Daniel Ciznadija, PhD1, Amir Sonnenblick, PhD2, Jennifer Jaskowiak, PhD1, Angela Davies, PhD1, and David Sidransky, PhD3
1Champions Oncology, Baltimore, USA. 2 Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem Israel. 3 Johns Hopkins University School of Medicine, Baltimore, USA
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.
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.
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.