Abstract 2816: Patient derived ovarian cancer xenograft (OC-PDX) to study the response of the PARP inhibitor olaparib
Authors: Bizzaro Francesca , Marchetti Alessia C. , Decio Alessandra , Ricci Francesca , O'Connor Mark J. , Taylor Molly A. , Lai Zhongwu , Barry Simon T. , Bani Maria R. , Giavazzi Raffaella 
Published: August 2018

Up to 50% of High Grade Serous (HGS) ovarian cancer patients exhibit homologous recombination deficiency (HRD) through various mechanisms including germline and somatic mutations in BRCA-1 or 2. Olaparib, a poly(ADP-ribose)polymerase (PARP) inhibitor, was recently approved for the treatment of patients with germline BRCA-mutated-advanced ovarian cancer. We have analyzed our panel of patient derived ovarian cancer xenografts (OC-PDX)1 to investigate the association of the somatic BRCA1/2 mutational status with the response to olaparib.

Whole Exome Sequencing (Illumina HiSeq4000) was performed on a panel (n=26) of OC-PDX to identify mutations in BRCA1/2. Next Generation Sequencing (NGS) results were confirmed by Sanger sequencing on tumor DNA and RNA. Thirteen OC-PDX were selected and treated with 100mg/kg olaparib for 4 weeks or as a maintenance regimen until progression. Cisplatin was used as reference drug. Efficacy was evaluated as the best T/C% (best growth inhibition) for subcutaneous (s.c) tumors. To mimick patient disease, OC-PDX were also established as intra-peritoneal models (i.p.) and best ILS% (best increment of lifespan) calculated.

Response to olaparib varied among the models with distinct responsive and non-responsive groups associated with BRCA mutational status.

OC-PDX with a homozygous frameshift mutation in BRCA1/2 (n=5), loss of BRCA1 (n=1) or no expression of BRCA1/2 (n=1) showed a sustained response to olaparib after 4 week treatment (T/C values from 2% to 40%; ILS of one representative OC-PDX = 74%), with complete responses following a longer term maintenance treatment. One BRCA1 mutated OC-PDX model was resistant, progressing rapidly under treatment. In this orthotopic model ILS% and tumor dissemination score of treated mice were similar to vehicle. Models responsive to olaparib were in general also sensitive to cisplatin. BRCA1/2 wild type OC-PDX models (n=4 s.c and n=1 i.p) did not respond to olaparib, even following a longer term treatment (T/C from 41% to 86%; ILS = 5%). NGS revealed a heterozygous mutation in BRCA2 in one OC-PDX. Sanger sequencing of the RNA confirmed the presence of both the wild type and the mutated BRCA2 transcripts. This OC- PDX was poorly responsive to olaparib (T/C = 57%).

Our data showed that in general tumors with a homozygous mutation, loss or no expression of BRCA1/2 responded to olaparib; the drug was not active on those with mutation in heterozygosis (BRCA2+/-) or wild type. These findings indicate that tumor somatic mutations play a role in the response to olaparib. Models of OC-PDX moderately responsive to olaparib offer the opportunity to assess the potential of combination treatments.

1 Ricci, F. et al. Patient-derived ovarian tumor xenografts recapitulate human clinicopathology and genetic alterations. Cancer Res 74, 6980–90 (2014)

Citation Format: Francesca Bizzaro, Alessia C. Marchetti, Alessandra Decio, Francesca Ricci, Mark J. O'Connor, Molly A. Taylor, Zhongwu Lai, Simon T. Barry, Maria R. Bani, Raffaella Giavazzi. Patient derived ovarian cancer xenograft (OC-PDX) to study the response of the PARP inhibitor olaparib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2816.