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. 2019 Dec 10;14(12):e0225082.
doi: 10.1371/journal.pone.0225082. eCollection 2019.

Establishment of chemosensitivity tests in triple-negative and BRCA-mutated breast cancer patient-derived xenograft models

Hyung Seok Park  1 , Jeong Dong Lee  2 , Jee Ye Kim  1 , Seho Park  1 , Joo Heung Kim  1 , Hyun Ju Han  3 , Yeon A Choi  3 , Ae Ran Choi  3 , Joo Hyuk Sohn  4 , Seung Il Kim  1
Affiliations

Establishment of chemosensitivity tests in triple-negative and BRCA-mutated breast cancer patient-derived xenograft models

Hyung Seok Park et al. PLoS One. .

Abstract

Purpose: A patient-derived xenograft (PDX) model is an in vivo animal model which provides biological and genomic profiles similar to a primary tumor. The characterization of factors that influence the establishment of PDX is crucial. Furthermore, PDX models can provide a platform for chemosensitivity tests to evaluate the effectiveness of a target agent before applying it in clinical trials.

Methods: We implanted 83 cases of breast cancer into NOD.Cg-Prkdcscid Il2rgtm1Sug/Jic mice, to develop PDX models. Clinicopathological factors of primary tumors were reviewed to identify the factors affecting engraftment success rates. After the establishment of PDX models, we performed olaparib and carboplatin chemosensitivity tests. We used PDX models from triple-negative breast cancer (TNBC) with neoadjuvant chemotherapy and/or germline BRCA1 mutations in chemosensitivity tests.

Results: The univariate analyses (p<0.05) showed factors which were significantly associated with successful engraftment of PDX models include poor histologic grade, presence of BRCA mutation, aggressive diseases, and death. Factors which were independently associated with successful engraftment of PDX models on multivariate analyses include poor histologic grade and aggressive diseases status. In chemosensitivity tests, a PDX model with the BRCA1 L1780P mutation showed partial response to olaparib and complete response to carboplatin.

Conclusions: Successful engraftment of PDX models was significantly associated with aggressive diseases. Patients who have aggressive diseases status, large tumors, and poor histologic grade are ideal candidates for developing successful PDX models. Chemosensitivity tests using the PDX models provide additional information about alternative treatment strategies for residual TNBC after neoadjuvant chemotherapy.

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Conflict of interest statement

HSP has received honoraria from Aastrazenca, Dakeda, Ethicon, and Intuitive Surgical. JDL, JYK, SP, JHK, HJH, YAC, ARC, JHS, and SIK have nothing to declare. The authors would like to declare the following patents/patent applications associated with this research: Germline Pathogenic Mutation of BRCA1, L1780P (Patent pending, reference number; DPB172272). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Proportions of successful engraftment of PDX models.
(A) Proportion of breast cancer subtypes. (B) Successful engraftment of PDX models were derived from TNBC patient with or without neoadjuvant chemotherapy.
Fig 2
Fig 2. Histopathological characteristics of successful engraftment of PDX models and patients.
(A) H&E staining and immunohistochemistry of PDX models and primary tumor of patients. (B) Ki67 expression of PDX models. (C) Positive control of ER, PR and HER2 in immunohistochemistry.
Fig 3
Fig 3. Successful engraftment of F1 to F3 in PDX models.
(A) Establishment periods of all successful PDX models (B) F1-F2 and F1-F3 intervals according to status of neoadjuvant chemotherapy.
Fig 4
Fig 4. Scheme and results of chemosensitivity tests using PDX models.
(A) PDX models were derived from patients who had BRCA1 mutation (n = 2) or wild-type BRCA1 (n = 1). Each model comprise nine mice, which were divided into three groups (1 group = 3 mouse, two single treatment groups and one vehicle group). (B-E) When implanted tumor reached an average size of 200–250 mm3 (Volume = 0.5×Length×Width^2), the chemosensitivity test was performed. Olaparib (50mg/kg, once a daily) and carboplatin (25mg/kg, once a weekly) were administered by an intra-peritoneal (i.p.) route. Phosphate buffered saline was used to as a vehicle.
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Grants and funding

This work was supported by a Faculty Research Grant of Yonsei University College of Medicine grant no. 6-2017-0072 to HSP, a Severance Surgeon's Alumni Research Grant grant no. 2016-01 to HSP, National Research Foundation of Korea grant 2018R1A2A2A15019814 to SIK, Korea Health Industry Development Institute grant HI14C1324 to JHS, National Research Foundation of Korea grant 2016R1D1A1B03934564 to HSP, and a Faculty Research Grant of Yonsei University College of Medicine grant no. 6-2010-0002 to SIK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.