Abstract 1474: Characterization of 148 ovarian cancer tumografts (Avatars) using BROCA-HR deep sequencing

Abstract

Ovarian cancer is the most lethal gynecologic malignancy and the fifth leading cause of cancer deaths among women. The current standard of care post surgical cytoreduction is combination platinum/taxane chemotherapy. The initial response varies widely; subsets of carcinomas demonstrate resistance or sensitivity from the onset. The underlying cause of this response heterogeneity remains incompletely understood. Patient-derived xenografts (PDX) serve as useful in vivo models to study molecular response markers and test the efficacy of targeted therapies. Our group has demonstrated a high engraftment rate (>70%) of ovarian cancer PDXs (Avatars) by injecting treatment naïve patient tumor directly into the peritoneal cavity of an in immunocompromised mouse host in an effort to better mimic the anatomic context by which ovarian cancer naturally develops. We now have 328 engrafted Avatar models representing the wide range of ovarian cancer subtypes, including serous (65%), mixed epithelial (10%), endometrioid (7%), clear cell (4%), mucinous (3%), carcinosarcoma (1%) and other (10%). Using these models, we are performing a massively parallel sequencing strategy referred to as BROCA-HR to detect all mutation classes (e.g. gene rearrangements, copy number variations, etc.) and gene aberrations within the Fanconi Anemia-BRCA homologous recombination (HR), non-homologous end joining (NHEJ), PTEN, and DNA Mismatch repair pathways. To date, 148 Avatar models have undergone BROCA sequencing. Observed deleterious mutations included 12 BRCA1 (8%), 6 BRCA2 (4%), and 4 PIK3CA (3%); additional loss of function mutations were also evident in the following genes: ATM, RAD51C, FANCM, FANCD2, FANCA, CHEK2, PALB2, MHS6, CDK12 and GEN1. These models are representative of mutations seen in the TCGA mutation set. Models harboring said mutations are currently being tested with platinum agents and/or PARP inhibitors. Taken together, the Avatars represent a high throughput model system for pre-clinical testing in vivo that effectively recapitulates ovarian cancer (e.g. mutations in BRCA1, BRCA2 and other DNA damage response proteins). We have been able to establish avatars at a high rate, including those with mutations in BRCA1, BRCA2 and other DNA damage response genes. These models will be a unique resource for future studies of biomarkers and novel therapeutic approaches. This work is funded by the Ovarian Cancer Research Fund (750563), Mayo Ovarian SPORE (CA136393), National Cancer Institute (RO1 CA184502). Note: This abstract was not presented at the meeting. Citation Format: Kunal A. Lodhia, Marc A. Becker, Xiaonan Hou, Kimberly R. Kalli, Maria I. Harrell, Elizabeth M. Swisher, John S. Weroha, Paul Haluska. Characterization of 148 ovarian cancer tumografts (Avatars) using BROCA-HR deep sequencing. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1474. doi:10.1158/1538-7445.AM2015-1474