Abstract 3129: Patient-derived tumor xenografts (PDXs) recapitulate the antitumor activity of novel therapies in metastatic breast cancer (MBC) patients (pts)
Authors: Oliveira Mafalda , Pascual Javier , Cruz Cristina , Gris Alberto , Palafox Marta , Llop Alba , Castroviejo Marta , Viaplana Cristina , Ibrahim Yasir H , Arribas Joaquin , Cortés Javier , Baselga José , Rodón Jordi , Balmaña Judith , Dienstmann Rodrigo , Saura Cristina , Serra Violeta 
Published: July 2017

Abstract
PDXs are preferred laboratory models that recapitulate the biology of pts’ tumors. We aimed to assess if the antitumor activity of novel therapies in PDXs correlates with the observed activity in the corresponding MBC patient, which would support cross-analysis of drug/genotype vulnerabilities.
MBC pts eligible for clinical trials were offered a research biopsy and establishment of PDX, under an IRB-approved protocol. Biopsies were implanted in nude mice subcutaneously. Upon successful engraftment, models were expanded for drug testing, specifically with the same drug/combination given to the patient. This is a retrospective analysis of our MBC patient/PDX (Pt/PDX) co-clinical trial cohort. Pts’ outcomes were measured as: RECIST response, clinical benefit [CB: partial response (PR) or stable disease (SD) &gt;4 months], and time to progression [TTP: time until RECIST progressive disease (PD), in months). PDX endpoints were measured as: TTP (time until 25% increase in tumor volume, in days), response (WHO criteria, at week 3), and relative area under the curve (rAUC) of treated versus vehicle. A concordant Pt/PDX response was defined as CB in pts whose paired PDX showed PR/SD, or no-CB in pts whose paired PDX showed PD. Pts outcomes and PDX endpoints were correlated using Spearman's test.
We identified 10 MBC pts (7 TNBC, 3 HR+; all biopsies from skin/subcutaneous lesions) with corresponding PDX, treated with paired therapies (7 molecularly matched): 3 lurbinectedin (BRCA1-mut), 3 olaparib (BRCA1-mut), 1 AZD5363 + fulvestrant (AKT1-mut), 1 AZD5363 + paclitaxel, 1 buparlisib, 1 eribulin. In 9/10 cases we found concordant Pt/PDX responses (6 cases with no-CB in patient/PD in PDX, 3 with CB/SD; and 1 lurbinectedin case with no-CB/PR). Two pts had biopsy for PDX implantation at progression of paired therapy and were excluded from TTP analyses. In cases with concordant Pt/PDX response, we found a significant correlation between RECIST response in pts and rAUC in PDX (ρ=0.82, p=0.03), a trend for comparable TTP in pts and TTP in PDX (ρ=0.67, p=0.10), but no correlation between RECIST response in pts and response at week 3 in PDX (ρ=0.46, p=0.30).
In this cohort of MBC pts, we found high concordance in Pt/PDX response. Our results suggest that rAUC in PDX may be the best read-out to identify relevant drug/genotype associations that can potentially be translated to patient benefit. Data will be updated with additional ongoing PDX experiments.
Citation Format: Mafalda Oliveira, Javier Pascual, Cristina Cruz, Alberto Gris, Marta Palafox, Alba Llop, Marta Castroviejo, Cristina Viaplana, Yasir H Ibrahim, Joaquin Arribas, Javier Cortés, José Baselga, Jordi Rodón, Judith Balmaña, Rodrigo Dienstmann, Cristina Saura, Violeta Serra. Patient-derived tumor xenografts (PDXs) recapitulate the antitumor activity of novel therapies in metastatic breast cancer (MBC) patients (pts) [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 3129. doi:10.1158/1538-7445.AM2017-3129