65O - Generation of mouse models for the identification of new driver pathways of drug resistance in human breast cancer (BC)

Date 08 May 2014
Event IMPAKT 2014
Session Best abstracts session
Topics Basic Science
Breast Cancer
Presenter Carmen Criscitiello
Citation Annals of Oncology (2014) 25 (suppl_1): i23-i24. 10.1093/annonc/mdu070
Authors C. Criscitiello1, A. Cicalese2, D. Bossi3, G. Pruneri4, F. Orsi5, M. Casiraghi6, S. Punzi3, L. Spaggiari6, G. Curigliano1, L. Lanfrancone3
  • 1Early Drug Development For Innovative Therapy Division, European Institute of Oncology, 20141 - Milan/IT
  • 22department Of Experimental Oncology, European Institute of Oncology, 20141 - Milan/IT
  • 3Department Of Experimental Oncology, European Institute of Oncology, 20141 - Milan/IT
  • 4Division Of Pathology, University Of Milan, School Of Medicine, Istituto Europeo di Oncologia, 20141 - Milano/IT
  • 5Unit Of Interventional Radiology, European Institute of Oncology, 20141 - Milan/IT
  • 6Division Of Thoracic Surgery, European Institute of Oncology, 20141 - Milan/IT

Abstract

Background:

We generated patient derived xenograft (PDX) from metastatic BC using fresh tissue biopsy samples obtained from triple negative (TN), HER2 positive (HER2+) and Luminal B (LB) metastatic BC progressing on standard of care. Our aim was to set up an in vivo RNAi screening in PDX to identify genes essential for tumor growth.

Methods:

1) Generation of breast patient-derived xenograft (PDX): metastatic breast tumor samples (3 mm3) have been disaggregated and orthotopically transplanted in the 4th mammary gland of immune-compromised mice to obtain PDX1s. PDX1s have been compared to the original tumors by immunohistochemistry (IHC) analysis, to evaluate whether they can represent an accurate phenocopy of the original tumors. Once PDX1 reached an adequate volume, the mouse was euthanized, the tumor was harvested and then divided for: transplantation into PDX2, genomic analysis, and IHC. 2) Set up of in vivo RNAi screening. 3) Whole exome sequencing. Genomic DNA has been collected from the blood samples of the patients, the metastatic tumor biopsies and the PDX1s and PDX2s. Exome capture was performed by Agilent protocol and sequences analysed by HTS. This study was approved by Institutional Review Board and Ethics Committee of European Institute of Oncology. Written informed consent was obtained from each patient prior to study enrollment.

Results:

Patients with LB, HER2+ and TN metastatic BC undergoing liver, lymph-node or lung biopsies were included. Tumors transplanted in mice grew in 11/22 samples with an engraftment rate of 50%, generating PDX1. The take rate was 47% for LBs, 33% for HER2+ and 75% for TN. Take rate was higher in TNBC than in other subtypes, despite the engraftment rate of LBs in our setting was outstanding as compared to previous data. Tumor latency of patient-derived samples was highly variable.

Conclusions:

Xenograft animal models derived from fresh metastatic tissue biopsy maintained the key characteristic features of the original tumors, suggesting that this in vivo platform can be useful for preclinical development of novel therapeutic approaches to metastatic BC.

Disclosure:

All authors have declared no conflicts of interest.