RT Journal Article
SR Electronic
T1 Capecitabine Efficacy Is Correlated with TYMP and RB1 Expression in PDX Established from Triple-Negative Breast Cancers
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 2605
OP 2615
DO 10.1158/1078-0432.CCR-17-3490
VO 24
IS 11
A1 Marangoni, Elisabetta
A1 Laurent, Cécile
A1 Coussy, Florence
A1 El-Botty, Rania
A1 Château-Joubert, Sophie
A1 Servely, Jean-Luc
A1 de Plater, Ludmilla
A1 Assayag, Franck
A1 Dahmani, Ahmed
A1 Montaudon, Elodie
A1 Nemati, Fariba
A1 Fleury, Justine
A1 Vacher, Sophie
A1 Gentien, David
A1 Rapinat, Audrey
A1 Foidart, Pierre
A1 Sounni, Nor Eddine
A1 Noel, Agnès
A1 Vincent-Salomon, Anne
A1 Lae, Marick
A1 Decaudin, Didier
A1 Roman-Roman, Sergio
A1 Bièche, Ivan
A1 Piccart, Martine
A1 Reyal, Fabien
YR 2018
UL http://clincancerres.aacrjournals.org/content/24/11/2605.abstract
AB 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.