Abstract 1092: Correlation of platinum sensitivity with donor patient treatment status in a panel of breast, ovary, uterine, and lung XPDX models
Authors: Simonson Alyssa , Flores Johnnie , Firova Lizette , Hernandez Christian , Harris Morgan , Papadopoulos Kyriakos , Rasco Drew , Patnaik Amita , White Allan , Smith Lon , Drengler Ronald , Lang Amy , Beeram Murali , Wick Michael J. 
Published: June 2022

Background: First-line treatment for some cancer types includes platinum-based therapy. While the rate of initial response to treatment is high, most patients develop platinum-resistant disease. Current salvage therapy provides benefit to some patients, demonstrating the need for additional effective therapies. To assist in identifying new therapies, we have established XenoSTART patient-derived xenograft (XPDX) models representing breast, ovary, uterine, and lung cancers. Each model was characterized by DNA/RNA analysis, sensitivity to platinum treatment, and annotated with donor patient treatment status at the time of sample collection.

Methods: 210 XPDX models were evaluated in this screen including 66 breast, 56 ovary, 36 uterine, and 52 lung xenografts. WES and RNAseq were performed on each model and patient treatment history and outcome annotated. For in vivo studies, models were implanted into female nudes and administered (IP; q7dx3) 3 m/k cisplatin or 60 m/k carboplatin. Study endpoints included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a %T/C of ≤ 20 versus control was considered sensitive.

Results: Study results are summarized below in Table 1:

Sequencing identified several variants in resistant, chemo-naïve models including point mutations in RAS/RAF/MET/PIK3CA genes and others, while sensitive models lacked common driver mutations.

Conclusion: We have characterized 210 XPDX models. Uterine models were most often resistant to platinum, while almost 1/2 of ovary and 1/3 of breast models were sensitive, regardless of treatment status. Only 15% of lung models were sensitive to platinum; cancer driver variants were found in several models. Overall, we report differential platinum sensitivity in a panel of diverse models useful in understanding mechanisms of resistance and for development of effective therapies in platinum-resistant cancers.

Table 1. Type Breast Ovary Uterine Lung Total 66 56 36 52 # Sensitive 25 25 9 8 % 38% 45% 25% 15% Naïve 11 16 8 5 % 44% 64% 89% 63% P-1st 6 6 1 2 % 24% 24% 11% 25% P-2nd+ 6 3 0 1 % 24% 12% 0% 13% # Insensitive 41 31 27 44 % 62% 55% 75% 85% Naïve 11 9 20 21 % 27% 29% 74% 48% P-1st 14 10 5 13 % 34% 32% 19% 30% P-2nd+ 16 12 2 10 % 39% 39% 7% 23% Naïve=No Prior Treatment; P-1st=Post 1st Line Therapy; P-2nd=Post 2nd+ Line Therapy

Citation Format: Alyssa Simonson, Johnnie Flores, Lizette Firova, Christian Hernandez, Morgan Harris, Kyriakos Papadopoulos, Drew Rasco, Amita Patnaik, Allan White, Lon Smith, Ronald Drengler, Amy Lang, Murali Beeram, Michael J. Wick. Correlation of platinum sensitivity with donor patient treatment status in a panel of breast, ovary, uterine, and lung XPDX models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1092.