A large collection of integrated genomically characterized patient‐derived xenografts highlighting the heterogeneity of triple‐negative breast cancer

Abstract

Triple‐negative breast cancer (TNBC) represents 10% of all breast cancers and is a very heterogeneous disease. Globally, women with TNBC have a poor prognosis, and the development of effective targeted therapies remains a real challenge. Patient‐derived xenografts (PDX) are clinically relevant models that have emerged as important tools for the analysis of drug activity and predictive biomarker discovery. The purpose of this work was to analyze the molecular heterogeneity of a large panel of TNBC PDX (n = 61) in order to test targeted therapies and identify biomarkers of response. At the gene expression level, TNBC PDX represent all of the various TNBC subtypes identified by the Lehmann classification except for immunomodulatory subtype, which is underrepresented in PDX. NGS and copy number data showed a similar diversity of significantly mutated gene and somatic copy number alteration in PDX and the Cancer Genome Atlas TNBC patients. The genes most commonly altered were TP53 and oncogenes and tumor suppressors of the PI3K/AKT/mTOR and MAPK pathways. PDX showed similar morphology and immunohistochemistry markers to those of the original tumors. Efficacy experiments with PI3K and MAPK inhibitor monotherapy or combination therapy showed an antitumor activity in PDX carrying genomic mutations of PIK3CA and NRAS genes. TNBC PDX reproduce the molecular heterogeneity of TNBC patients. This large collection of PDX is a clinically relevant platform for drug testing, biomarker discovery and translational research.

Copy Number Variation in Triple Negative Breast Cancer Samples Associated with Lymph Node Metastasis

“…The most frequent ampli cation in LNmets was in chromosomal regions 4q, 2p, 3q24, 1q, 10p, 12p, 8q, 20p, 21q and 6p, whereas deletions were identi ed in 1p, 4q (4q21.1, 4q26) and 5q. Similar to our results, other studies have also found frequent ampli cation in 1q, 3q, 8q, 10p and 12p and deletion in 5q and 17p in TNBC (33,34) suggesting these CNV regions may have a signi cant role in increasing genomic aberrations in TNBC.…”

Combination of PI3K and MEK inhibitors yields durable remission in PDX models of PIK3CA-mutated metaplastic breast cancers

“…In our cohort of 64TNBC PDX models (the description of the first 61 PDX were recently published [22]), nine displayed metaplastic differentiation (14%) ( Table 1). Three displayed fusiform differentiation, three had squamous characteristics, and three had mixed components (chondroid-fusiform or squamous-fusiform).…”

“…We analyzed 64 PDXs by the targeted NGS of 95 genes, chosen from the genes most frequently mutated in breast cancer (> 1%) and including potential therapeutic targets, as previously described [22]. Briefly, NGS was performed on an Illumina HiSeq 2500 sequencer, and the genomic variants were annotated with the COSMIC and 1000 genome databases.…”

Patient-Derived Xenograft Models of Breast Cancer and Their Application

“…Triple negative subtypes have the worst prognosis and show no therapeutic targets at the moment. As therapeutic strategies differ among these subtypes, the development of all types of PDX models is needed [2,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67] (Table 2).…”