Skip to main content
Top
Published in: European Radiology 9/2022

31-03-2022 | Kidney Cancer | Nuclear Medicine

[68Ga]Ga-PSMA-11 PET/CT has potential application in predicting tumor HIF-2α expression and therapeutic response to HIF-2α antagonists in patients with RCC

Authors: Longxiyu Meng, Shun Zhang, Jie Gao, Qinfeng Xu, Yao Fu, Yi-hua Zhou, Feng Wang, Hongqian Guo

Published in: European Radiology | Issue 9/2022

Login to get access

Abstract

Objective

To evaluate the efficacy of parameters derived from [68Ga]Ga-PSMA-11 PET/CT images in predicting pathological HIF-2α expression in primary tumors among patients with renal cell carcinoma (RCC).

Methods

Fifty-three RCC patients with preoperative [68Ga]Ga-PSMA-11 PET/CT scans and complete surgical specimens were retrospectively enrolled in this study. Radiographic parameters were obtained from PET/CT images, and immunohistochemistry was used to measure the expression of HIF-2α and PSMA. Continuous variables and categorical variables were analyzed by the Mann–Whitney U test and chi-square test, respectively. ROC analysis was used to test the efficacy of several preoperative parameters in identifying pathological HIF-2α expression. Univariable logistic regression analyses were performed for significant parameters to predict pathological HIF-2α expression in RCC.

Results

Of the 53 tumors, 29 (54.7%) had high expression of HIF-2α. The SUVmax was significantly different in the HIF-2α expression subgroups (p < 0.001). SUVmax emerged as the most significant parameter to differentiate HIF-2α expression subgroups (high vs. low), with the AUC of 0.93 (95% CI 0.85–1.00, p < 0.001), sensitivity of 90%, and specificity of 88%. Furthermore, SUVmax was confirmed as the most significant predictor of HIF-2α expression level by univariable logistic regression model analysis (odds ratio 1.39, 95% CI 1.17–1.65, p < 0.001). Consistent with the radiographic results of [68Ga]Ga-PSMA-11 PET/CT, the staining intensity of pathological PSMA was significantly higher in HIF-2α-high-expressing tumors (p = 0.003).

Conclusions

[68Ga]Ga-PSMA-11 PET/CT was superior in identifying pathological HIF-2α expression in primary tumors of RCC patients, demonstrating its potential application in predicting responses to HIF-2α antagonists.

Key Points

[68Ga]Ga-PSMA-11 PET/CT could potentially predict the HIF-2α expression of primary tumors among patients with RCC.
SUVmaxof [68Ga]Ga-PSMA-11 PET/CT was the most significant predictor of HIF-2α expression level.
This probability could help predict the therapeutic response of patients with RCC to HIF-2α antagonists.
Literature
1.
go back to reference Siegel RL, Miller KD, Fuchs HE, Jemal A (2021) Cancer statistics, 2021. CA Cancer J Clin 71:7–33PubMed Siegel RL, Miller KD, Fuchs HE, Jemal A (2021) Cancer statistics, 2021. CA Cancer J Clin 71:7–33PubMed
2.
go back to reference Shingarev R, Jaimes EA (2017) Renal cell carcinoma: new insights and challenges for a clinician scientist. Am J Physiol Renal Physiol 313:F145–F154CrossRef Shingarev R, Jaimes EA (2017) Renal cell carcinoma: new insights and challenges for a clinician scientist. Am J Physiol Renal Physiol 313:F145–F154CrossRef
3.
go back to reference Ferlay J, Parkin DM, Steliarova-Foucher E (2010) Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 46:765–781 Ferlay J, Parkin DM, Steliarova-Foucher E (2010) Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 46:765–781
4.
go back to reference Choueiri TK, Motzer RJ (2017) Systemic therapy for metastatic renal-cell carcinoma. N Engl J Med 376:354–366CrossRef Choueiri TK, Motzer RJ (2017) Systemic therapy for metastatic renal-cell carcinoma. N Engl J Med 376:354–366CrossRef
5.
go back to reference Motzer RJ, Bander NH, Nanus DM (1996) Renal-cell carcinoma. New Engl J Med 335:865–875CrossRef Motzer RJ, Bander NH, Nanus DM (1996) Renal-cell carcinoma. New Engl J Med 335:865–875CrossRef
6.
go back to reference Wu D, Potluri N, Lu J, Kim Y, Rastinejad F (2015) Structural integration in hypoxia-inducible factors. Nature 524:303–308CrossRef Wu D, Potluri N, Lu J, Kim Y, Rastinejad F (2015) Structural integration in hypoxia-inducible factors. Nature 524:303–308CrossRef
7.
go back to reference Wigerup C, Påhlman S, Bexell D (2016) Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharmacol Ther 164:152–169CrossRef Wigerup C, Påhlman S, Bexell D (2016) Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharmacol Ther 164:152–169CrossRef
9.
go back to reference Xiong Z, Xiong W, Xiao W et al (2021) NNT-induced tumor cell “slimming” reverses the pro-carcinogenesis effect of HIF2a in tumors. Clin Transl Med 11:e264CrossRef Xiong Z, Xiong W, Xiao W et al (2021) NNT-induced tumor cell “slimming” reverses the pro-carcinogenesis effect of HIF2a in tumors. Clin Transl Med 11:e264CrossRef
10.
go back to reference Martinez-Saez O, Gajate Borau P, Alonso-Gordoa T, Molina-Cerrillo J, Grande E (2017) Targeting HIF-2 alpha in clear cell renal cell carcinoma: a promising therapeutic strategy. Crit Rev Oncol Hematol 111:117–123CrossRef Martinez-Saez O, Gajate Borau P, Alonso-Gordoa T, Molina-Cerrillo J, Grande E (2017) Targeting HIF-2 alpha in clear cell renal cell carcinoma: a promising therapeutic strategy. Crit Rev Oncol Hematol 111:117–123CrossRef
12.
go back to reference Courtney KD, Infante JR, Lam ET et al (2018) Phase I dose-escalation trial of PT2385, a first-in-class hypoxia-inducible factor-2α antagonist in patients with previously treated advanced clear cell renal cell carcinoma.J Clin Oncol 36:867–874 Courtney KD, Infante JR, Lam ET et al (2018) Phase I dose-escalation trial of PT2385, a first-in-class hypoxia-inducible factor-2α antagonist in patients with previously treated advanced clear cell renal cell carcinoma.J Clin Oncol 36:867–874
13.
go back to reference Wallace EM, Rizzi JP, Han G et al (2016) A small-molecule antagonist of HIF2α is efficacious in preclinical models of renal cell carcinoma.Cancer Res 76:5491–5500 Wallace EM, Rizzi JP, Han G et al (2016) A small-molecule antagonist of HIF2α is efficacious in preclinical models of renal cell carcinoma.Cancer Res 76:5491–5500
14.
go back to reference Chen W, Hill H, Christie A et al (2016) Targeting renal cell carcinoma with a HIF-2 antagonist. Nature 539:112–117CrossRef Chen W, Hill H, Christie A et al (2016) Targeting renal cell carcinoma with a HIF-2 antagonist. Nature 539:112–117CrossRef
15.
go back to reference Cho H, Du X, Rizzi JP et al (2016) On-target efficacy of a HIF-2alpha antagonist in preclinical kidney cancer models. Nature 539:107–111CrossRef Cho H, Du X, Rizzi JP et al (2016) On-target efficacy of a HIF-2alpha antagonist in preclinical kidney cancer models. Nature 539:107–111CrossRef
16.
go back to reference Ruf M, Moch H, Schraml P (2016) PD-L1 expression is regulated by hypoxia inducible factor in clear cell renal cell carcinoma. Int J Cancer 139:396–403CrossRef Ruf M, Moch H, Schraml P (2016) PD-L1 expression is regulated by hypoxia inducible factor in clear cell renal cell carcinoma. Int J Cancer 139:396–403CrossRef
17.
go back to reference Rahbar K, Afshar-Oromieh A, Jadvar H, Ahmadzadehfar H (2018) PSMA theranostics: current status and future directions. Mol Imaging 17:1536012118776068CrossRef Rahbar K, Afshar-Oromieh A, Jadvar H, Ahmadzadehfar H (2018) PSMA theranostics: current status and future directions. Mol Imaging 17:1536012118776068CrossRef
18.
go back to reference Van de Wiele C, Sathekge M, de Spiegeleer B et al (2020) PSMA expression on neovasculature of solid tumors. Histol Histopathol 35:919–927PubMed Van de Wiele C, Sathekge M, de Spiegeleer B et al (2020) PSMA expression on neovasculature of solid tumors. Histol Histopathol 35:919–927PubMed
19.
go back to reference Evangelista L, Basso U, Maruzzo M, Novara G (2020) The role of radiolabeled prostate-specific membrane antigen positron emission tomography/computed tomography for the evaluation of renal cancer. Eur Urol Focus 6:146–150CrossRef Evangelista L, Basso U, Maruzzo M, Novara G (2020) The role of radiolabeled prostate-specific membrane antigen positron emission tomography/computed tomography for the evaluation of renal cancer. Eur Urol Focus 6:146–150CrossRef
20.
go back to reference Ahn T, Roberts MJ, Abduljabar A et al (2019) A review of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) in renal cell carcinoma (RCC). Mol Imaging Biol 21:799–807CrossRef Ahn T, Roberts MJ, Abduljabar A et al (2019) A review of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) in renal cell carcinoma (RCC). Mol Imaging Biol 21:799–807CrossRef
21.
go back to reference Mittlmeier LM, Unterrainer M, Todica A et al (2020) PSMA PET/CT for tyrosine-kinase inhibitor monitoring in metastatic renal cell carcinoma. Eur J Nucl Med Mol Imaging 47:2216–2217CrossRef Mittlmeier LM, Unterrainer M, Todica A et al (2020) PSMA PET/CT for tyrosine-kinase inhibitor monitoring in metastatic renal cell carcinoma. Eur J Nucl Med Mol Imaging 47:2216–2217CrossRef
22.
go back to reference Mittlmeier LM, Unterrainer M, Rodler S et al (2021) F-PSMA-1007 PET/CT for response assessment in patients with metastatic renal cell carcinoma undergoing tyrosine kinase or checkpoint inhibitor therapy: preliminary results. Eur J Nucl Med Mol Imaging 48:2031–2037CrossRef Mittlmeier LM, Unterrainer M, Rodler S et al (2021) F-PSMA-1007 PET/CT for response assessment in patients with metastatic renal cell carcinoma undergoing tyrosine kinase or checkpoint inhibitor therapy: preliminary results. Eur J Nucl Med Mol Imaging 48:2031–2037CrossRef
23.
go back to reference Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM (2016) The 2016 WHO classification of tumours of the urinary system and male genital organs-Part A: renal, penile, and testicular tumours. Eur Urol 70:93–105 Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM (2016) The 2016 WHO classification of tumours of the urinary system and male genital organs-Part A: renal, penile, and testicular tumours. Eur Urol 70:93–105
24.
go back to reference Delahunt B, Eble JN, Egevad L, Samaratunga H (2019) Grading of renal cell carcinoma. Histopathology 74:4–17 Delahunt B, Eble JN, Egevad L, Samaratunga H (2019) Grading of renal cell carcinoma. Histopathology 74:4–17
25.
go back to reference Spatz S, Tolkach Y, Jung K et al (2018) Comprehensive evaluation of prostate specific membrane antigen expression in the vasculature of renal tumors: implications for imaging studies and prognostic role. J Urol 199:370–377CrossRef Spatz S, Tolkach Y, Jung K et al (2018) Comprehensive evaluation of prostate specific membrane antigen expression in the vasculature of renal tumors: implications for imaging studies and prognostic role. J Urol 199:370–377CrossRef
26.
go back to reference Terakawa T, Miyake H, Kusuda Y, Fujisawa M (2013) Expression level of vascular endothelial growth factor receptor-2 in radical nephrectomy specimens as a prognostic predictor in patients with metastatic renal cell carcinoma treated with sunitinib. Urol Oncol 31:493–498CrossRef Terakawa T, Miyake H, Kusuda Y, Fujisawa M (2013) Expression level of vascular endothelial growth factor receptor-2 in radical nephrectomy specimens as a prognostic predictor in patients with metastatic renal cell carcinoma treated with sunitinib. Urol Oncol 31:493–498CrossRef
27.
go back to reference Jiang W, Wang D, Liu X et al (2021) PD-L1 and VEGFR-2 expression in synchronous metastatic renal cell carcinoma treated with targeted therapy following cytoreductive nephrectomy. Urol Oncol 39 Jiang W, Wang D, Liu X et al (2021) PD-L1 and VEGFR-2 expression in synchronous metastatic renal cell carcinoma treated with targeted therapy following cytoreductive nephrectomy. Urol Oncol 39
28.
go back to reference Gao J, Xu Q, Fu Y et al (2021) Comprehensive evaluation of Ga-PSMA-11 PET/CT parameters for discriminating pathological characteristics in primary clear-cell renal cell carcinoma. Eur J Nucl Med Mol Imaging 48:561–569CrossRef Gao J, Xu Q, Fu Y et al (2021) Comprehensive evaluation of Ga-PSMA-11 PET/CT parameters for discriminating pathological characteristics in primary clear-cell renal cell carcinoma. Eur J Nucl Med Mol Imaging 48:561–569CrossRef
Metadata
Title
[68Ga]Ga-PSMA-11 PET/CT has potential application in predicting tumor HIF-2α expression and therapeutic response to HIF-2α antagonists in patients with RCC
Authors
Longxiyu Meng
Shun Zhang
Jie Gao
Qinfeng Xu
Yao Fu
Yi-hua Zhou
Feng Wang
Hongqian Guo
Publication date
31-03-2022
Publisher
Springer Berlin Heidelberg
Published in
European Radiology / Issue 9/2022
Print ISSN: 0938-7994
Electronic ISSN: 1432-1084
DOI
https://doi.org/10.1007/s00330-022-08738-y

Other articles of this Issue 9/2022

European Radiology 9/2022 Go to the issue