Abstract 1049: Orthotopic implantation of aggressive breast cancer achieves better engraftment and larger tumor in patient-derived xenograft models

Abstract

Abstract Background: Breast cancer patient-derived xenograft (PDX) has come into the limelight to address the issue of intratumoral heterogeneity in preclinical studies; however, there are still some unsolved problems regarding its practical usage in translational research. There are no systematic studies that clarify the advantage of orthotopic implantation of the tumor as opposed to ectopic, or of the type of source tumor. Thus, we investigated the difference of tumor growth caused by these variables among breast cancer PDX model mice. Methods: We xenografted 10 patient breast cancer tumors into NSG mice. 2 tumors were derived from brain metastasis (B-met), whereas the others were from primary. 3 tumors were ER(+) HER2(-) and 7 tumors were triple negative (TN). Both of b-met tumors are ER(+) HER2(-). Using 2-3 mice per each patient sample, about 1mm3 tumor fragments were implanted surgically into four subcutaneous (SQ) sites ectopically and four sites (bilateral 2nd and 4th mammary fat pad) orthotopically (Orth). Tumors were passaged to another 2-4 mice as the next generation when the largest tumor grew to 1.5cm in diameter. Tumor “take” was defined as tumorigenesis of palpable tumor after implantation regardless of time it took. Results: PDX tumors were established in 7 out of 10 patient tumors. Histologic grade 3 tumors have significantly higher take rate than grade 2 tumors in 1st generation (3.4% [1/29 site] vs 51.9% [56/108 site], p<0.001) (excluding B-met), which is same as previous reports. The average take time for primary tumor was significantly longer in 1st generation compared to 2nd or 3rd generation (116.7 vs 61.7 days, p<0.001) (excluding B-met), but there is no significant difference between 2nd and 3rd generation. The overall take rate of primary tumor was 55.1% (190/345 site), which was significantly better in Orth compared to SQ (64.9% [120/185] vs 43.8% [70/160], p<0.001). Tumor weights were significantly heavier in Orth compared to SQ (0.65 vs 0.11g, p<0.001). Orth tumors significantly grow faster than SQ tumors (p<0.001), and have significantly more mitotic figures than SQ in H&E staining (19.2 vs 7.9, p<0.01, mean of 10 high power field). Take rates from primary TN and ER-positive tumors were 59.9% (187/312 site) and 3.4% (1/29 site), respectively, but that of ER positive B-met was 82.4% (112/136 site). In B-met, take rate was significantly better in Orth than SQ (94.1%, 64/68 vs 70.6%, 48/68, p=0.001), and tumor weights were significantly heavier in Orth compared to SQ (0.57g vs 0.25g, p<0.001). B-met tumors significantly grow faster than primary tumors (p<0.001). Conclusions: Orthotopic implantation showed better take rate and greater tumor size and weight than heterotopic implantation, regardless of the cancer subtypes and their sources. Citation Format: Maiko Okano, Tsutomu Kawaguchi, Kazuaki Takabe. Orthotopic implantation of aggressive breast cancer achieves better engraftment and larger tumor in patient-derived xenograft models [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 1049.