TY - JOUR
T1 - Plasma cell-free dna profiling of pten-pi3kakt pathway aberrations in metastatic castration-resistant prostate cancer
AU - Kwan, Edmond M.
AU - Dai, Chao
AU - Fettke, Heidi
AU - Hauser, Christine
AU - Docanto, Maria M.
AU - Bukczynska, Patricia
AU - Ng, Nicole
AU - Foroughi, Siavash
AU - Graham, Lisa Jane K.
AU - Mahon, Kate
AU - Tan, Winston
AU - Wang, Xiaohong
AU - Zhao, Zhixin
AU - Zheng, Tiantian
AU - Zhou, Kemin
AU - Yu, Jianjun
AU - Du, Pan
AU - Horvath, Lisa G.
AU - Jia, Shidong
AU - Kohli, Manish
AU - Azad, Arun A.
N1 - Publisher Copyright:
© 2021 American Society of Clinical Oncology. All rights reserved.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
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U2 - 10.1200/PO.20.00424
DO - 10.1200/PO.20.00424
M3 - Article
AN - SCOPUS:85114298710
SN - 2473-4284
VL - 5
SP - 622
EP - 637
JO - JCO Precision Oncology
JF - JCO Precision Oncology
ER -