Abstract 1672: Comparing subcutaneous to mammary fat pad implantation on the growth kinetics, histology and drug response of PDX breast cancer models

Abstract

Abstract Preclinical oncology studies frequently use patient-derived xenograft (PDX) tumor models and the efficacy of the test therapy is evaluated by measuring changes in tumor volume. Subcutaneous (SQ) implantation of tumors is most widely used in oncology studies due to ease of technique and tumor accessibility for caliper measurements. However, SQ tumors are then growing in a different environment compared to the tumor model. Conversely, orthotopic implantation provide tumors with a similar microenvironment for growth, but require surgical techniques which increase the amount of resources, time, and skill needed to perform these studies. Currently, the standard method for an orthotopic breast cancer involves surgically clearing the mammary fat pad (MFP) prior to engrafting the cells or tissue. In this study we developed a nonsurgical approach where PDX tissue is engrafted directly into a non-cleared MFP using a method similar to SQ engraftment. Using several different established breast cancer PDX models, this study compares the impact of SQ and MFP implantation on growth kinetics, tumor histology and drug efficacy. For each experiment, 8-week old female NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG; JAX strain #005557) mice were shaved on the right flank or MFP, earnotched and housed. PDX breast tumor tissue from donor mice was cleared of necrotic tissue and mouse tissue, minced and loaded into syringes capped with either 14G or 18G trocar needles. Mice were put under anesthesia and trocared with 50ul of PDX breast tumor model tissue. Non-cleared implantations were performed in all groups and tumor models. Tumor growth was monitored using caliper measurements until the study terminus. Slides generated from formalin-fixed and paraffin embedded tumor tissue were used for histological analysis. Cisplatin and Docetaxel were selected as standard of care agents to compare drug responses in SQ versus MFP engrafted tumors. In all tested models, tumors volumes in the MFP cohort are significantly higher compared to tumors implanted SQ. Tumors engrafted into the MFP reached 500mm3 significantly earlier than tumors engrafted SQ, but the doubling times remained unchanged. This suggests the environment of the MFP allows for a faster engraftment rather than a shorter doubling time. H&E staining shows no significant histological difference between tumor models engrafted in the SQ and MFP for this study. This likely because tumor models were established in the SQ for at least 3 rounds of engraftment before being engrafted in the MFP for this study. Histological differences may have been prominent if the tumor models were established in the appropriate locations (SQ or MFP) at model development. This study has important implications for ensuring a more clinically relevant growth environment for mouse studies using PDX breast models. Citation Format: Kyle M. Draheim, Raphaela R. Banzon, Marta M. Tewodros, Daniel VanBuskirk, Mingshan Cheng. Comparing subcutaneous to mammary fat pad implantation on the growth kinetics, histology and drug response of PDX breast cancer models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1672.