Mutation distributions and clinical correlations of PIK3CA gene mutations in breast cancer

Breast cancer (BCa) is the most common cancer and the second cause of death among women. Phosphoinositide 3-kinase (PI3K) signaling pathway has a crucial role in the cellular processes such as cell survival, growth, division, and motility. Moreover, oncogenic mutations in the PI3K pathway generally involve the activation phosphatidylinositol-4,5-bisphosphate 3-kinase-catalytic subunit alpha (PIK3CA) mutation which has been identified in numerous BCa subtypes. In this review, correlations between PIK3CA mutations and their clinicopathological parameters on BCa will be described. It is reported that PIK3CA mutations which have been localized mostly on exon 9 and 20 hot spots are detected 25–40 % in BCa. This relatively high frequency can offer an advantage for choosing the best treatment options for BCa. PIK3CA mutations may be used as biomarkers and have been major focus of drug development in cancer with the first clinical trials of PI3K pathway inhibitors currently in progress. Screening of PIK3CA gene mutations might be useful genetic tests for targeted therapeutics or diagnosis. Increasing data about PIK3CA mutations and its clinical correlations with BCa will help to introduce new clinical applications in the near future.

[1]  M. Troxell,et al.  Novel method for PIK3CA mutation analysis: locked nucleic acid--PCR sequencing. , 2013, The Journal of molecular diagnostics : JMD.

[2]  B. Park,et al.  Comparison of cell stabilizing blood collection tubes for circulating plasma tumor DNA. , 2015, Clinical biochemistry.

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

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

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

[6]  S. Chandarlapaty,et al.  Frequent Mutational Activation of the PI3K-AKT Pathway in Trastuzumab-Resistant Breast Cancer , 2012, Clinical Cancer Research.

[7]  C. Arteaga,et al.  HER (erbB) tyrosine kinase inhibitors in the treatment of breast cancer. , 2002, Seminars in oncology.

[8]  A. Janecka,et al.  Prognostic value of PIK3CA mutation status, PTEN and androgen receptor expression for metastasis-free survival in HER2-positive breast cancer patients treated with trastuzumab in adjuvant setting. , 2015, Polish journal of pathology : official journal of the Polish Society of Pathologists.

[9]  Analysing the mutational status of PIK3CA in circulating tumor cells from metastatic breast cancer patients , 2013, Molecular oncology.

[10]  S. Bicciato,et al.  Prospective Biomarker Analysis of the Randomized CHER-LOB Study Evaluating the Dual Anti-HER2 Treatment With Trastuzumab and Lapatinib Plus Chemotherapy as Neoadjuvant Therapy for HER2-Positive Breast Cancer. , 2015, The oncologist.

[11]  M. Sliwkowski,et al.  Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. , 2009, Cancer cell.

[12]  B. Park,et al.  Prevalence of PIK3CA mutations and the SNP rs17849079 in Arab breast cancer patients , 2013, Cancer biology & therapy.

[13]  Jong Soon Kang,et al.  Synergistic anticancer efficacy of MEK inhibition and dual PI3K/mTOR inhibition in castration‐resistant prostate cancer , 2015, The Prostate.

[14]  M. Troxell,et al.  Frequent PIK3CA Mutations in Radial Scars , 2013, Diagnostic molecular pathology : the American journal of surgical pathology, part B.

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

[16]  I. Weinstein,et al.  The origins of human cancer: molecular mechanisms of carcinogenesis and their implications for cancer prevention and treatment--twenty-seventh G.H.A. Clowes memorial award lecture. , 1988, Cancer research.

[17]  Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies , 2009, British Journal of Cancer.

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

[19]  T. Wilson,et al.  Changes in PIK3CA mutation status are not associated with recurrence, metastatic disease or progression in endocrine-treated breast cancer , 2014, Breast Cancer Research and Treatment.

[20]  Rosette Lidereau,et al.  PIK3CA mutation impact on survival in breast cancer patients and in ERα, PR and ERBB2-based subgroups , 2012, Breast Cancer Research.

[21]  C. George Priya Doss,et al.  Deciphering the impact of somatic mutations in exon 20 and exon 9 of PIK3CA gene in breast tumors among Indian women through molecular dynamics approach , 2016, Journal of biomolecular structure & dynamics.

[22]  J. Meyerhardt,et al.  Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer , 2009, British Journal of Cancer.

[23]  I. Campbell,et al.  The phosphatidylinositol 3'-kinase p85alpha gene is an oncogene in human ovarian and colon tumors. , 2001, Cancer research.

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

[25]  E. Ratner,et al.  PIK3CA oncogenic mutations represent a major mechanism of resistance to trastuzumab in HER2/neu overexpressing uterine serous carcinomas , 2015, British Journal of Cancer.

[26]  R. Weinberg,et al.  Oncogenes, antioncogenes, and the molecular bases of multistep carcinogenesis. , 1989, Cancer research.

[27]  S. Raju,et al.  Phosphatidylinositol 3-kinase (PI3KCA) oncogene mutation analysis and gene expression profiling in primary breast cancer patients. , 2013, Asian Pacific journal of cancer prevention : APJCP.

[28]  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.

[29]  R. Weigel,et al.  Ligand-dependent Interaction of Estrogen Receptor-α with Members of the Forkhead Transcription Factor Family* , 2001, The Journal of Biological Chemistry.

[30]  S. Shouman Combination of imatinib and clotrimazole enhances cell growth inhibition in T47D breast cancer cells , 2015 .

[31]  Next generation sequencing of triple negative breast cancer to find predictors for chemotherapy response , 2015, Breast Cancer Research.

[32]  T. Krech,et al.  Oncogenic PIK3CA mutations in lobular breast cancer progression , 2013, Genes, chromosomes & cancer.

[33]  Keda Yu,et al.  Favorable prognostic impact in loss of TP53 and PIK3CA mutations after neoadjuvant chemotherapy in breast cancer. , 2014, Cancer research.

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

[35]  Qun Zhou,et al.  Adipocyte activation of cancer stem cell signaling in breast cancer. , 2015, World journal of biological chemistry.

[36]  Gary L Gallia,et al.  PIK3CA Gene Mutations in Pediatric and Adult Glioblastoma Multiforme , 2006, Molecular Cancer Research.

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

[38]  Y. Zhang,et al.  PIK3CA mutations are a predictor of docetaxel plus epirubicin neoadjuvant chemotherapy clinical efficacy in breast cancer. , 2014, Neoplasma.

[39]  Pingzhao Hu,et al.  Ras Signaling Is a Key Determinant for Metastatic Dissemination and Poor Survival of Luminal Breast Cancer Patients. , 2015, Cancer research.

[40]  P. Petrow,et al.  PIK3CA Pathway Mutations Predictive of Poor Response Following Standard Radiochemotherapy ± Cetuximab in Cervical Cancer Patients , 2015, Clinical Cancer Research.

[41]  Jacob D. Jaffe,et al.  Abstract 1: Oncogenic extracellular domain mutations of ERBB2 in cancer , 2012 .

[42]  S. Loi,et al.  PIK3CA mutations in breast cancer: reconciling findings from preclinical and clinical data , 2014, Breast Cancer Research.

[43]  L. Cantley,et al.  Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation , 1985, Nature.

[44]  A. Schneeweiss,et al.  Dual Blockade with AFatinib and Trastuzumab as NEoadjuvant Treatment for Patients with Locally Advanced or Operable Breast Cancer Receiving Taxane–Anthracycline Containing Chemotherapy—DAFNE (GBG-70) , 2015, Clinical Cancer Research.

[45]  Jos Jonkers,et al.  Genetically engineered mouse models of PI3K signaling in breast cancer , 2013, Molecular oncology.

[46]  S. Fox,et al.  Mutational profiling of familial male breast cancers reveals similarities with luminal A female breast cancer with rare TP53 mutations , 2014, British Journal of Cancer.

[47]  L. Cantley,et al.  Evidence that the Rous sarcoma virus transforming gene product phosphorylates phosphatidylinositol and diacylglycerol. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[48]  H. Seow,et al.  Dual treatments targeting IGF-1R, PI3K, mTORC or MEK synergize to inhibit cell growth, induce apoptosis, and arrest cell cycle at G1 phase in MDA-MB-231 cell line. , 2015, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

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

[50]  M. Pestrin,et al.  Heterogeneity of PIK3CA mutational status at the single cell level in circulating tumor cells from metastatic breast cancer patients , 2015, Molecular oncology.

[51]  M. Troxell,et al.  PIK3CA-AKT pathway mutations in micropapillary breast carcinoma. , 2013, Human pathology.

[52]  E. Nexo,et al.  Expression of PIK3CA, PTEN mRNA and PIK3CA mutations in primary breast cancer: association with lymph node metastases , 2013, SpringerPlus.

[53]  Bing Wang,et al.  Multiplex detection of DNA mutations by the fluorescence fingerprint spectrum technique. , 2013, Angewandte Chemie.

[54]  Sandeep Reddy,et al.  Predictive Biomarker Profiling of > 6000 Breast Cancer Patients Shows Heterogeneity in TNBC, With Treatment Implications. , 2015, Clinical breast cancer.

[55]  I. Peker,et al.  Detection of PIK3CA gene mutations with HRM analysis and association with IGFBP-5 expression levels in breast cancer. , 2014, Asian Pacific journal of cancer prevention : APJCP.

[56]  Lu Wang,et al.  PIK3CA and TP53 Gene Mutations in Human Breast Cancer Tumors Frequently Detected by Ion Torrent DNA Sequencing , 2014, PloS one.

[57]  M. Rubin,et al.  Targeted next-generation sequencing of advanced prostate cancer identifies potential therapeutic targets and disease heterogeneity. , 2013, European urology.

[58]  R. Copeland,et al.  Effects of oncogenic p110α subunit mutations on the lipid kinase activity of phosphoinositide 3-kinase , 2008 .

[59]  S. Fox,et al.  Down-Regulation of Phosphatidylinositol 3′-Kinase/AKT/Molecular Target of Rapamycin Metabolic Pathway by Primary Letrozole-Based Therapy in Human Breast Cancer , 2008, Clinical Cancer Research.

[60]  L. Ellwein,et al.  Cell proliferation in carcinogenesis. , 1990, Science.

[61]  Razelle Kurzrock,et al.  PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[62]  R. Bast,et al.  Holland-Frei Cancer Medicine , 2016 .

[63]  J. Baselga,et al.  Management of breast cancer with targeted agents: importance of heterogenicity , 2010, Nature Reviews Clinical Oncology.

[64]  Aiko Sueta,et al.  An Integrative Analysis of PIK3CA Mutation, PTEN, and INPP4B Expression in Terms of Trastuzumab Efficacy in HER2-Positive Breast Cancer , 2014, PloS one.

[65]  Yuval Inbar,et al.  Mechanism of Two Classes of Cancer Mutations in the Phosphoinositide 3-Kinase Catalytic Subunit , 2007, Science.

[66]  L. Skoog,et al.  PIK3CA Mutations and PTEN Loss Correlate with Similar Prognostic Factors and Are Not Mutually Exclusive in Breast Cancer , 2007, Clinical Cancer Research.

[67]  M. Mandal,et al.  Breast Cancer: Classification Based on Molecular Etiology Influencing Prognosis and Prediction , 2011 .

[68]  J. Bergh,et al.  mTOR inhibitors counteract tamoxifen-induced activation of breast cancer stem cells. , 2015, Cancer letters.

[69]  C. Martin 2015 , 2015, Les 25 ans de l’OMC: Une rétrospective en photos.

[70]  H. Aslam,et al.  Carcinogenesis of PIK3CA , 2013, Hereditary Cancer in Clinical Practice.

[71]  Carsten Denkert,et al.  Analysis of PIK3CA Mutations in Breast Cancer Subtypes , 2014, Applied immunohistochemistry & molecular morphology : AIMM.

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

[73]  R. Bernards,et al.  PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-targeted therapies in breast cancer. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[74]  G. Rewcastle,et al.  Inhibitors of pan-PI3K Signaling Synergize with BRAF or MEK Inhibitors to Prevent BRAF-Mutant Melanoma Cell Growth , 2015, Front. Oncol..

[75]  Jingjing Liu,et al.  Effects of PI3K inhibitor NVP-BKM120 on overcoming drug resistance and eliminating cancer stem cells in human breast cancer cells , 2015, Cell Death and Disease.

[76]  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.

[77]  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.

[78]  R. Copeland,et al.  Effects of oncogenic p110alpha subunit mutations on the lipid kinase activity of phosphoinositide 3-kinase. , 2008, The Biochemical journal.

[79]  Xuexi Yang,et al.  Mutational analysis of key EGFR pathway genes in Chinese breast cancer patients. , 2012, Asian Pacific journal of cancer prevention : APJCP.

[80]  M. Ranson Epidermal growth factor receptor tyrosine kinase inhibitors , 2004, British Journal of Cancer.

[81]  S. Noguchi,et al.  PIK3CA mutations in serum DNA are predictive of recurrence in primary breast cancer patients , 2015, Breast Cancer Research and Treatment.

[82]  Reiko Nishihara,et al.  Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. , 2012, The New England journal of medicine.

[83]  M. Ando,et al.  Activated PI3K/AKT and MAPK pathways are potential good prognostic markers in node-positive, triple-negative breast cancer. , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[84]  N. Lindeman,et al.  PIK3CA Mutations are Common in Many Tumor Types and are Often Associated With Other Driver Mutations , 2016, Applied immunohistochemistry & molecular morphology : AIMM.

[85]  B. Evers,et al.  PKI-587 and sorafenib targeting PI3K/AKT/mTOR and Ras/Raf/MAPK pathways synergistically inhibit HCC cell proliferation. , 2012, The Journal of surgical research.

[86]  A. Spurdle,et al.  High-throughput interrogation of PIK3CA, PTEN, KRAS, FBXW7 and TP53 mutations in primary endometrial carcinoma. , 2013, Gynecologic oncology.

[87]  A. Jemal,et al.  Cancer Statistics, 2010 , 2010, CA: a cancer journal for clinicians.

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

[89]  Mark J. Ratain,et al.  Tumour heterogeneity in the clinic , 2013, Nature.

[90]  N. Dubrawsky Cancer statistics , 1989, CA: a cancer journal for clinicians.

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

[92]  P. Hawkins,et al.  PI3K Class IB Pathway in Neutrophils , 2007, Science's STKE.

[93]  J. Merlin,et al.  Analysis of PIK3CA exon 9 and 20 mutations in breast cancers using PCR-HRM and PCR-ARMS: correlation with clinicopathological criteria. , 2013, Oncology reports.

[94]  H. Gogas,et al.  Significance of PIK3CA Mutations in Patients with Early Breast Cancer Treated with Adjuvant Chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG) Study , 2015, PloS one.

[95]  Takeshi Yamaguchi,et al.  Comprehensive DNA Methylation and Extensive Mutation Analyses of HER2-Positive Breast Cancer , 2015, Oncology.

[96]  Lu Shi Racial differences in breast cancer patterns. , 2010, Science.

[97]  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.

[98]  R. Vadlamudi,et al.  Role of Estrogen Receptor Signaling in Breast Cancer Metastasis , 2011, International journal of breast cancer.

[99]  S. Sleijfer,et al.  Hotspot mutations in PIK3CA associate with first-line treatment outcome for aromatase inhibitors but not for tamoxifen , 2013, Breast Cancer Research and Treatment.

[100]  B. Park,et al.  Mutation of the PIK3CA oncogene in human cancers , 2006, British Journal of Cancer.

[101]  S. Paik,et al.  Intrinsic subtypes, PIK3CA mutation, and the degree of benefit from adjuvant trastuzumab in the NSABP B-31 trial. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[102]  H. Gómez,et al.  PIK3CA mutations in Peruvian patients with HER2-amplified and triple negative non-metastatic breast cancers. , 2014, Hematology/oncology and stem cell therapy.

[103]  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.

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

[105]  Xiao-bin Cui,et al.  Compound HRAS/PIK3CA mutations in Chinese patients with alveolar rhabdomyosarcomas. , 2014, Asian Pacific journal of cancer prevention : APJCP.

[106]  S. Toyoshima,et al.  Evaluation of PTEN loss and PIK3CA mutations and their correlation with efficacy of trastuzumab treatment in HER2-positive metastatic breast cancer: A retrospective study (KBC-SG 1001). , 2013, Molecular and clinical oncology.

[107]  PIK3CA mutations are frequently observed in BRCAX but not BRCA2 -associated male breast cancer , 2013, Breast Cancer Research.

[108]  Arasambattu Kannan Munirajan,et al.  Oncogenic mutations of the PIK3CA gene in head and neck squamous cell carcinomas. , 2008, International journal of oncology.

[109]  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.

[110]  R. Kimmig,et al.  Preemptive tumor profiling for biomarker-stratified early clinical drug development in metastatic breast cancer patients , 2013, Breast Cancer Research and Treatment.

[111]  H. Klocker,et al.  Genetic alterations in the PI3K pathway in prostate cancer. , 2009, Anticancer research.

[112]  K. Okkenhaug Signaling by the phosphoinositide 3-kinase family in immune cells. , 2013, Annual review of immunology.

[113]  Yuan Qi,et al.  Mutation profiling identifies numerous rare drug targets and distinct mutation patterns in different clinical subtypes of breast cancers , 2012, Breast Cancer Research and Treatment.

[114]  G. Mills,et al.  Oncogenic PIK 3 CA-driven mammary tumors frequently recur via PI 3 K pathway – dependent and PI 3 K pathway – independent mechanisms , 2011 .

[115]  Gordon B Mills,et al.  PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors , 2014, Breast Cancer Research.

[116]  I. Cree,et al.  Targeting EGFR and PI3K pathways in ovarian cancer , 2012, British Journal of Cancer.

[117]  S. Chandarlapaty,et al.  PI3K Pathway Activation in High-Grade Ductal Carcinoma In Situ—Implications for Progression to Invasive Breast Carcinoma , 2014, Clinical Cancer Research.

[118]  C. Denny,et al.  Molecular mechanisms of cancer. , 1991, The Western journal of medicine.

[119]  B. Vanhaesebroeck,et al.  Glucose-Potentiated Chemotaxis in Human Vascular Smooth Muscle Is Dependent on Cross-Talk Between the PI3K and MAPK Signaling Pathways , 2004, Circulation research.

[120]  Q. Lv,et al.  Correlation between Activation of PI3K/AKT/mTOR Pathway and Prognosis of Breast Cancer in Chinese Women , 2015, PloS one.

[121]  Kai Yuan,et al.  Phospho-PRAS40Thr246 predicts trastuzumab response in patients with HER2-positive metastatic breast cancer , 2014, Oncology letters.

[122]  W. Jochum,et al.  Rare PIK3CA hotspot mutations in carcinomas of the biliary tract , 2008, Genes, chromosomes & cancer.

[123]  Hong Sun,et al.  Rapid detection of genetic mutations in individual breast cancer patients by next-generation DNA sequencing , 2015, Human Genomics.

[124]  J. L. Tang,et al.  PIK3CA exon 20 mutations as a potential biomarker for resistance to anti-EGFR monoclonal antibodies in KRAS wild-type metastatic colorectal cancer: a systematic review and meta-analysis. , 2012, Annals of oncology : official journal of the European Society for Medical Oncology.

[125]  I. Bièche,et al.  Outcome impact of PIK3CA mutations in HER2-positive breast cancer patients treated with trastuzumab , 2013, British Journal of Cancer.

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

[127]  A. Jimeno,et al.  New phosphatidylinositol 3-kinase inhibitors for cancer , 2011, Expert opinion on investigational drugs.

[128]  N. Demartines,et al.  Targeting renal cell carcinoma with NVP-BEZ235, a dual PI3K/mTOR inhibitor, in combination with sorafenib , 2011, Molecular Cancer.

[129]  M. Dowsett,et al.  Relationship of PIK3CA mutation and pathway activity with antiproliferative response to aromatase inhibition , 2014, Breast Cancer Research.

[130]  M. Nagai,et al.  PIK3CA exon 20 mutations are associated with poor prognosis in breast cancer patients , 2012, Clinics.

[131]  Carsten Denkert,et al.  PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2 (her2) therapy in primary HER2-overexpressing breast cancer. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[132]  B. Neel,et al.  The docking molecule gab2 is induced by lymphocyte activation and is involved in signaling by interleukin-2 and interleukin-15 but not other common gamma chain-using cytokines. , 2000, The Journal of biological chemistry.

[133]  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.

[134]  M. Westphal,et al.  Frequent genetic alterations in EGFR- and HER2-driven pathways in breast cancer brain metastases. , 2013, The American journal of pathology.

[135]  J. Engelman,et al.  Measurement of PIP3 levels reveals an unexpected role for p110β in early adaptive responses to p110α-specific inhibitors in luminal breast cancer. , 2015, Cancer cell.

[136]  K. Blackwell,et al.  Phase I/II dose-escalation study of PI3K inhibitors pilaralisib or voxtalisib in combination with letrozole in patients with hormone-receptor-positive and HER2-negative metastatic breast cancer refractory to a non-steroidal aromatase inhibitor , 2015, Breast Cancer Research and Treatment.