@article{4842286592634a0a955c4d14a43319da,
title = "Deciphering intratumoral molecular heterogeneity in clear cell renal cell carcinoma with a radiogenomics platform",
abstract = "Purpose: Intratumoral heterogeneity (ITH) challenges the molecular characterization of clear cell renal cell carcinoma (ccRCC) and is a confounding factor for therapy selection. Most approaches to evaluate ITH are limited by two-dimensional ex vivo tissue analyses. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can noninvasively assess the spatial landscape of entire tumors in their natural milieu. To assess the potential of DCE-MRI, we developed a vertically integrated radiogenomics colocalization approach for multi-region tissue acquisition and analyses. We investigated the potential of spatial imaging features to predict molecular subtypes using histopathologic and transcriptome correlatives. Experimental Design: We report the results of a prospective study of 49 patients with ccRCC who underwent DCE-MRI prior to nephrectomy. Surgical specimens were sectioned to match the MRI acquisition plane. RNA sequencing data from multi-region tumor sampling (80 samples) were correlated with percent enhancement on DCE-MRI in spatially colocalized regions of the tumor. Independently, we evaluated clinical applicability of our findings in 19 patients with metastatic RCC (39 metastases) treated with first-line antiangiogenic drugs or checkpoint inhibitors. Results: DCE-MRI identified tumor features associated with angiogenesis and inflammation, which differed within and across tumors, and likely contribute to the efficacy of antiangiogenic drugs and immunotherapies. Our vertically integrated analyses show that angiogenesis and inflammation frequently coexist and spatially anti-correlate in the same tumor. Furthermore, MRI contrast enhancement identifies phenotypes with better response to antiangiogenic therapy among patients with metastatic RCC. Conclusions: These findings have important implications for decision models based on biopsy samples and highlight the potential of more comprehensive imaging-based approaches.",
author = "Durga Udayakumar and Ze Zhang and Yin Xi and Dwivedi, {Durgesh K.} and Michael Fulkerson and Sydney Haldeman and Tiffani McKenzie and Qurratulain Yousuf and Allison Joyce and Asghar Hajibeigi and Hollis Notgrass and {Diaz De Leon III}, Alberto and Qing Yuan and Lewis, {Matthew A.} and Madhuranthakam, {Ananth J.} and Sibley, {Robert C.} and Roy Elias and Junyu Guo and Alana Christie and McKay, {Ren{\'e}e M.} and Cadeddu, {Jeffrey A.} and Aditya Bagrodia and Vitaly Margulis and James Brugarolas and Tao Wang and Payal Kapur and Ivan Pedrosa",
note = "Funding Information: This work was partially funded by grants NIH # 5R01CA154475 (D. Udayakumar, Y. Xi, D.K. Dwivedi, P. Kapur, M. Fulkerson, S. Haldeman, Q. Yuan, J. Guo, J.A. Cadeddu, and I. Pedrosa), P50CA196516 (J.A. Cadeddu, P. Kapur, A. Christie, R.M. McKay, I. Pedrosa, and J. Brugarolas), U01CA207091 (A.J. Madhuranthakam and I. Pedrosa), R01CA258584 (Z. Zhang and T. Wang), CPRIT RP190208 (T. Wang), and Cancer Center Support Grant 5P30CA142543. Funding Information: D. Udayakumar reports grants from NIH-NCI R01CA154475 during the conduct of the study. Y. Xi reports grants from NIH, CPRIT, and Cancer Center Support Grant during the conduct of the study. D.K. Dwivedi reports grants from NIH-NCI R01CA154475 during the conduct of the study. M.A. Lewis reports grants from NIH and CPRIT during the conduct of the study. A.J. Madhuranthakam reports grants from NIH/NCI (U01CA207091) during the conduct of the study, grants from Novartis Institute for Biomedical Research outside the submitted work, and nonfinancial research support from Philips Healthcare. A. Christie reports grants from NIH during the conduct of the study, as well as grants from NIH and CPRIT outside the submitted work. J. Brugarolas reports grants from NCI during the conduct of the study. I. Pedrosa reports grants from NIH during the conduct of the study; personal fees from Bayer Healthcare and Merck, other support from Health Tech International, and nonfinancial support from Philips Healthcare outside the submitted work; and a patent for EP3047293B1 issued to European Patent Office, US10408904B2 issued to United States Patent Office, US20210055364A1 issued to United States Patent Office, US20190246940A1 issued to United States Patent Office, and WO2018187338A1 pending to United States Patent Office. No disclosures were reported by the other authors. Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research.",
year = "2021",
month = sep,
day = "1",
doi = "10.1158/1078-0432.CCR-21-0706",
language = "English (US)",
volume = "27",
pages = "4794--4806",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "17",
}