Breast Cancer Research and Treatment

, Volume 147, Issue 1, pp 211–219 | Cite as

Changes in PIK3CA mutation status are not associated with recurrence, metastatic disease or progression in endocrine-treated breast cancer

  • L. M. Arthur
  • A. K. Turnbull
  • L. Renshaw
  • J. Keys
  • J. S. Thomas
  • T. R. Wilson
  • M. R. Lackner
  • A. H. Sims
  • J. M. Dixon
Brief Report


The phosphatidylinositol-3-kinase pathway plays an important role in proliferation, migration and survival in breast cancer and may play a role in resistance to endocrine therapy. Pathway activation occurs as a result of mutations in PIK3CA or loss of functional PTEN. Matched primary and recurrent samples from 120 breast cancer patients treated with endocrine therapy were profiled with a qPCR-based mutation assay covering eight mutational hotspots in PIK3CA. PTEN was assayed by immunohistochemistry. Samples were well characterized with respect to anatomic location of recurrence (metastatic nodal or local recurrence as opposed to contralateral or ipsilateral new primary cancers). In total, 43 % of patients had at least one PIK3CA mutation at diagnosis, and 41 % had a mutation at the time of recurrence. Only 8 % of patients with local recurrence, metastatic disease or progression on primary endocrine treatment changed their PIK3CA mutation status (four gains, two losses, total 76). The most common changes in PIK3CA mutation status were seen in patients who developed a new cancer either in the treated or contralateral breast (64 %, three gains, four losses, total 11). PIK3CA mutation status does not change in the majority of patients with breast cancer and the acquisition of mutations in PIK3CA is not responsible for the development of endocrine resistance. PTEN loss at diagnosis is associated with a significantly shorter time to progression compared with tumours in which PTEN was retained. These are the most comprehensive data currently available correlating PIK3CA status, site of recurrence and endocrine resistance.


PIK3CA Breast cancer Mutation PTEN Endocrine Resistance 



This work was supported by Breakthrough Breast Cancer and Cancer Research UK who provided infrastructure for assembling and cutting the tissue blocks used in thus study. The authors acknowledge support of the department of pathology who stored these tissues.The authors would like to thank Victoria Brophy and colleagues from Roche Molecular Systems for development and transfer of the PIK3CA mutation assay to the central laboratory.

Conflict of interests

TRW and MRL are employees of Genentech and have equity in Roche.

Ethical standards

All patients gave informed consent to be included in the study which had been approved by the local ethics committee (LREC; 2001/8/80 and 2001/8/81).


  1. 1.
    Kang S, Bader AG, Vogt PK (2005) Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci USA 102(3):802–807CrossRefPubMedCentralPubMedGoogle Scholar
  2. 2.
    (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418): 61–70Google Scholar
  3. 3.
    Dunlap J et al (2010) Phosphatidylinositol-3-kinase and AKT1 mutations occur early in breast carcinoma. Breast Cancer Res Treat 120(2):409–418CrossRefPubMedGoogle Scholar
  4. 4.
    Kalinsky K et al (2009) PIK3CA mutation associates with improved outcome in breast cancer. Clin Cancer Res 15(16):5049–5059CrossRefPubMedGoogle Scholar
  5. 5.
    Saal LH 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(7):2554–2559CrossRefPubMedGoogle Scholar
  6. 6.
    Karakas B, Bachman KE, Park BH (2006) Mutation of the PIK3CA oncogene in human cancers. Br J Cancer 94(4):455–459CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Campbell IG et al (2004) Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res 64(21):7678–7681CrossRefPubMedGoogle Scholar
  8. 8.
    Bachman KE et al (2004) The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 3(8):772–775CrossRefPubMedGoogle Scholar
  9. 9.
    Levine DA et al (2005) Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin Cancer Res 11(8):2875–2878CrossRefPubMedGoogle Scholar
  10. 10.
    Hennessy BT et al (2009) Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res 69(10):4116–4124CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    Bartlett JM (2010) Biomarkers and patient selection for PI3 K/Akt/mTOR targeted therapies: current status and future directions. Clin Breast Cancer 10(Suppl 3):S86–S95CrossRefPubMedGoogle Scholar
  12. 12.
    Campbell RA et al (2001) Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J Biol Chem 276(13):9817–9824CrossRefPubMedGoogle Scholar
  13. 13.
    Ma CX, Crowder RJ, Ellis MJ (2011) Importance of PI3-kinase pathway in response/resistance to aromatase inhibitors. Steroids 76(8):750–752CrossRefPubMedGoogle Scholar
  14. 14.
    Ellis MJ et al (2010) Phosphatidyl-inositol-3-kinase alpha catalytic subunit mutation and response to neoadjuvant endocrine therapy for estrogen receptor positive breast cancer. Breast Cancer Res Treat 119(2):379–390CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Baselga J 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(16):2630–2637CrossRefPubMedGoogle Scholar
  16. 16.
    Baselga J et al (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. New Engl J Med 366(6):520–529CrossRefPubMedGoogle Scholar
  17. 17.
    Aleskandarany MA et al (2010) PIK3CA expression in invasive breast cancer: a biomarker of poor prognosis. Breast Cancer Res Treat 122(1):45–53CrossRefPubMedGoogle Scholar
  18. 18.
    Cuorvo LV et al (2013) PI3KCA mutation status is of limited prognostic relevance in ER-positive breast cancer patients treated with hormone therapy. Virchows Arch 464(1):85–93CrossRefGoogle Scholar
  19. 19.
    Song MS, Salmena L, Pandolfi PP (2012) The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol 13(5):283–296PubMedGoogle Scholar
  20. 20.
    Shoman N et al (2005) Reduced PTEN expression predicts relapse in patients with breast carcinoma treated by tamoxifen. Modern pathol 18(2):250–259CrossRefGoogle Scholar
  21. 21.
    Perez-Tenorio G 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(12):3577–3584CrossRefPubMedGoogle Scholar
  22. 22.
    Kirkegaard T et al (2005) AKT activation predicts outcome in breast cancer patients treated with tamoxifen. J Pathol 207(2):139–146CrossRefPubMedGoogle Scholar
  23. 23.
    Tokunaga E et al (2006) Activation of PI3K/Akt signaling and hormone resistance in breast cancer. Breast cancer 13(2):137–144CrossRefPubMedGoogle Scholar
  24. 24.
    Kerdivel G, Flouriot G, Pakdel F (2013) Modulation of estrogen receptor alpha activity and expression during breast cancer progression. Vitam Horm 93:135–160CrossRefPubMedGoogle Scholar
  25. 25.
    Toy W et al (2013) ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet 45(12):1439–1445CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.
    Robinson DR et al (2013) Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet 45(12):1446–1451CrossRefPubMedCentralPubMedGoogle Scholar
  27. 27.
    Aitken SJ et al (2010) Quantitative analysis of changes in ER, PR and HER2 expression in primary breast cancer and paired nodal metastases. Ann Oncol 21(6):1254–1261CrossRefPubMedGoogle Scholar
  28. 28.
    Thompson AM et al (2010) Prospective comparison of switches in biomarker status between primary and recurrent breast cancer: the breast recurrence in tissues study (BRITS). Breast Cancer Res 12(6):R92CrossRefPubMedCentralPubMedGoogle Scholar
  29. 29.
    Criscitiello C, André F, Thompson AM, De Laurentiis M, Esposito A, Fumagalli L, Locatelli M, Minchella I, Orsi F, Goldhirsch A, Curigliano G (2014) Biopsy confirmation of metastatic sites in breast cancer patients: clinical impact and future perspectives. Breast Cancer Res 16:205CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    Gonzalez-Angulo AM et al (2011) PI3K pathway mutations and PTEN levels in primary and metastatic breast cancer. Mol Cancer Ther 10(6):1093–1101CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.
    Dupont Jensen J et al (2011) PIK3CA mutations may be discordant between primary and corresponding metastatic disease in breast cancer. Clin Cancer Res 17(4):667–677CrossRefPubMedGoogle Scholar
  32. 32.
    Spoerke JM et al (2012) Phosphoinositide 3-kinase (PI3K) pathway alterations are associated with histologic subtypes and are predictive of sensitivity to PI3K inhibitors in lung cancer preclinical models. Clin Cancer Res 18(24):6771–6783CrossRefPubMedGoogle Scholar
  33. 33.
    Schlag P, Hoeppner C, Bristol A, Kaur N, Quashnick S, Ravirala R J Kramer, Negash M, Brophy V, Lee S, Soviero S (2013) A real-time PCR assay for the detection of PIK3CA mutations in formalin-fixed paraffin embedded tissue (FFPET) specimens of breast cancer (BC). [abstract]. Cancer Res 2013. In: Proceedings of the 104th Annual meeting of the american association for cancer research, 73(8 Suppl), p Abstract nr 4217Google Scholar
  34. 34.
    Barbareschi M et al (2012) PI3KCA mutations and/or PTEN loss in Her2-positive breast carcinomas treated with trastuzumab are not related to resistance to anti-Her2 therapy. Virchows Arch 461(2):129–139CrossRefPubMedGoogle Scholar
  35. 35.
    Barbi S et al (2010) The analysis of PIK3CA mutations in gastric carcinoma and metanalysis of literature suggest that exon-selectivity is a signature of cancer type. J Exp Clin Cancer Res 29:32CrossRefPubMedCentralPubMedGoogle Scholar
  36. 36.
    Barbareschi M 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(20):6064–6069CrossRefPubMedGoogle Scholar
  37. 37.
    Kandula M et al (2013) Phosphatidylinositol 3-kinase (PI3KCA) oncogene mutation analysis and gene expression profiling in primary breast cancer patients. Asian Pac J Cancer Prev 14(9):5067–5072CrossRefPubMedGoogle Scholar
  38. 38.
    Sanchez CG et al (2011) Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer. Breast Cancer Res 13(2):R21CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.
    Loi S et al (2010) PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer. Proc Natl Acad Sci USA 107(22):10208–10213CrossRefPubMedCentralPubMedGoogle Scholar
  40. 40.
    Loi S et al (2013) PIK3CA genotype and a PIK3CA mutation-related gene signature and response to everolimus and letrozole in estrogen receptor positive breast cancer. PLoS ONE 8(1):e53292CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • L. M. Arthur
    • 1
  • A. K. Turnbull
    • 1
  • L. Renshaw
    • 1
  • J. Keys
    • 1
  • J. S. Thomas
    • 1
  • T. R. Wilson
    • 2
  • M. R. Lackner
    • 2
  • A. H. Sims
    • 1
  • J. M. Dixon
    • 1
  1. 1.Edinburgh Breast UnitWestern General HospitalEdinburghUK
  2. 2.Genentech IncSouth San FranciscoUSA

Personalised recommendations