Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas

A. Gallardo, E. Lerma, D. Escuin, A. Tibau, J. Muñoz, B. Ojeda, A. Barnadas, E. Adrover, L. Sánchez-Tejada, D. Giner, F. Ortiz-Martínez, G. Peiró

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Abstract

Background: Trastuzumab resistance hampers its well-known efficacy to control HER2-positive breast cancer. The involvement of PI3K/Akt pathway in this mechanism is still not definitively confirmed. Methods: We selected 155 patients treated with trastuzumab after development of metastasis or as adjuvant/neoadjuvant therapy. We performed immunohistochemistry for HER2, ER/PR, epidermal growth factor 1-receptor (EGFR), α-insulin-like growth factor 1-receptor (IGF1R), phosphatase and tensin homologue (PTEN), p110α, pAkt, pBad, pmTOR, pMAPK, MUC1, Ki67, p53 and p27; mutational analysis of PIK3CA and PTEN, and PTEN promoter hypermethylation. Results: We found 46% ER/PR-positive tumours, overexpression of EGFR (15%), α-IGF1R (25%), p110α (19%), pAkt (28%), pBad (22%), pmTOR (23%), pMAPK (24%), MUC1 (80%), PTEN loss (20%), and PTEN promoter hypermethylation (20%). PIK3CA and PTEN mutations were detected in 17% and 26% tumours, respectively. Patients receiving adjuvant trastuzumab with α-IGF1R or pBad overexpressing tumours presented shorter progression-free survival (PFS) (all P≤0.043). Also, p110α and mTOR overexpression, liver and brain relapses implied poor overall survival (OS) (all P≤0.041). In patients with metastatic disease, decreased PFS correlated with p110α expression (P=0.024), whereas for OS were the presence of vascular invasion and EGFR expression (P≤0.019; Cox analysis). Conclusion: Our results support that trastuzumab resistance mechanisms are related with deregulation of PTEN/PI3K/Akt/mTOR pathway, and/or EGFR and IGF1R overexpression in a subset of HER2-positive breast carcinomas. © 2012 Cancer Research UK.
Original languageEnglish
Pages (from-to)1367-1373
JournalBritish Journal of Cancer
Volume106
DOIs
Publication statusPublished - 10 Apr 2012

Keywords

  • EGFR
  • HER2
  • IGF1R
  • PTEN/PI3K/Akt pathway
  • breast cancer
  • trastuzumab resistance

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    Gallardo, A., Lerma, E., Escuin, D., Tibau, A., Muñoz, J., Ojeda, B., Barnadas, A., Adrover, E., Sánchez-Tejada, L., Giner, D., Ortiz-Martínez, F., & Peiró, G. (2012). Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas. British Journal of Cancer, 106, 1367-1373. https://doi.org/10.1038/bjc.2012.85