PI3K inhibition to overcome endocrine resistance in breast cancer

ABSTRACT Introduction: Activation of the phosphatidylinositol-3 kinase (PI3K) pathway is a critical step in oncogenesis and plays a role in the development of treatment resistance for both estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) positive breast cancers. Hence, there have been efforts to therapeutically inhibit this pathway. Areas covered: Several inhibitors of PI3K are now progressing through clinical trials with varying degrees of efficacy and toxicity to date. Numerous unresolved questions remain concerning the optimal isoform selectivity of PI3K inhibitors and use of predictive biomarkers. This review examines the most important PI3K inhibitors in ER positive breast cancer to date, with a particular focus on their role in overcoming endocrine therapy resistance and the possible use of PIK3CA mutations as a predictive biomarker. Expert opinion: We discuss some of the emerging challenges and questions encountered during the development of PI3K inhibitors from preclinical to phase III studies, including other novel biomarkers and future combinations to overcome endocrine resistance.

[1]  William Pao,et al.  Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer , 2009, Proceedings of the National Academy of Sciences.

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

[3]  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.

[4]  W. McGuire,et al.  Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. , 1987, Science.

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

[6]  J. Engelman,et al.  The PI3K pathway as drug target in human cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  G. Mills,et al.  HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells , 2003, Oncogene.

[8]  G. Mills,et al.  ERα-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. , 2011, Cancer discovery.

[9]  C. Arteaga,et al.  Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt Is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. , 2002, Cancer research.

[10]  J. Olson,et al.  PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. , 2009, Cancer research.

[11]  J. Utikal,et al.  Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. , 2014, The New England journal of medicine.

[12]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[13]  Christian A. Rees,et al.  Molecular portraits of human breast tumours , 2000, Nature.

[14]  M. Loda,et al.  The oncogenic properties of mutant p110α and p110β phosphatidylinositol 3-kinases in human mammary epithelial cells , 2005 .

[15]  C. Isaacs,et al.  Molecular Alterations and Everolimus Efficacy in Human Epidermal Growth Factor Receptor 2-Overexpressing Metastatic Breast Cancers: Combined Exploratory Biomarker Analysis From BOLERO-1 and BOLERO-3. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  B. Park,et al.  Targeting the PI3K/Akt/mTOR Pathway for Breast Cancer Therapy , 2012, Journal of Mammary Gland Biology and Neoplasia.

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

[18]  H. Rugo,et al.  SOLAR-1: A phase III study of alpelisib + fulvestrant in men and postmenopausal women with HR+/HER2– advanced breast cancer (BC) progressing on or after prior aromatase inhibitor therapy. , 2016 .

[19]  A. Garg,et al.  Correlative Analysis of Genetic Alterations and Everolimus Benefit in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From BOLERO-2. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  Tak W. Mak,et al.  Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis , 2006, Nature Reviews Cancer.

[21]  H. Wu,et al.  PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Jordi Rodon,et al.  Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  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.

[24]  G. Hortobagyi,et al.  Correlation between PIK3CA mutations in cell-free DNA and everolimus efficacy in HR+, HER2− advanced breast cancer: results from BOLERO-2 , 2017, British Journal of Cancer.

[25]  Rachel Schiff,et al.  Mechanisms of endocrine resistance in breast cancer. , 2011, Annual review of medicine.

[26]  Gordon B Mills,et al.  Targeting the Phosphatidylinositol 3-Kinase / Akt Pathway for Enhancing Breast Cancer Cells to Radiotherapy 1 , 2003 .

[27]  Li Zhao,et al.  Oncogenic PI3K deregulates transcription and translation , 2005, Nature Reviews Cancer.

[28]  H. Burris,et al.  Overcoming acquired resistance to anticancer therapy: focus on the PI3K/AKT/mTOR pathway , 2013, Cancer Chemotherapy and Pharmacology.

[29]  R. Schiff,et al.  Unraveling the Mechanisms of Endocrine Resistance in Breast Cancer: New Therapeutic Opportunities , 2007, Clinical Cancer Research.

[30]  P. Lønning,et al.  Abstract S4-07: BELLE-3: A phase III study of buparlisib + fulvestrant in postmenopausal women with HR+, HER2–, aromatase inhibitor-treated, locally advanced or metastatic breast cancer, who progressed on or after mTOR inhibitor-based treatment , 2017 .

[31]  S. Cosimo,et al.  Human epidermal growth factor receptor 2 (HER2)-positive and hormone receptor-positive breast cancer: new insights into molecular interactions and clinical implications. , 2013, Annals of oncology : official journal of the European Society for Medical Oncology.

[32]  J. Engelman,et al.  Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. , 2005, Cancer research.

[33]  G. Hortobagyi,et al.  Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  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.

[35]  M. Campone,et al.  Abstract A118: PIKHER2: A phase Ib study evaluating oral BKM120 in combination with lapatinib in trastuzumab-resistant HER2-positive advanced breast cancer , 2015 .

[36]  Tomohiko Maehama,et al.  The Tumor Suppressor, PTEN/MMAC1, Dephosphorylates the Lipid Second Messenger, Phosphatidylinositol 3,4,5-Trisphosphate* , 1998, The Journal of Biological Chemistry.

[37]  Kyung Song,et al.  Abstract S6-04: The PI3K inhibitor, taselisib, has enhanced potency in PIK3CA mutant models through a unique mechanism of action , 2016 .

[38]  C. Sotiriou,et al.  Somatic Mutation Profiling and Associations With Prognosis and Trastuzumab Benefit in Early Breast Cancer , 2013, Journal of the National Cancer Institute.

[39]  J. Harney,et al.  Effects of PI3K inhibition and low docosahexaenoic acid on cognition and behavior , 2010, Physiology & Behavior.

[40]  M. Ellis,et al.  Mechanisms of aromatase inhibitor resistance , 2015, Nature Reviews Cancer.

[41]  Hailing Cheng,et al.  The p110α isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation , 2006, Proceedings of the National Academy of Sciences.

[42]  Giulia Bianchi,et al.  Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. , 2012, The Lancet. Oncology.

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

[44]  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.

[45]  Massimo Libra,et al.  PIK3CA mutations in human solid tumors: Role in sensitivity to various therapeutic approaches , 2009, Cell cycle.

[46]  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. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[47]  Gordon B Mills,et al.  mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. , 2006, Cancer research.

[48]  C. Arteaga,et al.  Optimal targeting of HER2-PI3K signaling in breast cancer: mechanistic insights and clinical implications. , 2013, Cancer research.

[49]  Yiling Lu,et al.  Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery , 2005, Nature Reviews Drug Discovery.

[50]  L. Cantley,et al.  New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[51]  G. Mills,et al.  PI3K Pathway Mutations and PTEN Levels in Primary and Metastatic Breast Cancer , 2011, Molecular Cancer Therapeutics.

[52]  A. Lash,et al.  Frequent Mutation of the PIK3CA Gene in Ovarian and Breast Cancers , 2005, Clinical Cancer Research.

[53]  J. Baselga,et al.  SANDPIPER: Phase III study of the PI3-kinase (PI3K) inhibitor taselisib (GDC-0032) plus fulvestrant in patients (pts) with estrogen receptor (ER)-positive, HER2-negative locally advanced or metastatic breast cancer (BC) enriched for pts with PIK3CA-mutant tumors. , 2016 .

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

[55]  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.

[56]  Jeffrey A. Engelman,et al.  Targeting PI3K signalling in cancer: opportunities, challenges and limitations , 2009, Nature Reviews Cancer.

[57]  Robbie Loewith,et al.  A Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin Signaling , 2006, Cell.

[58]  P. Morris,et al.  Recent advances in novel targeted therapies for HER2-positive breast cancer , 2012, Anti-cancer drugs.

[59]  Pixu Liu,et al.  Targeting the phosphoinositide 3-kinase pathway in cancer , 2009, Nature Reviews Drug Discovery.

[60]  S. Loi,et al.  Abstract OT2-6-08: Phase II, randomized, parallel-cohort study of neoadjuvant buparlisib (BKM120) in combination with trastuzumab and paclitaxel in women with HER2-positive, PIK3CA mutant and PIK3CA wild-type primary breast cancer – NeoPHOEBE , 2013 .

[61]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[62]  George Thomas,et al.  A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib (BEZ235) Combined with Everolimus in Patients with Advanced Solid Malignancies , 2017, Targeted Oncology.

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

[64]  R. Nahta,et al.  Her2 cross talk and therapeutic resistance in breast cancer. , 2008, Frontiers in bioscience : a journal and virtual library.

[65]  M. Belvin,et al.  Isoform-specific phosphoinositide 3-kinase inhibitors exert distinct effects in solid tumors. , 2010, Cancer research.

[66]  Wayne A. Phillips,et al.  Mutation of the PIK3CA Gene in Ovarian and Breast Cancer , 2004, Cancer Research.

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

[68]  P. Dennis,et al.  Activation of the PI3K/Akt pathway and chemotherapeutic resistance. , 2002, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[69]  M. Loda,et al.  The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[70]  S. Loi,et al.  Phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway inhibition: a breakthrough in the management of luminal (ER+/HER2−) breast cancers? , 2012, Current opinion in oncology.

[71]  D. Rea,et al.  Mutational analysis of PI3K/AKT signaling pathway in tamoxifen exemestane adjuvant multinational pathology study. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[72]  Lewis C Cantley,et al.  The phosphoinositide 3-kinase pathway. , 2002, Science.

[73]  I. Ellis,et al.  PIK3CA expression in invasive breast cancer: a biomarker of poor prognosis , 2010, Breast Cancer Research and Treatment.

[74]  B. Hennessy,et al.  A preclinical evaluation of the PI3K alpha/delta dominant inhibitor BAY 80-6946 in HER2-positive breast cancer models with acquired resistance to the HER2-targeted therapies trastuzumab and lapatinib , 2014, Breast Cancer Research and Treatment.

[75]  Ralph Weissleder,et al.  Effective Use of PI3K and MEK Inhibitors to Treat Mutant K-Ras G12D and PIK3CA H1047R Murine Lung Cancers , 2008, Nature Medicine.

[76]  José Luis de la Pompa,et al.  Negative Regulation of PKB/Akt-Dependent Cell Survival by the Tumor Suppressor PTEN , 1998, Cell.

[77]  J. Baselga,et al.  SANDPIPER: Phase III study of the PI3-kinase (PI3K) inhibitor taselisib (GDC-0032) plus fulvestrant in patients (pts) with estrogen receptor (ER)-positive, HER2-negative locally advanced or metastatic breast cancer (BC) enriched for pts with PIK3CA-mutant tumors. , 2016 .

[78]  M. Piccart,et al.  Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. , 2012, The New England journal of medicine.

[79]  Paul Workman,et al.  Drugging PI3K in cancer: refining targets and therapeutic strategies , 2015, Current opinion in pharmacology.

[80]  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.

[81]  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.

[82]  F. Khuri,et al.  Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. , 2005, Cancer research.

[83]  C. Hudis.  Trastuzumab--mechanism of action and use in clinical practice. , 2007, The New England journal of medicine.

[84]  L. Pusztai,et al.  A phase II study of the PI3K inhibitor taselisib (GDC-0032) combined with fulvestrant (F) in patients (pts) with HER2-negative (HER2-), hormone receptor-positive (HR+) advanced breast cancer (BC). , 2016 .

[85]  L. Holmberg,et al.  Prognostic and predictive value of c-erbB-2 overexpression in primary breast cancer, alone and in combination with other prognostic markers. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[86]  E. Winer,et al.  Phase I/II study of pilaralisib (SAR245408) in combination with trastuzumab or trastuzumab plus paclitaxel in trastuzumab-refractory HER2-positive metastatic breast cancer , 2014, Breast Cancer Research and Treatment.

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

[88]  Yosef Yarden,et al.  Molecular mechanisms underlying ErbB2/HER2 action in breast cancer , 2000, Oncogene.

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

[90]  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.

[91]  F. Maurer,et al.  The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[92]  Suk Woo Nam,et al.  PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas , 2005, Oncogene.

[93]  M. Ellis,et al.  Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer , 2011, Breast Cancer Research.

[94]  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.

[95]  E. Winer,et al.  Abstract PD5-5: Phase I study of the PI3Kα inhibitor BYL719 plus fulvestrant in patients withPIK3CA-altered and wild type ER+/HER2- locally advanced or metastatic breast cancer , 2015 .

[96]  Michael G. Kharas,et al.  PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor–positive breast cancer , 2015, Science Translational Medicine.

[97]  A. Jemal,et al.  Global cancer statistics, 2012 , 2015, CA: a cancer journal for clinicians.

[98]  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.

[99]  J. Balko,et al.  Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[100]  Guy Jerusalem,et al.  Phase Ib Study of Buparlisib plus Trastuzumab in Patients with HER2-Positive Advanced or Metastatic Breast Cancer That Has Progressed on Trastuzumab-Based Therapy , 2014, Clinical Cancer Research.

[101]  G. Sundaresan,et al.  Mechanism and Management of AKT Inhibitor-Induced Hyperglycemia , 2009, Clinical Cancer Research.

[102]  J. Baselga,et al.  NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. , 2008, Cancer research.

[103]  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.

[104]  J. Barrett,et al.  PIK3CA Mutations May Be Discordant between Primary and Corresponding Metastatic Disease in Breast Cancer , 2010, Clinical Cancer Research.

[105]  Gottfried Konecny,et al.  Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. , 2003, Journal of the National Cancer Institute.

[106]  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. , 2018, Annals of oncology : official journal of the European Society for Medical Oncology.

[107]  Z. Szallasi,et al.  Clonal status of actionable driver events and the timing of mutational processes in cancer evolution , 2015, Science Translational Medicine.

[108]  J. Ptak,et al.  High Frequency of Mutations of the PIK3CA Gene in Human Cancers , 2004, Science.

[109]  R. Shah.  Hyperglycaemia Induced by Novel Anticancer Agents: An Undesirable Complication or a Potential Therapeutic Opportunity? , 2017, Drug Safety.

[110]  Simak Ali,et al.  Endocrine-responsive breast cancer and strategies for combating resistance , 2002, Nature Reviews Cancer.

[111]  E. Winer,et al.  A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2− Metastatic Breast Cancer , 2016, Clinical Cancer Research.

[112]  Jordi Rodon,et al.  Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of SAR245408 (XL147), an Oral Pan-Class I PI3K Inhibitor, in Patients with Advanced Solid Tumors , 2013, Clinical Cancer Research.