Background: Little is known about the mechanisms of resistance to trastuzumab (T). We investigated markers which may indicate resistance to trastuzumab in a cohort of HER2 positive patients treated in a neoadjuvant phase 3 trial.

Patients and methods: In the neoadjuvant GeparQuattro trial 1495 patients with operable and locally advanced tumors were randomized to 3 different chemotherapy regimens (4 x EC ≥4 x docetaxel (D) vs 4 x EC ≥4 x D/capecitabine (C) vs 4 x EC ≥4x D ≥4 X C). All HER2 positive patients (n=445 assessed by local testing) received trastuzumab concurrently with chemotherapy. 216 pretherapeutic core biopsies were available for tissue microarrays (TMA). For this evaluation only cases with sufficient tumor tissue on TMA (>30%) and positive HER2 status by central reassessment (IHC and CISH) were used (n=153). Expression of different markers possibly associated with resistance to T-based treatment were immunohistochemically (IHC) investigated. Marker expression was assessed with Immunoreactive-Score (IRS) combining intensity and % of positive cells. Resistance to treatment was defined as minimal or no microscopic changes in surgically excised tumor tissue (regression grade RG 0-1 according to Sinn et al).

Results: The 153 centrally HER2 positive cases were taken for analysis. Median age was 49 years (22-78). Clinical T stadium was T1,2,3,4a-c/4d in 3%/70%/11%/8%/8% respectively, 59%/41% of these tumors were G2/G3; 51% hormone receptor (HR) positive. 44 (29%) did not show any response to treatment (RG 0-1) indicating resistance. In the chi2 test (2-sided) the following parameters were significantly associated with resistance (RG0- 1) to combined trastuzumab-cytotoxic therapy: insulin like growth factor receptor-1 (IGFR-1; IRS >3 resistant; p=0.029, insulin receptor (IR: IRS >1 resistant; p=0.028), Notch1(IRS>8 resistant; p= 0.037), ALDH1(IRS > 4 resistant; p=0.001), p4E-BP1 (IRS> 4resistant; p =0.017), p27 (IRS > 4 resistant; p=0.032). In multivariable testing (backward selection) ALDH 1 (OR 6.65 95%CI 1.78-24.76; p= 0.005) and p4E-BP1 (OR 3.2595% CI 1.36-9.06 p=0.009) remained significantly associated with resistance to trastuzumab containing therapy.

Univariate and multivariate analysis for resistance markers to trastuzumab

Conclusions: Our results suggest that an activated mTOR pathway characterized by increased levels of p4EBP1 and stem cell features described by enhanced ALDH1 expression are involved in resistance to trastuzumab containing treatment in primary HER2 positive breast cancer. These resistance markers will be validated in the neoadjuvant GeparQuinto trial investigating in a randomized design the effect of trastuzumab compared to lapatinib in HER2 positive primary breast cancer patients in addition to EC-D.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD02-06.