Correlation of Src Activation with Trastuzumab Response in Patients with HER2-Positive Breast Carcinoma
Alberto Gallardo, Enrique Lerma, Fernando Ortiz-Martinez, Ariadna Perez-Balaguer, Encarna Adrover, Ariadna Tibau, Agusti Barnadas, FI Aranda, Gloria Peiro. Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; University General Hospital, Alicante, Spain
Background: Src is a non-receptor tyrosine kinase, experimental data indicate that activated Src inhibits the PI3K/Akt/mTOR pathway which is related to trastuzumab resistance. Little is known about the clinical relevance of Src activation in the response to trastuzumab. We investigated proteins involved in the PI3K/Akt/mTOR pathway and Src in a cohort of HER2+ breast carcinomas (BC) patients treated with and without trastuzumab protocols.
Design: We selected 278 HER2+ BC patients: 65 with trastuzumab in the initial treatment, 76 in the metastatic disease and 124 without trastuzumab. Patients with neoadjuvant treatment or stage IV were excluded from the survival analysis. We examined immunohistochemically pSrc (Tyr416) and pMAPK, ER, PR, HER2, EGFR, Ki67, p110a, pAkt and p-mTOR on paraffin-embedded tissue microarrays. Expression was assessed combining intensity and percentage (score 0-300): in the membrane for pSrc-416 (cut-off >12), pMAPK, p110a, pAkt (cut-offs >150), EGFR (cut-off >10), p-mTOR (cut-off >30) or Ki67 (nuclei, cut-off >14). IHC, clinicopathological factors and prognosis were correlated.
Results: Active pSrc-416 was seen in 35% of the tumors, predominantly of grade 3 (67%;p=0.09), with vascular invasion (32%/p=0.02), metastasis to the central nervous system (28%/p=0.01), pMAPK activation (28%/p=0.04), loss of ER/PR (53%/p=0.04) and no EGFR expression (9%/p=0.01). Increased active Src implied poor overall survival only in the group of patients with first line trastuzumab treatment.
|Trastuzumab in metastatic disease.(n=53)||Trastuzumab in first-line.(n=40)||No Trastuzumab treatment.(n=116)|