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1. Predicting Prostate Cancer Molecular Subtype With Deep Learning on Histopathologic Images

Author

Erak, Eric, Oliveira, Lia DePaula, Mendes, Adrianna A., Dairo, Oluwademilade, Ertunc, Onur, Kulac, Ibrahim, Baena-Del Valle, Javier A., Jones, Tracy, Hicks, Jessica L., Glavaris, Stephanie, Guner, Gunes, Vidal, Igor Damasceno, Markowski, Mark, de la Calle, Claire, Trock, Bruce J., Meena, Avaneesh, Joshi, Uttara, Kondragunta, Chaith, Bonthu, Saikiran, Singhal, Nitin, De Marzo, Angelo M., and Lotan, Tamara L.

Published
2023
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3. Validation of a digital pathology-based multimodal artificial intelligence model in oligometastatic castration-sensitive prostate cancer, including in patients from the STOMP and ORIOLE phase II randomized clinical trials.

Author

Sutera, Philip Anthony, primary, Deek, Matthew Pierre, additional, Mendes, Adrianna, additional, Song, Yang, additional, Shetty, Amol, additional, Van der Eecken, Kim, additional, Chen, Emmalyn, additional, Showalter, Timothy N, additional, Royce, Trevor Joseph, additional, Todorovic, Tamara, additional, Huang, Huei-Chung, additional, Houck, Scott, additional, Yamashita, Rikiya, additional, Kiess, Ana Ponce, additional, Song, Daniel, additional, Lotan, Tamara L., additional, Esteva, Andre, additional, Feng, Felix Y, additional, Tran, Phuoc T., additional, and Ost, Piet, additional

Published
2024
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4. PD13-08 ERG STATUS IN MRI VISIBLE TUMORS PREDICTS GRADE RECLASSIFICATION IN ACTIVE SURVEILLANCE

Author

de la Calle, Claire M., primary, Dairo, Oluwademilade O., additional, Su, Zhuo Tony, additional, Jing, Yuezhou, additional, Wang, Zitong, additional, Nishimura, Aki, additional, Mendes, Adrianna A., additional, Oliveira, Lia D., additional, Erak, Eric, additional, Salles, Daniela C., additional, Pavlovich, Christian P., additional, and Lotan, Tamara L., additional

Published
2024
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5. Definitions of disease burden across the spectrum of metastatic castration-sensitive prostate cancer: comparison by disease outcomes and genomics

Author

Sutera, Philip, Van Der Eecken, Kim, Kishan, Amar U., Hamid, Anis, Grist, Emily, Attard, Gerhardt, Lotan, Tamara, Mendes, Adrianna A., Paller, Channing J., Carducci, Michael A., Ross, Ashley, Wang, Hao, Pienta, Ken, Feng, Felix Y., Antonarakis, Emmanuel S., Ost, Piet, Song, Daniel Y., Greco, Stephen, Deville, Curtiland, DeWeese, Theodore, Tran, Phuoc T., and Deek, Matthew P.

Published
2022
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8. FIGURE 4 from FASN Gene Methylation is Associated with Fatty Acid Synthase Expression and Clinical-genomic Features of Prostate Cancer

Author

Dairo, Oluwademilade, primary, DePaula Oliveira, Lia, primary, Schaffer, Ethan, primary, Vidotto, Thiago, primary, Mendes, Adrianna A., primary, Lu, Jiayun, primary, Huynh, Sophie Vo, primary, Hicks, Jessica, primary, Sowalsky, Adam G., primary, De Marzo, Angelo M., primary, Joshu, Corrine E., primary, Hanratty, Brian, primary, Sfanos, Karen S., primary, Isaacs, William B., primary, Haffner, Michael C., primary, and Lotan, Tamara L., primary

Published
2024
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9. Supplementary Figure S2 from FASN Gene Methylation is Associated with Fatty Acid Synthase Expression and Clinical-genomic Features of Prostate Cancer

Author

Dairo, Oluwademilade, primary, DePaula Oliveira, Lia, primary, Schaffer, Ethan, primary, Vidotto, Thiago, primary, Mendes, Adrianna A., primary, Lu, Jiayun, primary, Huynh, Sophie Vo, primary, Hicks, Jessica, primary, Sowalsky, Adam G., primary, De Marzo, Angelo M., primary, Joshu, Corrine E., primary, Hanratty, Brian, primary, Sfanos, Karen S., primary, Isaacs, William B., primary, Haffner, Michael C., primary, and Lotan, Tamara L., primary

Published
2024
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10. FIGURE 3 from FASN Gene Methylation is Associated with Fatty Acid Synthase Expression and Clinical-genomic Features of Prostate Cancer

Author

Dairo, Oluwademilade, primary, DePaula Oliveira, Lia, primary, Schaffer, Ethan, primary, Vidotto, Thiago, primary, Mendes, Adrianna A., primary, Lu, Jiayun, primary, Huynh, Sophie Vo, primary, Hicks, Jessica, primary, Sowalsky, Adam G., primary, De Marzo, Angelo M., primary, Joshu, Corrine E., primary, Hanratty, Brian, primary, Sfanos, Karen S., primary, Isaacs, William B., primary, Haffner, Michael C., primary, and Lotan, Tamara L., primary

Published
2024
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11. Data from FASN Gene Methylation is Associated with Fatty Acid Synthase Expression and Clinical-genomic Features of Prostate Cancer

Author

Dairo, Oluwademilade, primary, DePaula Oliveira, Lia, primary, Schaffer, Ethan, primary, Vidotto, Thiago, primary, Mendes, Adrianna A., primary, Lu, Jiayun, primary, Huynh, Sophie Vo, primary, Hicks, Jessica, primary, Sowalsky, Adam G., primary, De Marzo, Angelo M., primary, Joshu, Corrine E., primary, Hanratty, Brian, primary, Sfanos, Karen S., primary, Isaacs, William B., primary, Haffner, Michael C., primary, and Lotan, Tamara L., primary

Published
2024
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12. Supplementary Tables S1-S7 from FASN Gene Methylation is Associated with Fatty Acid Synthase Expression and Clinical-genomic Features of Prostate Cancer

Author

Dairo, Oluwademilade, primary, DePaula Oliveira, Lia, primary, Schaffer, Ethan, primary, Vidotto, Thiago, primary, Mendes, Adrianna A., primary, Lu, Jiayun, primary, Huynh, Sophie Vo, primary, Hicks, Jessica, primary, Sowalsky, Adam G., primary, De Marzo, Angelo M., primary, Joshu, Corrine E., primary, Hanratty, Brian, primary, Sfanos, Karen S., primary, Isaacs, William B., primary, Haffner, Michael C., primary, and Lotan, Tamara L., primary

Published
2024
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13. FIGURE 5 from FASN Gene Methylation is Associated with Fatty Acid Synthase Expression and Clinical-genomic Features of Prostate Cancer

Author

Dairo, Oluwademilade, primary, DePaula Oliveira, Lia, primary, Schaffer, Ethan, primary, Vidotto, Thiago, primary, Mendes, Adrianna A., primary, Lu, Jiayun, primary, Huynh, Sophie Vo, primary, Hicks, Jessica, primary, Sowalsky, Adam G., primary, De Marzo, Angelo M., primary, Joshu, Corrine E., primary, Hanratty, Brian, primary, Sfanos, Karen S., primary, Isaacs, William B., primary, Haffner, Michael C., primary, and Lotan, Tamara L., primary

Published
2024
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14. FIGURE 6 from FASN Gene Methylation is Associated with Fatty Acid Synthase Expression and Clinical-genomic Features of Prostate Cancer

Author

Dairo, Oluwademilade, primary, DePaula Oliveira, Lia, primary, Schaffer, Ethan, primary, Vidotto, Thiago, primary, Mendes, Adrianna A., primary, Lu, Jiayun, primary, Huynh, Sophie Vo, primary, Hicks, Jessica, primary, Sowalsky, Adam G., primary, De Marzo, Angelo M., primary, Joshu, Corrine E., primary, Hanratty, Brian, primary, Sfanos, Karen S., primary, Isaacs, William B., primary, Haffner, Michael C., primary, and Lotan, Tamara L., primary

Published
2024
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15. FIGURE 2 from FASN Gene Methylation is Associated with Fatty Acid Synthase Expression and Clinical-genomic Features of Prostate Cancer

Author

Dairo, Oluwademilade, primary, DePaula Oliveira, Lia, primary, Schaffer, Ethan, primary, Vidotto, Thiago, primary, Mendes, Adrianna A., primary, Lu, Jiayun, primary, Huynh, Sophie Vo, primary, Hicks, Jessica, primary, Sowalsky, Adam G., primary, De Marzo, Angelo M., primary, Joshu, Corrine E., primary, Hanratty, Brian, primary, Sfanos, Karen S., primary, Isaacs, William B., primary, Haffner, Michael C., primary, and Lotan, Tamara L., primary

Published
2024
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16. TABLE 2 from FASN Gene Methylation is Associated with Fatty Acid Synthase Expression and Clinical-genomic Features of Prostate Cancer

Author

Dairo, Oluwademilade, primary, DePaula Oliveira, Lia, primary, Schaffer, Ethan, primary, Vidotto, Thiago, primary, Mendes, Adrianna A., primary, Lu, Jiayun, primary, Huynh, Sophie Vo, primary, Hicks, Jessica, primary, Sowalsky, Adam G., primary, De Marzo, Angelo M., primary, Joshu, Corrine E., primary, Hanratty, Brian, primary, Sfanos, Karen S., primary, Isaacs, William B., primary, Haffner, Michael C., primary, and Lotan, Tamara L., primary

Published
2024
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17. TABLE 1 from FASN Gene Methylation is Associated with Fatty Acid Synthase Expression and Clinical-genomic Features of Prostate Cancer

Author

Dairo, Oluwademilade, primary, DePaula Oliveira, Lia, primary, Schaffer, Ethan, primary, Vidotto, Thiago, primary, Mendes, Adrianna A., primary, Lu, Jiayun, primary, Huynh, Sophie Vo, primary, Hicks, Jessica, primary, Sowalsky, Adam G., primary, De Marzo, Angelo M., primary, Joshu, Corrine E., primary, Hanratty, Brian, primary, Sfanos, Karen S., primary, Isaacs, William B., primary, Haffner, Michael C., primary, and Lotan, Tamara L., primary

Published
2024
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18. FIGURE 1 from FASN Gene Methylation is Associated with Fatty Acid Synthase Expression and Clinical-genomic Features of Prostate Cancer

Author

Dairo, Oluwademilade, primary, DePaula Oliveira, Lia, primary, Schaffer, Ethan, primary, Vidotto, Thiago, primary, Mendes, Adrianna A., primary, Lu, Jiayun, primary, Huynh, Sophie Vo, primary, Hicks, Jessica, primary, Sowalsky, Adam G., primary, De Marzo, Angelo M., primary, Joshu, Corrine E., primary, Hanratty, Brian, primary, Sfanos, Karen S., primary, Isaacs, William B., primary, Haffner, Michael C., primary, and Lotan, Tamara L., primary

Published
2024
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19. FASN Gene Methylation is Associated with Fatty Acid Synthase Expression and Clinical-Genomic Features of Prostate Cancer

Author

Dairo, Oluwademilade O, primary, DePaula Oliveira, Lia, additional, Schaffer, Ethan, additional, Vidotto, Thiago, additional, Mendes, Adrianna A A, additional, Lu, Jiayun, additional, Huynh, Sophie Vo, additional, Hicks, Jessica L., additional, Sowalsky, Adam G., additional, De Marzo, Angelo M, additional, Joshu, Corinne E, additional, Hanratty, Brian, additional, Sfanos, Karen S, additional, Isaacs, William B., additional, Haffner, Michael C., additional, and Lotan, Tamara L, additional

Published
2023
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20. Plasma cells are enriched in localized prostate cancer in Black men and are associated with improved outcomes

Author

Weiner, Adam B., Vidotto, Thiago, Liu, Yang, Mendes, Adrianna A., Salles, Daniela C., Faisal, Farzana A., Murali, Sanjana, McFarlane, Matthew, Imada, Eddie L., Zhao, Xin, Li, Ziwen, Davicioni, Elai, Marchionni, Luigi, Chinnaiyan, Arul M., Freedland, Stephen J., Spratt, Daniel E., Wu, Jennifer D., Lotan, Tamara L., and Schaeffer, Edward M.

Published
2021
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25. Clinical and Genomic Differences Between Advanced Molecular Imaging-detected and Conventional Imaging-detected Metachronous Oligometastatic Castration-sensitive Prostate Cancer

Author

Sutera, Philip, primary, Song, Yang, additional, Van der Eecken, Kim, additional, Shetty, Amol C., additional, English, Keara, additional, Hodges, Theresa, additional, Chang, Jinhee, additional, Fonteyne, Valérie, additional, Rana, Zaker, additional, Ren, Lei, additional, Mendes, Adrianna A., additional, Lumen, Nicolaas, additional, Delrue, Louke, additional, Verbeke, Sofie, additional, De Man, Kathia, additional, Song, Daniel Y., additional, Pienta, Kenneth, additional, Feng, Felix Y., additional, Joniau, Steven, additional, Lotan, Tamara, additional, Lane, Barton, additional, Kiess, Ana, additional, Rowe, Steven, additional, Pomper, Martin, additional, DeWeese, Theodore, additional, Deek, Matthew, additional, Sweeney, Christopher, additional, Ost, Piet, additional, and Tran, Phuoc T., additional

Published
2023
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26. Association of self-identified race and genetic ancestry with the immunogenomic landscape of primary prostate cancer

Author

Vidotto, Thiago, primary, Imada, Eddie L., additional, Faisal, Farzana, additional, Murali, Sanjana, additional, Mendes, Adrianna A., additional, Kaur, Harsimar, additional, Zheng, Siqun, additional, Xu, Jianfeng, additional, Schaeffer, Edward M., additional, Isaacs, William B., additional, Sfanos, Karen S., additional, Marchionni, Luigi, additional, and Lotan, Tamara L., additional

Published
2023
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27. Long-Term Outcomes and Genetic Predictors of Response to Metastasis-Directed Therapy Versus Observation in Oligometastatic Prostate Cancer: Analysis of STOMP and ORIOLE Trials

Author

Deek, Matthew P., primary, Van der Eecken, Kim, additional, Sutera, Philip, additional, Deek, Rebecca A., additional, Fonteyne, Valérie, additional, Mendes, Adrianna A., additional, Decaestecker, Karel, additional, Kiess, Ana Ponce, additional, Lumen, Nicolaas, additional, Phillips, Ryan, additional, De Bruycker, Aurélie, additional, Mishra, Mark, additional, Rana, Zaker, additional, Molitoris, Jason, additional, Lambert, Bieke, additional, Delrue, Louke, additional, Wang, Hailun, additional, Lowe, Kathryn, additional, Verbeke, Sofie, additional, Van Dorpe, Jo, additional, Bultijnck, Renée, additional, Villeirs, Geert, additional, De Man, Kathia, additional, Ameye, Filip, additional, Song, Daniel Y., additional, DeWeese, Theodore, additional, Paller, Channing J., additional, Feng, Felix Y., additional, Wyatt, Alexander, additional, Pienta, Kenneth J., additional, Diehn, Maximillian, additional, Bentzen, Soren M., additional, Joniau, Steven, additional, Vanhaverbeke, Friedl, additional, De Meerleer, Gert, additional, Antonarakis, Emmanuel S., additional, Lotan, Tamara L., additional, Berlin, Alejandro, additional, Siva, Shankar, additional, Ost, Piet, additional, and Tran, Phuoc T., additional

Published
2022
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28. Long-term outcomes and genetic predictors of response to metastasis-directed therapy versus observation in oligometastatic castration-sensitive prostate cancer: A pooled analysis of the STOMP and ORIOLE trials.

Author

Deek, Mathew Pierre, primary, Van der Eecken, Kim, additional, Sutera, Phillip, additional, Deek, Rebecca A, additional, Fonteyne, Valerie, additional, Mendes, Adrianna, additional, Lumen, Nicolaas, additional, Phillips, Ryan, additional, Delrue, Louke, additional, Verbeke, Sofie, additional, De Man, Kathia, additional, Song, Daniel Y., additional, Paller, Channing Judith, additional, Joniau, Steven, additional, De Meerleer, Gert, additional, Lotan, Tamara L., additional, Berlin, Alejandro, additional, Siva, Shankar, additional, Ost, Piet, additional, and Tran, Phuoc T., additional

Published
2022
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29. Association of B7-H3 expression with racial ancestry, immune cell density, and androgen receptor activation in prostate cancer

Author

Lack, Nathan Alan (ORCID 0000-0001-7399-5844 & YÖK ID 120842); Tekoğlu, Emirhan, Mendes, Adrianna A.; Lu, Jiayun; Kaur, Harsimar B.; Zheng, Siqun L.; Xu, Jianfeng; Hicks, Jessica; Weiner, Adam B.; Schaeffer, Edward M.; Ross, Ashley E.; Balk, Steven P.; Taplin, Mary-Ellen, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine; Graduate School of Sciences and Engineering, Department of Chemical and Biological Engineering, Lack, Nathan Alan (ORCID 0000-0001-7399-5844 & YÖK ID 120842); Tekoğlu, Emirhan, Mendes, Adrianna A.; Lu, Jiayun; Kaur, Harsimar B.; Zheng, Siqun L.; Xu, Jianfeng; Hicks, Jessica; Weiner, Adam B.; Schaeffer, Edward M.; Ross, Ashley E.; Balk, Steven P.; Taplin, Mary-Ellen, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine; Graduate School of Sciences and Engineering, and Department of Chemical and Biological Engineering

Abstract

Background: B7 homolog 3 (B7-H3) is an immunomodulatory molecule that is highly expressed in prostate cancer (PCa) and belongs to the B7 superfamily, which includes PD-L1. Immunotherapies (antibodies, antibody-drug conjugates, and chimeric antigen receptor T cells) targeting B7-H3 are currently in clinical trials; therefore, elucidating the molecular and immune microenvironment correlates of B7-H3 expression may help to guide trial design and interpretation. The authors tested the interconnected hypotheses that B7-H3 expression is associated with genetic racial ancestry, immune cell composition, and androgen receptor signaling in PCa. Methods: an automated, clinical-grade immunohistochemistry assay was developed by to digitally quantify B7-H3 protein expression across 2 racially diverse cohorts of primary PCa (1 with previously reported transcriptomic data) and pretreatment and posttreatment PCa tissues from a trial of intensive neoadjuvant hormonal therapy. Results: B7-H3 protein expression was significantly lower in self-identified Black patients and was inversely correlated with the percentage African ancestry. This association with race was independent of the significant association of B7-H3 protein expression with ERG/ETS and PTEN status. B7-H3 messenger RNA expression, but not B7-H3 protein expression, was significantly correlated with regulatory (FOXP3-positive) T-cell density. Finally, androgen receptor activity scores were significantly correlated with B7-H3 messenger RNA expression, and neoadjuvant intensive hormonal therapy was associated with a significant decrease in B7-H3 protein expression. Conclusions: the current data underscore the importance of studying racially and molecularly diverse PCa cohorts in the immunotherapy era. This study is among the first to use genetic ancestry markers to add to the emerging evidence that PCa in men of African ancestry may have a distinct biology associated with B7-H3 expression. Lay Summary: B7-H3 is an immunomodul, National Institutes of Health; National Cancer Institute Prostate Specialized Centers Research Excellence; Congressionally Directed Medical Research Programs Prostate Cancer Research Program (CDMRP- PCRP) Health Disparity Research Awards; Young Investigator Award and Congressionally Directed Medical Research Programs

Published
2022

30. Association of B7‐H3 expression with racial ancestry, immune cell density, and androgen receptor activation in prostate cancer

Author

Mendes, Adrianna A., primary, Lu, Jiayun, additional, Kaur, Harsimar B., additional, Zheng, Siqun L., additional, Xu, Jianfeng, additional, Hicks, Jessica, additional, Weiner, Adam B., additional, Schaeffer, Edward M., additional, Ross, Ashley E., additional, Balk, Steven P., additional, Taplin, Mary‐Ellen, additional, Lack, Nathan A., additional, Tekoglu, Emirhan, additional, Maynard, Janielle P., additional, De Marzo, Angelo M., additional, Antonarakis, Emmanuel S., additional, Sfanos, Karen S., additional, Joshu, Corinne E., additional, Shenderov, Eugene, additional, and Lotan, Tamara L., additional

Published
2022
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31. Abstract PO-100: Association of B7-H3 expression with racial ancestry, immune cell density and AR activation in prostate cancer

Author

Mendes, Adrianna A., primary, Lu, Jiayun, additional, Kaur, Harsimar B, additional, Zheng, Siqun, additional, Xu, Jianfeng, additional, Schaeffer, Edward M., additional, Sfanos, Karen S., additional, Maynard, Janielle, additional, Ross, Ashley E., additional, Balk, Steven P., additional, Taplin, Mary-Ellen, additional, Antonarakis, Emmanuel S., additional, Joshu, Corinne E., additional, Shenderov, Eugene, additional, and Lotan, Tamara L., additional

Published
2022
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34. Comparison of Pathologist and Artificial Intelligence–based Grading for Prediction of Metastatic Outcomes After Radical Prostatectomy

Author

Oliveira, Lia D., Lu, Jiayun, Erak, Eric, Mendes, Adrianna A., Dairo, Oluwademilade, Ertunc, Onur, Kulac, Ibrahim, Baena-Del Valle, Javier A., Jones, Tracy, Hicks, Jessica L., Glavaris, Stephanie, Guner, Gunes, Vidal, Igor D., Trock, Bruce J., Joshi, Uttara, Kondragunta, Chaith, Bonthu, Saikiran, Joshu, Corinne, Singhal, Nitin, De Marzo, Angelo M., and Lotan, Tamara L.

Abstract

Artificial intelligence–based prostate cancer grading algorithms using a single representative slide of the dominant tumor nodule perform similarly to contemporary expert pathology grading for association with metastasis.

Published
2024
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35. PTEN Loss Is Associated with Adverse Outcomes in the Setting of Salvage Radiation Therapy

Author

Lee, Emerson, Oliveira, Lia DePaula, Dairo, Oluwademilade, Abadchi, Sanaz Nourmohammadi, Cha, Eumee, Mendes, Adrianna A., Wang, Jarey H., Song, Daniel Y., and Lotan, Tamara L.

Abstract

This study identifies PTEN loss as an independent adverse prognostic factor for biochemical recurrence-free and metastasis-free survival in prostate cancer patients treated with salvage radiotherapy, a notable finding given a relative paucity of studies on molecular biomarkers in the salvage setting.

Published
2024
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36. Association between pathogenic germline mutations in <italic>BRCA2</italic> and <italic>ATM</italic> and tumor-infiltrating lymphocytes in primary prostate cancer.

Author

Kaur, Harsimar B., Vidotto, Thiago, Mendes, Adrianna A., Salles, Daniela C., Isaacs, William B., Antonarakis, Emmanuel S., and Lotan, Tamara L.

Abstract

Pathogenic mutations in homologous recombination (HR) DNA repair genes may be associated with increased tumor mutational burden and numbers of tumor-infiltrating lymphocytes (TIL). Though HR-deficient prostate tumors have been anecdotally associated with improved responses to immunotherapy, it is unclear whether HR mutations or HR deficiency (HRD) scores predict for increased T-cell densities in this cancer. We evaluated 17 primary prostate tumors from patients with pathogenic germline BRCA2 mutations (gBRCA2) and 21 primary prostate tumors from patients with pathogenic germline ATM (gATM) mutations, which were compared to 19 control tumors lacking HR gene mutations, as well as the TCGA prostate cancer cohort. HRD score was estimated by targeted sequencing (gBRCA2 and gATM) or by SNP microarray (TCGA). Tumor-associated T-cell densities were assessed using validated automated digital image analysis of CD8 and FOXP3 immunostaining (gBRCA2 or gATM) or by methylCIBERSORT (TCGA). CD8 + and FOXP3 + T-cell densities were significantly correlated with each other in gBRCA2 and gATM cases. There was no significant difference between CD8 + or FOXP3 + TIL densities in gBRCA2 or gATM cases compared to controls. In the TCGA cohort, HRD score was associated with predicted CD8 + and FOXP3 + TILs. Associations were also seen for HRD score and TIL density among the germline-mutated cases. In contrast to mismatch repair-deficient primary prostate tumors, cancers from germline BRCA2 or ATM mutation carriers do not appear to be associated with elevated TIL density. However, measures of genomic scarring, such as HRD score, may be associated with increased tumor-infiltrating T-cells. [ABSTRACT FROM AUTHOR]

Published
2021
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37. Association of B7‐H3 expression with racial ancestry, immune cell density, and androgen receptor activation in prostate cancer

Author

Adrianna A. Mendes, Jiayun Lu, Harsimar B. Kaur, Siqun L. Zheng, Jianfeng Xu, Jessica Hicks, Adam B. Weiner, Edward M. Schaeffer, Ashley E. Ross, Steven P. Balk, Mary‐Ellen Taplin, Nathan A. Lack, Emirhan Tekoglu, Janielle P. Maynard, Angelo M. De Marzo, Emmanuel S. Antonarakis, Karen S. Sfanos, Corinne E. Joshu, Eugene Shenderov, Tamara L. Lotan, Lack, Nathan Alan (ORCID 0000-0001-7399-5844 & YÖK ID 120842), Tekoğlu, Emirhan, Mendes, Adrianna A., Lu, Jiayun, Kaur, Harsimar B., Zheng, Siqun L., Xu, Jianfeng, Hicks, Jessica, Weiner, Adam B., Schaeffer, Edward M., Ross, Ashley E., Balk, Steven P., Taplin, Mary-Ellen, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Graduate School of Sciences and Engineering, and Department of Chemical and Biological Engineering

Subjects
Male, African American, Androgen receptor (AR), B7 homolog 3 (B7-H3), ERG, Prostatic adenocarcinoma, PTEN, T cells, Tumor-infiltrating lymphocytes, Cancer Research, B7 Antigens, Oncology, Receptors, Androgen, Androgens, Tumor Microenvironment, Humans, Prostatic Neoplasms, Cell Count, RNA, Messenger, B7-H1 Antigen
Abstract

Background: B7 homolog 3 (B7-H3) is an immunomodulatory molecule that is highly expressed in prostate cancer (PCa) and belongs to the B7 superfamily, which includes PD-L1. Immunotherapies (antibodies, antibody-drug conjugates, and chimeric antigen receptor T cells) targeting B7-H3 are currently in clinical trials; therefore, elucidating the molecular and immune microenvironment correlates of B7-H3 expression may help to guide trial design and interpretation. The authors tested the interconnected hypotheses that B7-H3 expression is associated with genetic racial ancestry, immune cell composition, and androgen receptor signaling in PCa. Methods: an automated, clinical-grade immunohistochemistry assay was developed by to digitally quantify B7-H3 protein expression across 2 racially diverse cohorts of primary PCa (1 with previously reported transcriptomic data) and pretreatment and posttreatment PCa tissues from a trial of intensive neoadjuvant hormonal therapy. Results: B7-H3 protein expression was significantly lower in self-identified Black patients and was inversely correlated with the percentage African ancestry. This association with race was independent of the significant association of B7-H3 protein expression with ERG/ETS and PTEN status. B7-H3 messenger RNA expression, but not B7-H3 protein expression, was significantly correlated with regulatory (FOXP3-positive) T-cell density. Finally, androgen receptor activity scores were significantly correlated with B7-H3 messenger RNA expression, and neoadjuvant intensive hormonal therapy was associated with a significant decrease in B7-H3 protein expression. Conclusions: the current data underscore the importance of studying racially and molecularly diverse PCa cohorts in the immunotherapy era. This study is among the first to use genetic ancestry markers to add to the emerging evidence that PCa in men of African ancestry may have a distinct biology associated with B7-H3 expression. Lay Summary: B7-H3 is an immunomodulatory molecule that is highly expressed in prostate cancer and is under investigation in clinical trials. The authors determined that B7-H3 protein expression is inversely correlated with an individual's proportion of African ancestry. The results demonstrate that B7-H3 messenger RNA expression is correlated with the density of tumor T-regulatory cells. Finally, in the first paired analysis of B7-H3 protein expression before and after neoadjuvant intensive hormone therapy, the authors determined that hormone therapy is associated with a decrease in B7-H3 protein levels, suggesting that androgen signaling may positively regulate B7-H3 expression. These results may help to guide the design of future clinical trials and to develop biomarkers of response in such trials., National Institutes of Health; National Cancer Institute Prostate Specialized Centers Research Excellence; Congressionally Directed Medical Research Programs Prostate Cancer Research Program (CDMRP- PCRP) Health Disparity Research Awards; Young Investigator Award and Congressionally Directed Medical Research Programs

Published
2022

38. Association of Genomic Prostate Score at positive margin with recurrence after radical prostatectomy.

Author

Nourmohammadi Abadchi S, Salles DC, Flannery C, Sama V, Baehner FL, Zambon JP, Mendes AA, DePaula Oliveira L, Han M, Jing Y, Partin AW, Trock BJ, and Lotan TL

Abstract

Objectives: To evaluate the utility of the 17-gene Genomic Prostate Score® (GPS; MDxHealth, Irvine, CA, USA) performed on prostate cancer at the positive margin of the radical prostatectomy (RP) for its association with risk of subsequent biochemical recurrence (BCR)., Patients and Methods: We designed a case-cohort for the outcome of BCR, selecting 223 from a cohort of 813 RP patients treated at Johns Hopkins from 2008 to 2017 with positive margins and available clinical data; of these, 213 had available tissue and clinical data. RNA was isolated from formalin-fixed paraffin-embedded tumour tissue adjacent to the positive surgical margin and the GPS was evaluable in 203 of these patients with a score ranging from 0 to 100, with higher scores indicating higher risk. All patients underwent RP with or without adjuvant radiation therapy (ART). The statistical analysis employed Cox proportional hazards regression models for outcome of BCR weighted for case-cohort design., Results: In univariable analysis, every 20-unit increase in the GPS was associated with a nearly threefold increase in risk of BCR (hazard ratio [HR] per 20 units 2.82, P < 0.001). In a multivariable Cox model adjusted for age, race, Cancer of the Prostate Risk Assessment Postsurgical score, Grade Group at the positive margin, and ART, the GPS was significantly associated with BCR (HR 1.56 per 20 units; 95% confidence interval 1.11-2.19; P = 0.011). The study is limited by its retrospective and single institution design., Conclusions: The GPS at the positive surgical margin could help stratify prognosis and inform clinical decision-making regarding adjuvant therapy after RP., (© 2024 BJU International.)

Published
2024
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39. FASN Gene Methylation is Associated with Fatty Acid Synthase Expression and Clinical-genomic Features of Prostate Cancer.

Author

Dairo O, DePaula Oliveira L, Schaffer E, Vidotto T, Mendes AA, Lu J, Huynh SV, Hicks J, Sowalsky AG, De Marzo AM, Joshu CE, Hanratty B, Sfanos KS, Isaacs WB, Haffner MC, and Lotan TL

Subjects
Male, Humans, Fatty Acid Synthases genetics, DNA Methylation genetics, Fatty Acids, Genomics, Fatty Acid Synthase, Type I genetics, Epigenesis, Genetic genetics, Prostatic Neoplasms genetics
Abstract

Fatty acid synthase (FASN) catalyzes the synthesis of long-chain saturated fatty acids and is overexpressed during prostatic tumorigenesis, where it is the therapeutic target in several ongoing trials. However, the mechanism of FASN upregulation in prostate cancer remains unclear. Here, we examine FASN gene CpG methylation pattern by InfiniumEPIC profiling and whole-genome bisulfite sequencing across multiple racially diverse primary and metastatic prostate cancer cohorts, comparing with FASN protein expression as measured by digitally quantified IHC assay and reverse phase protein array analysis or FASN gene expression. We demonstrate that the FASN gene body is hypomethylated and overexpressed in primary prostate tumors compared with benign tissue, and FASN gene methylation is significantly inversely correlated with FASN protein or gene expression in both primary and metastatic prostate cancer. Primary prostate tumors with ERG gene rearrangement have increased FASN expression and we find evidence of FASN hypomethylation in this context. FASN expression is also significantly increased in prostate tumors from carriers of the germline HOXB13 G84E mutation compared with matched controls, consistent with a report that HOXB13 may contribute to epigenetic regulation of FASN in vitro. However, in contrast to previous studies, we find no significant association of FASN expression or methylation with self-identified race in models that include ERG status across two independent primary tumor cohorts. Taken together, these data support a potential epigenetic mechanism for FASN regulation in the prostate which may be relevant for selecting patients responsive to FASN inhibitors., Significance: Here, we leverage multiple independent primary and metastatic prostate cancer cohorts to demonstrate that FASN gene body methylation is highly inversely correlated with FASN gene and protein expression. This finding may shed light on epigenetic mechanisms of FASN regulation in prostate cancer and provides a potentially useful biomarker for selecting patients in future trials of FASN inhibitors., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Published
2024
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