Abstract 3097: Patient-derived renal cell carcinoma xenografts engraftment identifies patients at risk of disease relapse, progression and death
Authors: Martins Vilma Regina , Beserra Adriano , Estevan Ethiene C. , Bezerra Stephania , Torrezan Giovana T. , Ikegani Amanda , Humberto Dellê , Cunha Isabela V. , Meira Isabella T. , Carraro Dirce M. , Lara Primo N. , Zequi Stenio , Santos Tiago G. 
Published: June 2022

Abstract
Renal cell carcinoma (RCC) represents up to 90% of all kidney tumors, with 30% of patients presenting metastasis at diagnosis while 20-50% of those treated for curable localized disease experience recurrence. A better understanding of RCC biology is necessary to define the most efficient and personalized treatment or develop better antineoplastic drugs. Patient-derived xenografts (PDX) have emerged as one of the most promising approaches for that. This tool was generated by using surgical specimens of 87 patients implanted in immunodeficient NOD/SCID/gamma (NSG) mice, 17 of those subcutaneously and 70 at the renal subcapsular space. A total of 19 PDX developed only after orthotopic implantation and included 15 cases of clear cell RCC subtype, 3 cases of papillary subtype, and one unclassifiable tumor. One case of a PDX of a clear cell RCC recapitulated the phenotype of vena cava tumor thrombus extension that had been diagnosed in the source patient. The overall take rate was 27%, and the time to observed tumor growth varied from 5 to 13 months. An association between tumor growth and take rate was suggested by increasing take rates of 18%, 36%, and 100% among pT1 (pT1a + pT1b), pT3a, and pT3b stage tumors, respectively. PDX take rate was unrelated to tumor size (p =0.071). Patients whose tumor fragments engrafted experienced worse overall survival (OS) than those whose tumor fragments did not engraft (p = 0.003). Data also suggested a similar trend of association with metastasis-free survival (MFS) (p = 0.063). The median MFS for patients with successful PDX was 21.6 months (95% CI: 14.9, 28.3;), compared to a median of 34.4 months (95% CI: 30.4, 38.5 p = 0.003) among PDX engraftment-negative patients. PDX characterization by immunohistochemistry and targeted sequencing of the 21 most frequently mutated genes in the kidney indicated that all PDXs preserved RCC identity and major molecular alterations. From 19 PDX, the sequences of 13 patients’ tumor samples were compared with their respective PDX. In most patients (92% - 11/12), at least one mutation in patients’ tumor was identified in the PDX and in one case, no alterations were mapped. The most frequently mutated genes were VHL (50% - 6/12) and PBRM1 (41.7% - 5/12), followed by SETD2 (25% - 3/12), BAP1 and KDM5C (both 16.7% - 2/12), and ARID1A (8.3% - 1/12), indicating that all PDXs preserved RCC identity and major molecular alterations. These findings suggest that tumor engraftment capacity can identify patients at increased risk of relapse or death. Furthermore, pT1 stage tumors with the ability to engraft could also facilitate the identification of risk factors related to the rare pT1 cases with disease progression. These results suggest that the orthotopic xenograft model of RCC represents a suitable tool to study RCC biology, identify biomarkers, and test therapeutic candidates.
Citation Format: Vilma Regina Martins, Adriano Beserra, Ethiene C. Estevan, Stephania Bezerra, Giovana T. Torrezan, Amanda Ikegani, Dellê Humberto, Isabela V. Cunha, Isabella T. Meira, Dirce M. Carraro, Primo N. Lara, Stenio Zequi, Tiago G. Santos. Patient-derived renal cell carcinoma xenografts engraftment identifies patients at risk of disease relapse, progression and death [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 3097.