Efficacy of PI3K inhibitors in advanced breast cancer

Abstract The phosphoinositide 3 (PI3)-kinase/Akt signaling pathway has always been a focus of interest in breast cancer due to its role in cell growth, cell proliferation, cell migration and deregulated apoptosis. Its activation has been linked to endocrine resistance and worse prognosis in certain subgroups of breast cancer. In addition, deregulation of the PI3K/Akt pathway including PIK3CA activating mutation is frequently present in breast cancer. Multiple efforts have been carried out to target this pathway, initially with pan-PI3K inhibitors with some hint of activity but hampered by their limiting side-effects. A recent large randomized trial in patients with endocrine-resistant PIK3CA-mutant hormone receptor (HR)-positive tumors led to the approval of the first PI3K inhibitor, alpelisib, in combination with fulvestrant. The specificity of alpelisib against the p110α catalytic isoform provided additional efficacy and a better toxicity profile. In this review, we summarize the main research with PI3K inhibitors in breast cancer and we provide some insight of potential future combinations of this treatment in breast cancer patients.

[1]  Spyro Mousses,et al.  A transforming mutation in the pleckstrin homology domain of AKT1 in cancer , 2007, Nature.

[2]  R. Bernards,et al.  PIK3CA mutations are associated with reduced pathological complete response rates in primary HER2-positive breast cancer: pooled analysis of 967 patients from five prospective trials investigating lapatinib and trastuzumab. , 2019, Annals of oncology : official journal of the European Society for Medical Oncology.

[3]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumours , 2013 .

[4]  Lewis C. Cantley,et al.  The PI3K Pathway in Human Disease , 2017, Cell.

[5]  D. Erdmann,et al.  Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials , 2014, Molecular Cancer Therapeutics.

[6]  M. Campone,et al.  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) , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[7]  J. Isola,et al.  Trastuzumab-DM1 causes tumour growth inhibition by mitotic catastrophe in trastuzumab-resistant breast cancer cells in vivo , 2011, Breast Cancer Research.

[8]  François Bertucci,et al.  PIKHER2: A phase IB study evaluating buparlisib in combination with lapatinib in trastuzumab-resistant HER2-positive advanced breast cancer. , 2017, European journal of cancer.

[9]  J. Baselga,et al.  Phase I Dose-Escalation Study of Taselisib, an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors. , 2017, Cancer discovery.

[10]  Holger Gerhardt,et al.  Angiogenesis selectively requires the p110α isoform of PI3K to control endothelial cell migration , 2008, Nature.

[11]  H. Rugo,et al.  Alpelisib for PIK3CA‐Mutated, Hormone Receptor–Positive Advanced Breast Cancer , 2019, The New England journal of medicine.

[12]  S. Fox,et al.  Increased pathological complete response rate after a long-term neoadjuvant letrozole treatment in postmenopausal oestrogen and/or progesterone receptor-positive breast cancer , 2013, British Journal of Cancer.

[13]  Obi L. Griffith,et al.  Convergent loss of PTEN leads to clinical resistance to a PI3Kα inhibitor , 2014, Nature.

[14]  Lei Nie,et al.  FDA Approval: Idelalisib Monotherapy for the Treatment of Patients with Follicular Lymphoma and Small Lymphocytic Lymphoma , 2015, Clinical Cancer Research.

[15]  A. Bardia,et al.  Neoadjuvant Endocrine Therapy for Estrogen Receptor-Positive Breast Cancer: A Systematic Review and Meta-analysis. , 2016, JAMA oncology.

[16]  K. Gelmon,et al.  Palbociclib and Letrozole in Advanced Breast Cancer. , 2016, The New England journal of medicine.

[17]  M. Piccart,et al.  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. , 2019, The Lancet. Oncology.

[18]  C. Heldin,et al.  The PI 3-kinase isoforms p110(alpha) and p110(beta) have differential roles in PDGF- and insulin-mediated signaling. , 2000, Journal of cell science.

[19]  B. Link.  Will a Better Understanding of the Problem With Transformed Follicular Lymphoma Lead to Better Outcomes? , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  Robert L Sutherland,et al.  PI3K pathway activation in breast cancer is associated with the basal‐like phenotype and cancer‐specific mortality , 2010, International journal of cancer.

[21]  K. Okkenhaug,et al.  PI3K in lymphocyte development, differentiation and activation , 2003, Nature Reviews Immunology.

[22]  F. André,et al.  Combining PI3K and PARP inhibitors for breast and ovarian cancer treatment. , 2017, Annals of oncology : official journal of the European Society for Medical Oncology.

[23]  C. Perou,et al.  Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies , 2013, Proceedings of the National Academy of Sciences.

[24]  A. Bilancio,et al.  Signalling by PI3K isoforms: insights from gene-targeted mice. , 2005, Trends in biochemical sciences.

[25]  S. Loi,et al.  The Genetic Landscape and Clonal Evolution of Breast Cancer Resistance to Palbociclib plus Fulvestrant in the PALOMA-3 Trial. , 2018, Cancer discovery.

[26]  Shipeng Sun,et al.  Prognostic role of PIK3CA mutations and their association with hormone receptor expression in breast cancer: a meta-analysis , 2014, Scientific Reports.

[27]  K. Okkenhaug,et al.  Critical role for the p110α phosphoinositide-3-OH kinase in growth and metabolic regulation , 2006, Nature.

[28]  R. Laing,et al.  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. , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[29]  P. Pandolfi,et al.  Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer. , 2012, Cancer discovery.

[30]  Norikazu Masuda,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. , 2017, The Lancet. Oncology.

[31]  M. Wigler,et al.  PTEN, a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate Cancer , 1997, Science.

[32]  Steve Price,et al.  Discovery of 2-{3-[2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (GDC-0032): a β-sparing phosphoinositide 3-kinase inhibitor with high unbound exposure and robust in vivo antitumor activity. , 2013, Journal of medicinal chemistry.

[33]  J. Pérez-García,et al.  The next era of treatment for hormone receptor-positive, HER2-negative advanced breast cancer: Triplet combination-based endocrine therapies. , 2017, Cancer treatment reviews.

[34]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumors , 2012, Nature.

[35]  J. Baselga,et al.  Alpelisib Plus Fulvestrant in PIK3CA-Altered and PIK3CA-Wild-Type Estrogen Receptor–Positive Advanced Breast Cancer: A Phase 1b Clinical Trial , 2019, JAMA oncology.

[36]  C Caldas,et al.  Consensus on precision medicine for metastatic cancers: a report from the MAP conference. , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[37]  L. Cavanna,et al.  Double-blind, placebo-controlled, multicenter, randomized, phase IIb neoadjuvant study of letrozole-lapatinib in postmenopausal hormone receptor-positive, human epidermal growth factor receptor 2-negative, operable breast cancer. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[38]  Ji Luo,et al.  The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism , 2006, Nature Reviews Genetics.

[39]  J. Baselga,et al.  Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-line metastatic breast cancer. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[40]  L. Bryan,et al.  Spotlight on copanlisib and its potential in the treatment of relapsed/refractory follicular lymphoma: evidence to date , 2018, OncoTargets and therapy.

[41]  L. Chow,et al.  Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. , 2019, The New England journal of medicine.

[42]  Gary Box,et al.  The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer . , 2008, Journal of medicinal chemistry.

[43]  M. Goetz,et al.  MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[44]  Dejan Juric,et al.  Phosphatidylinositol 3-Kinase α-Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study. , 2018, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[45]  D. Juric,et al.  Abstract P3-14-01: Phase Ib/II study of ribociclib and alpelisib and letrozole in ER+, HER2– breast cancer: Safety, preliminary efficacy and molecular analysis , 2016 .

[46]  A. Robertson,et al.  PI 3-kinase p110β: a new target for antithrombotic therapy , 2005, Nature Medicine.

[47]  G. Mills,et al.  Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. , 2010, The Journal of clinical investigation.

[48]  Carsten Denkert,et al.  Neoadjuvant buparlisib plus trastuzumab and paclitaxel for women with HER2+ primary breast cancer: A randomised, double-blind, placebo-controlled phase II trial (NeoPHOEBE). , 2017, European journal of cancer.

[49]  F. Bertucci,et al.  Outcome and mutational landscape of patients with PIK3CA-mutated metastatic breast cancer (mBC). , 2019, Annals of oncology : official journal of the European Society for Medical Oncology.

[50]  S. Loi,et al.  Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. , 2016, The Lancet. Oncology.

[51]  Ben H. Park,et al.  Detection of Tumor PIK3CA Status in Metastatic Breast Cancer Using Peripheral Blood , 2012, Clinical Cancer Research.

[52]  P. Lønning,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. , 2018, The Lancet. Oncology.

[53]  S. Chandarlapaty,et al.  Molecular profiling of ER+ metastatic breast cancers to reveal association of genomic alterations with acquired resistance to CDK4/6 inhibitors. , 2019, Journal of Clinical Oncology.

[54]  P. Musiani,et al.  Phosphoinositide 3-Kinase p110β Activity: Key Role in Metabolism and Mammary Gland Cancer but Not Development , 2008, Science Signaling.

[55]  A. D. Van den Abbeele,et al.  Stand up to cancer phase Ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[56]  Keda Yu,et al.  PIK3CA mutations define favorable prognostic biomarkers in operable breast cancer: a systematic review and meta-analysis , 2014, OncoTargets and therapy.

[57]  Obi L. Griffith,et al.  A Phase I Trial of BKM120 (Buparlisib) in Combination with Fulvestrant in Postmenopausal Women with Estrogen Receptor–Positive Metastatic Breast Cancer , 2015, Clinical Cancer Research.

[58]  D. A. Rodrigues,et al.  Duvelisib: A 2018 Novel FDA-Approved Small Molecule Inhibiting Phosphoinositide 3-Kinases , 2019, Pharmaceuticals.

[59]  R. Bernards,et al.  PIK3CA mutations are associated with reduced pathological complete response rates in primary HER2-positive breast cancer: pooled analysis of 967 patients from five prospective trials investigating lapatinib and trastuzumab. , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[60]  J. Lehár,et al.  CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. , 2014, Cancer cell.

[61]  W. Sellers,et al.  Identification and Characterization of NVP-BKM120, an Orally Available Pan-Class I PI3-Kinase Inhibitor , 2011, Molecular Cancer Therapeutics.

[62]  M. Zvelebil,et al.  p110δ, a novel phosphoinositide 3-kinase in leukocytes , 1997 .

[63]  Jungsil Ro,et al.  Relationship between Tumor Biomarkers and Efficacy in EMILIA, a Phase III Study of Trastuzumab Emtansine in HER2-Positive Metastatic Breast Cancer , 2016, Clinical Cancer Research.

[64]  J. Cheng,et al.  Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas , 1995, International journal of cancer.

[65]  J. Olson,et al.  Phosphatidyl-inositol-3-kinase alpha catalytic subunit mutation and response to neoadjuvant endocrine therapy for estrogen receptor positive breast cancer , 2009, Breast Cancer Research and Treatment.

[66]  M. Ellis,et al.  Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial. , 2016, The Lancet. Oncology.

[67]  W. Gerald,et al.  PIK3CA Mutation Associates with Improved Outcome in Breast Cancer , 2009, Clinical Cancer Research.

[68]  J. Baselga,et al.  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. , 2018, Journal of Clinical Oncology.

[69]  A. Rademaker,et al.  Phase I study of alpelisib (BYL-719) and trastuzumab emtansine (T-DM1) in HER2-positive metastatic breast cancer (MBC) after trastuzumab and taxane therapy , 2018, Breast Cancer Research and Treatment.

[70]  N. Turner,et al.  Targeting the PI3-kinase pathway in triple-negative breast cancer. , 2019 .

[71]  C. Kahn,et al.  Specific roles of the p110alpha isoform of phosphatidylinsositol 3-kinase in hepatic insulin signaling and metabolic regulation. , 2010, Cell metabolism.

[72]  P. Romero,et al.  Navigating metabolic pathways to enhance antitumour immunity and immunotherapy , 2019, Nature Reviews Clinical Oncology.

[73]  Yahia Adnani,et al.  Genomic characterization of metastatic breast cancers , 2019, Nature.

[74]  E. Polley,et al.  New insights on PI3K/AKT pathway alterations and clinical outcomes in breast cancer. , 2016, Cancer treatment reviews.

[75]  S. Goel,et al.  CDK4/6 Inhibition in Cancer: Beyond Cell Cycle Arrest. , 2018, Trends in cell biology.

[76]  J. Ware,et al.  First-in-Human Phase I Study of Pictilisib (GDC-0941), a Potent Pan–Class I Phosphatidylinositol-3-Kinase (PI3K) Inhibitor, in Patients with Advanced Solid Tumors , 2014, Clinical Cancer Research.

[77]  K. Ley,et al.  Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase , 2000, Nature.

[78]  N. Turner,et al.  Targeting the PI3-kinase pathway in triple negative breast cancer. , 2019, Annals of oncology : official journal of the European Society for Medical Oncology.

[79]  A. Laenkholm,et al.  PIK3CA mutations, PTEN, and pHER2 expression and impact on outcome in HER2-positive early-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab. , 2012 .

[80]  H. Iwata,et al.  Abstract GS3-08: Alpelisib + fulvestrant for advanced breast cancer: Subgroup analyses from the phase III SOLAR-1 trial , 2019, General Session Abstracts.

[81]  J. Baselga,et al.  Abstract LB-64: GDC-0032, a beta isoform-sparing PI3K inhibitor: Results of a first-in-human phase Ia dose escalation study. , 2013 .

[82]  B. Vanhaesebroeck,et al.  The emerging mechanisms of isoform-specific PI3K signalling , 2010, Nature Reviews Molecular Cell Biology.

[83]  J. Tabernero,et al.  Picking the Point of Inhibition: A Comparative Review of PI3K/AKT/mTOR Pathway Inhibitors , 2014, Molecular Cancer Therapeutics.

[84]  J. Arribas,et al.  Characterization of the mechanism of action and efficacy of MEN1611 (PA799), a novel PI3K inhibitor, in breast cancer preclinical models , 2019, Annals of Oncology.

[85]  Hanina Hibshoosh,et al.  PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. , 2005, Cancer research.

[86]  M. Belvin,et al.  Abstract DDT02-01: Discovery of GDC-0032: A beta-sparing PI3K inhibitor active against PIK3CA mutant tumors. , 2013 .

[87]  P. Fasching,et al.  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) , 2019, Clinical Cancer Research.

[88]  M. Dowsett,et al.  Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor-Positive Breast Cancer. , 2016, Cancer research.

[89]  Zhi Hu,et al.  An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. , 2008, Cancer research.

[90]  S. Chan,et al.  Phase II study of buparlisib (BKM120) and trastuzumab in patients with HER2+ locally advanced or metastatic breast cancer resistant to trastuzumab-based therapy , 2018, Breast Cancer Research and Treatment.