Activity of chemotherapy drugs in patient-derived xenografts (PDXs) from chemotherapy naïve local-regional triple negative breast cancer (LR-TNBC) patients
Authors: M. Martín, R. Ramos-Medina, J.Á. Garcia Sáenz, M. del Monte-Millán, M. Cebollero, F. Moreno, I. Echavarria, Y. Jerez, T. Massarrah, S. Lopez-Tarruella Cobo
Journal: Annals of Oncology (2019)

Background: LR-TNBC is responsive to polychemotherapy regimens including anthracyclines, taxanes and, more recently, carboplatin. However, we are ignorant of the individual contribution of each of these agents to the global activity of the combinations. Identifying single drug activity in the clinical setting is challenging. We used instead PDXs from LR-TNBC to test single chemotherapy drugs and combinations. Methods: PDXs were generated from chemotherapy-naïve LR-TNBC patients, later treated with neoadjuvant docetaxel plus carboplatin. Tumor biopsies were implanted orthotopically into NOD.Cg-Prkdcscid IL2rgtm1Wjl (NSG) female mice (F0) and those that engrafted were later expanded in two successive mice cohorts (passages F1 and F2). PDXs from F2 were allocated into the following five (10-mice) groups: (a) vehicle (ethanol); (b) Docetaxel 8.10 mg/kg i.v once a week; (c) Carboplatin 48.64 mg/kg i.p once a week; (d) combination Docetaxel+Carboplatin 8.10mg/kg +48.64 mg/kg i.v+i.p once a week; (e) Doxorubicin 2.5 mg/kg i.p once a week. Tumor volume was calculated using the following formula: Tumor Volume = [tumor length x tumor width2]/2. Tumor growth inhibition (%TGI) was calculated as (1-(Average relative tumor volume treatment group/Average relative tumor volume vehicle group)*100). Results: PDXs from 5 LR-TNBC patients, BRCA 1-2 wild type, with different pathological responses to docetaxel+carboplatin, were included. The antitumor activity of drugs in PDXs is shown in the Table. Conclusions: In this model, carboplatin and docetaxel showed higher single drug activity than doxorubicin. The combination of docetaxel and carboplatin offered the best antitumor activity. Legal entity responsible for the study: Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM). Funding: Fundación Salud2000-FundaciónSEOM, Roche Pharma and CiberONC. Disclosure: M. Martín: Remuneration: Pfizer, Lilly; Consultant/advisory honorarium: Roche, Novartis, Pfizer, AstraZeneca, Lilly, Glaxo, PharmaMar, Taiho; Funding: Roche, Novartis. J.Á. Garcia Sáenz: Consultant/advisory honorarium: Novartis, Roche, Lilly, Celgene, Roche; Funding: AstraZeneca. F. Moreno: Consultant/advisory honorarium: Roche, Pfizer, Novartis, AstraZeneca. T. Massarrah: Consulting or advisory boards: AstraZeneca, Novartis, Roche; Travel grants: Novartis, AstraZeneca. S. Lopez-Tarruella Cobo: Consultant/advisory honorarium: AstraZeneca, Novartis, Roche, Pfizer, Gelgene, Pierre-Fabre, Eisai, Lilly. All other authors have declared no conflicts of interest. Table53PDrug(s)*Fifty mice per group Only one out of five PDXs showed some sensitivity to doxorubicin, while four out of five showed sensitivity to docetaxel and carboplatin single agents. All five PDXs showed sensitivity to the combination of docetaxel plus carboplatin.Final tumor volume (mean +/-SD)mm3Final tumor cellularity (%)TGI (vs vehicle) (%)P value for Final tumor volume (vs vehicle)Vehicle822.2±281.786NANAdoxorubicin500.2±305.374.50390.135carboplatin238.4±207.17071.10.0041docetaxel285.8±402.26265.30.0427docetaxel plus carboplatin94±161.44488.60.0037* Fifty mice per group Only one out of five PDXs showed some sensitivity to doxorubicin, while four out of five showed sensitivity to docetaxel and carboplatin single agents. All five PDXs showed sensitivity to the combination of docetaxel plus carboplatin. Open table in a new tab