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The response of phyllodes tumor of the breast to anticancer therapy: An in vitro and ex vivo study.

ABSTRACT: Phyllodes tumors of the breast (PTB) are uncommon stromal-epithelial neoplasms, with the main recommended treatment being surgical removal. However, even with adequate resection, the risk of recurrence in the malignant form remains as high as 40%, and there is no recognized consensus on the most effective drugs for PTB. In the present study, an ex vivo model of malignant phyllodes and derived primary cell cultures were used to evaluate the effectiveness of a panel of different drugs, including the Bcl-2/Bcl-xL inhibitor ABT-263, salinomycin (SAL), doxorubicin (DOX), paclitaxel (TAX), vincristine (VCR), colchicine (COL) and cisplatin (CIS). ABT-263, SAL and DOX were highly effective towards phyllodes spindle cells when assessed in the ex vivo model, contributing to ~98% tumor cell death. Furthermore, ABT-263 was highly selective for tumor cells in this system, and exhibited little toxic effect on adjacent normal epithelial cells. Furthermore, consistent with findings in the ex vivo model, ABT-263 was significantly less toxic towards MCF 10A non-tumorigenic breast epithelial cells compared with SAL and DOX. A conditional reprogramming strategy was subsequently used, involving Rho kinase inhibition, to successfully generate primary phyllodes tumor cells that could be cultured for several passages. The primary cells were sensitive to DOX with an IC50 of 0.40±0.07 µM in a standard viability assay and the preliminary results were obtained indicating sensitivity to ABT-263 and SAL. The present study demonstrated the feasibility of using explants and primary cells for drug discovery, selectively targeting PTB cells.

SUBMITTER: Urbaniak A

PROVIDER: S-EPMC6781661 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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The response of phyllodes tumor of the breast to anticancer therapy: An in vitro and ex vivo study.

Urbaniak Alicja A Jousheghany Fariba F Yuan Youzhong Y Piña-Oviedo Sergio S Huczyński Adam A Delgado Magdalena M Kieber-Emmons Thomas T Monzavi-Karbassi Behjatolah B Chambers Timothy C TC

Oncology letters 20190906 5

Phyllodes tumors of the breast (PTB) are uncommon stromal-epithelial neoplasms, with the main recommended treatment being surgical removal. However, even with adequate resection, the risk of recurrence in the malignant form remains as high as 40%, and there is no recognized consensus on the most effective drugs for PTB. In the present study, an ex vivo model of malignant phyllodes and derived primary cell cultures were used to evaluate the effectiveness of a panel of different drugs, incl ...[more]

PMID: 31612021

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Project description:BackgroundIn vitro models of prostate cancer (PCa) are not always reliable to evaluate anticancer treatment efficacy. This limitation may be overcome by using viable tumor slice material. Here we report on the establishment of an optimized ex vivo method to culture tissue slices from patient-derived xenografts (PDX) of prostate cancer (PCa), to assess responses to PCa treatments.MethodsThree PDX models were used that are characterized by different androgen receptor (AR) expression and different homology directed DNA repair capacities, due to a breast cancer associated two (BRCA2) wild-type or mutated status. Tumors were removed from mice, sliced using a vibratome and cultured for a maximum of 6 days. To test the sensitivity to androgen antagonist, tumor slices from the AR-expressing and AR-negative PDX tumors were treated with the anti-androgen enzalutamide. For sensitivity to DNA repair intervention, tumors slices from BRCA2 wild-type and mutated PDXs were treated with the poly (ADP-ribose) polymerase-1 inhibitor olaparib. Treatment response in these tumor slices was determined by measuring slice morphology, cell proliferation, apoptosis, AR expression level, and secretion of prostate specific antigen (PSA).ResultsWe compared various culture conditions (support materials, growth media, and use of a 3D smooth rocking platform) to define the optimal condition to maintain tissue viability and proliferative capacity up to least 6 days. Under optimized conditions, enzalutamide treatment significantly decreased proliferation, increased apoptosis, and reduced AR-expression and PSA secretion of AR-expressing tumor slices compared to AR-negative slices, that did not respond to the intervention. Olaparib treatment significantly increased cell death in BRCA2 mutated tumors slices as compared to slices from BRCA2 wild type tumors.ConclusionsEx vivo treatment of PCa PDX tumor slices with enzalutamide and olaparib recapitulates responses previously observed in vivo. The faithful retention of tissue structure and function in this ex vivo model offers an ideal opportunity for treatment efficacy screening, thereby reducing costs and numbers of experimental animals.

Project description:BackgroundGiant breast malignant phyllodes tumor or sarcoma (GBPS) are rare entities with diameter larger than 10 cm and variously histological pleomorphisms. This disease poses a significant threat to the quality of life of individuals, and its prognosis remains unclear. This study aimed to explore the differential diagnosis, treatment, and prognosis of GBPS in a real-world retrospective cohort.MethodsWe collected GBPS (diameter > 10 cm, n = 10) and BPS (diameter ≤ 10 cm, n = 126) from patients diagnosed with sarcoma or malignant phyllodes tumor between 2008 and 2022. We analyzed clinical characteristics, histological status, treatment, and local recurrence using the Fisher's exact test between GBPS (diameter > 10 cm) and BPS (diameter ≤ 10 cm) cohort. We described overall survival (OS) and disease-free survival (DFS) using Kaplan-Meier curves and identified risk factors for local recurrence using logistic regression. The tumor size, age at diagnosis, and differential immunohistochemistry markers of breast sarcoma or phyllodes tumor to determine the prognosis of GBPS.ResultsIn our retrospective analysis of breast malignancies, we identified 10 cases of GBPS and 126 cases of BPS, corresponding to a GBPS prevalence of 0.17% (10/6000). The median age was 38.5 years (inter-quartile range, IQR: 28.25-48.5 years). During the follow-up of period (median: 80.5 months, IQR: 36.75-122 months), the local recurrence (LR) rate was 40% and 20.6%, respectively. Clinical characteristics of young age (HR:2.799, 95%CI -00.09276-0.017, p < 0.05) and cytological characteristics of marked stromal atypia (HR:0.88, 95% CI 0.39-1.40, p < 0.05) were risk factors for the poor prognosis of GBPS by COX regression model analysis. The Kaplan-Meier curves of GBPS 5-year disease-free survival (DFS) and overall survival (OS) were 31.5 months and 40 months, respectively, and were not associated with adjuvant radiation or chemotherapy.ConclusionWe recommend mastectomy with a clear surgical margin as the preferred treatment for GBPS. Age and stromal atypia are significantly associated with recurrence. Adjuvant radiation therapy is advised; however, there was no improvement in overall survival. There is no consensus on the effectiveness of adjuvant chemotherapy and genetic methods, highlighting the need for further research into this aggressive tumor. We recommend a multidisciplinary approach involving a dedicated team for the management of GBPS.

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The response of phyllodes tumor of the breast to anticancer therapy: An in vitro and ex vivo study.

Publications

The response of phyllodes tumor of the breast to anticancer therapy: An <i>in vitro</i> and <i>ex vivo</i> study.

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