Molecular features of exceptional response to neoadjuvant anti-androgen therapy in high-risk localized prostate cancer

Cell Rep. 2021 Sep 7;36(10):109665. doi: 10.1016/j.celrep.2021.109665.


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.

Keywords: AR; PTEN; RNA-seq; SPOP; SPOPL; TGF-β; TP53; neoadjuvant androgen pathway inhibition; phylogenetics; whole exome sequencing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Vesicular Transport
  • Androgen Antagonists / therapeutic use*
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Humans
  • Male
  • Neoadjuvant Therapy / methods
  • Nuclear Proteins / drug effects*
  • Prostate-Specific Antigen / drug effects*
  • Prostatectomy / methods
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / pathology
  • Repressor Proteins / drug effects*
  • Risk


  • Adaptor Proteins, Vesicular Transport
  • Androgen Antagonists
  • Antineoplastic Agents, Hormonal
  • Nuclear Proteins
  • Repressor Proteins
  • SPOP protein, human
  • Prostate-Specific Antigen