Abstract 1467: Feasibility and relevance of “animal clinical trials” using breast cancer patient-derived xenografts (PDX) in mice
Authors: Lewis Michael T. , Dobrolecki Lacey E. , Petrovic Ivana , Hilsenbeck Susan G. 
Published: August 2015

Background: Clinical oncology trials in humans have major limitations, including high cost, long duration, the frequent inability to use untreated patients as controls, the inability to predict treatment response prospectively, the inability to treat a single tumor with multiple drugs simultaneously to identify the most effective treatment options, and the inability to evaluate drug sequencing efficiently. In theory, these limitations can be overcome using an “animal clinical trial” platform that exploits collections of human cancer patient-derived xenograft (PDX) model.

Clinically, breast cancers are divided into three distinct groups: those that express the estrogen hormone receptor (ER+) (which typically also express the progesterone hormone receptor (PR+), those that are amplified or overexpress the ErbB2 (HER2) oncogene (HER2+), and those that express none of these three markers (termed “triple negative” breast cancer TNBC).

Unlike ER+ and HER2+ breast cancers, there are currently no targeted therapies against TNBC. Treatment of TNBC entails surgery coupled with radio- or chemotherapy, or both. Chemotherapy options include Taxanes (e.g. Docetaxel, Paclitaxel), Anthracyclin based therapies (Adriamycin/Doxorubicin plus Cytoxan (cyclophosphamide) (AC), and more recently, and platinum-based agents (e.g. Cisplatin, Carboplatin). However, treatment decisions are not guided by a molecular diagnostic, but instead represent “best guesses” by the clinician.

Given that these three agents kill dividing cancer cells via three different molecular mechanisms, we hypothesized that any given patient might respond to only one of these three agents. If so, patients may needlessly receive ineffectual treatment simply because it is not possible to predict ahead of time which patient is most likely to respond to which chemotherapeutic agent.

Materials and Methods: We tested this hypothesis in an “animal clinical trial” using 20 PDX treated with three chemotherapies vs. control.

Results: We show that animal clinical trials are feasible, and can be conducted efficiently, using minimal staff. Further, we extend our previous analysis showing that treatment responses observed clinically are recapitulated in the PDX lines, thereby establishing clinical relevance of observed responses. Finally, we demonstrate that PDX show largely non-overlapping sensitivity to only one of the three agents tested.

Conclusions: Together, these data suggest that PDX models can be useful for generating predictors of treatment response. Ultimately, if robust genetic, epigenetic, or molecular predictors of differential treatment response can be identified and applied clinically, it may be possible to avoid ineffective treatments, minimize exposure to cytotoxic agents, and ultimately increase survivorship.

Citation Format: Michael T. Lewis, Lacey E. Dobrolecki, Ivana Petrovic, Susan G. Hilsenbeck. Feasibility and relevance of “animal clinical trials” using breast cancer patient-derived xenografts (PDX) in mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1467. doi:10.1158/1538-7445.AM2015-1467