Harnessing the power of liquid biopsy for understanding the genetic and immunological mechanisms of immunotherapy failures in metastatic castration-resistant prostate cancer

Authors

  • C Li
  • A Baj
  • CY Seo
  • NT Terrigino
  • JR Bright
  • ST Hennigan
  • IM King
  • S Wilkinson
  • SY Trostel
  • WD Figg
  • WL Dahut
  • JM Lee
  • DY Takeda
  • F Karzai
  • AG Sowalsky

Abstract

Metastatic castration-resistant prostate cancer (mCRPC) is a class of advanced prostate cancer with a high mortality which is largely due to the frequent emergence of therapy resistance. Combination therapy that targets PD-L1 and PARP1 initially showed promising results, yet most patients suffered from disease progression within a year. Liquid biopsy, such as circulating-tumor DNA (ctDNA), offers tremendous opportunities for interrogating the genomic and immunological impacts without invasive tissue sampling. Therefore, we hypothesized that mCRPCs that failed to respond to the combination therapy carried distinct genomic and immunological profiles, which were captured in plasma ctDNA and could be computationally resolved using whole-genome sequencing (WGS). To address this question, we obtained plasma cell-free DNA (cfDNA), a mixture of ctDNA and other tissue-derived DNA, from 38 individuals treated with the combination therapy (NCT02484404). WGS (median coverage: 139x) was performed using cfDNA and fragmented buffy coat DNA as germline control. Through various computational strategies, we observed a negative association between baseline cfDNA tumor fraction and therapy response. Even though predisposed BRCA2 alterations predict favorable outcomes as expected, oncogenic mutations in TP53 are negatively associated with therapy response. Patients with favorable response also have a greater reservoir of T cell clonotypes defined by CDR3 sequence diversity from the buffy coat DNA, which often implicates a stronger antigenic recognition. Copy number loss of MHC genes are associated with some individuals with poor therapy outcomes and low clonotype diversity. Transcriptomic profiling of the buffy coat is currently being performed to identify critical immune determinants of therapy outcome.

Scientific Focus Area: Genetics and Genomics

This page was last updated on Tuesday, August 6, 2024

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