Plasma cell-free dna profiling of pten-pi3kakt pathway aberrations in metastatic castration-resistant prostate cancer

Edmond M. Kwan, Chao Dai, Heidi Fettke, Christine Hauser, Maria M. Docanto, Patricia Bukczynska, Nicole Ng, Siavash Foroughi, Lisa Jane K. Graham, Kate Mahon, Winston Tan, Xiaohong Wang, Zhixin Zhao, Tiantian Zheng, Kemin Zhou, Jianjun Yu, Pan Du, Lisa G. Horvath, Shidong Jia, Manish KohliArun A. Azad

Research output: Contribution to journalArticlepeer-review


PURPOSE Tumor tissue frommetastatic castration-resistant prostate cancer (mCRPC) harbors frequent copy number variations (CNVs) in the PTEN-PI3K-AKT pathway. However, identifying CNVs in plasma cell-free DNA (cfDNA) has proven to be challenging. With emerging data supporting Akt inhibition in PTEN-deficientmCRPC, we profiled PTENPI3K- AKT pathway aberrations in patients with mCRPC using a novel cfDNA assay optimized for CNV detection. METHODS A next-generation sequencing-based cfDNA assay was used to profile 231 patients with mCRPC from two independent cohorts (Australian, n = 78; United States, n = 153). PTEN-PI3K-AKT pathway genomic aberrations were correlated with clinical outcomes, including progression-free survival and overall survival (OS). RESULTS PTEN loss and PIK3CA gain were detected in 37% (85 of 231) and 17% (39 of 231) of patients, respectively. Poorer outcomes were observed in patients with PTEN-PI3K-AKT pathway aberrations, including those with dual PTEN loss and PIK3CA gain (hazard ratio 2.3, 95% CI 1.2 to 4.4). Cumulative CNV burden in the PTEN-PI3K-AKT and androgen receptor (AR) pathways was associated with significantly worse clinical outcomes (0 v 1 v ≥ 2 CNVs in Australian cohort: Median OS 33.5 v 17.2 v 9.7 months, P<001; 0 v 1 v ≥ 2 CNVs in US cohort: Median OS 35.5 v 14.3 v 9.2 months, P <.001). Notably, 21% (31 of 146) of PTEN-neutral patients harbored alternative PTEN-PI3K-AKT pathway aberrations. CONCLUSION PTEN-PI3K-AKT pathway CNVs were readily detected using our cfDNA assay, with the prevalence of PTEN loss comparable with tissue-based studies. Additional PTEN-PI3K-AKT pathway aberrations were found in one fifth of PTEN-neutral cases. Concurrent CNVs in the PTEN-PI3K-AKT and AR pathways portended poor survival, and identifying this high-risk patient subset for dual AR/Akt inhibition may optimize precision treatment with Akt inhibitors in mCRPC.

Original languageEnglish (US)
Pages (from-to)622-637
Number of pages16
JournalJCO Precision Oncology
StatePublished - 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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