Abstract C74: Establishment and characterization of a HER2-positive, TDM1-resistant PDX breast model
Authors: Wick Michael J. , Vaught Teresa L. , Meade Justin , Farley Monica , Diaz Armando , Tolcher Anthony W. , Rasco Drew W. , Patnaik Amita , Beeram Murali , Papadopoulos Kyriakos P. 
Published: May 2016

Background: Ado-trastuzumab emtansine (T-DM1), a recently approved antibody-drug conjugate (ADC), is approved for treatment of high HER2 expressing (3+), trastuzumab resistant breast and gastric cancers. While this agent is effective, resistance often develops. To better understand the mechanisms for resistance to TDM1 in high HER2 expressing breast cancer we collected tissue from a patient following response and progression to TDM1 and established a xenograft model for preclinical drug screening. The resulting model ST1360B was genomically characterized and screened in vivo using high dose TDM1; anti-tumor activity was compared with two trastuzumab-resistant but TDM-1 sensitive HER2 (3+) breast PDX models designated ST225 and ST340.

Methods: The high HER2 expressing (3+) TDM1 resistant breast PDX model ST1360B was established in athymic mice using pleural fluid collected from a thoracentesis. Establishment of the HER2 (3+) ST225 and ST340 models has been previously described. Clinical and PDX tissues were subjected to genomic analysis; for each model, DNA was extracted and subjected to comparative genomic hybridization and exon sequencing of known oncogenes; growth factor receptor and ligand densities was interrogated using immunohistochemistry. Drug sensitivity studies were performed evaluating sensitivity of models to single agent T-DM1, administered intravenously at 10 mg/kg on Day 0; weekly TDM1 dosing at 5 mg/kg was also evaluated in the ST1360B model Study endpoints included tumor volume and time from treatment initiation with tumor growth inhibition, delay and regression reported at study completion.

Results: Genomic analysis of ST1360B identified amplified HER2 and TOP2A; interestingly CD44 was found highly amplified, suggesting a possible mechanism for TDM1 resistance in this model. Mutations were not identified in PIK3CA or other relevant genes. In efficacy studies TDM1 was confirmed active towards ST225 and ST340 model including tumor regressions and durable complete responses in both models (TGI&gt;100%). However TDM1 was not effective in ST1360B, with only transient tumor growth inhibition even with weekly drug administration.

Conclusion: We have established a model of TDM1 HER2 3+ resistant breast cancer and have characterized the model using comparative genomic hybridization and exon sequencing of known oncogenes, identifying amplified CD44 as a potential mechanism for drug resistance. This model can be utilized to better understand and to develop novel therapies to TDM1 resistance.

Citation Format: Michael J. Wick, Teresa L. Vaught, Justin Meade, Monica Farley, Armando Diaz, Anthony W. Tolcher, Drew W. Rasco, Amita Patnaik, Murali Beeram, Kyriakos P. Papadopoulos. Establishment and characterization of a HER2-positive, TDM1-resistant PDX breast model. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C74.