Abstract P3-14-13: eIF4E/4EBP1 axis and response to neoadjuvant trastuzumab-based treatment in HER2+ breast cancer – Results of a multicentre French retrospective cohort
Authors: F Dalenc, S Le Guellec, L Arnould, B Coudert, S Vagner, T Bachelot, I Treilleux, M Debled, G MacGrogan, W Jacot, F Bibeau, L Vanlemmens, F André, M-C Mathieu, P Augereau, V Verriele, F Penault-Llorca, M Lacroix-Triki, T Filleron
Journal: Cancer Research (2013)

Abstract Background Despite a growing number of studies exploring the underlying mechanisms, resistance to trastuzumab (TTZ) in HER2+ breast cancer (BC) remains elusive and an important issue in clinical practice. Among the proposed mechanisms, involvement of the PI3K/Akt/mTOR pathway is one of the best characterized. In a previous preclinical and clinical study (n = 54) (Bergé Y et al, SABCS 2009 and [1]), we have shown a significant correlation between eIF4E (a downstream effector of the PI3K/Akt/mTOR pathway) expression level as determined by immunohistochemistry (IHC) on initial tumor biopsy and pathological complete response (pCR) in patients with HER2+ BC treated with a neoadjuvant TTZ-containing regimen. The aim of this study was to validate these findings on an independent and larger cohort of HER2+ BC treated in neoadjuvant setting. Method In this multicenter (n = 9) study, 274 patients (pts) with HER2+ BC treated were included. All pts received neoadjuvant chemotherapy regimen containing TTZ, consisting mostly of 3-4 cycles of FEC (5FU, Epirubicin, Cyclophosphamid) followed by 3-4 cycles of TTZ–Docetaxel (n = 116). 74 pts received 6 cycles of TTZ–Docetaxel, 18 received 6 cycles of TTZ–Docetaxel-Cyclophosphamid, 12 received 6 cycles of TTZ–Docetaxel-carbolpatine, and the remaining 54 pts received other regimens. Pathological response was assessed according to Sataloff and Chevallier criteria. Unstained slides from the initial tumor biopsy were centrally collected for biomarkers analysis. Expression levels of eIF4E, p-4EBP1 and pS6 were determined by IHC. An immunoreactive score (IRS) combining the percentage of stained tumor cells and staining intensity was assessed by two pathologists. Results Median age at diagnosis was 50 years [range 22–84]. Most pts presented with T2 (52.6%), N1 (53.9%) stage, with a median tumor size of 40mm [range 0-150mm] as determined on clinical examination. Tumors were mainly invasive ductal of no special type (93.8%), of histological grade III (50%) and II (45%), ER+ (54.4%). Breast conserving surgery with free margins was achieved in 50.9% of pts. pCR (breast Sataloff TA) was observed in 53% of pts, and in 47.6% when considering both breast and lymph node response. Out of the 274 pts, 257 had sufficient tumor on the initial biopsy for biomarker analysis. Preliminary results showed a median eIF4E IRS of 6 [range 1-12], with 52.1% of cases displaying a low eIF4E expression level (IRS£6). The agreement for inter-observer assessment of eIF4E status was good (k = 0.618, 95% CI [0.523-0.713]). Scoring of p-4EBP1 and pS6 are ongoing and correlations of pCR with eIF4E/4EBP1 axis will be presented. Conclusion In this large multicentre retrospective study, the rate of pCR obtained in neoadjuvant setting of HER2+ BC is similar to those described in the literature. Thorough tumor collection allows biomarkers analysis, which has been specifically focused on downstream effectors of the PI3K/Akt/mTOR pathway. Reference[1] Zindy P, Bergé Y, Allal B et al. Formation of the eIF4F translation-initiation complex determines sensitivity to anticancer drugs targeting the EGFR and HER2 receptors. Cancer Res. 2011;71(12):4068-73. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-14-13.