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Nascent prostate cancer heterogeneity drives evolution and resistance to intense hormonal therapy [article]

Scott Wilkinson, Huihui Ye, Fatima Karzai, Stephanie A. Harmon, Nicholas T. Terrigino, David J. VanderWeele, John R. Bright, Rayann Atway, Shana Y. Trostel, Nicole V. Carrabba, Nichelle C. Whitlock, Stephanie M. Walker (+16 others)
2020 medRxiv   pre-print

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Localized prostate cancer is distinctively characterized by intratumoral heterogeneity, and tumors with more complex evolutionary paths display more aggressive characteristics. In clinical trials of intense neoadjuvant androgen deprivation therapy (inADT), patients with complete or near-complete responses experience durable remissions. However, the molecular characteristics distinguishing exceptional responders and nonresponders at baseline have not been established. Here, we present the
more » ... ted histologic and genomic analysis of pre-treatment baseline tissue from our recent Phase 2 clinical study of inADT. Multiregion sampling demonstrated that patients with incomplete and nonresponding tumors demonstrate greater tumor diversity as estimated by phylogenetic tree reconstruction from DNA sequencing and automated analysis of immunohistochemical stains. Development of a four-factor binary model to predict poor response correlated with increased genomic diversity in our 37-patient cohort and a validation cohort of 188 Gleason score 8-10 prostate cancers. Together, these findings demonstrate that even in the primary setting, more highly evolved tumors have increased fitness to resist therapy.
doi:10.1101/2020.09.29.20199711 fatcat:dzro75luzjhr7lhaxkgtrr76ou
Citation

Scott Wilkinson, Huihui Ye, Fatima Karzai, Stephanie A. Harmon, Nicholas T. Terrigino, David J. VanderWeele, John R. Bright, Rayann Atway, Shana Y. Trostel, Nicole V. Carrabba, Nichelle C. Whitlock, Stephanie M. Walker, Rosina T. Lis, Houssein A. Sater, Brian J. Capaldo, Ravi A. Madan, James L. Gulley, Guinevere Chun, Maria J. Merino, Peter A. Pinto, Daniela C. Salles, Harsimar B. Kaur, Tamara L. Lotan, David J. Venzon, Peter L. Choyke, Baris Turkbey, William L. Dahut, Adam G. Sowalsky. "Nascent prostate cancer heterogeneity drives evolution and resistance to intense hormonal therapy." medRxiv (2020)