Ability to Generate Patient-Derived Breast Cancer Xenografts Is Enhanced in Chemoresistant Disease and Predicts Poor Patient Outcomes

Abstract

BackgroundBreast cancer patients who are resistant to neoadjuvant chemotherapy (NeoCT) have a poor prognosis. There is a pressing need to develop in vivo models of chemo resistant tumors to test novel therapeutics. We hypothesized that patient-derived breast cancer xenografts (BCXs) from chemo- naïve and chemotherapy-exposed tumors can provide high fidelity in vivo models for chemoresistant breast cancers.MethodsPatient tumors and BCXs were characterized with short tandem repeat DNA fingerprinting, reverse phase protein arrays, molecular inversion probe arrays, and next generation sequencing.ResultsForty-eight breast cancers (24 post-chemotherapy, 24 chemo-naïve) were implanted and 13 BCXs were established (27%). BCX engraftment was higher in TNBC compared to hormone-receptor positive cancer (53.8% vs. 15.6%, p = 0.02), in tumors from patients who received NeoCT (41.7% vs. 8.3%, p = 0.02), and in patients who had progressive disease on NeoCT (85.7% vs. 29.4%, p = 0.02). Twelve patients developed metastases after surgery; in five, BCXs developed before distant relapse. Patients whose tumors developed BCXs had a lower recurrence-free survival (p = 0.015) and overall survival (p<0.001). Genomic losses and gains could be detected in the BCX, and three models demonstrated a transformation to induce mouse tumors. However, overall, somatic mutation profiles including potential drivers were maintained upon implantation and serial passaging. One BCX model was cultured in vitro and re-implanted, maintaining its genomic profile.ConclusionsBCXs can be established from clinically aggressive breast cancers, especially in TNBC patients with poor response to NeoCT. Future studies will determine the potential of in vivo models for identification of genotype-phenotype correlations and individualization of treatment.

Conditional reprogramming and long-term expansion of normal and tumor cells from human biospecimens

“…Furthermore, CR cultures make an in-depth analysis of tumor heterogeneity possible, as they preserve the cellular diversity of tumors. Finally, CR cell cultures can be generated from xenograft and organoid tissue, suggesting that these three platforms can work in synergy to advance research into both normal and cancer cell biology using primary human-tissue-derived cells 51 .…”

A Population of Heterogeneous Breast Cancer Patient-Derived Xenografts Demonstrate Broad Activity of PARP Inhibitor in BRCA1/2 Wild-Type Tumors

“…More recently, these TNBC subtypes have been further narrowed to 4 major subtypes by excluding the IM and MSL subtypes due to their strong overlap with immune cells (IM) and tumor stroma (MSL) gene expression, respectively (13). We reclassified the PDXs based on this report by classifying those models in the IM or MSL subtype to the subtype with the next highest correlation (Supplementary Table 3).…”

“…Following collection, the first 13 PDXs were established by implanting tumor fragments to the flank of nude mice as previously described (13). The latter models were established using a similar surgical procedure but involved placing the fragment on the bilateral 4 th mammary fat pads of female nude mice (Department of Radiation Oncology-MD Anderson Cancer Center) or NOD.Cg-Prkdcscid Il2rgtm1Sug/JicTac (Taconic).…”

“…The sequencing procedure and genes included in the T200 panel have been previously reported (T200 panel contained 202 genes, and T200.1 included 264 genes) (16). T200 data for BCX.006, BCX.010, BCX.011, BCX.017, BCX.022, and BCX.024 has been previously published (13). …”

Heterogeneous perivascular cell coverage affects breast cancer metastasis and response to chemotherapy

“…The methodology to generate the PDX (also referred to herein as the BCX) has been previously described (58). Briefly, surgically resected breast tumors were cut into 3-mm 3 fragments and inserted into the subcutaneous space on the flank or mammary gland of immune-deficient mice.…”