Abstract P4-15-06: Correlation between ERBB2 mRNA levels, HER2-dependence and susceptibility to trastuzumab in human breast cancer

Abstract

Abstract While results thus far demonstrate the clinical benefit of trastuzumab in breast cancer, some patients do not respond to this reagent. Identifying a robust clinical or molecular predictor of adjuvant trastuzumab benefit has proven challenging and even the most obvious candidate biomarker for a predictor of trastuzumab benefit, HER2 expression as assessed by immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH), has proven to be surprisingly ambiguous in realizing benefit from the antibody. Results of a recent study that profiled expression of select genes in archived formalin-fixed, paraffin-embedded (FFPE) tumor blocks from a randomized study of breast cancer patients treated with adjuvant trastuzumab support a relationship between ERBB2/ESR1 mRNA levels and trastuzumab sensitivity. Based on that observation, we conducted whole-genome profiling by DASL technology of archival FFPE tumor blocks from 53 HercepTest 3+/2+ FISH-positive patients treated with adjuvant trastuzumab in our Institute; 308 genes were significantly associated with relapse-free survival by Cox proportional hazard model (α<0.005; permutation test p<0.01). We then developed a relapse risk 41-gene classifier (TRAR) able to discriminate cases mainly according to ERBB2 and ESR1 mRNA expression levels and to predict tumor relapse in both trastuzumab adjuvant and neoadjuvant settings. No correlation was found between ERBB2 mRNA and HER2 protein expression (the latter assessed by IHC on FFPE tumor sections using serial dilutions of anti-HER2 antibody), nor did HER2 protein expression correlate with relapse risk in these tumors. Analysis of HER2-amplified breast carcinoma cell lines revealed higher levels of ERBB2 mRNA in oncogene-addicted than in non-addicted cells in correlation with HER2 activation assed by Western blot but not with total HER2 protein amount. Moreover, ERBB2 mRNA expression levels in HER2-amplified breast carcinoma cells correlated with trastuzumab-mediated cellular cytotoxicity (ADCC) in vitro (r=0.96, p=0.038), whereas no correlation was found between ADCC and membrane-associated HER2. Together, our findings strongly suggest that ERBB2 mRNA, but not protein levels, mirror HER2 activity and thus oncogene addiction of tumor cells and susceptibility to trastuzumab in amplified HER2-positive tumors. Supported by AIRC. Citation Format: Elda Tagliabue, Viola Regondi, Loris De Cecco, Serenella M Pupa, Manuela Campiglio, Maria Luisa Carcangiu, Sylvie Ménard, Tiziana Triulzi. Correlation between ERBB2 mRNA levels, HER2-dependence and susceptibility to trastuzumab in human breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-06.