

Lu Y., Chiu J., Airoldi M., Margeli Vila M., Ponce Lorenzo J., Ghaznawi F., Guadenzi F., Ridolfi A., Lorenzo I., Ruiz Borrego M. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors for alpelisib (ALP)-induced hyperglycemia: A report of 6 cases from SOLAR-1 [301P] Ann. Oncol. 2020;31:S363. doi: 10.1016/j.annonc.2020.08.403. DOI

Andre F., Mills D., Taran T. Alpelisib for PIK3CA-mutated advanced breast cancer. Reply. N. Engl. J. Med. 2019;381:687 PubMed

Juric D., Rodon J., Tabernero J., Janku F., Burris H.A., Schellens J.H.M., Middleton M.R., Berlin J., Schuler M., Gil-Martin M., et al. Phosphatidylinositol 3-kinase alpha-selective inhibition with alpelisib (BYL719) in PIK3CA-altered solid tumors: Results from the first-in-human study. J. Clin. Oncol. 2018;36:1291–1299. doi: 10.1200/JCO.2017.72.7107. PubMed DOI PMC

Farah S.J., Masri N., Ghanem H., Azar M. Diabetic ketoacidosis associated with alpelisib treatment of metastatic breast cancer. AACE Clin. Case Rep. 2020;6:e349–e351. doi: 10.4158/ACCR-2020-0452. PubMed DOI PMC