The Role of EGFR and IGF1R in MAPK and PI3K/Akt Signaling Pathways in HER2-Positive Breast Carcinoma
G Peiro, M Planelles, FI Aranda, E Adrover, L Sanchez-Tejada, D Giner, FJ Gutierrez-Avino, E Lerma. Hospital General Universitari, Alacant, Spain; Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Background: The Ras-Raf-MAPK (mitogen-activated protein kinase)-Erk and PI3K/Akt signaling pathways are critical in the regulation of cell growth and survival, respectively. Aberrant activation by growth factors or ligands of tyrosine kinase receptors has been reported in human malignancies. The aim of our study was to analyze the role of EGFR (epidermal growth factor receptor) and IGF1R (Insulin-like growth factor 1 receptor) in the activation of the MAPK Erk1/2 and PI3/Akt pathways in a series of HER2-positive breast carcinoma (BC).
Design: 257 patients with HER2-positive BC, treated at the University General Hospital of Alicante, were included in this study. FISH and/or CISH did confirmation of HER2 status in all 2+ and <30% 3+ tumors. We examined immunohistochemically phosphorylation of p44/42 MAPK (Thr202/Tyr204), Akt (Ser473) and p110 (alpha), and expression of ER, EGFR and IGF1R (alpha). Aberrant expression was correlated with tumor characteristics and outcome.
Results: Patients' mean age was 55 years (SD+/-14 years) and mean follow-up was 71 months (SD+/-48 months); 25.3% patients received trastuzumab combined with other treatment modalities. Tumors were predominantly >2cm (56%), of ductal type (96%), grade 3 (68%), with necrosis (53%) and vascular invasion (55%). ER was positive in 52% cases, increased IGF1R in 42%, EGFR in 16%, p110 in 51%, pAkt in 45% and pMAPK in 21% cases. Tumors with EGFR overexpression were larger than 2cm (p=0.038), of high grade (p=0.024), with vascular invasion (p=0.12), positive lymph nodes (p=0.021), ER-negative (p<0.000) and increased p110/pAkt (p=0.006), but no correlation was found with MAPK phosphorylation status (p=ns). On the other hand, those with IGF1R overexpression were <2cm (p=0.02), without necrosis (p=0.021) or vascular invasion (p=0.01), negative lymph-nodes (p=0.16), ER-positive (p=0.01), and coexpressed p110/pAKT (p=0.021) or pMAPK (p=0.07). However, only a trend towards a better disease-free survival was seen for patients with EGFR-negative tumors (69% vs 61%; p=0.13).
Conclusions: EGFR is expressed in tumors with poor prognostic factors and activation of PI3K/Akt signaling. In contrast, IGF1R correlates with good prognostic factors and activation of both pathways. Our data indicate that inhibition of the MAPK and/or PI3K/Akt pathways targeting EGFR or IGF1R is a promising treatment strategy in a subgroup of HER2-positive BC patients.
Tuesday, March 23, 2010 9:30 AM
Poster Session III # 66, Tuesday Morning