Skip to main content

Advertisement

SpringerLink
Log in

Evaluation of the association of PIK3CA mutations and PTEN loss with efficacy of trastuzumab therapy in metastatic breast cancer

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

Abstract

Trastuzumab (T) is effective in metastatic breast cancer (MBC) with HER2 overexpression and/or amplification, but resistance to T develops in a significant number of HER2-positive patients. Understanding the mechanisms of resistance is critical to the care of these patients. Formalin-fixed paraffin-embedded tumor tissue samples were collected from 256 patients with T-treated MBC. Clinical information was collected retrospectively from the patients’ medical records. Central review of HER2 status by fluorescent in situ hybridization (FISH) and/or immunohistochemistry (IHC) revealed that of the 227 eligible patients only 139 (61%) were truly HER2-positive. PTEN, ER, PgR, and Ki67 were evaluated by IHC, while PTEN status was evaluated by FISH as well. PIK3CA mutations were identified with single nucleotide polymorphism (SNP) genotyping. Median time to progression (TTP) was 14.4 months for the HER2-positive and 10.3 for the HER2-negative patients (log-rank, P = 0.22). Survival from the initiation of T (survivalT) was 50.4 months for the HER2-positive and 35.3 for the HER2-negative subgroups (P = 0.006). Higher risk of progression was associated with HER2-positive status and the presence of PIK3CA mutations (P = 0.014). PTEN loss, as determined by IHC, was associated with lower survivalT in the whole population (P = 0.029) and in the HER2-positive population (P = 0.017). PIK3CA mutations and/or PTEN loss status were evaluated together as a single parameter, to estimate the impact of activation of the PI3K/AKT molecular pathway, and it was significantly associated with both decreased TTP (P = 0.003 in the total population, P = 0.004 in HER2-positive patients) and survival (survivalT, P = 0.011 in total, P = 0.006 in HER2-positive). In this trastuzumab-treated breast cancer population, PIK3CA activating mutations were associated with shorter TTP and PTEN loss with decreased survival. The activation of the PI3K/AKT pathway from either defect was associated with both TTP and survival, indicating the adverse effect of this pathway’s status on trastuzumab efficacy.

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

Similar content being viewed by others

References

  1. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235(4785):177–182

    Article  PubMed  CAS  Google Scholar 

  2. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783–792. doi:10.1056/NEJM200103153441101

    Article  PubMed  CAS  Google Scholar 

  3. Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M, Shak S, Stewart SJ, Press M (2002) Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20(3):719–726

    Article  PubMed  CAS  Google Scholar 

  4. Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M, Chan S, Grimes D, Anton A, Lluch A, Kennedy J, O’Byrne K, Conte P, Green M, Ward C, Mayne K, Extra JM (2005) Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol 23(19):4265–4274. doi:10.1200/JCO.2005.04.173

    Article  PubMed  CAS  Google Scholar 

  5. Nahta R, Yu D, Hung MC, Hortobagyi GN, Esteva FJ (2006) Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nat Clin Pract Oncol 3(5):269–280. doi:10.1038/ncponc0509

    Article  PubMed  CAS  Google Scholar 

  6. Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M, Beijersbergen RL, Mills GB, van de Vijver MJ, Bernards R (2007) A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12(4):395–402. doi:10.1016/j.ccr.2007.08.030

    Article  PubMed  CAS  Google Scholar 

  7. Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, Hortobagyi GN, Hung MC, Yu D (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6(2):117–127. doi:10.1016/j.ccr.2004.06.022

    Article  PubMed  CAS  Google Scholar 

  8. Fujita T, Doihara H, Kawasaki K, Takabatake D, Takahashi H, Washio K, Tsukuda K, Ogasawara Y, Shimizu N (2006) PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer. Br J Cancer 94(2):247–252. doi:10.1038/sj.bjc.6602926

    Article  PubMed  CAS  Google Scholar 

  9. Fabi A, Metro G, Di Benedetto A, Nistico C, Vici P, Melucci E, Antoniani B, Perracchio L, Sperduti I, Milella M, Cognetti F, Mottolese M (2010) Clinical significance of PTEN and p-Akt co-expression in HER2-positive metastatic breast cancer patients treated with trastuzumab-based therapies. Oncology 78(2):141–149. doi:10.1159/000312656

    Article  PubMed  CAS  Google Scholar 

  10. Gori S, Sidoni A, Colozza M, Ferri I, Mameli MG, Fenocchio D, Stocchi L, Foglietta J, Ludovini V, Minenza E, De Angelis V, Crino L (2009) EGFR, pMAPK, pAkt and PTEN status by immunohistochemistry: correlation with clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab. Ann Oncol 20(4):648–654. doi:10.1093/annonc/mdn681

    Article  PubMed  CAS  Google Scholar 

  11. Pandolfi PP (2004) Breast cancer—loss of PTEN predicts resistance to treatment. N Engl J Med 351(22):2337–2338. doi:10.1056/NEJMcibr043143

    Article  PubMed  CAS  Google Scholar 

  12. Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, Yu JS, Malmstrom PO, Mansukhani M, Enoksson J, Hibshoosh H, Borg A, Parsons R (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):2554–2559. doi:10.1158/0008-5472-CAN-04-3913

    Article  PubMed  CAS  Google Scholar 

  13. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2006) REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 100(2):229–235. doi:10.1007/s10549-006-9242-8

    Article  PubMed  Google Scholar 

  14. Fountzilas G, Bobos M, Kalogera-Fountzila A, Xiros N, Murray S, Linardou H, Karayannopoulou G, Koutras AK, Bafaloukos D, Samantas E, Christodoulou C, Economopoulos T, Kalogeras KT, Kosmidis P (2008) Gemcitabine combined with gefitinib in patients with inoperable or metastatic pancreatic cancer: a phase II Study of the Hellenic Cooperative Oncology Group with biomarker evaluation. Cancer Invest 26(8):784–793. doi:10.1080/07357900801918611

    Article  PubMed  CAS  Google Scholar 

  15. Gogas H, Pectasides D, Kostopoulos I, Lianos E, Skarlos D, Papaxoinis G, Bobos M, Kalofonos HP, Petraki K, Pavlakis K, Bafaloukos D, Fountzilas G (2010) Paclitaxel and carboplatin as neoadjuvant chemotherapy in patients with locally advanced breast cancer: a phase II Trial of the Hellenic Cooperative Oncology Group. Clin Breast Cancer 10(3):230–237. doi:10.3816/CBC.2010.n.031

    Article  PubMed  CAS  Google Scholar 

  16. Bamias A, Karina M, Papakostas P, Kostopoulos I, Bobos M, Vourli G, Samantas E, Christodoulou C, Pentheroudakis G, Pectasides D, Dimopoulos MA, Fountzilas G (2010) A randomized phase III study of adjuvant platinum/docetaxel chemotherapy with or without radiation therapy in patients with gastric cancer. Cancer Chemother Pharmacol 65(6):1009–1021. doi:10.1007/s00280-010-1256-6

    Article  PubMed  CAS  Google Scholar 

  17. Hugh J, Hanson J, Cheang MC, Nielsen TO, Perou CM, Dumontet C, Reed J, Krajewska M, Treilleux I, Rupin M, Magherini E, Mackey J, Martin M, Vogel C (2009) Breast cancer subtypes and response to docetaxel in node-positive breast cancer: use of an immunohistochemical definition in the BCIRG 001 trial. J Clin Oncol 27(8):1168–1176. doi:10.1200/JCO.2008.18.1024

    Article  PubMed  CAS  Google Scholar 

  18. Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF (2007) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25(1):118–145. doi:10.1200/JCO.2006.09.2775

    Article  PubMed  CAS  Google Scholar 

  19. Cheang MC, Chia SK, Voduc D, Gao D, Leung S, Snider J, Watson M, Davies S, Bernard PS, Parker JS, Perou CM, Ellis MJ, Nielsen TO (2009) Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 101(10):736–750. doi:10.1093/jnci/djp082

    Article  PubMed  CAS  Google Scholar 

  20. Christodoulou C, Kostopoulos I, Kalofonos HP, Lianos E, Bobos M, Briasoulis E, Gogas H, Razis E, Skarlos DV, Fountzilas G (2009) Trastuzumab combined with pegylated liposomal doxorubicin in patients with metastatic breast cancer: phase II Study of the Hellenic Cooperative Oncology Group (HeCOG) with biomarker evaluation. Oncology 76(4):275–285. doi:10.1159/000207504

    Article  PubMed  CAS  Google Scholar 

  21. Bohmann K, Hennig G, Rogel U, Poremba C, Mueller BM, Fritz P, Stoerkel S, Schaefer KL (2009) RNA extraction from archival formalin-fixed paraffin-embedded tissue: a comparison of manual, semiautomated, and fully automated purification methods. Clin Chem 55(9):1719–1727. doi:10.1373/clinchem.2008.122572

    Article  PubMed  CAS  Google Scholar 

  22. Perez-Tenorio G, Alkhori L, Olsson B, Waltersson MA, Nordenskjold B, Rutqvist LE, Skoog L, Stal O (2007) PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer. Clin Cancer Res 13(12):3577–3584. doi:10.1158/1078-0432.CCR-06-1609

    Article  PubMed  CAS  Google Scholar 

  23. Pohlmann PR, Mayer IA, Mernaugh R (2009) Resistance to trastuzumab in breast cancer. Clin Cancer Res 15(24):7479–7491. doi:10.1158/1078-0432.CCR-09-0636

    Article  PubMed  CAS  Google Scholar 

  24. Kakarala M, Wicha MS (2008) Implications of the cancer stem-cell hypothesis for breast cancer prevention and therapy. J Clin Oncol 26(17):2813–2820. doi:10.1200/JCO.2008.16.3931

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank Ms. Thalia Spinari for tissue collection, Ms. Dimitra Katsala for monitoring the study, Ms. Maria Moschoni for coordinating the data management, and Ms. Stella Dallidou for secretarial assistance. The study was supported by a Hellenic Cooperative Oncology Group grant HER_11P/05.

Author information

Authors and Affiliations

  1. First Department of Medical Oncology, “Hygeia” Hospital, Er. Stavrou & Kifissias Av, 151 23, Maroussi, Athens, Greece

    E. Razis & G. Rigakos

  2. Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece

    M. Bobos & V. Kotoula

  3. Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece

    M. Bobos, V. Kotoula & I. Kostopoulos

  4. Section of Biostatistics, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece

    A. G. Eleftheraki

  5. Division of Oncology, Department of Medicine, University Hospital of Patras, Rion, Greece

    H. P. Kalofonos

  6. Department of Pathology, Obstetrical and Gynaecological Center “Iasso”, Athens, Greece

    K. Pavlakis

  7. Department of Oncology, “Hippokration” Hospital, Athens, Greece

    P. Papakostas

  8. Third Department of Medical Oncology, “Agii Anargiri” Cancer Hospital, Athens, Greece

    G. Aravantinos

  9. Department of Pathology, “Papageorgiou” Hospital, Thessaloniki, Greece

    I. Efstratiou

  10. Department of Pathology, “Metropolitan” Hospital, Piraeus, Greece

    K. Petraki

  11. First Department of Medical Oncology, “Metropolitan” Hospital, Athens, Greece

    D. Bafaloukos

  12. Oncology Section, Second Propaedeutic Department of Internal Medicine, University General Hospital “Attikon”, Athens, Greece

    D. Pectasides

  13. Department of Medical Oncology, “Papageorgiou” Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece

    K. T. Kalogeras & G. Fountzilas

  14. Translational Research Section, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece

    K. T. Kalogeras

  15. Second Department of Medical Oncology, “Metropolitan” Hospital, Athens, Greece

    D. Skarlos

Authors
  1. E. Razis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Bobos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V. Kotoula
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. G. Eleftheraki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H. P. Kalofonos
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K. Pavlakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. P. Papakostas
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. G. Aravantinos
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. G. Rigakos
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. I. Efstratiou
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. K. Petraki
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. D. Bafaloukos
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. I. Kostopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. D. Pectasides
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. K. T. Kalogeras
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. D. Skarlos
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. G. Fountzilas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. Razis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Razis, E., Bobos, M., Kotoula, V. et al. Evaluation of the association of PIK3CA mutations and PTEN loss with efficacy of trastuzumab therapy in metastatic breast cancer. Breast Cancer Res Treat 128, 447–456 (2011). https://doi.org/10.1007/s10549-011-1572-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-011-1572-5

Keywords

Search

Navigation