Abstract 3859: Efficacy of capecitabine in chemoresistant PDX established from triple-negative breast cancers with residual disease after neoadjuvant chemotherapy
Authors: Marangoni Elisabetta , Laurent Cécile , Coussy Florence , Botty Rania El , Plater Ludmilla de , Assayag Franck , Vacher Sophie , Bièche Ivan , Reyal Fabien 
Published: July 2017

Background: triple-negative breast cancer (TNBC) patients with residual disease following neoadjuvant chemotherapy have a high risk of relapse and poor survival. Conventional treatments for relapsed patients are limited, particularly, because standard chemotherapeutic regimens containing anthracyclines and taxanes have usually already been given in the neoadjuvant settings. Our objectives were 1) to identify efficient chemotherapies in patient-derived xenografts (PDX) established from residual TNBC and 2) to determine feasibility of PDX establishment and drug testing before tumor recurrence in patients. Methods: tumors from 51 patients with residual disease at surgery were transplanted in nude mice. Established TNBC PDX were treated with different chemotherapies used in early stages and metastatic settings: anthracyclines combined to cyclophosphamide (AC), taxanes, platins, capecitabine and gemcitabine. Drug responses in PDX were compared to responses in patients who recurred after surgery and were treated in the metastatic setting. Results: overall tumor take of residual tumors was 40% and 75% for TNBC, with 15/20 PDX established, more than twice the tumor take of treatment naïve TNBC (34%). Median latency time, defined as time from implantation till first tumour growth, was only 60 days and was further reduced to 3-4 weeks during successive tumor passages. On the 8 TNBC PDX evaluated for chemosensitivity, 7 exhibited a multidrug-resistance phenotype with resistance or limited response to AC, taxanes and platins. Capecitabine, a chemotherapy given in the advanced stage as second or third line, was efficient in 5 out of 8 PDX tested with 3 models showing stable disease and 2 models durable tumor regressions. Interestingly, capecitabine efficacy was decreased when xenografts were pre-treated with a first line containing platins, suggesting that in some tumors capecitabine might have superior activity when given in the adjuvant setting or as a first line. In one third of TNBC patients, time to recurrence, comprised between 7 and 12 months after surgery, was compatible with xenograft establishment and drug testing. Conclusions and perspectives: we established a unique panel of PDX models from patients with residual disease after neoadjuvant chemotherapy. These aggressive PDX recapitulate the resistance phenotype of patients’ tumors to treatments given in neo-adjuvant and metastatic settings. We identified capecitabine as efficient first line chemotherapy for residual chemoresistant PDX. In 30% of cases, PDX models could have been used to evaluate chemotherapy responses before tumor recurrence occur in patients. In order to identify predictive biomarkers of capecitabine response, additional experiments are ongoing in 25 supplementary TNBC PDX, established from treatment-naïve patients.

Citation Format: Elisabetta Marangoni, Cécile Laurent, Florence Coussy, Rania El Botty, Ludmilla de Plater, Franck Assayag, Sophie Vacher, Ivan Bièche, Fabien Reyal. Efficacy of capecitabine in chemoresistant PDX established from triple-negative breast cancers with residual disease after neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3859. doi:10.1158/1538-7445.AM2017-3859