Abstract 1836: Patient-derived xenograft (PDX) models expressing HER2 reflect clinical responses to targeted HER2 inhibition
Authors: Ciznadija Daniel , Sonnenblick Amir , Jaskowiak Jennifer , Davies Angela , Sidransky David 
Published: July 2017

Background While HER2-directed agents are most often used for treating breast cancer, there is increasing evidence that these therapies may be of value in other solid tumors. Sequencing efforts and immunohistochemistry (IHC) have identified mutations, amplifications, and overexpression of HER2 in ovarian, HNSCC, NSCLC, and GI cancers. PDX models could permit evaluation of HER2 response/resistance mechanisms to optimize therapeutic strategies. In this pilot study, we evaluated the response of PDX models to HER2-targeted therapies and correlated responses to clinical outcomes.

Materials and Methods PDX models were developed from a variety of patient solid tumors, evaluated by IHC for HER2 expression and next-generation sequencing for genomic alterations in HER2 (mutations, amplifications/deletions, and expression levels). Models were screened against single agent HER2-directed therapies including trastuzumab (n=15), trastuzumab emtansine (n=23), and lapatinib (n=10). Tumor regression (TR) values and RECIST criteria were determined and correlated with known literature-based response rates (RR) as well as individual patient outcomes.

Results 32 PDX models from 30 patients were interrogated (primarily breast and colorectal). Twenty (63%) models have been sequenced to date; 13 (65%) harbor amplification at ERBB2 gene locus. Further, 56% (18/32) have been evaluated by IHC for HER2 to date: 50% have 2+ HER2 staining, 17% 3+ staining, and 33% 1+/- staining. Based on PDX tumor growth, stable disease/regression was observed in 10% of models screened against lapatinib (CR/PR=0%), 50% screened against trastuzumab (CR/PR=8%), and 67% tested against trastuzumab emtansine (CR/PR=14%). Only models with +2/+3 HER2 staining showed regression with HER2-targeted treatment, with nearly 70% of +1/- HER2 models showing progressive disease. Finally, there were 4 correlations to patient clinical outcomes available, with 3/4 (75%) of the PDX model responses mimicking those of the patient to the same treatment.

Conclusion and Future Directions Extensive sequencing of human cancers has demonstrated HER2 amplification or mutation in numerous solid tumors, suggesting HER2-directed therapy could be applied more broadly in the clinic. Consistent with clinical findings, HER2 therapy responses depended upon the strength of HER2 expression (based on IHC). Nevertheless, response rates in PDX models varied depending on which HER2-targeted agent was deployed, highlighting the potential existence of differential mechanisms of de novo resistance/sensitivity. Comprehensive sequencing and drug testing of these PDX models is planned and could allow a deeper understanding of such mechanisms. In this context, application of PDX models for translational modeling of HER2 drug responses, particularly in the context of co-clinical trials, will continue to evolve.

Citation Format: Daniel Ciznadija, Amir Sonnenblick, Jennifer Jaskowiak, Angela Davies, David Sidransky. Patient-derived xenograft (PDX) models expressing HER2 reflect clinical responses to targeted HER2 inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1836. doi:10.1158/1538-7445.AM2017-1836