Animal models for exploring the pharmacokinetics of breast cancer therapies

Abstract

Introduction Despite massive expenditures in research and development to cure breast cancer, few agents that pass preclinical trials demonstrate efficacy in humans. Although this endeavor relies on murine models to screen for efficacy before progressing to clinical trials, historically there has been little focus on the validation of these models, even in the era of targeted therapy where understanding the genetic signatures of tumors under study is critical. Areas covered This review includes the transgenic, xenograft, and syngeneic murine breast cancer models, the ectopic, orthotopic and intravenous methods of cell implantation, and the ethics of animal experimentation. It also includes the latest data on tumor gene expression and the issues to consider when exploring the pharmacokinetics and efficacy of breast cancer therapies. Expert opinion Breast cancer drug development is expensive and inefficient without a consensus preclinical murine model. Investigators must approach the choice of murine model with the same sophistication that is applied to the choice of in vitro assays to improve efficiency. Understanding the limitations of each model available, including the nuances of tumor gene signatures, is critical for investigators exploring the phamacokinetics and efficacy of breast cancer therapies, especially in the context of gene profiling and individualized targeted therapy.

Murine breast cancer mastectomy model that predicts patient outcomes for drug development

“…Although billions of US dollars have been invested in treating breast cancer, large portions of these investments have been lost in efforts that have failed to deliver (2, 3). Given the huge cost required for human clinical trials that a drug needs to pass to prove its efficacy for patients, it is conducted only for drugs that show significant promise in preclinical animal experiments (2).…”

“…Although billions of US dollars have been invested in treating breast cancer, large portions of these investments have been lost in efforts that have failed to deliver (2, 3). Given the huge cost required for human clinical trials that a drug needs to pass to prove its efficacy for patients, it is conducted only for drugs that show significant promise in preclinical animal experiments (2). However, despite these efforts, most drugs that passed murine studies still failed in human clinical trials (4), which at least partly can be explained by the use of murine models that do not represent human conditions (2).…”

“…Given the huge cost required for human clinical trials that a drug needs to pass to prove its efficacy for patients, it is conducted only for drugs that show significant promise in preclinical animal experiments (2). However, despite these efforts, most drugs that passed murine studies still failed in human clinical trials (4), which at least partly can be explained by the use of murine models that do not represent human conditions (2). In order to predict the outcome of human clinical trials, murine models for preclinical study need to reproduce the condition of human cancer (2, 3, 5, 6).…”

“…To date, the most commonly used murine breast cancer models evaluate drug efficacy against primary tumors, either in orthotopic (mammary pads) or ectopic sites (subcutaneous tissues) (2, 3, 5, 6). Although drugs are sometimes used in humans as a neoadjuvant therapy to treat the primary breast tumor, the vast majority is used as adjuvant therapy where drugs are given after surgery to reduce the risk of recurrence by treating undetectable remaining or metastatic cancer (2, 3, 5).…”

Congenic and functional analysis of rat mammary cancer susceptibility.

“…Different approaches (e.g. cell culture studies, animal model based studies, and genome wide association studies) are being used to study breast cancer, each with its own advantages and disadvantages [157,187,188].…”