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Plasma Cell-Free DNA Profiling of PTEN-PI3K-AKT Pathway Aberrations in Metastatic Castration-Resistant Prostate Cancer


Tumor tissue from metastatic 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-deficient mCRPC, we profiled PTEN-PI3K-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.

Type Journal
ISBN 2473-4284 (Electronic) 2473-4284 (Linking)
Authors Kwan, E. M.; Dai, C.; Fettke, H.; Hauser, C.; Docanto, M. M.; Bukczynska, P.; Ng, N.; Foroughi, S.; Graham, L. K.; Mahon, K.; Tan, W.; Wang, X.; Zhao, Z.; Zheng, T.; Zhou, K.; Yu, J.; Du, P.; Horvath, L. G.; Jia, S.; Kohli, M.; Azad, A. A.
Responsible Garvan Author A/Prof Lisa Horvath
Publisher Name JCO Precision Oncology
Published Date 2021-04-30
Published Volume 5
Published Pages PO.20.00424
Status Published in-print
DOI 10.1200/PO.20.00424
URL link to publisher's version