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Published on: February 4, 2021
A Novel Patient-Derived Xenograft Model of Inflammatory Breast Cancer
Princess Ekpo1, Monica Khattak2, Tiffany Cheung2
1Cleveland Clinic Lerner Research Institute, Cleveland Clinic Lerner School of Medicine.
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
Insights
A new patient-derived xenograft (PDX) model of HER2-positive inflammatory breast cancer (IBC) was created. This model, refractory to chemotherapy, showed that targeting the PI3K/mTOR pathway may overcome treatment resistance in HER2-positive IBC.
Area of Science:
- Oncology
- Translational Research
- Genomics
Background:
- Inflammatory breast cancer (IBC) lacks adequate models for experimental therapeutics.
- A novel patient-derived xenograft (PDX) was developed from a HER2-positive IBC patient resistant to neoadjuvant chemotherapy.
Purpose of the Study:
- To characterize a new PDX model of HER2-positive IBC.
- To evaluate therapeutic strategies targeting resistance mechanisms.
Main Methods:
- Established a PDX model from a chemotherapy-refractory IBC patient.
- Performed short-tandem repeat (STR) profiling, tumor growth analysis, immunohistochemistry (IHC), and clinical genomic assays.
- Utilized 10X Genomics for single-cell transcriptome analysis.
Main Results:
- The PDX model accurately reflected the original tumor's genetic profile, including PIK3CA H1047R mutation and HER2 amplification.
- Alpelisib plus everolimus significantly reduced tumor growth in the PDX model (p=0.006).
- TCHP-resistant cells downregulated HER2, which was restored by alpelisib/everolimus treatment.
Conclusions:
- A functional PDX model for HER2-positive, PIK3CA-mutated IBC refractory to TCHP was successfully established.
- Targeting the PI3K/mTOR pathway presents a potential strategy to overcome resistance in this IBC subtype.
