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Capecitabine efficacy is correlated with TYMP and RB1 expression in PDX established from triple-negative breast cancers
- Source :
- Clinical Cancer Research, Clinical Cancer Research, American Association for Cancer Research, 2018, 24 (11), pp.2605-2615. ⟨10.1158/1078-0432.CCR-17-3490⟩
- Publication Year :
- 2018
- Publisher :
- HAL CCSD, 2018.
-
Abstract
- Purpose: Triple-negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy have a poor outcome. We developed patient-derived xenografts (PDX) from residual tumors to identify efficient chemotherapies and predictive biomarkers in a context of resistance to anthracyclines- and taxanes-based treatments. Experimental Design: PDX were established from residual tumors of primary breast cancer patients treated in neoadjuvant setting. TNBC PDX were treated by anthracyclines, taxanes, platins, and capecitabine. Predictive biomarkers were identified by transcriptomic and immunohistologic analysis. Downregulation of RB1 was performed by siRNA in a cell line established from a PDX. Results: Residual TNBC PDX were characterized by a high tumor take, a short latency, and a poor prognosis of the corresponding patients. With the exception of BRCA1/2-mutated models, residual PDX were resistant to anthracyclines, taxanes, and platins. Capecitabine, the oral prodrug of 5-FU, was highly efficient in 60% of PDX, with two models showing complete responses. Prior treatment of a responder PDX with 5-FU increased expression of thymidylate synthase and decreased efficacy of capecitabine. Transcriptomic and IHC analyses of 32 TNBC PDX, including both residual tumors and treatment-naïve derived tumors, identified RB1 and TYMP proteins as predictive biomarkers for capecitabine response. Finally, RB1 knockdown in a cell line established from a capecitabine-responder PDX decreased sensitivity to 5-FU treatment. Conclusions: We identified capecitabine as efficient chemotherapy in TNBC PDX models established from residual disease and resistant to anthracyclines, taxanes, and platins. RB1 positivity and high expression of TYMP were significantly associated with capecitabine response. Clin Cancer Res; 24(11); 2605–15. ©2018 AACR.
- Subjects :
- 0301 basic medicine
Cancer Research
Antimetabolites, Antineoplastic
endocrine system
medicine.medical_treatment
Ubiquitin-Protein Ligases
Context (language use)
Triple Negative Breast Neoplasms
[SDV.CAN]Life Sciences [q-bio]/Cancer
Thymidylate synthase
digestive system
Capecitabine
03 medical and health sciences
Mice
0302 clinical medicine
Breast cancer
[SDV.CAN] Life Sciences [q-bio]/Cancer
Medicine
Neoplasm
Animals
Humans
Gene Silencing
RNA, Small Interfering
Cell Proliferation
Chemotherapy
Thymidine Phosphorylase
biology
business.industry
Gene Expression Profiling
Cancer
medicine.disease
Xenograft Model Antitumor Assays
3. Good health
Disease Models, Animal
Retinoblastoma Binding Proteins
030104 developmental biology
Oncology
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
Cancer research
biology.protein
Immunohistochemistry
Female
Fluorouracil
business
hormones, hormone substitutes, and hormone antagonists
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 10780432 and 15573265
- Database :
- OpenAIRE
- Journal :
- Clinical Cancer Research, Clinical Cancer Research, American Association for Cancer Research, 2018, 24 (11), pp.2605-2615. ⟨10.1158/1078-0432.CCR-17-3490⟩
- Accession number :
- edsair.doi.dedup.....33773044137af2b398e31aa39e56c1db