Skip to main content

Advertisement

SpringerLink
Log in

Approaches and limitations of phosphatidylinositol-3-kinase pathway activation status as a predictive biomarker in the clinical development of targeted therapy

  • Review
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

The central role played by the class IA phosphatidylinositol-3-kinase (PI3K) signaling node in human cancer is highlighted in the multiple mechanisms by which these signals become dysregulated. Many studies suggest that constitutive PI3K activation in human cancer contributes to drug resistance, including targeted agents and standard cytotoxic therapy. The combination of activation mechanisms and the multiple downstream cascades that emanate from the PI3K node contributes to the difficulty in measuring PI3K activation as a biomarker. Although many agents suppress the pathway in models, the challenge remains to translate this biology into a patient selection strategy (i.e., identify patients with “PI3K activated” tumors) and subsequently link this biomarker definition to drug responses in patients. The various genetic and epigenetic lesions resulting in pathway activation necessitate combined approaches using genetic, genomic, and protein biomarkers to accurately characterize “PI3K activated” tumors. Such a combined approach to pathway status can be assessed using a statistical stratification of patients in a randomized trial into “pathway on” and “pathway off” subsets to compare the treatment effect in each arm. Instead of considering individual biomarkers for their predictive ability, this strategy proposes the use of a collection of biomarkers to identify a specific “pathway on” patient population predicted to have clinical benefit from a pathway inhibitor. Here, we review the current understanding of the mechanisms of PI3K activation in breast cancer and discuss a pathway-based approach using PI3K as a predictive biomarker in clinical development, which is currently in use in a global phase 3 setting.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Sawyers CL (2008) The cancer biomarker problem. Nature 452:548–552

    Article  CAS  PubMed  Google Scholar 

  2. Allegra CJ, Jessup JM, Somerfield MR et al (2009) American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol 27:2091–2096

    Article  PubMed  Google Scholar 

  3. Nevins JR, Potti A (2007) Mining gene expression profiles: expression signatures as cancer phenotypes. Nat Rev Genet 8:601–609

    Article  CAS  PubMed  Google Scholar 

  4. Bonnefoi H, Potti A, Delorenzi M et al (2007) Validation of gene signatures that predict the response of breast cancer to neoadjuvant chemotherapy: a substudy of the EORTC 10994/BIG 00-01 clinical trial. Lancet Oncol 8:1071–1078

    Article  CAS  PubMed  Google Scholar 

  5. Rubio-Viqueira B, Jimeno A, Cusatis G et al (2006) An in vivo platform for translational drug development in pancreatic cancer. Clin Cancer Res 12:4652–4661

    Article  CAS  PubMed  Google Scholar 

  6. Berns K, Horlings HM, Hennessy BT et al (2007) A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12:395–402

    Article  CAS  PubMed  Google Scholar 

  7. Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296:1655–1657

    Article  CAS  PubMed  Google Scholar 

  8. Engelman JA (2009) Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9:550–562

    Article  CAS  PubMed  Google Scholar 

  9. Zhao L, Vogt PK (2008) Class I PI3K in oncogenic cellular transformation. Oncogene 27:5486–5496

    Article  CAS  PubMed  Google Scholar 

  10. Guertin DA, Stevens DM, Thoreen CC et al (2006) Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 11:859–871

    Article  CAS  PubMed  Google Scholar 

  11. Stokoe D, Stephens LR, Copeland T et al (1997) Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. Science 277:567–570

    Article  CAS  PubMed  Google Scholar 

  12. Yuan TL, Cantley LC (2008) PI3K pathway alterations in cancer: variations on a theme. Oncogene 27:5497–5510

    Article  CAS  PubMed  Google Scholar 

  13. Vasudevan KM, Barbie DA, Davies MA et al (2009) AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 16:21–32

    Article  CAS  PubMed  Google Scholar 

  14. Keniry M, Parsons R (2008) The role of PTEN signaling perturbations in cancer and in targeted therapy. Oncogene 27:5477–5485

    Article  CAS  PubMed  Google Scholar 

  15. Hynes NE, Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5:341–354

    Article  CAS  PubMed  Google Scholar 

  16. Zhou Q, Cheung YB, Jada SR et al (2006) EGFR Intron 1 polymorphism in Asian Populations and its correlation with EGFR gene expression and amplification in breast tumor tissues. Cancer Biol Ther 5:1445–1449

    Article  CAS  PubMed  Google Scholar 

  17. Buerger H, Packeisen J, Boecker A et al (2004) Allelic length of a CA dinucleotide repeat in the egfr gene correlates with the frequency of amplifications of this sequence—first results of an inter-ethnic breast cancer study. J Pathol 203:545–550

    Article  CAS  PubMed  Google Scholar 

  18. Bose S, Wang SI, Terry MB et al (1998) Allelic loss of chromosome 10q23 is associated with tumor progression in breast carcinomas. Oncogene 17:123–127

    Article  CAS  PubMed  Google Scholar 

  19. Blanco-Aparicio C, Renner O, Leal JF et al (2007) PTEN, more than the AKT pathway. Carcinogenesis 28:1379–1386

    Article  CAS  PubMed  Google Scholar 

  20. Maurer M, Su T, Saal LH et al (2009) 3-Phosphoinositide-dependent kinase 1 potentiates upstream lesions on the phosphatidylinositol 3-kinase pathway in breast carcinoma. Cancer Res 69:6299–6306

    Article  CAS  PubMed  Google Scholar 

  21. Eichhorn PJ, Gili M, Scaltriti M et al (2008) Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 68:9221–9230

    Article  CAS  PubMed  Google Scholar 

  22. Nagata Y, Lan KH, Zhou X et al (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients [see comment]. Cancer Cell 6:117–127

    Article  CAS  PubMed  Google Scholar 

  23. Bedard PL, Cardoso F, Piccart-Gebhart MJ (2009) Stemming resistance to HER-2 targeted therapy. J Mammary Gland Biol Neoplasia 14:55–66

    Article  PubMed  Google Scholar 

  24. Li M, Balch C, Montgomery JS et al (2009) Integrated analysis of DNA methylation and gene expression reveals specific signaling pathways associated with platinum resistance in ovarian cancer. BMC Med Genomics 2:34

    Article  PubMed  Google Scholar 

  25. Kolasa IK, Rembiszewska A, Felisiak A et al (2009) PIK3CA amplification associates with resistance to chemotherapy in ovarian cancer patients. Cancer Biol Ther 8:21–26

    CAS  PubMed  Google Scholar 

  26. Maehama T, Taylor GS, Slama JT et al (2000) A sensitive assay for phosphoinositide phosphatases. Anal Biochem 279:248–250

    Article  CAS  PubMed  Google Scholar 

  27. Swanton C, Szallasi Z, Brenton JD et al (2008) Functional genomic analysis of drug sensitivity pathways to guide adjuvant strategies in breast cancer. Breast Cancer Res 10:214

    Article  PubMed  Google Scholar 

  28. Saal LH, Johansson P, Holm K et al (2007) Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proc Natl Acad Sci USA 104:7564–7569

    Article  CAS  PubMed  Google Scholar 

  29. Mehrian-Shai R, Chen CD, Shi T et al (2007) Insulin growth factor-binding protein 2 is a candidate biomarker for PTEN status and PI3K/Akt pathway activation in glioblastoma and prostate cancer. Proc Natl Acad Sci USA 104:5563–5568

    Article  CAS  PubMed  Google Scholar 

  30. Barker AD, Sigman CC, Kelloff GJ et al (2009) I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin Pharmacol Ther 86:97–100

    Article  CAS  PubMed  Google Scholar 

  31. Bonnefoi H, Underhill C, Iggo R et al (2009) Predictive signatures for chemotherapy sensitivity in breast cancer: are they ready for use in the clinic? Eur J Cancer 45:1733–1743

    Article  CAS  PubMed  Google Scholar 

  32. Sotiriou C, Piccart MJ (2007) Taking gene-expression profiling to the clinic: when will molecular signatures become relevant to patient care? Nat Rev Cancer 7:545–553

    Article  CAS  PubMed  Google Scholar 

  33. Rabindran SK, Discafani CM, Rosfjord EC et al (2004) Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res 64:3958–3965

    Article  CAS  PubMed  Google Scholar 

  34. Kwak EL, Sordella R, Bell DW et al (2005) Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci USA 102:7665–7670

    Article  CAS  PubMed  Google Scholar 

  35. Samuels Y, Wang Z, Bardelli A et al (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304:554

    Article  CAS  PubMed  Google Scholar 

  36. Samuels Y, Ericson K (2006) Oncogenic PI3K and its role in cancer. Curr Opin Oncol 18:77–82

    Article  CAS  PubMed  Google Scholar 

  37. Wu G, Xing M, Mambo E et al (2005) Somatic mutation and gain of copy number of PIK3CA in human breast cancer. Breast Cancer Res 7:R609–R616

    Article  CAS  PubMed  Google Scholar 

  38. Campbell IG, Russell SE, Choong DY et al (2004) Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res 64:7678–7681

    Article  CAS  PubMed  Google Scholar 

  39. Bachman KE, Argani P, Samuels Y et al (2004) The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 3:772–775

    Article  CAS  PubMed  Google Scholar 

  40. Saal LH, Holm K, Maurer M et al (2005) 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

    Article  CAS  PubMed  Google Scholar 

  41. Huang CH, Mandelker D, Gabelli SB et al (2008) Insights into the oncogenic effects of PIK3CA mutations from the structure of p110alpha/p85alpha. Cell Cycle 7:1151–1156

    CAS  PubMed  Google Scholar 

  42. Huang CH, Mandelker D, Schmidt-Kittler O et al (2007) The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science 318:1744–1748

    Article  CAS  PubMed  Google Scholar 

  43. Miled N, Yan Y, Hon WC et al (2007) Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science 317:239–242

    Article  CAS  PubMed  Google Scholar 

  44. Kang S, Bader AG, Vogt PK (2005) Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci USA 102:802–807

    Article  CAS  PubMed  Google Scholar 

  45. Ikenoue T, Kanai F, Hikiba Y et al (2005) Functional analysis of PIK3CA gene mutations in human colorectal cancer. Cancer Res 65:4562–4567

    Article  CAS  PubMed  Google Scholar 

  46. Bader AG, Kang S, Vogt PK (2006) Cancer-specific mutations in PIK3CA are oncogenic in vivo. Proc Natl Acad Sci USA 103:1475–1479

    Article  CAS  PubMed  Google Scholar 

  47. Board RE, Thelwell NJ, Ravetto PF et al (2008) Multiplexed assays for detection of mutations in PIK3CA. Clin Chem 54:757–760

    Article  CAS  PubMed  Google Scholar 

  48. Li SY, Rong M, Grieu F et al (2006) PIK3CA mutations in breast cancer are associated with poor outcome. Breast Cancer Res Treat 96:91–95

    Article  CAS  PubMed  Google Scholar 

  49. Lai YL, Mau BL, Cheng WH et al (2008) PIK3CA exon 20 mutation is independently associated with a poor prognosis in breast cancer patients. Ann Surg Oncol 15:1064–1069

    Article  PubMed  Google Scholar 

  50. Barbareschi M, Buttitta F, Felicioni L et al (2007) Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Clin Cancer Res 13:6064–6069

    Article  CAS  PubMed  Google Scholar 

  51. Baselga J, Semiglazov V, van Dam P et al (2009) Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol 27:2630–2637

    Article  CAS  PubMed  Google Scholar 

  52. Salvesen HB, Carter SL, Mannelqvist M et al (2009) Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activation. Proc Natl Acad Sci USA 106:4834–4839

    Article  CAS  PubMed  Google Scholar 

  53. Woenckhaus J, Steger K, Sturm K et al (2007) Prognostic value of PIK3CA and phosphorylated AKT expression in ovarian cancer. Virchows Arch 450:387–395

    Article  CAS  PubMed  Google Scholar 

  54. Wu G, Mambo E, Guo Z et al (2005) Uncommon mutation, but common amplifications, of the PIK3CA gene in thyroid tumors. J Clin Endocrinol Metab 90:4688–4693

    Article  CAS  PubMed  Google Scholar 

  55. Redon R, Muller D, Caulee K et al (2001) A simple specific pattern of chromosomal aberrations at early stages of head and neck squamous cell carcinomas: PIK3CA but not p63 gene as a likely target of 3q26-qter gains. Cancer Res 61:4122–4129

    CAS  PubMed  Google Scholar 

  56. Shayesteh L, Lu Y, Kuo WL et al (1999) PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet 21:99–102

    Article  CAS  PubMed  Google Scholar 

  57. Ma YY, Wei SJ, Lin YC et al (2000) PIK3CA as an oncogene in cervical cancer. Oncogene 19:2739–2744

    Article  CAS  PubMed  Google Scholar 

  58. Adelaide J, Finetti P, Bekhouche I et al (2007) Integrated profiling of basal and luminal breast cancers. Cancer Res 67:11565–11575

    Article  CAS  PubMed  Google Scholar 

  59. Kytola S, Rummukainen J, Nordgren A et al (2000) Chromosomal alterations in 15 breast cancer cell lines by comparative genomic hybridization and spectral karyotyping. Genes Chromosomes Cancer 28:308–317

    Article  CAS  PubMed  Google Scholar 

  60. Steck PA, Pershouse MA, Jasser SA et al (1997) Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15:356–362

    Article  CAS  PubMed  Google Scholar 

  61. Li J, Yen C, Liaw D et al (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer [see comment]. Science 275:1943–1947

    Article  CAS  PubMed  Google Scholar 

  62. Li DM, Sun H (1997) TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res 57:2124–2129

    CAS  PubMed  Google Scholar 

  63. Li DM, Sun H (1998) PTEN/MMAC1/TEP1 suppresses the tumorigenicity and induces G1 cell cycle arrest in human glioblastoma cells. Proc Natl Acad Sci USA 95:15406–15411

    Article  CAS  PubMed  Google Scholar 

  64. Bose S, Crane A, Hibshoosh H et al (2002) Reduced expression of PTEN correlates with breast cancer progression. Hum Pathol 33:405–409

    Article  CAS  PubMed  Google Scholar 

  65. Rubin MA, Gerstein A, Reid K et al (2000) 10q23.3 loss of heterozygosity is higher in lymph node-positive (pT2-3, N+) versus lymph node-negative (pT2-3, N0) prostate cancer. Hum Pathol 31:504–508

    Article  CAS  PubMed  Google Scholar 

  66. Depowski PL, Rosenthal SI, Ross JS (2001) Loss of expression of the PTEN gene protein product is associated with poor outcome in breast cancer. Mod Pathol 14:672–676

    Article  CAS  PubMed  Google Scholar 

  67. Sun H, Lesche R, Li DM et al (1999) PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5-trisphosphate and Akt/protein kinase B signaling pathway. Proc Natl Acad Sci USA 96:6199–6204

    Article  CAS  PubMed  Google Scholar 

  68. Lu Y, Lin YZ, LaPushin R et al (1999) The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells. Oncogene 18:7034–7045

    Article  CAS  PubMed  Google Scholar 

  69. Parsons R, Simpson L (2003) PTEN and cancer. Methods Mol Biol 222:147–166

    CAS  PubMed  Google Scholar 

  70. Maehama T (2007) PTEN: its deregulation and tumorigenesis. Biol Pharm Bull 30:1624–1627

    Article  CAS  PubMed  Google Scholar 

  71. Perez-Tenorio G, Alkhori L, Olsson B et al (2007) PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer. Clin Cancer Res 13:3577–3584

    Article  CAS  PubMed  Google Scholar 

  72. Perren A, Weng LP, Boag AH et al (1999) Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast. Am J Pathol 155:1253–1260

    CAS  PubMed  Google Scholar 

  73. Maehama T, Taylor GS, Dixon JE (2001) PTEN and myotubularin: novel phosphoinositide phosphatases. Annu Rev Biochem 70:247–279

    Article  CAS  PubMed  Google Scholar 

  74. Ali IU, Schriml LM, Dean M (1999) Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity. J Natl Cancer Inst 91:1922–1932

    Article  CAS  PubMed  Google Scholar 

  75. Garcia JM, Silva J, Pena C et al (2004) Promoter methylation of the PTEN gene is a common molecular change in breast cancer. Genes Chromosomes Cancer 41:117–124

    Article  CAS  PubMed  Google Scholar 

  76. Meng F, Henson R, Wehbe-Janek H et al (2007) MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 133:647–658

    Article  CAS  PubMed  Google Scholar 

  77. Huang TH, Wu F, Loeb GB et al (2009) Upregulation of miR-21 by HER2/neu signaling promotes cell invasion. J Biol Chem 284:18515–18524

    Article  CAS  PubMed  Google Scholar 

  78. Yim EK, Peng G, Dai H et al (2009) Rak functions as a tumor suppressor by regulating PTEN protein stability and function. Cancer Cell 15:304–314

    Article  CAS  PubMed  Google Scholar 

  79. Bettendorf O, Schmidt H, Staebler A et al (2008) Chromosomal imbalances, loss of heterozygosity, and immunohistochemical expression of TP53, RB1, and PTEN in intraductal cancer, intraepithelial neoplasia, and invasive adenocarcinoma of the prostate. Genes Chromosomes Cancer 47:565–572

    Article  CAS  PubMed  Google Scholar 

  80. Hager M, Haufe H, Kemmerling R et al (2007) PTEN expression in renal cell carcinoma and oncocytoma and prognosis. Pathology 39:482–485

    Article  CAS  PubMed  Google Scholar 

  81. Pantuck AJ, Seligson DB, Klatte T et al (2007) Prognostic relevance of the mTOR pathway in renal cell carcinoma: implications for molecular patient selection for targeted therapy. Cancer 109:2257–2267

    Article  CAS  PubMed  Google Scholar 

  82. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A et al (2008) An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 68:6084–6091

    Article  CAS  PubMed  Google Scholar 

  83. Zhou J, Wulfkuhle J, Zhang H et al (2007) Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc Natl Acad Sci USA 104:16158–16163

    Article  CAS  PubMed  Google Scholar 

  84. Yang H, Kong W, He L et al (2008) MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. Cancer Res 68:425–433

    Article  CAS  PubMed  Google Scholar 

  85. Massarweh S, Schiff R (2007) Unraveling the mechanisms of endocrine resistance in breast cancer: new therapeutic opportunities. Clin Cancer Res 13:1950–1954

    Article  CAS  PubMed  Google Scholar 

  86. Campbell RA, Bhat-Nakshatri P, Patel NM et al (2001) Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J Biol Chem 276:9817–9824

    Article  CAS  PubMed  Google Scholar 

  87. Kahlert S, Nuedling S, van Eickels M et al (2000) Estrogen receptor alpha rapidly activates the IGF-1 receptor pathway. J Biol Chem 275:18447–18453

    Article  CAS  PubMed  Google Scholar 

  88. Fan P, Wang J, Santen RJ et al (2007) Long-term treatment with tamoxifen facilitates translocation of estrogen receptor alpha out of the nucleus and enhances its interaction with EGFR in MCF-7 breast cancer cells. Cancer Res 67:1352–1360

    Article  CAS  PubMed  Google Scholar 

  89. Chung YL, Sheu ML, Yang SC et al (2002) Resistance to tamoxifen-induced apoptosis is associated with direct interaction between Her2/neu and cell membrane estrogen receptor in breast cancer. Int J Cancer 97:306–312

    Article  CAS  PubMed  Google Scholar 

  90. Flageng MH, Moi LL, Dixon JM et al (2009) Nuclear receptor co-activators and HER-2/neu are upregulated in breast cancer patients during neo-adjuvant treatment with aromatase inhibitors. Br J Cancer 101:1253–1260

    Article  PubMed  Google Scholar 

  91. Dowsett M, Johnston S, Martin LA et al (2005) Growth factor signalling and response to endocrine therapy: the Royal Marsden Experience. Endocr Relat Cancer 12(suppl 1):S113–S117

    Article  CAS  PubMed  Google Scholar 

  92. Osborne CK, Shou J, Massarweh S et al (2005) Crosstalk between estrogen receptor and growth factor receptor pathways as a cause for endocrine therapy resistance in breast cancer. Clin Cancer Res 11:865s–870s

    CAS  PubMed  Google Scholar 

  93. Miller TW, Perez-Torres M, Narasanna A et al (2009) Loss of Phosphatase and Tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in breast cancer. Cancer Res 69:4192–4201

    Article  CAS  PubMed  Google Scholar 

  94. Knowlden JM, Hutcheson IR, Barrow D et al (2005) Insulin-like growth factor-I receptor signaling in tamoxifen-resistant breast cancer: a supporting role to the epidermal growth factor receptor. Endocrinology 146:4609–4618

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Editorial support was provided by Jamie L. Kistler, Ph.D. of MedErgy (Yardley, PA) and supported by Wyeth Research, which was acquired by Pfizer Inc. in October 2009.

Author information

Authors and Affiliations

  1. Clinical Research and Development, Pfizer Oncology, 500 Arcola Road, Collegeville, PA, 19426, USA

    Christina M. Coughlin & Jay M. Feingold

  2. Translational Medicine, Pfizer Oncology, Collegeville, PA, USA

    Daniel S. Johnston

  3. Clinical Research and Development, Pfizer Oncology, Cambridge, MA, USA

    Jay M. Feingold, Charles Zacharchuk & Anna Berkenblit

  4. Biostatistics, Pfizer Oncology, Cambridge, MA, USA

    Andrew Strahs

  5. Pfizer Inc., Collegeville, PA, USA

    Michael E. Burczynski

  6. TMD, Scientific Development Group, Quintiles Central Laboratories, Westmont, IL, USA

    Sarah Bacus & Jason Hill

Authors
  1. Christina M. Coughlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel S. Johnston
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew Strahs
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael E. Burczynski
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sarah Bacus
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jason Hill
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jay M. Feingold
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Charles Zacharchuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Anna Berkenblit
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christina M. Coughlin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Coughlin, C.M., Johnston, D.S., Strahs, A. et al. Approaches and limitations of phosphatidylinositol-3-kinase pathway activation status as a predictive biomarker in the clinical development of targeted therapy. Breast Cancer Res Treat 124, 1–11 (2010). https://doi.org/10.1007/s10549-010-1108-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-010-1108-4

Keywords

Search

Navigation