Influence of EIF4E and HER2 Protein Expression on the Response to Neoadjuvant Chemotherapy and Trastuzumab in Breast Cancer.
Authors: Bergé Y. , Filleron T. , Zindy P. , Charitansky H. , Gaston A. , Silvagni C. , Roché H. , Vagner S. , Lacroix-Triki M. , Dalenc F. 
Published: December 2010

Background:Resistance to trastuzumab (TTZ) is still poorly understood. Many proteins implicated in signaling pathways of breast cancer cells have so far been studied as potential markers of TTZ resistance in preclinical models.Method:63 consecutive patients were treated for HER2 + breast cancer with a neoadjuvant chemotherapy regimen containing TTZ between December 2003 and July 2008. This regimen was mostly 4 cycles of FEC 100 (5FU, Epirubicin and Cyclophosphamide) followed by 4 cycles of TTZ – Docetaxel 100mg/m².Immunohistochemistry (IHC) was used to analyse, in the initial biopsy, the expression of HER family receptors (EGFR, HER3, HER4 and HER2), PTEN, cMyc and p27. We also analyzed the expression of two proteins (eIF4E and 4EBP1) involved in translational control of mRNAs. 4EBP1 is a small protein that represses the initiation of protein translation through its association with eIF4E, the mRNA cap-binding subunit of the eIF4F complex. mTOR-dependent phosphorylation of 4E-BP1 decreases the affinity of the protein for eIF4E, which facilitates the formation of eIF4F complex. Furthermore, the expression of eIF4E is elevated in many cancers.We analysed the pathologic response rate (pRR) after chemotherapy + TTZ, and we established correlations between the expression of these markers and pRR.Results:Among the 63 patients, 54 had a valuable pre-chemotherapy biopsy.For those 54 patients, median age was 48 years (range [21;80]), median tumor size was 50 mm clinically (range [20;120]), and 26 mm by ultrasound (range [10;80]). Respectively 63%, 57% and 52% were estrogen receptor (ER) negative, progesterone receptor (PR) negative and ER/PR negative. Histology type was ductal infiltrant carcinoma for 91% of patients. Respectively 28% and 72% were grade SBR (EE) II and III.A pathologic complete response (pCR) (Sataloff TA) was observed on 63% of patients, 28% had a partial response but superior to 50% (Sataloff TB) and 9% had a poor or absent pathologic response (Sataloff TC and TD).This pCR was not statistically linked to any initial clinical characteristics (age, grade, hormonal status and tumoral size).pCR was strongly correlated with weak eIf4E and with percentage of HER2 strong-stained cells (respectively p=0,0114 et 0,0056). 93% of tumors with an eIF4E IRS &lt;7 (n=13/14) had a pCR, and only 5% (1/19) with an incomplete pRR had an eIF4E IRS &lt;7. Moreover, 78% (25/32) of tumors with 100% of tumoral cells harboring a strong intensity of HER2 had a pCR versus 41% (9/22) of tumors with less than 100% of cells expressing HER2 with a strong staining.Conclusion:Our study shows a strong correlation between eIF4E expression or HER2 expression and pRR in patients with HER2 + breast treated with a neoadjuvant TTZ-containing regimen. IHC of eIF4E might be a powerful test to predict sensitivity to TTZ.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2043.