Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas
Por:
Gallardo, A, Lerma, E, Escuin, D, Tibau, A, Munoz, J, Ojeda, B, Barnadas, A, Adrover, E, Sanchez-Tejada, L, Giner, D, Ortiz-Martinez, F, Peiro, G
Publicada:
10 abr 2012
Resumen:
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), alpha-insulin-like growth factor 1-receptor (IGF1R), phosphatase and tensin homologue (PTEN), p110 alpha, 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%), alpha-IGF1R (25%), p110 alpha (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 alpha-IGF1R or pBad overexpressing tumours presented shorter progression-free survival (PFS) (all P <= 0.043). Also, p110a 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 p110 alpha 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. British Journal of Cancer (2012) 106, 1367-1373. doi: 10.1038/bjc.2012.85 www.bjcancer.com Published online 27 March 2012 (C) 2012 Cancer Research UK
Filiaciones:
Gallardo, A:
Autonomous Univ Barcelona, Dept Pathol, Hosp Santa Creu & St Pau, Barcelona 08025, Spain
Lerma, E:
Autonomous Univ Barcelona, Dept Pathol, Hosp Santa Creu & St Pau, Barcelona 08025, Spain
Escuin, D:
Hosp Santa Creu & Sant Pau, Inst Recerca, Dept Clin Oncol, Barcelona, Spain
Tibau, A:
Autonomous Univ Barcelona, Dept Clin Oncol, Hosp Santa Creu & St Pau, Barcelona 08025, Spain
Munoz, J:
Autonomous Univ Barcelona, Dept Pathol, Hosp Santa Creu & St Pau, Barcelona 08025, Spain
Ojeda, B:
Autonomous Univ Barcelona, Dept Clin Oncol, Hosp Santa Creu & St Pau, Barcelona 08025, Spain
Barnadas, A:
Autonomous Univ Barcelona, Dept Clin Oncol, Hosp Santa Creu & St Pau, Barcelona 08025, Spain
Adrover, E:
Hosp Gen Univ, Dept Clin Oncol, Alicante, Spain
Sanchez-Tejada, L:
Hosp Gen Univ, Res Unit, Alicante, Spain
Giner, D:
Hosp Gen Univ, Res Unit, Alicante, Spain
Ortiz-Martinez, F:
Hosp Gen Univ, Res Unit, Alicante, Spain
Peiro, G:
Hosp Gen Univ, Res Unit, Alicante, Spain
Green Published, Hybrid Gold
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