Abstract C104: Preclinical sensitivity of low and high-HER2 expressing START-PDX breast models to T-DM1 and effects of HER3 expression on drug antitumor activity.
Authors: Wick Michael J. , Brown Jennifer , Vaught Teresa L. , Meade Justin , Tolcher Anthony W. , Rasco Drew , Patnaik Amita , Lang Amy , Beeram Murali , Papadopoulos Kyriakos P. 
Published: August 2014

Background: Ado-trastuzumab emtansine (T-DM1), a recently approved antibody-drug conjugate (ADC), is comprised of the monoclonal antibody trastuzumab linked to the cytotoxic agent mertansine. Trastuzumab targets and inhibits growth of HER2/neu-receptor expressing tumors and mertansine enters and kills the cells by binding to tubulin. Trastuzumab alone is sufficient to effectively treat high (3+) HER2-expressing breast cancers; however, whether T-DM1 is effective in lower HER2-expressing cancers is unclear. To better understand how HER-2 expression correlates with activity of trastuzumab or T-DM1 we characterized HER2 expression in our START-PDX breast panel and screened trastuzumab and T-DM1 efficacy in each model. Study endpoints included tumor volume and time from treatment initiation. Reported results included tumor growth inhibition or delay and regression.

Methods: Methods: START-PDX breast models were established in immune-deficient mice from primary or metastatic patient tissue and once established were confirmed by histologic comparative analysis and linked with patient treatment and outcome data. For each model, DNA was extracted and subjected to exon sequencing of 207 known oncogenes; growth factor receptor and ligand densities were interrogated using immunohistochemistry and quantitative RNA in situ hybridization. Drug sensitivity studies were performed evaluating sensitivity of models to single agent trastuzumab and T-DM1, administered for at least four weeks. Study endpoints included tumor volume and time from treatment initiation with tumor growth inhibition, delay and regression reported at study completion.

Results: HER2 or HER3 and comparative heregulin expression occurred in 67% of models. EGFR expression was reported in 50% of models Efficacy studies revealed T-DM1 but not trastuzumab was active both in several high- and low-HER2 expressing models. Interestingly, models reporting higher T-DM1 sensitivity had no detectable HER3 expression. For example ST996 and ST910 showed similar HER2 and EGFR expression but ST996 (HER3 3+) was insensitive to T-DM1 whereas ST910 (HER3 0+) reported significant tumor growth inhibition compared with control.

Conclusion: We have established a panel of breast PDX models and characterized mutation status, receptor and ligand density and drug sensitivity. We found T-DM1 active towards a number of breast PDX models even with low HER2 expression. HER3 co-expression may serve as a negative predictor for T-DM1 activity.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C104.

Citation Format: Michael J. Wick, Jennifer Brown, Teresa L. Vaught, Justin Meade, Anthony W. Tolcher, Drew Rasco, Amita Patnaik, Amy Lang, Murali Beeram, Kyriakos P. Papadopoulos. Preclinical sensitivity of low and high-HER2 expressing START-PDX breast models to T-DM1 and effects of HER3 expression on drug antitumor activity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C104.