Patient-derived xenograft models of breast cancer and their predictive power

Abstract

Despite advances in the treatment of patients with early and metastatic breast cancer, mortality remains high due to intrinsic or acquired resistance to therapy. Increased understanding of the genomic landscape through massively parallel sequencing has revealed somatic mutations common to specific subtypes of breast cancer, provided new prognostic and predictive markers, and highlighted potential therapeutic targets. Evaluating new targets using established cell lines is limited by the inexact correlation between responsiveness observed in cell lines versus that elicited in the patient. Patient-derived xenografts (PDXs) generated from fresh tumor specimens recapitulate the diversity of breast cancer and reflect histopathology, tumor behavior, and the metastatic properties of the original tumor. The high degree of genomic preservation evident across primary tumors and their matching PDXs over serial passaging validate them as important preclinical tools. Indeed, there is accumulating evidence that PDXs can recapitulate treatment responses of the parental tumor. The finding that tumor engraftment is an independent and poor prognostic indicator of patient outcome represents the first step towards personalized medicine. Here we review the utility of breast cancer PDX models to study the clonal evolution of tumors and to evaluate novel therapies and drug resistance.

Figure 1

Derivation of patient-derived xenograft models of human breast cancer in mice. Tumor slices are implanted into the cleared inguinal fat pad of mice (MFP) concurrently with a subcutaneous estradiol pellet. Following growth of the tumor in passage 1 (T1), a single-cell suspension or tumor fragments can be prepared for sequential passage of the tumor. It is advisable to prepare frozen aliquots of cell suspensions or tumor fragments at T1 and T2, as a source of early passage tumor.

Figure 2

Evaluation of response of primary tumor and its metastases using patient-derived xenograft models. Upper panel: A cohort of immunocompromised mice are divided into two arms and treated with either vehicle or drug A. A relapsed tumor can be passaged in mice to generate a resistant tumor line for genomic and gene expression analyses. Lower panel: Genomic and expression profiling of the primary tumor and metastasis (for example, the lung) may identify potential therapeutic targets for metastasis. In the case shown, drug X eradicated the primary tumor but not all metastases. CNA, copy number alterations; Tx, treatment.

Figure 3

Idealized personalized medicine strategy integrating data from mouse patient-derived xenograft models with patient treatment. Rather than directly assigning breast cancer patients to standard therapy, patients are treated on the basis of genomic and gene expression analyses. Blood from the patient is used as a reference for copy number alteration (CNA) analysis. In parallel, tumor fragments are xenografted into mice to establish a patient-derived xenograft (PDX) model. The patient tumor and their corresponding PDX tumor at transplant 3 (T3) undergo comparative genomic and gene expression analyses. Mice are treated with inhibitors (chemotherapy, antibodies or small molecules) based on initial genetic analysis of the patient tumor, in order to identify/validate the agents to be used for clinical treatment and to identify refractory tumors. If relapse occurs, re-biopsy and analysis of the metastatic/recurrent tumor together with the refractory PDX model could be used to reveal pathway activation. A database of mutations, expression profiles, and tumor response from multiple patients can be created to guide therapy for future patients. Rx, treatment of patient.