TY - JOUR
T1 - Platelet-coated circulating tumor cells are a predictive biomarker in patients with metastatic castrate-resistant prostate cancer
AU - Chai, Shoujie
AU - Matsumoto, Nicholas
AU - Storgard, Ryan
AU - Peng, Chen Ching
AU - Aparicio, Ana
AU - Ormseth, Benjamin
AU - Rappard, Kate
AU - Cunningham, Katherine
AU - Kolatkar, Anand
AU - Nevarez, Rafael
AU - Tu, Kai Han
AU - Hsu, Ching Ju
AU - Malihi, Paymaneh
AU - Corn, Paul
AU - Zurita, Amado
AU - Hicks, James
AU - Kuhn, Peter
AU - Ruiz-Velasco, Carmen
N1 - Funding Information:
S. Chai reports grants from Prostate Cancer Foundation Award; and grants from David and Janet Polak Foundation Fellowship in Convergent Science during the conduct of the study; in addition, S. Chai has a patent for USC Serial No.: 62/914,763 issued to University of Southern California. B. Ormseth reports a patent for US Serial No. 62/914,763 issued to University of Southern California. K. Cunningham reports other support from Epic Sciences outside the submitted work. A. Kolatkar reports personal fees from Epic Sciences outside the submitted work; in addition, A. Kolatkar has a patent for US10613089B2 issued. J. Hicks reports personal fees from Epic Sciences outside the submitted work. P. Kuhn reports grants from Prostate Cancer Foundation Award, Breast Cancer Research Foundation; nonfinancial support from NCI’s USC Norris Comprehensive Cancer Center (CORE) Support; other support from Vicky Joseph Research Fund, Vassiliadis Research Fund, Susan Pekarovics during the conduct of the study; other support from Epic Sciences outside the submitted work; in addition, P. Kuhn has a patent for Systems, Methods and Assays for Outlier Clustering Unsupervised Learning Automated Report (OCULAR) issued to US Serial No. 62/914,763. No disclosures were reported by the other authors.
Funding Information:
The authors would like to thank all the patients who participated in this study, Dr. Jeremy Mason, Dr. Stephanie Shishido, Dr. Rishvanth Prabakar, and Nikki Higa for critical reviewing, comments, and statistical advice, Xiomara Villaseñor for scheduling staining and scanning, Libere Ndacayisaba for project discussions, reimaging, and picking, Aidan Plant for enumerating mes.CTCs and reimaging, Annie Amacker for curating NBD reports, Elvia Nuñez and Allison Welsh for project/ financial management, Lisa Welter, Nikki Higa, Jiyoun Seo, Liya Xu, Sonia Maryam Setayesh, Drahomír Kolen≤cík, Carlisle Maney, Dean Tessone, Sean Solomon, Daniel Liu, Eric Yang, Ali Hashemi, Amanda Hmelar, Olivia Hart, Mihir Kumar, Arushi Agrawal, Isabelle Vu, Sachin Narayan, and Ayeshna Desai for reimaging and picking, and BioRender.com with which we created the visual overview. This work is supported fully or partially by the Prostate Cancer Foundation Award 17CHAL01 (A. Aparicio, P. Kuhn, J. Hicks, and S. Chai), Breast Cancer Research Foundation Award BCRF-20-089 (J. Hicks and P. Kuhn), NCI’s USC Norris Comprehensive Cancer Center (CORE) Support 5P30CA014089-40 (P. Kuhn), the Solon Scott III Prostate Cancer Research Fund (P. Corn), David and Janet Polak Foundation Fellowship in Convergent Science (S. Chai and P. Malihi), USC-Taiwan Postdoctoral Scholars Program (C.C. Peng), USC Provost Undergraduate Research Fellowship (R. Storgard), Vicky Joseph Research Fund, Vassiliadis Research Fund, and Susan Pekarovics.
Publisher Copyright:
© 2021 American Association for Cancer Research
PY - 2021/12
Y1 - 2021/12
N2 - Metastatic castration-resistant prostate cancer (mCRPC) includes a subset of patients with particularly unfavorable prognosis characterized by combined defects in at least two of three tumor suppressor genes: PTEN, RB1, and TP53 as aggressive variant prostate cancer molecular signature (AVPC-MS). We aimed to identify circulating tumor cells (CTC) signatures that could inform treatment decisions of patients with mCRPC with cabazitaxel-carboplatin combination therapy versus cabazitaxel alone. Liquid biopsy samples were collected prospectively from 79 patients for retrospective analysis. CTCs were detected, classified, enumerated through a computational pipeline followed by manual curation, and subjected to single-cell genome-wide copy-number profiling for AVPC-MS detection. On the basis of immunofluorescence intensities, detected rare cells were classified into 8 rare-cell groups. Further morphologic characterization categorized CTC subtypes from 4 cytokeratin-positive rare-cell groups, utilizing presence of mesenchymal features and platelet attachment. Of 79 cases, 77 (97.5%) had CTCs, 24 (30.4%) were positive for platelet-coated CTCs (pc.CTCs) and 25 (38.5%) of 65 sequenced patients exhibited AVPC-MS in CTCs. Survival analysis indicated that the presence of pc.CTCs identified the subset of patients who were AVPC-MS-positive with the worst prognosis and minimal benefit from combination therapy. In AVPC-MS-negative patients, its presence showed significant survival improvement from combination therapy. Our findings suggest the presence of pc.CTCs as a predictive biomarker to further stratify AVPC subsets with the worst prognosis and the most significant benefit of additional platinum therapy.
AB - Metastatic castration-resistant prostate cancer (mCRPC) includes a subset of patients with particularly unfavorable prognosis characterized by combined defects in at least two of three tumor suppressor genes: PTEN, RB1, and TP53 as aggressive variant prostate cancer molecular signature (AVPC-MS). We aimed to identify circulating tumor cells (CTC) signatures that could inform treatment decisions of patients with mCRPC with cabazitaxel-carboplatin combination therapy versus cabazitaxel alone. Liquid biopsy samples were collected prospectively from 79 patients for retrospective analysis. CTCs were detected, classified, enumerated through a computational pipeline followed by manual curation, and subjected to single-cell genome-wide copy-number profiling for AVPC-MS detection. On the basis of immunofluorescence intensities, detected rare cells were classified into 8 rare-cell groups. Further morphologic characterization categorized CTC subtypes from 4 cytokeratin-positive rare-cell groups, utilizing presence of mesenchymal features and platelet attachment. Of 79 cases, 77 (97.5%) had CTCs, 24 (30.4%) were positive for platelet-coated CTCs (pc.CTCs) and 25 (38.5%) of 65 sequenced patients exhibited AVPC-MS in CTCs. Survival analysis indicated that the presence of pc.CTCs identified the subset of patients who were AVPC-MS-positive with the worst prognosis and minimal benefit from combination therapy. In AVPC-MS-negative patients, its presence showed significant survival improvement from combination therapy. Our findings suggest the presence of pc.CTCs as a predictive biomarker to further stratify AVPC subsets with the worst prognosis and the most significant benefit of additional platinum therapy.
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U2 - 10.1158/1541-7786.MCR-21-0383
DO - 10.1158/1541-7786.MCR-21-0383
M3 - Article
C2 - 34462330
AN - SCOPUS:85120819120
SN - 1541-7786
VL - 19
SP - 2036
EP - 2045
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 12
ER -