Login Register Cart 0
Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Systematic Review Article

Efficacy and Safety of Phosphatidylinositol 3-kinase Inhibitors for Patients with Breast Cancer: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Author(s): Yi Wang, Xianling Du, Hongqiang Xin and Ruimin Xu*

Volume 24, Issue 9, 2024

Published on: 24 January, 2024

Page: [941 - 951] Pages: 11

DOI: 10.2174/0115680096266181231207110048

Price: $65

Open Access Journals Promotions 2
Abstract

Background: Phosphatidylinositol 3-kinase (PI3K) inhibitors belong to the class of drugs that inhibit the activity of the PI3K protein, which is commonly overexpressed in breast cancer cells. However, there is a need to summarize the evidence to provide conclusive advice on the benefit of PI3K inhibitors in breast cancer patients. Therefore, this review assessed the effectiveness and safety of the PI3K inhibitors amongst breast cancer patients.

Methods: Searches were made in PubMed Central, EMBASE, MEDLINE, SCOPUS, CENTRAL, WHO trial registry and Clinicaltrials.gov up to December 2022. Meta-analysis was executed using the random-effects model. Pooled hazard ratio (HR)/risk ratio (RR) was reported with 95% confidence intervals (CIs).

Results: In total, 13 studies were included in the analysis. Most were multi-country studies and had a higher risk of bias. Regarding the efficacy parameters, pooled HR for progression-free survival was 0.79 (95%CI: 0.67-0.92), pooled RR for complete response was 1.54 [95%CI: 1.14 to 2.09], partial response was 1.18 [95%CI: 0.87-1.61], overall response was 1.20 [95%CI: 0.93-1.56], stable disease was 1.09 [95%CI: 0.78-1.53], progressive disease was 0.80 [95%CI: 0.74 to 0.87], and clinical benefit was 1.08 [95%CI: 0.80-1.49]. For safety parameters, pooled RR for hyperglycemia was 4.57 [95%CI: 3.15-6.62], and gastrointestinal toxicity was 1.82 [95%CI: 1.56 to 2.14].

Conclusion: PI3K inhibitors had better efficacy than the present standard of concern for patients with breast cancer, especially among patients with PIK3CA mutations. Hence, clinicians and oncologists can provide this drug for the target population with extra caution for diabetes patients.

Keywords: Breast cancer, meta-analysis, phosphatidylinositol 3-kinase inhibitors, systematic review, overall survival, progression free survival.

« Previous Next »
Graphical Abstract

[1]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
National Cancer Institute. Breast Cancer Risk and Prevention., 2021. Available from: https://www.cancer.gov/types/breast/risk/prevention (Accessed on: on 3 December 2022).
[3]
American Cancer Society. Breast Cancer Treatment (PDQ®)–Patient Version. 2020. Available from: https://www.cancer.org/content/dam/CRC/PDF/Public/8793.00.pdf (Accessed on: 3 December 2022).
[4]
Ellis, H.; Ma, C.X. PI3K inhibitors in breast cancer therapy. Curr. Oncol. Rep., 2019, 21(12), 110.
[http://dx.doi.org/10.1007/s11912-019-0846-7] [PMID: 31828441]
[5]
Narayan, P.; Prowell, T.M.; Gao, J.J.; Fernandes, L.L.; Li, E.; Jiang, X.; Qiu, J.; Fan, J.; Song, P.; Yu, J.; Zhang, X.; King-Kallimanis, B.L.; Chen, W.; Ricks, T.K.; Gong, Y.; Wang, X.; Windsor, K.; Rhieu, S.Y.; Geiser, G.; Banerjee, A.; Chen, X.; Reyes Turcu, F.; Chatterjee, D.K.; Pathak, A.; Seidman, J.; Ghosh, S.; Philip, R.; Goldberg, K.B.; Kluetz, P.G.; Tang, S.; Amiri-Kordestani, L.; Theoret, M.R.; Pazdur, R.; Beaver, J.A. FDA approval summary: Alpelisib plus fulvestrant for patients with HR-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer. Clin. Cancer Res., 2021, 27(7), 1842-1849.
[http://dx.doi.org/10.1158/1078-0432.CCR-20-3652] [PMID: 33168657]
[6]
Di Leo, A.; Johnston, S.; Lee, K.S.; Ciruelos, E.; Lønning, P.E.; Janni, W.; O’Regan, R.; Mouret-Reynier, M.A.; Kalev, D.; Egle, D.; Csőszi, T.; Bordonaro, R.; Decker, T.; Tjan-Heijnen, V.C.G.; Blau, S.; Schirone, A.; Weber, D.; El-Hashimy, M.; Dharan, B.; Sellami, D.; Bachelot, T. 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(1), 87-100.
[http://dx.doi.org/10.1016/S1470-2045(17)30688-5] [PMID: 29223745]
[7]
Johnson, J.; Chow, Z.; Napier, D.; Lee, E.; Weiss, H.L.; Evers, B.M.; Rychahou, P. Targeting PI3K and AMPKα signaling alone or in combination to enhance radiosensitivity of triple negative breast cancer. Cells, 2020, 9(5), 1253.
[http://dx.doi.org/10.3390/cells9051253] [PMID: 32438621]
[8]
Kaboli, P.J.; Imani, S.; Jomhori, M.; Ling, K.H. Chemoresistance in breast cancer: PI3K/Akt pathway inhibitors vs the current chemotherapy. Am. J. Cancer Res., 2021, 11(10), 5155-5183.
[PMID: 34765318]
[9]
Raphael, J.; Desautels, D.; Pritchard, K.I.; Petkova, E.; Shah, P.S. Phosphoinositide 3-kinase inhibitors in advanced breast cancer: A systematic review and meta-analysis. Eur. J. Cancer, 2018, 91, 38-46.
[http://dx.doi.org/10.1016/j.ejca.2017.12.010] [PMID: 29331750]
[10]
Luo, Q.; Lu, H.; Zhou, X.; Wang, Y. The efficacy and safety of neoadjuvant buparlisib for breast cancer. Medicine, 2019, 98(44), e17614.
[http://dx.doi.org/10.1097/MD.0000000000017614] [PMID: 31689768]
[11]
Page, M.J.; McKenzie, J.E.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Moher, D. Updating guidance for reporting systematic reviews: Development of the PRISMA 2020 statement. J. Clin. Epidemiol., 2021, 134, 103-112.
[http://dx.doi.org/10.1016/j.jclinepi.2021.02.003] [PMID: 33577987]
[12]
Sterne, J.A.C.; Savović, J.; Page, M.J.; Elbers, R.G.; Blencowe, N.S.; Boutron, I.; Cates, C.J.; Cheng, H.Y.; Corbett, M.S.; Eldridge, S.M.; Emberson, J.R.; Hernán, M.A.; Hopewell, S.; Hróbjartsson, A.; Junqueira, D.R.; Jüni, P.; Kirkham, J.J.; Lasserson, T.; Li, T.; McAleenan, A.; Reeves, B.C.; Shepperd, S.; Shrier, I.; Stewart, L.A.; Tilling, K.; White, I.R.; Whiting, P.F.; Higgins, J.P.T. RoB 2: A revised tool for assessing risk of bias in randomised trials. BMJ, 2019, 366, l4898.
[http://dx.doi.org/10.1136/bmj.l4898] [PMID: 31462531]
[13]
Cochrane handbook for systematic reviews of interventions; Higgins, J.P.; Green, S., Eds.; John Wiley & Sons, 2011.
[14]
Mayer, I.A.; Prat, A.; Egle, D.; Blau, S.; Fidalgo, J.A.P.; Gnant, M.; Fasching, P.A.; Colleoni, M.; Wolff, A.C.; Winer, E.P.; Singer, C.F.; Hurvitz, S.; Estévez, L.G.; van Dam, P.A.; Kümmel, S.; Mundhenke, C.; Holmes, F.; Babbar, N.; Charbonnier, L.; Diaz-Padilla, I.; Vogl, F.D.; Sellami, D.; Arteaga, C.L. A phase II randomized study of neoadjuvant letrozole plus alpelisib for hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer (NEO-ORB). Clin. Cancer Res., 2019, 25(10), 2975-2987.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-3160] [PMID: 30723140]
[15]
Martín, M.; Chan, A.; Dirix, L.; O’Shaughnessy, J.; Hegg, R.; Manikhas, A.; Shtivelband, M.; Krivorotko, P.; Batista López, N.; Campone, M.; Ruiz Borrego, M.; Khan, Q.J.; Beck, J.T.; Ramos Vázquez, M.; Urban, P.; Goteti, S.; Di Tomaso, E.; Massacesi, C.; Delaloge, S. A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2– advanced breast cancer (BELLE-4). Ann. Oncol., 2017, 28(2), 313-320.
[http://dx.doi.org/10.1093/annonc/mdw562] [PMID: 27803006]
[16]
André, F.; Ciruelos, E.; Rubovszky, G.; Campone, M.; Loibl, S.; Rugo, H.S.; Iwata, H.; Conte, P.; Mayer, I.A.; Kaufman, B.; Yamashita, T.; Lu, Y.S.; Inoue, K.; Takahashi, M.; Pápai, Z.; Longin, A.S.; Mills, D.; Wilke, C.; Hirawat, S.; Juric, D. Alpelisib for PIK3CA -mutated, hormone receptor–positive advanced breast cancer. N. Engl. J. Med., 2019, 380(20), 1929-1940.
[http://dx.doi.org/10.1056/NEJMoa1813904] [PMID: 31091374]
[17]
Baselga, J.; Im, S.A.; Iwata, H.; Cortés, J.; De Laurentiis, M.; Jiang, Z.; Arteaga, C.L.; Jonat, W.; Clemons, M.; Ito, Y.; Awada, A.; Chia, S.; Jagiełło-Gruszfeld, A.; Pistilli, B.; Tseng, L.M.; Hurvitz, S.; Masuda, N.; Takahashi, M.; Vuylsteke, P.; Hachemi, S.; Dharan, B.; Di Tomaso, E.; Urban, P.; Massacesi, C.; Campone, M. 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(7), 904-916.
[http://dx.doi.org/10.1016/S1470-2045(17)30376-5] [PMID: 28576675]
[18]
Oliveira, M.; Baird, R.D.; Voorthuis, R.A.B.; De Boo, L.; van Rossum, A.G.J.; Garrigos, C.L.; Muñoz, S.; López-García, D.; Saura Manich, C.; Schrier, M.; Mandjes, I.; Sikorska, K.; Schot, M.; Kateb, A.; Mather, C.; Beelen, K.; Cortés, J.; Caldas, C.; Linn, S.C. LBA18 POSEIDON randomized phase II trial: Tamoxifen (TAM) + taselisib or placebo (PLA) in patients (pts) with hormone receptor positive (HR+)/HER2- metastatic breast cancer (MBC). Ann. Oncol., 2021, 32, S1291-S1292.
[http://dx.doi.org/10.1016/j.annonc.2021.08.2091]
[19]
Vuylsteke, P.; Huizing, M.; Petrakova, K.; Roylance, R.; Laing, R.; Chan, S.; Abell, F.; Gendreau, S.; Rooney, I.; Apt, D.; Zhou, J.; Singel, S.; Fehrenbacher, L. Pictilisib PI3Kinase inhibitor (a phosphatidylinositol 3-kinase [PI3K] inhibitor) plus paclitaxel for the treatment of hormone receptor-positive, HER2-negative, locally recurrent, or metastatic breast cancer: Interim analysis of the multicentre, placebo-controlled, phase II randomised PEGGY study. Ann. Oncol., 2016, 27(11), 2059-2066.
[http://dx.doi.org/10.1093/annonc/mdw320] [PMID: 27573562]
[20]
Loibl, S.; de la Pena, L.; Nekljudova, V.; Zardavas, D.; Michiels, S.; Denkert, C.; Rezai, M.; Bermejo, B.; Untch, M.; Lee, S.C.; Turri, S.; Urban, P.; Kümmel, S.; Steger, G.; Gombos, A.; Lux, M.; Piccart, M.J.; Von Minckwitz, G.; Baselga, J.; Loi, S. Neoadjuvant buparlisib plus trastuzumab and paclitaxel for women with HER2+ primary breast cancer: A randomised, double-blind, placebo-controlled phase II trial (NeoPHOEBE). Eur. J. Cancer, 2017, 85, 133-145.
[http://dx.doi.org/10.1016/j.ejca.2017.08.020] [PMID: 28923573]
[21]
Saura, C.; Hlauschek, D.; Oliveira, M.; Zardavas, D.; Jallitsch-Halper, A.; de la Peña, L.; Nuciforo, P.; Ballestrero, A.; Dubsky, P.; Lombard, J.M.; Vuylsteke, P.; Castaneda, C.A.; Colleoni, M.; Santos, B.G.; Ciruelos, E.; Fornier, M.; Boer, K.; Bardia, A.; Wilson, T.R.; Stout, T.J.; Hsu, J.Y.; Shi, Y.; Piccart, M.; Gnant, M.; Baselga, J.; de Azambuja, E. Neoadjuvant letrozole plus taselisib versus letrozole plus placebo in postmenopausal women with oestrogen receptor-positive, HER2-negative, early-stage breast cancer (LORELEI): A multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol., 2019, 20(9), 1226-1238.
[http://dx.doi.org/10.1016/S1470-2045(19)30334-1] [PMID: 31402321]
[22]
Schmid, P.; Pinder, S.E.; Wheatley, D.; Macaskill, J.; Zammit, C.; Hu, J.; Price, R.; Bundred, N.; Hadad, S.; Shia, A.; Sarker, S.J.; Lim, L.; Gazinska, P.; Woodman, N.; Korbie, D.; Trau, M.; Mainwaring, P.; Gendreau, S.; Lackner, M.R.; Derynck, M.; Wilson, T.R.; Butler, H.; Earl, G.; Parker, P.; Purushotham, A.; Thompson, A. Phase II randomized preoperative window-of-opportunity study of the PI3K inhibitor pictilisib plus anastrozole compared with anastrozole alone in patients with estrogen receptor–positive breast cancer. J. Clin. Oncol., 2016, 34(17), 1987-1994.
[http://dx.doi.org/10.1200/JCO.2015.63.9179] [PMID: 26976426]
[23]
Dent, S.; Cortés, J.; Im, Y.H.; Diéras, V.; Harbeck, N.; Krop, I.E.; Wilson, T.R.; Cui, N.; Schimmoller, F.; Hsu, J.Y.; He, J.; De Laurentiis, M.; Sousa, S.; Drullinsky, P.; Jacot, W. Phase III randomized study of taselisib or placebo with fulvestrant in estrogen receptor-positive, PIK3CA-mutant, HER2-negative, advanced breast cancer: The SANDPIPER trial. Ann. Oncol., 2021, 32(2), 197-207.
[http://dx.doi.org/10.1016/j.annonc.2020.10.596] [PMID: 33186740]
[24]
Krop, I.E.; Mayer, I.A.; Ganju, V.; Dickler, M.; Johnston, S.; Morales, S.; Yardley, D.A.; Melichar, B.; Forero-Torres, A.; Lee, S.C.; de Boer, R.; Petrakova, K.; Vallentin, S.; Perez, E.A.; Piccart, M.; Ellis, M.; Winer, E.; Gendreau, S.; Derynck, M.; Lackner, M.; Levy, G.; Qiu, J.; He, J.; Schmid, P. Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol., 2016, 17(6), 811-821.
[http://dx.doi.org/10.1016/S1470-2045(16)00106-6] [PMID: 27155741]
[25]
Lehmann, B.D.; Abramson, V.G.; Sanders, M.E.; Mayer, E.L.; Haddad, T.C.; Nanda, R.; Van Poznak, C.; Storniolo, A.M.; Nangia, J.R.; Gonzalez-Ericsson, P.I.; Sanchez, V.; Johnson, K.N.; Abramson, R.G.; Chen, S.C.; Shyr, Y.; Arteaga, C.L.; Wolff, A.C.; Pietenpol, J.A. TBCRC 032 IB/II multicenter study: Molecular insights to AR antagonist and PI3K inhibitor efficacy in patients with AR+ metastatic triple-negative breast cancer. Clin. Cancer Res., 2020, 26(9), 2111-2123.
[http://dx.doi.org/10.1158/1078-0432.CCR-19-2170] [PMID: 31822498]
[26]
Costa, R.L.B.; Han, H.S.; Gradishar, W.J. Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: A review. Breast Cancer Res. Treat., 2018, 169(3), 397-406.
[http://dx.doi.org/10.1007/s10549-018-4697-y] [PMID: 29417298]
[27]
Khan, M.A.; Jain, V.K.; Rizwanullah, M.; Ahmad, J.; Jain, K. PI3K/AKT/mTOR pathway inhibitors in triple-negative breast cancer: A review on drug discovery and future challenges. Drug Discov. Today, 2019, 24(11), 2181-2191.
[http://dx.doi.org/10.1016/j.drudis.2019.09.001] [PMID: 31520748]
[28]
Fuso, P.; Muratore, M.; D’Angelo, T.; Paris, I.; Carbognin, L.; Tiberi, G.; Pavese, F.; Duranti, S.; Orlandi, A.; Tortora, G.; Scambia, G.; Fabi, A. PI3K inhibitors in advanced breast cancer: The past, the present, new challenges and future perspectives. Cancers, 2022, 14(9), 2161.
[http://dx.doi.org/10.3390/cancers14092161] [PMID: 35565291]
[29]
Fruman, D.A.; Rommel, C. PI3K and cancer: Lessons, challenges and opportunities. Nat. Rev. Drug Discov., 2014, 13(2), 140-156.
[http://dx.doi.org/10.1038/nrd4204] [PMID: 24481312]
[30]
Khan, K.H.; Wong, M.; Rihawi, K.; Bodla, S.; Morganstein, D.; Banerji, U.; Molife, L.R. Hyperglycemia and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) inhibitors in phase I trials: Incidence, predictive factors, and management. Oncologist, 2016, 21(7), 855-860.
[http://dx.doi.org/10.1634/theoncologist.2015-0248] [PMID: 27151652]
[31]
Castel, P.; Toska, E.; Engelman, J.A.; Scaltriti, M. The present and future of PI3K inhibitors for cancer therapy. Nat. Can., 2021, 2(6), 587-597.
[http://dx.doi.org/10.1038/s43018-021-00218-4] [PMID: 35118422]
[32]
Wu, Y-L.; Cheng, Y.; Zhou, X.; Lee, K.H.; Nakagawa, K.; Niho, S.; Tsuji, F.; Linke, R.; Rosell, R.; Corral, J.; Migliorino, M.R.; Pluzanski, A.; Sbar, E.I.; Wang, T.; White, J.L.; Nadanaciva, S.; Sandin, R.; Mok, T.S. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small- cell lung cancer (ARCHER 1050): A randomised, open-label, phase 3 trial. Lancet Oncol., 2017, 18(11), 1454-1466.
[http://dx.doi.org/10.1016/S1470-2045(17)30608-3]
[33]
Liu, D.; Weintraub, M.A.; Garcia, C.; Goncalves, M.D.; Sisk, A.E.; Casas, A.; Harding, J.J.; Harnicar, S.; Drilon, A.; Jhaveri, K.; Flory, J.H. Characterization, management, and risk factors of hyperglycemia during PI3K or AKT inhibitor treatment. Cancer Med., 2022, 11(8), 1796-1804.
[http://dx.doi.org/10.1002/cam4.4579] [PMID: 35212193]
[34]
Fiascarelli, A.; Merlino, G.; Capano, S.; Talucci, S.; Bisignano, D.; Bressan, A.; Bellarosa, D.; Carrisi, C.; Paoli, A.; Bigioni, M.; Tunici, P.; Irrissuto, C.; Salerno, M.; Arribas, J.; de Stanchina, E.; Scaltriti, M.; Binaschi, M. Antitumor activity of the PI3K δ-sparing inhibitor MEN1611 in PIK3CA mutated, trastuzumab-resistant HER2 + breast cancer. Breast Cancer Res. Treat., 2023, 199(1), 13-23.
[http://dx.doi.org/10.1007/s10549-023-06895-2] [PMID: 36913051]
[35]
Graupera, M.; Potente, M. Regulation of angiogenesis by PI3K signaling networks. Exp. Cell Res., 2013, 319(9), 1348-1355.
[http://dx.doi.org/10.1016/j.yexcr.2013.02.021] [PMID: 23500680]
[36]
Hirsch, E.; Ciraolo, E.; Franco, I.; Ghigo, A.; Martini, M. PI3K in cancer–stroma interactions: Bad in seed and ugly in soil. Oncogene, 2014, 33(24), 3083-3090.
[http://dx.doi.org/10.1038/onc.2013.265] [PMID: 23893246]
[37]
Liu, P.; Cheng, H.; Roberts, T.M.; Zhao, J.J. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat. Rev. Drug Discov., 2009, 8(8), 627-644.
[http://dx.doi.org/10.1038/nrd2926] [PMID: 19644473]
[38]
Engelman, J.A.; Luo, J.; Cantley, L.C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat. Rev. Genet., 2006, 7(8), 606-619.
[http://dx.doi.org/10.1038/nrg1879] [PMID: 16847462]

Rights & Permissions Print Cite
Article Metrics
26
2
Wayfinder Image
Open Access Journals Promotions
© 2024 Bentham Science Publishers | Privacy Policy