Drug Evaluation

*Author for correspondence: Tel.: +49 621 383 5188;

E-mail Address: athanasios.mavratzas@umm.de

Department of Obstetrics & Gynecology Mannheim, Section of Conservative Gynecologic Oncology, Experimental & Translational Gynecologic Oncology, Medical Faculty Mannheim of University Heidelberg University Hospital, Mannheim, Theodor-Kutzer-Ufer 1-3, 68167, Mannheim, Germany

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Frederik Marmé

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Published Online:23 Sep 2020https://doi.org/10.2217/fon-2020-0464

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Abstract

Since the US FDA approval of everolimus/exemestane in July 2012, and of the first CDK 4/6 inhibitor, palbociclib, combined with endocrine treatment in February 2015, a third class of therapeutic compounds, the PI3K inhibitors, has been introduced to the arsenal of targeted therapies overcoming endocrine resistance in hormone receptor-positive metastatic breast cancer. Alpelisib (PIQRAY^®) is the first of these novel agents yielding promising clinical results, giving an impetus to further development of tailored endocrine anticancer treatments. Herein, we review its pharmacodynamic and pharmacokinetic properties, safety and efficacy data, as well as Phase III SOLAR-1 trial, prompting FDA approval of alpelisib in hormone receptor-positive metastatic breast cancer harboring PIK3CA mutations. Furthermore, implications for clinical use and current research will also be discussed.

Keywords:

Papers of special note have been highlighted as: • of interest

References

1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68(6), 394–424 (2018).
MedlineGoogle Scholar
2. Mariotto AB, Etzioni R, Hurlbert M, Penberthy L, Mayer M. Estimation of the number of women living with metastatic breast cancer in the United States. Cancer Epidemiol. Biomarkers Prev. 26(6), 809–815 (2017).
MedlineGoogle Scholar
3. Cardoso F, Costa A, Senkus E, Aapro M, Andre F, Barrios CH 3rd. ESO–ESMO international consensus guidelines for advanced breast cancer (ABC 3). Ann. Oncol. 28, 16–33 (2017).
Medline CASGoogle Scholar
4. Wesolowski R, Ramaswamy B. Gene expression profiling: changing face of breast cancer classification and management. Gene Expr. 15, 105–115 (2011).
MedlineGoogle Scholar
5. Lobbezoo DJA, van Kampen RJW, Voogd AC, Dercksen MW, van den Berkmortel F, Smilde TJ. Prognosis of metastatic breast cancer subtypes: the hormone receptor/HER2-positive subtype is associated with the most favorable outcome. Breast Cancer Res. Treat. 141, 507–514 (2013).
Medline CASGoogle Scholar
6. Schiff R,Fuqua SA. Clinical aspects of estrogen and progesterone receptors. In: Diseases of the Breast, 4th Edition . Harris JRLippman MEOsborne CKMorrow M (Eds). Wolters Kluwer/ Lippincott Williams & Wilkins, PA, USA, 408–430 (2009).
Google Scholar
7. Caswell-Jin JL, Plevritis SK, Tian L, Cadham CJ, Xu C, Stout NK. Change in survival in metastatic breast cancer with treatment advances: meta-analysis and systematic review. JNCI Cancer Spectr. 2(4), pky062 (2018).
MedlineGoogle Scholar
8. Cole MP, Jones CTA, Todd IDH. A new anti-oestrogenic agent in late breast cancer: an early clinical appraisal of ICI46474. Br. J. Cancer 25(2), 270–275 (1971).
Medline CASGoogle Scholar
9. Buzdar AU, Jonat W, Howell A, Jones SE, Blomqvist CP, Vogel CL. Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from two mature Phase III trials. Arimidex Study Group. Cancer 83(6), 1142–1152 (1998).
Medline CASGoogle Scholar
10. Dombernowsky P, Smith I, Falkson G, Leonard R, Panasci L, Bellmunt J. Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J. Clin. Oncol. 16(2), 453–461 (1998).
Medline CASGoogle Scholar
11. Kaufmann M, Bajetta E, Dirix LY, Fein LE, Jones SE, Zilembo N. Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a Phase III randomized double-blind trial. The Exemestane Study Group. J. Clin. Oncol. 18(7), 1399–1411 (2000).
Medline CASGoogle Scholar
12. Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R. Results of the CONFIRM Phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J. Clin. Oncol. 28(30), 4594–4600 (2010).
MedlineGoogle Scholar
13. Robertson JFR, Bondarenko IM, Trishkina E, Dvorkin M, Panasci L, Manikhas A. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, Phase III trial. Lancet 388(10063), 2997–3005 (2016).
Medline CASGoogle Scholar
14. Mouridsen H, Gershanovich M, Sun Y, Pérez-Carrión R, Boni C, Monnier A. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a Phase III study of the International Letrozole Breast Cancer Group. J. Clin. Oncol. 19(10), 2596–2606 (2001).
Medline CASGoogle Scholar
15. Bonneterre J, Buzdar A, Nabholtz JM, Robertson JF, Thürlimann B, von Euler M. Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma. Cancer 92(9), 2247–2258 (2001).
Medline CASGoogle Scholar
16. Paridaens RJ, Dirix LY, Beex LV, Nooij M, Cameron DA, Cufer T. Phase III study comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women: the European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group. J. Clin. Oncol. 26(30), 4883–4890 (2008).
Medline CASGoogle Scholar
17. Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 366, 520–529 (2012).
Medline CASGoogle Scholar
18. Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G. Randomized Phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J. Clin. Oncol. 30(22), 2718–2724 (2012).
Medline CASGoogle Scholar
19. Kornblum N, Zhao F, Manola J, Klein P, Ramaswamy B, Brufsky A. Randomized Phase II trial of fulvestrant plus everolimus or placebo in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer resistant to aromatase inhibitor therapy: results of PrE0102. J. Clin. Oncol. 36(16), 1556–1563 (2018).
Medline CASGoogle Scholar
20. Wolff AC, Lazar AA, Bondarenko I, Garin AM, Brincat S, Chow L. Randomized Phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer. J. Clin. Oncol. 31(2), 195–202 (2013).
Medline CASGoogle Scholar
21. Schmid P, Zaiss M, Harper-Wynne C, Ferreira M, Dubey S, Chan S. Fulvestrant plus vistusertib vs fulvestrant plus everolimus vs fulvestrant alone for women with hormone receptor–positive metastatic breast cancer. The MANTA Phase II randomized clinical trial. JAMA Oncol. 5(11), 1556–1563 (2019).
MedlineGoogle Scholar
22. Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im S. Overall survival (OS) results of the Phase III MONALEESA-3 trial of postmenopausal patients with hormone receptor positive (HR +), human epidermal growth factor 2-negative (HER2-) advanced breast cancer (ABC) treated with fulvestrant (FUL) ± ribociclib (RIB). Ann. Oncol. 30(Suppl. 5), v851–v934 (2019).
Google Scholar
23. Im S-A, Lu Y-S, Bardia A, Harbeck N, Colleoni M, Franke F. Overall survival with ribociclib plus endocrine therapy in breast cancer. N. Engl. J. Med. 381, 307–316 (2019).
Medline CASGoogle Scholar
24. Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X. The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor–positive, ERBB2-negative breast cancer that progressed on endocrine therapy – MONARCH 2, a randomized clinical trial. AMA Oncol. 6(1), 116–124 (2020).
Google Scholar
25. Johnston S, Martin M, Di Leo A, Im SA, Awada A, Forrester T. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer 5, 5 (2019).
MedlineGoogle Scholar
26. Finn RS, Martin M, Rugo HS, Jones S, Im S-A, Gelmon K. Palbociclib and letrozole in advanced breast cancer. N. Engl. J. Med. 375, 1925–1936 (2016).
Medline CASGoogle Scholar
27. Turner NC, Slamon DJ, Ro J, Bondarenko I, Im S-A, Masuda N. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N. Engl. J. Med. 379, 1926–1936 (2018).
Medline CASGoogle Scholar
28. Hortobagyi GN, Stemmer SM, Burris HA, Yap Y-S, Sonke GS, Paluch-Shimon S. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N. Engl. J. Med. 375, 1738–1748 (2016).
Medline CASGoogle Scholar
29. O'Leary B, Cutts RJ, Liu Y, Hrebien S, Huang X, Fenwick K. The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial. Cancer Discov. 8(11), 1390–1403 (2018).
MedlineGoogle Scholar
30. Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu. Rev. Med. 62, 233–247 (2011). • Important review analyzing genomic and nongenomic estrogen receptor response pathways, as well as chief mechanisms of endocrine resistance.
Medline CASGoogle Scholar
31. Klinge CM. Estrogen receptor interaction with estrogen response elements. Nucleic Acids Res. 29(14), 2905–2919 (2001).
Medline CASGoogle Scholar
32. Kushner PJ, Agard DA, Greene GL, Scanlan TS, Shiau AK, Uht RM. Estrogen receptor pathways to AP-1. J. Steroid Biochem. Mol. Biol. 74(5), 311–317 (2000).
Medline CASGoogle Scholar
33. Toy W, Shen Y, Won H, Green B, Sakr RA, Will M. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat. Genet. 45(12), 1439–1445 (2013).
Medline CASGoogle Scholar
34. Robinson DR, Wu YM, Vats P, Su F, Lonigro RJ, Cao X. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat. Genet. 45(12), 1446–1451 (2013).
Medline CASGoogle Scholar
35. Schiavon G, Hrebien S, Garcia-Murillas I, Cutts RJ, Pearson A, Tarazona N. Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Sci. Transl. Med. 7(313), 313ra182 (2015).
MedlineGoogle Scholar
36. Fribbens C, O'Leary B, Kilburn L, Hrebien S, Garcia-Murillas I, Beaney M. Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer. J. Clin. Oncol. 34(25), 2961–2968 (2016).
Medline CASGoogle Scholar
37. Jeselsohn R, Yelensky R, Buchwalter G, Frampton G, Meric-Bernstam F, Gonzalez-Angulo AM. Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor positive breast cancer. Clin. Cancer Res. 20(7), 1757–1767 (2014).
Medline CASGoogle Scholar
38. Jeselsohn R, Buchwalter G, De Angelis C, Brown M, Schiff R. ESR1 mutations as a mechanism for acquired endocrine resistance in breast cancer. Nat. Rev. Clin. Oncol. 12(10), 573–583 (2015).
Medline CASGoogle Scholar
39. Herrera-Abreu MT, Palafox M, Asghar U, Rivas MA, Cutts RJ, Garcia-Murillas I. Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer. Cancer Res. 76(8), 2301–2313 (2016).
Medline CASGoogle Scholar
40. Caldon CE, Musgrove EA. Distinct and redundant functions of cyclin E1 and cyclin E2 in development and cancer. Cell Div. 5, 2 (2010).
MedlineGoogle Scholar
41. Turner NC, Liu Y, Zhu Z, Loi S, Colleoni M, Loibl S. Cyclin E1 expression and palbociclib efficacy in previously treated hormone receptor–positive metastatic breast cancer. J. Clin. Oncol. 37, 1169–1178 (2019).
Medline CASGoogle Scholar
42. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised Phase II study. Lancet 16(1), 25–35 (2015).
Medline CASGoogle Scholar
43. Schiff R, Massarweh SA, Shou J, Bharwani L, Mohsin SK, Osborne CK. Cross-talk between estrogen receptor and growth factor pathways as a molecular target for overcoming endocrine resistance. Clin. Cancer Res. 10(1), 331–336 (2004).
Google Scholar
44. Lee AV, Cui X, Oesterreich S. Cross-talk among estrogen receptor, epidermal growth factor, and insulin-like growth factor signaling in breast cancer. Clin. Cancer Res. 7, 4429–4435 (2001).
Google Scholar
45. Nicholson RI, Hutcheson IR, Hiscox SE, Knowlden JM, Giles M, Barrow D. Growth factor signalling and resistance to selective oestrogen receptor modulators and pure anti-oestrogens: the use of anti-growth factor therapies to treat or delay endocrine resistance in breast cancer. Endocr. Relat. Cancer 12(Suppl. 1), 29–36 (2005).
Google Scholar
46. Vasan N, Toska E, Scaltriti M. Overview of the relevance of PI3K pathway in HR-positive breast cancer. Ann. Oncol. 30(Suppl. 10), x3–x11 (2019). • Excellent review of the estrogen receptor and PI3K/AKT/mTOR pathway cross-talk, elucidating the role of the KMT2D-negative feedback loop under current PI3K inhibitiors.
Medline CASGoogle Scholar
47. Zardavas D, Phillips WA, Loi S. PIK3CA mutations in breast cancer: reconciling findings from preclinical and clinical data. Breast Cancer Res. 16, 201 (2014). • Overview of clinical relevance of PIK3CA mutations in early and advanced breast cancer.
MedlineGoogle Scholar
48. Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase–AKT pathway in human cancer. Nat. Rev. Cancer 2, 489–501 (2002).
Medline CASGoogle Scholar
49. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu. Rev. Cell Dev. Biol. 17, 615–675 (2001).
Medline CASGoogle Scholar
50. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat. Rev. Genet. 7(8), 606–619 (2006).
Medline CASGoogle Scholar
51. Chagpar RB, Links PH, Pastor MC, Furber LA, Hawrysh AD, Chamberlain MD. Direct positive regulation of PTEN by the p85 subunit of phosphatidylinositol 3-kinase. Proc. Natl Acad. Sci. USA 107(12), 5471–5476 (2010).
Medline CASGoogle Scholar
52. Corvera S, Czech MP. Direct targets of phosphoinositide 3-kinase products in membrane traffic and signal transduction. Trends Cell Biol. 8(11), 442–446 (1998).
Medline CASGoogle Scholar
53. Van der Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat. Cell Biol. 9(3), 316–323 (2007).
MedlineGoogle Scholar
54. Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc. Natl Acad. Sci. USA 96(8), 4240–4245 (1999).
Medline CASGoogle Scholar
55. Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H. Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor α. J. Biol. Chem. 276(13), 9817–9824 (2001).
Medline CASGoogle Scholar
56. Miller TW, Hennessy BT, Gonzalez-Argulo AM, Fox EM, Mills GB, Chen H. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J. Clin. Invest. 120(7), 2406–2413 (2010).
Medline CASGoogle Scholar
57. Crowder RJ, Phommaly C, Tao Y, Hoog J, Luo J, Perou CM. PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor positive breast cancer. Cancer Res. 69(9), 3955–3962 (2009).
Medline CASGoogle Scholar
58. Bosch A, Li Z, Bergamaschi A, Ellis H, Toska E, Prat A. PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer. Sci. Transl. Med. 7(283), 283ra51 (2015).
MedlineGoogle Scholar
59. Toska E, Osmanbeyoglu HU, Castel P, Chan C, Hendrickson RC, Elkabets M. PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D. Science 355(6331), 1324–1330 (2017).
Medline CASGoogle Scholar
60. Samuels Y, Velculescu VE. Oncogenic mutations of PIK3CA in human cancers. Cell Cycle 3(10), e17–e19 (2004).
Google Scholar
61. Karakas B, Bachmann KE, Park BH. Mutation of the PIK3CA oncogene in human cancers. Br. J. Cancer 94, 455–459 (2006). • Analytic report on somatic PIK3CA mutations in human cancers.
Medline CASGoogle Scholar
62. Campbell IG, Russell SE, Choong DYH, Montgomery KG, Ciaravella ML, Hooi CSF. Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res. 64, 7678–7681 (2004).
Medline CASGoogle Scholar
63. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004).
Medline CASGoogle Scholar
64. Bachmann KE, Argani P, Samuels Y, Silliman N, Ptak J, Szabo S. The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol. Ther. 3, 772–775 (2004).
MedlineGoogle Scholar
65. Miller TW, Rexer BN, Garrett JT, Arteaga CL. Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res. 13, 224 (2011).
Medline CASGoogle Scholar
66. Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 65, 2554–2559 (2005).
Medline CASGoogle Scholar
67. Lehmann BD, Bauer JA, Schafer JM, Pendleton CS, Tang L, Johnson KC. PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors. Breast Cancer Res. 16(4), 406 (2014).
MedlineGoogle Scholar
68. Burke JE, Perisic O, Masson GR, Vadas O, Williams RL. Oncogenic mutations mimic and enhance dynamic events in the natural activation of phosphoinositide 3-kinase p110 α (PIK3CA). PNAS 109(38), 15259–15264 (2012). • Mapping of PIK3CA mutations on the crystal structure of p110α/p85α and analysis of conformational changes for hotspot mutations on the catalytic site.
Medline CASGoogle Scholar
69. Perez-Tenorio G, Alkhori L, Olsson B, Waltersson MA, Nordenskjöld B, Rutqvist LE. PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer. Clin. Cancer Res. 13(12), 3577–3584 (2007).
Medline CASGoogle Scholar
70. Rudolph M, Anzeneder T, Schulz A, Beckmann G, Byrne AT, Jeffers M. AKT1E17K mutation profiling in breast cancer: prevalence, concurrent oncogenic alterations, and blood-based detection. BMC Cancer 16, 622 (2016).
MedlineGoogle Scholar
71. Miron A, Varadi M, Carrasco D, Li H, Luongo L, Kim HJ. PIK3CA mutations in in situ and invasive breast carcinomas. Cancer Res. 70(14), 5674–5678 (2010).
Medline CASGoogle Scholar
72. Dunlap J, Le C, Shukla A, Patterson J, Presnell A, Heinrich MC. Phosphatidylinositol-3-kinase and AKT1 mutations occur early in breast carcinoma. Breast Cancer Res. Treat. 120(2), 409–418 (2010).
Medline CASGoogle Scholar
73. Isakoff SJ, Engelmann JA, Irie HY, Brachmann SM, Pearline RV, Cantley LC. Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res. 65(23), 10992–11000 (2005).
Medline CASGoogle Scholar
74. Zhao JJ, Liu Z, Wang L, Shin E, Loda MF, Roberts TM. The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells. Proc. Natl Acad. Sci. USA 102(51), 18443–18448 (2005).
Medline CASGoogle Scholar
75. Kalinsky K, Jacks LM, Heguy A, Patil S, Drobnjak M, Umeshkumar K. PIK3CA mutation associates with improved outcome in breast cancer. Clin. Cancer Res. 15(16), 5049–5059 (2009). • First retrospective analysis of correlation between PIK3CA mutations and clinical outcome in early breast cancer.
Medline CASGoogle Scholar
76. Cizkova M, Susini A, Vacher S, Cizeron-Clairac G, Andrieu C, Driouch K. PIK3CA mutation impact on survival in breast cancer patients and in ERα, PR and ERBB2-based subgroups. Breast Cancer Res. 14, R28 (2012).
Medline CASGoogle Scholar
77. Ellis MJ, Lin L, Crowder R, Tao Y, Hoog J, Snider J. Phosphatidyl-inositol-3-kinase aplha catalytic subunit mutation and response to neoadjuvant endocrine therapy for estrogen receptor positive breast cancer. Breast Cancer Res. Treat. 119(2), 379–390 (2010). • Large metaanalysis analyzing interaction of PIK3CA mutations with response to neoadjuvant treatment in early breast cancer.
Medline CASGoogle Scholar
78. Lopez-Knowles E, Segal CV, Gao Q, Garcia-Murillas I, Turner NC, Smith I. Relationship of PIK3CA mutation and pathway activity with antiproliferative response to aromatase inhibition. Breast Cancer Res. 16, R68 (2014).
MedlineGoogle Scholar
79. Sabine VS, Crozier C, Brookes CL, Drake C, Piper T, van de Velde CJH. Mutational analysis of PI3K/AKT signaling pathway in tamoxifen exemestane adjuvant multinational pathology study. J. Clin. Oncol. 32(27), 2951–2959 (2014).
Medline CASGoogle Scholar
80. Beelen K, Opdam M, Severson TM, Koornstra RHT, Vincent AD, Wesseling J. PIK3CA mutations, phosphatase and tensin homolog, human epidermal growth factor receptor 2, and insulin-like growth factor 1 receptor and adjuvant tamoxifen resistance in postmenopausal breast cancer patients. Breast Cancer Res. 16, R13 (2014).
MedlineGoogle Scholar
81. Loi S, Michiels S, Lambrechts D, Fumagalli D, Claes B, Kellokumpu-Lehtinen P-L. Somatic mutation profiling and associations with prognosis and trastuzumab benefit in early breast cancer. JNCI 105(13), 960–967 (2013).
Medline CASGoogle Scholar
82. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, Neve RM, Kuo W-L, Davies M. An integrative genomic and proteomic analysis of PIK3CA PTEN and AKT mutations in breast cancer. Cancer Res. 68(15), 6084–6091 (2008).
Medline CASGoogle Scholar
83. Pang B, Cheng S, Sun S-P, An C, Liu Z-Y, Feng X. Prognostic role of PIK3CA mutations and their association with hormone receptor expression in breast cancer: a meta-analysis. Sci. Rep. 4, 6255 (2014).
Medline CASGoogle Scholar
84. Barbareschi M, Buttitta F, Felicioni L, Cotrupi S, Barassi F, Del Grammastro M. Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Clin. Cancer Res. 13(20), 6064–6069 (2007).
Medline CASGoogle Scholar
85. Mangone FR, Bobrovnitchaia IG, Salaorni S, Manuli E, Nagai MA. PIK3CA exon 20 mutations are associated with poor prognosis in breast cancer patients. Clinics (Sao Paulo) 67(11), 1285–1290 (2012).
MedlineGoogle Scholar
86. Yuan H, Chen J, Liu Y, Ouyang T, Li J, Wang T. Association of PIK3CA mutation status before and after neoadjuvant chemotherapy with response to chemotherapy in women with breast cancer. Clin Cancer Res. 21(19), 4365–4372 (2015).
Medline CASGoogle Scholar
87. Micalizzi DS, Juric D, Niemierko A, Reynolds KL, Borger D, Vora SR. Abstract P1-13-03: association of PIK3CA mutation with clinical response to specific endocrine therapies in metastatic hormone receptor positive (HR+) breast cancer. Cancer Res. 75(Suppl. 9), Abstract nr P1-13-03 (2015).
Google Scholar
88. Ramirez-Ardila DE, Helmijr JC, Look MP, Lurkin I, Ruigrok-Ritstier K, van Laere S. Hotspot mutations in PIK3CA associate with first-line treatment outcome for aromatase inhibitors but not for tamoxifen. Breast Cancer Res. Treat. 139, 39–49 (2013).
Medline CASGoogle Scholar
89. Moynahan ME, Chen D, He W, Sung P, Samoila A, You D. Correlation between PIK3CA mutations in cell-free DNA and everolimus efficacy in HR +, HER2 − advanced breast cancer: results from BOLERO-2. Br. J. Cancer 116, 726–730 (2017).
Medline CASGoogle Scholar
90. Sanchez CG, Ma CX, Crowder RJ, Guintoli T, Phommaly C, Gao F. Preclinical modeling of combined phosphatidsylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer. Breast Cancer Res. 13, R21 (2011).
Medline CASGoogle Scholar
91. Mosele F, Stefanovska B, Lusque A, Tran Dien A, Garberis I, Droin N. Outcome and molecular landscape of patients with PIK3CA-mutated metastatic breast cancer. Ann. Oncol. 31(3), 377–386 (2020).
Medline CASGoogle Scholar
92. Krop IE, Mayer IA, Ganju V, Dickler M, Johnston S, Morales S. Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomized, double-blind, placebo-controlled, Phase II trial. Lancet 17, 811–821 (2016).
Medline CASGoogle Scholar
93. Baselga J, Im S-A, Iwata H, Cortes J, De Laurentiis M, Jiang Z. Buparlisib plus fulvestrant versus placebo in postmenopausal, hormone receptor-positive, HER-2 negative, advanced breast cancer (BELLE-2): a randomized, double-blind, placebo-controlled, Phase III trial. Lancet 18, 904–916 (2017).
Medline CASGoogle Scholar
94. Di Leo A, Johnston S, Lee KS, Ciruelos E, Lonning PE, Janni W. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomized, double-blind, placebo-controlled Phase III trial. Lancet 19, 87–100 (2018).
MedlineGoogle Scholar
95. Fritsch C, Huang A, Chatenay-Rivauday C, Schnell C, Reddy A, Liu M. Characterization of the novel and specific PI3Ka inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials. Mol. Cancer Ther. 13(5), 1117–1129 (2014).
Medline CASGoogle Scholar
96. Furet P, Guagnano V, Fairhurst RA, Imbach-Weese P, Bruce I, Knapp M. Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation. Bioorg. Med. Chem. Lett. 23(13), 3741–3748 (2013).
Medline CASGoogle Scholar
97. Huang A, Fritsch C, Wilson C, Reddy A, Liu M, Lehar J. Abstract 3749: single agent activity of PIK3CA inhibitor BYL719 in a broad cancer cell line panel. Cancer Res. 72(Suppl. 8), Abstract nr 3749 (2012).
Google Scholar
98. Manna P, Jain SK. PIP3 but not PIP2 increases GLUT4 surface expression and glucose metabolism mediated by AKT/PKCzeta/lambda phosphorylation in 3T3L1 adipocytes. Mol. Cell. Biochem. 381(0), 291–299 (2013). • Research article elucidates mechanisms of hyperglycemia under inhibition of the PI3K/AKT/mTOR pathway.
Medline CASGoogle Scholar
99. Sano H, Eguez L, Teruel MN, Fukuda M, Chuang TD, Chavez JA. Rab10, a target of the AS160 Rab GAP, is required for insulin-stimulated translocation of GLUT4 to the adipocyte plasma membrane. Cell Metabolism 5(4), 293–303 (2007).
Medline CASGoogle Scholar
100. Friedrichsen M, Birk JB, Richter EA, Ribel-Madsen R, Pehmoller C, Hansen BF. AKT2 influences glycogen synthase activity in human skeletal muscle through regulation of NH(2)-terminal (sites 2 + 2a) phosphorylation. Am. J. Physiol. Endocrinol. Metab. 304(6), E631–E639 (2013).
Medline CASGoogle Scholar
101. Schnell CR, Ferrat T, Wyss D, Tinetto W, Tobler S, Fritsch C. Abstract 3933: circadian timing regimen for alpelisib (NVP-BYL719), a selective inhibitor of the class Ia PI3K isoform alpha to maximize therapeutic index. Cancer Res. 78(Suppl. 13), Abstract nr 3933 (2018).
Google Scholar
102. James A, Blumenstein L, Glaenzel U, Jin Y, Demailly A, Jakab A. Absorption, distribution, metabolism, and excretion of [¹⁴C]BYL719 (alpelisib) in healthy male volunteers. Cancer Chemother. Pharmacol. 76, 751–760 (2015). • First absorption, distribution, metabolism and excretion trial characterizing metabolism of alpelisib in humans.
Medline CASGoogle Scholar
103. Juric D, Rodon J, Tabernero J, Janku F, Burris HA, Schellens JHM. Phosphatidylinositol 3-kinase α-selective inhibition with alpelisib (BYL719) in PIK3CA-altered solid tumors: results from the first-in-human study. J. Clin. Oncol. 36(13), 1291–1299 (2018). • First-in-man trial of alpelisib in patients with PIK3CA-altered solid tumors.
Medline CASGoogle Scholar
104. De Buck SS, Jakab A, Boehm M, Bootle D, Juric D, Quadt C. Population pharmacokinetics and pharmacodynamics of BYL719, a phosphoinositide 3-kinase antagonist, in adult patients with advanced solid malignancies. Br. J. Clin. Pharmacol. 78(3), 543–555 (2014).
MedlineGoogle Scholar
105. Ando Y, Iwasa S, Takahashi S, Saka H, Kakizume T, Natsume K. Phase I study of alpelisib (BYL719), an α-specific PI3K inhibitor, in Japanese patients with advanced solid tumors. Cancer Sci. 110, 1021–1031 (2019).
Medline CASGoogle Scholar
106. Munster PN, Hamilton EP, Estevez LG, De Boer RH, Mayer IA, Campone M. Phase IB study of LEE011 and BYL719 in combination with letrozole in ER+, HER2-breast cancer. J. Clin. Oncol. 32(Suppl. 26), 143–143 (2014).
Google Scholar
107. Juric D, Janku F, Rodon J, Burris HA, Mayer IA, Schuler M. Alpelisib plus fulvestrant in PIK3CA-altered and PIK3CA-wildtype estrogen receptor-positive advanced breast cancer. A Phase Ib clinical trial. JAMA Oncol. 5(2), e184475 (2018).
Google Scholar
108. Nunnery SE, Mayer IA. Management of toxicity to isoform α-specific PI3K inhibitors. Ann. Oncol. 30(Suppl. 10), x21–x26 (2019). • Important overview of guidelines for treatment of alpelisib-related untoward effects.
CASGoogle Scholar
109. Liu Z, Zhu G, Getzenberg RH, Veltri RW. The upregulation of PI3K/Akt and MAP kinase pathways is associated with resistance of microtubule-targeting drugs in prostate cancer. J. Cell. Biochem. 116, 1341–1349 (2015).
Medline CASGoogle Scholar
110. Rodon J, Curigliano G, Delord J-P, Harb W, Azaro A, Han Y. A Phase Ib, open-label, dose-finding study of alpelisib in combination with paclitaxel in patients with advanced solid tumors. Oncotarget 9(60), 31709–31718 (2018).
MedlineGoogle Scholar
111. Vuylsteke P, Huizing M, Petrakova K, Roylance R, Laing R, Chan S. Pictilisib PIK3Kinase inhibitor (a phosphatidylinositol 3-kinase [PI3K] inhibitor) plus paclitaxel for the treatment of hormone receptor-positive, HER-2 negative, locally recurrent, or metastatic breast cancer: interim analysis of the multicenter, placebo-controlled, Phase II randomized PEGGY study. Ann. Oncol. 27, 2059–2066 (2016).
Medline CASGoogle Scholar
112. Martin M, Chan A, Ririx L, O'Shaughnessy J, Hegg R, Manikhas A. 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. 28, 313–320 (2017).
Medline CASGoogle Scholar
113. Sharma P, Abramson VG, O'Dea A, Lewis S, Scott JN, Ward J. Safety and efficacy results from Phase I study of BYL719 plus nab-paclitaxel in HER-2 negative metastatic breast cancer. Cancer Res. 77(Suppl. 4), Abstract nr P6-11-08 (2017).
Google Scholar
114. Jain S, Shah AN, Santa-Maria CA, Siziopikou K, Rademaker A, Helenowski I. Phase I study of alpelisib (BYL-719) and trastuzumab emtansine (T-DM1) in HER2-positive metastatic breast cancer (MBC) after trastuzumab and taxane therapy. Breast Cancer Res. Treat. 171, 371–381 (2018).
Medline CASGoogle Scholar
115. Mayer IA, Abramson VG, Formisano L, Balko JM, Estrada MV, Sanders ME. A Phase Ib study of alpelisib (BYL719), a PI3Kα-specific inhibitor, with letrozole in ER+/HER2− metastatic breast cancer. Clin. Cancer Res. 23(1), 26–34 (2016).
MedlineGoogle Scholar
116. Mayer IA, Prat A, Egle D, Blau S, Fidalgo JAP, Gnant M. 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. 25(10), 2975–2987 (2019).
Medline CASGoogle Scholar
117. Ma CX, Luo J, Naughton M, Ademuyiwa F, Suresh R, Griffith M. A Phase 1 trial of BKM120 (Buparlisib) in combination with fulvestrant in postmenopausal women with estrogen receptor positive metastatic breast cancer. Clin. Cancer Res. 22(7), 1583–1591 (2016).
Medline CASGoogle Scholar
118. André F, Ciruelos E, Rubovsky G, Campone M, Loibl S, Rugo HS. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N. Engl. J. Med. 380(20), 1929–1940 (2019). • Phase III trial leading to the US FDA approval of alpelisib in combination with fulvestrant in PIK3CA-mutated hormone receptor-positive metastatic breast cancer.
Medline CASGoogle Scholar
119. Franz MJ, Bantle JP, Beebe CA, Brunzell JD, Chiasson JL, Garg A. Nutrition principles and recommendations in diabetes. Diabetes Care 27(Suppl. 1), S36 (2004).
MedlineGoogle Scholar
120. Busaidy NL, Farooki A, Dowlati A, Perentesis JP, Dancey JE, Doyle LA. Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt-mTOR Pathway. J. Clin. Oncol. 30, 2919–2928 (2012).
Medline CASGoogle Scholar
121. Hopkins BD, Pauli C, Du X, Wang DG, Li X, Wu D. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature 560(7719), 499–503 (2018).
Medline CASGoogle Scholar
122. Calautti E, Li J, Saoncella S, Brissette JL, Goetinck PF. Phosphoinositide 3-kinase signaling to Akt promotes keratinocyte differentiation versus death. J. Biol. Chem. 280(38), 32856–32865 (2005).
Medline CASGoogle Scholar
123. Dickler MN, Saura C, Richards DA, Krop IE, Cervantes A, Bedard PL. Phase II study of Taselisib (GDC-0032) in combination with fulvestrant in patients with HER-2 negative, hormone-receptor positive advanced breast cancer. Clin. Cancer Res. 24(18), 4380–4387 (2018).
Medline CASGoogle Scholar
124. Greenwell IB, Ip A, Cohen JB. PI3K inhibitors: understanding toxicity mechanisms and management. Oncology (Williston Park) 31(11), 821–828 (2017).
MedlineGoogle Scholar
125. Benson AB, Ajani JA, Catalano RB, Engelking C, Kornblau SM, Martenson JA. Recommended guidelines for the treatment of cancer treatment-induced diarrhea. J. Clin. Oncol. 22, 2918–2926 (2004).
Medline CASGoogle Scholar
126. Cheson BD, O'Brien S, Ewer MS, Goncalves MD, Farooki A, Lenz G. Optimal management of adverse events from copanlisib in the treatment of patients with Non-Hodgkin lymphomas. Clin. Lymphoma, Myeloma Leuk. 19(3), 135–141 (2019).
MedlineGoogle Scholar
127. Laurent P-A, Hechler B, Solinhac R, Ragab A, Cabou C, Anquetil T. Impact of PI3Kα (phosphoinositide 3-kinase alpha) inhibition on hemostasis and thrombosis. Arterioscler. Thromb. Vasc. Biol. 38(9), 2041–2053 (2018).
Medline CASGoogle Scholar
128. Yang T, Meoli DF, Moslehi J, Roden DM. Inhibition of the α-subunit of phosphoinositide 3-kinase in heart increases late sodium current and is arrhythmogenic. J. Pharmacol. Exp. Ther. 365(3), 460–466 (2018).
Medline CASGoogle Scholar
129. Huw LY, O'Brien C, Pandita A, Mohan S, Spoerke JM, Lu S. Acquired PIK3CA amplification causes resistance to selective phosphoinositide 3-kinase inhibitors in breast cancer. Oncogenesis 2(e83), 1–7 (2013).
Google Scholar
130. Nakanishi Y, Walter K, Spoerke JM, O'Brien C, Huw LY, Hampton GM. Activating mutations in PIK3CB confer resistance to PI3K inhibition and define a novel oncogenic role for p110β. Cancer Res. 76(5), 1193–1203 (2016).
Medline CASGoogle Scholar
131. Juric D, Castel P, Griffith M, Griffith OL, Won HH, Ellis H et al. Convergent loss of PTEN leads to clinical resistance to a PI(3)Ka inhibitor. Nature 518(7538), 240–244 (2015).
Medline CASGoogle Scholar
132. Costa C, Ebi H, Martini M, Beausoleil SA, Faber AC, Jakubik CT. Measurement of PIP3 levels reveals an unexpected role for p110β in early adaptive responses to p110α-specific inhibitors in luminal breast cancer. Cancer Cell. 27(1), 97–108 (2015).
Medline CASGoogle Scholar
133. Schwartz S, Wongvipat J, Trigwell CB, Hancox U, Carver BS, Rodrik-Outmezguine V. Feedback suppression of PI3Kα signaling in PTEN mutated tumors is relieved by selective inhibition of PI3Kβ. Cancer Cell 27(1), 109–122 (2015).
Medline CASGoogle Scholar
134. Razavi P, Dickler MN, Shah PD, Toy W, Brown DN, Won HH. Alterations in PTEN and ESR1 promote clinical resistance to alpelisib plus aromatase inhibitors. Nat. Cancer. 1, 382–393 (2020).
MedlineGoogle Scholar
135. Elkabets M, Vora S, Juric D, Morse N, Mino-Kenudson M, Muranen T. mTORC1 inhibition is required for sensitivity to PI3K p110α inhibitors in PIK3CA-mutant breast cancer. Sci. Transl. Med. 5(196), 196ra99 (2013).
MedlineGoogle Scholar
136. Baselga J, Curigliano G, Martín M, André F, Beck JT, Tortora G. Abstract CT061: a Phase Ib study of alpelisib (BYL719) + everolimus ± exemestane in patients with advanced solid tumors or HR+/HER2−breast cancer. Cancer Res. 76(Suppl. 14), (2016).
MedlineGoogle Scholar
137. Varghese AM, Moore KN, Hamilton EP, Hyman DM, Jhaveri KL, Wang XA. Safety and tolerability of the dual PI3K/mTOR inhibitor LY3023414 in combination with fulvestrant in treatment refractory advanced breast cancer patients. J. Clin. Oncol. 35(Suppl. 15), 1064–1064 (2017).
Google Scholar
138. Radovich M, Solzak JP, Hancock BA, Storniolo AMV, Schneider BP, Miller KD. Abstract OT3-06-02: an initial safety study of gedatolisib plus PTK7-ADC for metastatic triple-negative breast cancer. Cancer Res. 79(Suppl. 4), (2019).
Google Scholar
139. Britschgi A, Andraos R, Brinkhaus H, Klebba I, Romanet V, Mueller U. JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: a rationale for cotargeting these pathways in metastatic breast cancer. Cancer Cell. 22, 796–811 (2012).
Medline CASGoogle Scholar
140. Dey N, Leyland-Jones B, De P. MYC-xing it up with PIK3CA mutation and resistance to PI3K inhibitors: summit of two giants in breast cancers. Am. J. Cancer Res. 5(1), 1–19 (2015).
Medline CASGoogle Scholar
141. Le X, Antony R, Razavi P, Treacy DJ, Luo F, Ghandi M. Systematic functional characterization of resistance to PI3K inhibition in breast cancer. Cancer Discov. 6(10), 1134–1147 (2016).
Medline CASGoogle Scholar
142. Serra V, Eichhorn PJ, García-García C, Ibrahim YH, Prudkin L, Sánchez G. RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer. J. Clin. Invest. 123(6), 2551–2563 (2013).
Medline CASGoogle Scholar
143. Durrant ST, Nagler A, Guglielmelli P, Lavie D, le Coutre P, Gisslinger H. Results from HARMONY: an open-label, multicenter, 2-arm, Phase Ib, dose-finding study assessing the safety and efficacy of the oral combination of ruxolitinib and buparlisib in patients with myelofibrosis. Haematologica 104(12), e551–e554 (2019).
Medline CASGoogle Scholar
144. Cortes J, Tamura K, DeAngelo DJ, de Bono J, Lorente D, Minden M. Phase I studies of AZD1208, a proviral integration Moloney virus kinase inhibitor in solid and haematological cancers. Br. J. Cancer 118, 1425–1433 (2018).
Medline CASGoogle Scholar
145. Averous J, Fonseca BD, Proud CG. Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1. Oncogene 27(8), 1106–1113 (2008).
Medline CASGoogle Scholar
146. Vora SR, Juric D, Kim N, Mino-Kenudson M, Huynh T, Costa C et al. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell. 26(1), 136–149 (2014).
Medline CASGoogle Scholar
147. Rehman FL, Lord CJ, Ashworth A. The promise of combining inhibition of PI3K and PARP as cancer therapy. Cancer Discov. 2(11), 982–984 (2012).
Medline CASGoogle Scholar
148. Konstantinopoulos PA, Barry WT, Birrer M, Westin SN, Cadoo KA, Shapiro GI. Olaparib and α-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion Phase Ib trial. Lancet 20(4), 570–580 (2019).
Medline CASGoogle Scholar
149. Brandao M, Caparica R, Eiger D, de Azambuja E. Biomarkers of response and resistance to PI3K inhibitors in estrogen receptor-positive breast cancer patients and combination therapies involving PI3K inhibitors. Ann. Oncol. 30(Suppl. 10), x27–x42 (2019).
CASGoogle Scholar
150. Chakrabarty A, Sánchez V, Kuba MG, Rinehart C, Arteaga CL. Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. PNAS 8(109), 2718–2723 (2012).
Google Scholar
151. Serra V, Scaltriti M, Prudkin L, Eichhorn PJA, Ibrahim YH, Chandarlapaty S. PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer. Oncogene 30, 2547–2557 (2011).
Medline CASGoogle Scholar
152. Filho OM, Goel S, Barry WT, Hamilton EP, Tolaney SM, Yardley DA. A mouse-human Phase I co-clinical trial of taselisib in combination with TDM1 in advanced HER2-positive breast cancer (MBC). J. Clin. Oncol. 35(Suppl. 15), 1030–1030 (2017).
Google Scholar
153. Keegan NM, Walshe JM, Toomey S, Gullo G, Kennedy MJ, Bulger KN. A Phase Ib trial of copanlisib and trastuzumab in pretreated recurrent or metastatic HER2-positive breast cancer “PantHER”. J. Clin. Oncol. 36(Suppl. 15), 1036–1036 (2018).
Google Scholar
154. Coussy F, Botty RE, Lavigne M, Gu C, Fuhrmann L, Briaux A. Combination of PI3K and MEK inhibitors yields durable remission in PDX models of PIK3CA-mutated metaplastic breast cancers. J. Hematol. Oncol. 13(13), 1–10 (2020).
MedlineGoogle Scholar
155. Banerji U, Smith AD, Zivi A, Lorente D, Rihawi K, Tunariu N. Dual targeting of RAF-MEK-ERK and PI3K-AKT-mTOR pathways in RAS-mutant cancers: preclinical insights and institutional experience from a clinical trial of binimetinib (MEK162) plus BYL719. J. Clin. Oncol. 32(Suppl. 15), 13559–13559 (2014).
Google Scholar
156. Wheler JJ, Atkins JT, Janku F, Moulder SL, Stephens PJ, Yelensky R. Presence of both alterations in FGFR/FGF and PI3K/AKT/mTOR confer improved outcomes for patients with metastatic breast cancer treated with PI3K/AKT/mTOR inhibitors. Oncoscience 3(5–6), 164–172 (2016).
MedlineGoogle Scholar
157. Hyman DM, Tran B, Jaime JC, Garralda E, Machiels J-PH, Schellens JHM. Phase Ib study of BGJ398 in combination with BYL719 in patients (pts) with select advanced solid tumors. J. Clin. Oncol. 34(Suppl. 15), 2500–2500 (2016).
Google Scholar
158. Usman MW, Gao J, Zheng T, Rui C, Li T, Bian X. Macrophages confer resistance to PI3K inhibitor GDC-0941 in breast cancer through the activation of NF-κB signaling. Cell Death Disease. 9(809), 1–12 (2018).
MedlineGoogle Scholar
159. Ali K, Soond DR, Pineiro R, Hagemann T, Pearce W, Lim EL. Inactivation of the PI3K p110δ breaks regulatory T cell-mediated immune tolerance to cancer. Nature 510(7505), 407–411 (2014).
Medline CASGoogle Scholar
160. Schmid MC, Avraamides CJ, Dippold HC, Franco I, Foubert P, Ellies LG. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3Kγ, a single convergent point promoting tumor inflammation and progression. Cancer Cell. 19(6), 715–727 (2011).
Medline CASGoogle Scholar
161. Fokas E, Im JH, Hill S, Xameen S, Stratford M, Beech J. Dual inhibition of the PI3K/mTOR pathway increases tumor radiosensitivity by normalizing tumor vasculature. Cancer Res. 72(1), 239–248 (2012).
Medline CASGoogle Scholar
162. Cretella D, Digiacomo G, Giovanetti E, Cavazonni A. PTEN alterations as a potential mechanism for tumor cell escape from PD-1/PD-L1 inhibition. Cancers 11(1318), 1–17 (2019).
Google Scholar
163. Sun C, Mezzadra R, Schumacher TN. Regulation and function of the PD-L1 checkpoint. Immunity 48, 434–452 (2018).
Medline CASGoogle Scholar
164. Sai J, Owens P, Novitskiy SV, Hawkins OE, Vilgelm AE, Yang J. PI3K inhibition reduces mammary tumor growth and facilitates anti-tumor immunity and anti-PD1 responses. Clin. Cancer Res. 23(13), 3371–3384 (2017).
Medline CASGoogle Scholar
165. Baselga J, Dent SF, Cortés J, Im Y-H, Diéras V, Harbeck N. Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA-mutant (MUT), locally advanced or metastatic breast cancer (MBC): primary analysis from SANDPIPER. J. Clin. Oncol. 36(Suppl. 18), 1006–1006 (2018).
Google Scholar
166. Rugo HS, Bianchi GV, Chia SKL, Turner NC, Juric D, Jacot W. BYLieve: a Phase II study of alpelisib (ALP) with fulvestrant (FUL) or letrozole (LET) for treatment of PIK3CA mutant, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (aBC) progressing on/after cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy. J. Clin. Oncol. 36(Suppl. 15), TPS1107–TPS1107 (2018).
Google Scholar
167. Rugo HS, Lerebours F, Ciruelos E, Drullinsky P, Borrego MR, Neven P. Alpelisib (ALP) + fulvestrant (FUL) in patients (pts) with PIK3CA-mutated (mut) 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. 38(Suppl; abstr 1006), (2020).
Google Scholar
168. Vernieri C, Corti F, Nichetti F, Ligorio F, Manglaviti S, Zattarin E. Everolimus versus alpelisib in advanced hormone receptor-positive HER2-negative breast cancer: targeting different nodes of /AKT/mTORC1 pathway with different clinical implications. Breast Cancer Res. 22(33), 1–13 (2020).
Google Scholar

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Received 9 May 2020

Accepted 12 August 2020

Published online 23 September 2020

Published in print January 2021

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Author contributions

A Mavratzas and F Marmé designed the article, A Mavratzas performed literature research and wrote the manuscript. F Marmé reviewed the article. All the authors approved the final version.

Acknowledgments

The authors apologize to those researchers whose original research could not be mentioned due to a limited numbers of references.

Financial & competing interests disclosure

F Marmé received honoraria from Roche, Amgen, AstraZeneca, Eisai, Celgene, Novartis, Pfizer, Genomic Health and acted as a consultant to Roche, AstraZeneca and Novartis. A Mavratzas received travel sponsoring from Pfizer, Eisai and Celgene, as well as honoraria from Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Company review disclosure

In addition to the peer-review process, with the authors’ consent, the manufacturer of the product discussed in this article was given the opportunity to review the manuscript for factual accuracy. Changes were made by the authors at their discretion and based on scientific or editorial merit only. The authors maintained full control over the manuscript, including content, wording and conclusions.

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Alpelisib in the treatment of metastatic HR+ breast cancer with PIK3CA mutations

Abstract

References