Significance of Src Activation Status in Trastuzumab Response in HER2-Positive Breast Carcinoma
Alberto Gallardo, Enrique Lerma, Fernando Ortiz-Martinez, Encarna Adrover, Ariadna Tibau, Agusti Barnadas, Daniel Giner, Francisco Ignacio Aranda, Francisco Jose Gutierrez-Avino, Gloria Peiro. Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain; Hospital General Universitario, Alicante, Spain
Background: Src kinase plays an important role in cell growth and differentiation. Recently, its phosphorylationhas been suggested being related with the HER2 family receptors. Little is known about the correlation between the degree of this kinase activation and the response to Trastuzumab. Therefore, we investigated the activation status of Src kinase and its correlation with several biomarkers in a cohort of HER2-positive breast carcinoma (BC) patients treated with Trastuzumab.
Design: From a series of 155 BC patients treated with Trastuzumab, we selected 95 patients: 36 with this drug in the initial treatment, 51 in the metastatic disease and 8 patients where this was not précised. Patients. We examined immunohistochemically the phosphorylation status of Src (Tyr416) and p44/42 MAPK (Thr202/Tyr204), ER, PR, HER2, IGF1R (alpha), and p27 on paraffin-embedded tissue microarrays. Markers expression was assessed combining intensity and percentage of positive cells (score 0-300): for pSrc-416 and pMAPK (positive cut-off ≥150), IGF1R (cut-off ≥220) or in the nuclei for p27 (cut-off =20%). Correlations between IHC results, clinicopathological factors and prognosis were analyzed.
Results: Active pSrc-416 was seen in 28% (27/95) tumors in association with positive lymph node status (83%; p=0.041) and metastasis to the central nervous system (33%; p=0.12), but no correlation with other clinical-pathological data was found. Further, a positive correlation was observed between pSrc with pMAPK activation (35%; p=0.036), p27 (70%; p=0.013) or IGF1R overexpression (22%; p=0.13), and no association was seen for ER/PR (21%; p=ns). Survival analysis (Kaplan-Meier) showed only in the group of patients with first line Trastuzumab treatment, that increased active pSrc-416 was associated with poor overall survival (25% vs. 4%; p=0.02); and a trend toward shorter disease free survival (25% vs 7%; p=0.074).
Conclusions: Our results suggest that increased Src kinase activity is involved in promoting Trastuzumab resistance in combination with MAPK and IGF1R, in a subset of primary HER2-positive BC. Therefore, blocking this axis may prevent the development of Trastuzumab resistance in those patients.
Wednesday, March 21, 2012 1:00 PM
Poster Session VI # 17, Wednesday Afternoon