High-risk localized prostate cancer (HRLPC) is associated with a substantial risk of recurrence and disease mortality. Recent clinical trials have shown that intensifying anti-androgen therapies administered before prostatectomy can induce pathologic complete responses or minimal residual disease, called exceptional response, although the molecular determinants of these clinical outcomes are largely unknown. Here, we perform whole-exome and transcriptome sequencing on pre-treatment multi-regional tumor biopsies from exceptional responders (ERs) and non-responders (NRs, pathologic T3 or lymph node-positive disease) to intensive neoadjuvant anti-androgen therapies. Clonal SPOP mutation and SPOPL copy-number loss are exclusively observed in ERs, while clonal TP53 mutation and PTEN copy-number loss are exclusively observed in NRs. Transcriptional programs involving androgen signaling and TGF-β signaling are enriched in ERs and NRs, respectively. These findings may guide prospective validation studies of these molecular features in large HRLPC clinical cohorts treated with neoadjuvant anti-androgens to improve patient stratification.
Cell reports. 2021 Sep 07 [Epub]
Alok K Tewari, Alexander T M Cheung, Jett Crowdis, Jake R Conway, Sabrina Y Camp, Stephanie A Wankowicz, Dimitri G Livitz, Jihye Park, Rosina T Lis, Alice Bosma-Moody, Meng Xiao He, Saud H AlDubayan, Zhenwei Zhang, Rana R McKay, Ignaty Leshchiner, Myles Brown, Steven P Balk, Gad Getz, Mary-Ellen Taplin, Eliezer M Van Allen
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Graduate Program in Bioinformatics and Integrative Genomics, Boston, MA 02115, USA., Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Graduate Program in Biophysics, Boston, MA 02115, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA., Division of Hematology/Oncology, University of California San Diego, San Diego, CA 92037, USA., Division of Cancer Biology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA., Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: ., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: .