A Novel Patient-Derived Xenograft Model of Inflammatory Breast Cancer.

Few models exist for studying experimental therapeutics in inflammatory breast cancer (IBC). Our study objective was to characterize a novel patient-derived xenograft (PDX) from a HER2 positive IBC patient refractory to neoadjuvant chemotherapy. We derived a novel PDX from a patient with hormone receptor negative, HER2-positive IBC refractory to neoadjuvant chemotherapy with Docetaxel, Carboplatin, Trastuzumab, and Pertuzumab (TCHP). Tumor was implanted into NOD/SCID/γ mice (NSG) and used for serial propagation of PDX. We performed short-tandem repeat (STR) profiling, plotted tumor growth curves for mice treated with alpelisib/everolimus vs. untreated, and immunohistochemistry (IHC), and performed clinical genomic assays. Paired Student's t-tests were used to compare tumor growth curves. We used 10X Genomics for single cell transcriptome analysis of 1000 cells derived from the PDX. ctDNA sequencing revealed amplifications in MYC, ERBB2 (HER2), androgen receptor (AR), PIK3CA, vMYB and loss of CDKN2A. Tumor sequencing found a H1047R mutation in PIK3CA. STR profiling showed the propagated PDX tumor matched the original tumor. The engraftment rate was 12/15 (80%) and median tumor volume doubling was 24.5 days (range 9.2-175 days) for n = 15 untreated controls. Alpelisib plus everolimus decreased tumor growth in our PDX (p = 0.006). TCHP-resistant tumor cells downregulated HER2 expression, which was re-expressed after treatment with alpelisib and everolimus. We established a PDX of a HER2-positive IBC tumor with a PIK3CA hotspot mutation (H1047R) refractory to TCHP. Targeting the PI3K/mTOR pathway may be useful to overcome resistance in HER2-positive IBC with a H1047R mutation in PIK3CA.