Background: Breast cancer (BC) is a clinically and molecularly heterogeneous disease where tailoring therapy to specific tumor subtypes is a focus of today's clinical developments. The availability of relevant preclinical models replicating BC's molecular diversity is therefore of crucial importance for the success of IND translation to the clinic. We present a collection of 34 BC tumor xenografts established directly onto Nude mice from patients' tumor sample for in vivo preclinical evaluation of drug efficacy. These in vivo models reproduce accurately the molecular and drug response profile of human tumors, and provide an invaluable tool for translational research. Methods: Post-surgery tumor specimens were transplanted either by grafting tumor fragments in the interscapular region of nude mice or by injection of tumor cells into the fat pad of NOD-Scid mice; this fat pad being previously cleared of murine gland and humanized by injection of normal human fibroblasts. BC xenografts were amplified by serial transplantation, and tissue samples were retained at each passage for comparison with the patient's tumor. Molecular analyses included gene expression (Affymetrix® Hu133), gene copy number (Affymetrix® Human Genome 6.0) and IHC markers on FFPE samples. In vivo drug efficacy assays were performed with standards of care as single agent or in combinations. Results: Among the 34 BC xenografts, 32 are ductal carcinoma, 2 lobular carcinomas and among them 4 are inflammatory breast cancers. Twenty two tumors express low or no hormone receptors and do not overexpress ERBB2, they can be considered as triple-negative tumors. Five tumors overexpress ERBB2, one of which also express hormonal receptors. Seven tumors express both estrogen and progesterone receptors and do not overexpress ERBB2, they can thus be considered as luminal-like tumors. Hence, this panel mostly reflects the molecular heterogeneity of breast cancer. To confirm this further, tumorgraft gene expression data were crossed with patient datasets, and hierarchical clustering was performed by using patient-derived gene lists that stratify breast cancer according to molecular phenotype. This analysis showed that breast cancer tumorgrafts evenly distributed among human samples and properly classified within the molecular subtypes corresponding to their histopathological features. A panel of standard chemotherapies was tested in vivo (adriamycin/cyclophosphamide, capecitabine, docetaxel, trastuzumab and lapatinib) to generate a profile of drug sensitivity for each model. Conclusion: This panel of 34 BC xenografts allows preclinical assays in clinically relevant models encompassing the molecular diversity of BC. Its broadness and extensive molecular characterization will also be useful to identify molecular determinants of drug response. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B11.
Abstract B11: A panel of patient-derived xenografts for preclinical efficacy studies in various breast cancer molecular subtypes
Stefano Cairo;
2011
Abstract
Background: Breast cancer (BC) is a clinically and molecularly heterogeneous disease where tailoring therapy to specific tumor subtypes is a focus of today's clinical developments. The availability of relevant preclinical models replicating BC's molecular diversity is therefore of crucial importance for the success of IND translation to the clinic. We present a collection of 34 BC tumor xenografts established directly onto Nude mice from patients' tumor sample for in vivo preclinical evaluation of drug efficacy. These in vivo models reproduce accurately the molecular and drug response profile of human tumors, and provide an invaluable tool for translational research. Methods: Post-surgery tumor specimens were transplanted either by grafting tumor fragments in the interscapular region of nude mice or by injection of tumor cells into the fat pad of NOD-Scid mice; this fat pad being previously cleared of murine gland and humanized by injection of normal human fibroblasts. BC xenografts were amplified by serial transplantation, and tissue samples were retained at each passage for comparison with the patient's tumor. Molecular analyses included gene expression (Affymetrix® Hu133), gene copy number (Affymetrix® Human Genome 6.0) and IHC markers on FFPE samples. In vivo drug efficacy assays were performed with standards of care as single agent or in combinations. Results: Among the 34 BC xenografts, 32 are ductal carcinoma, 2 lobular carcinomas and among them 4 are inflammatory breast cancers. Twenty two tumors express low or no hormone receptors and do not overexpress ERBB2, they can be considered as triple-negative tumors. Five tumors overexpress ERBB2, one of which also express hormonal receptors. Seven tumors express both estrogen and progesterone receptors and do not overexpress ERBB2, they can thus be considered as luminal-like tumors. Hence, this panel mostly reflects the molecular heterogeneity of breast cancer. To confirm this further, tumorgraft gene expression data were crossed with patient datasets, and hierarchical clustering was performed by using patient-derived gene lists that stratify breast cancer according to molecular phenotype. This analysis showed that breast cancer tumorgrafts evenly distributed among human samples and properly classified within the molecular subtypes corresponding to their histopathological features. A panel of standard chemotherapies was tested in vivo (adriamycin/cyclophosphamide, capecitabine, docetaxel, trastuzumab and lapatinib) to generate a profile of drug sensitivity for each model. Conclusion: This panel of 34 BC xenografts allows preclinical assays in clinically relevant models encompassing the molecular diversity of BC. Its broadness and extensive molecular characterization will also be useful to identify molecular determinants of drug response. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B11.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
