Plasma cell-free DNA (cfDNA) profiling of PTEN-PI3K-AKT ...
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• PTEN-PI3K-AKT CNVs were readily detected using Predicine cfDNA assay, with prevalence of PTEN loss comparable to tissue studies. • Over one-fifth of PTEN-neutral patients had other activating aberrations in the PTEN-PI3K-AKT pathway. • Plasma cfDNA profiling of PTEN-PI3K-AKT and AR pathway aberrations may identify a poor-risk cohort primed for dual AR/Akt targeted therapy. RESULTS CONCLUSION INTRODUCTION Plasma cell-free DNA (cfDNA) profiling of PTEN-PI3K-AKT pathway aberrations in two multi-institutional independent metastatic castration-resistant prostate cancer (mCRPC) cohorts AIM • Tumor tissue from mCRPC harbors frequent copy number variations (CNVs) in the PTEN-PI3K-AKT pathway, but identifying them in plasma cfDNA has proven challenging, especially PTEN copy number loss. • With emerging data supporting Akt inhibition in PTEN-deficient mCRPC, cfDNA assays that robustly characterize PTEN-PI3K-AKT pathway aberrations are urgently needed. Edmond M Kwan 1,2 ; Chao Dai 3, ; Heidi Fettke 1, ; Christine Hauser 4 ; Maria M Docanto 1 ; Patricia Bukczynska 4 ; Nicole Ng 4,5,6 ; Siavash Foroughi 5,6 ; Lisa-Jane K Graham 7 ; Kate Mahon 7,8,9 ; Winston Tan 10 ; Xiaohong Wang, 3 ; Zhixin Zhao 3 ; Tiantian Zheng 3 ; Kemin Zhou 3 ; Jianjun Yu 3 ; Pan Du 3 ; Lisa G Horvath 7,8,9,11 ; Shidong Jia 3 ; Manish Kohli 12 ; Arun A Azad 1,13,14 1. Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, Australia. 2. Department of Medical Oncology, Monash Health, Melbourne, Australia 3. Predicine Inc., Hayward, California, USA 4. Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia 5. Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia 6. Department of Medical Biology, The University of Melbourne, Melbourne, Australia 7. Medical Oncology, Chris O’Brien Lifehouse, Sydney, Australia 8. University of Sydney, Sydney, Australia 9. Garvan Institute of Medical Research, Sydney, Australia 10. Division of Medical Oncology, Department of Medicine, Mayo Clinic, Jacksonville, FL, USA 11. Royal Prince Alfred Hospital, Sydney, Australia 12. Division of Oncology, Department of Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA 13. Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia 14. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia Using a validated cfDNA liquid biopsy assay in two independent mCRPC cohorts totalling 231 patients, our aims were to: 1. Characterize the mutational landscape of PTEN-PI3K-AKT pathway aberrations, with an emphasis on robust detection of PTEN loss. 2. Correlate genomic aberrations with longitudinal clinical outcomes. METHODS Cohort description and targeted cfDNA sequencing • Pre-treatment plasma samples were collected from mCRPC patients (pts) across two cohorts in Australia (AU; n=78) and USA (n=153). • Plasma PTEN-PI3K-AKT pathway aberrations were characterized using the CLIA-certified Predicine targeted panel-based NGS cfDNA assay. 1,2 • We included AR aberrations recognizing reciprocal PI3K regulation. 3,4 Outcomes and analysis • Kaplan-Meier curves and multivariable Cox proportional-hazards models assessed associations between PTEN-PI3K-AKT and AR pathway aberrations and overall survival. Patient cohort • Median follow-up was 28.0 and 80.7 months in AU and US cohorts, respectively; patient characteristics for each cohort shown in Table 1. • In the AU cohort, 49 pts (63%) commenced AR pathway inhibitors (ARPI; abiraterone or enzalutamide) and 29 pts (37%) commenced taxane chemotherapy (docetaxel or cabazitaxel). Figure 2: Kaplan-Meier analysis of OS according to PTEN copy number status (A,B) and cumulative CNVs in PTEN-PI3K-AKT and AR pathways (C,D). References: 1. Fettke H et al. Eur Urol 2020;78:173-80. 2. Kohli M et al. EbioMedicine 2020;54:102728. 3. Carver BS et al. Cancer Cell 2011;19:575-86. 4. Mulholland DJ et al. Cancer Cell 2011;19:792-804. Fig 1: Genomic landscape of PTEN-PI3K-AKT and AR pathway aberrations in AU (top) and US (bottom) cohorts. Table 2: MVA AU cohort (n = 78) a US cohort (n = 153) b HR 95% CI p HR 95% CI p CNVs PTEN loss 3.0 1.5-5.7 0.001 1.9 1.3-2.9 0.002 PIK3CA gain 2.9 1.5-5.5 0.001 1.7 0.92-3.0 0.09 AR gain 2.2 1.2-4.1 0.02 2.3 1.5-3.4 <0.001 Cumulative PTEN-PI3K-AKT and AR pathway CNVs 0 REF - - REF - - 1 6.2 2.3-17 <0.001 1.8 1.2-2.8 0.006 ≥2 9.3 3.5-25 <0.001 3.2 2.0-5.3 <0.001 a Covariates in multivariable variable analysis (MVA): ctDNA% ≥2%, prior chemotherapy, prior ARPI, visceral metastases, baseline pain and ECOG PS ≥2. b Covariates in MVA: ctDNA% ≥2%, prior chemotherapy, alkaline phosphatase (log 10 ). Cumulative CNVs in PTEN-PI3K-AKT and AR pathways • Considering PTEN loss, PIK3CA gain and AR gain, cumulative CNVs (0 vs 1 vs ≥2 CNVs) in the PTEN-PI3K-AKT and AR pathways were significantly associated with worse clinical outcomes (Fig 2 & Table 2). Table 1: Patient characteristics AU cohort n = 78 Age Median [interquartile range] 72 (63-78) Gleason score ≤ 7 ≥ 8 No biopsy / unknown 19 (24) 30 (50) 20 (26) Local treatment type, N (%) Radical prostatectomy RT +/- adjuvant ADT None or metastases at dx Primary ADT 22 (28) 13 (16) 40 (52) 3 (4) Prior treatment, N (%) Prior chemotherapy only Prior ARPI only Prior chemotherapy and ARPI 12 (21) 26 (46) 18 (32) Baseline biochemistry, N(%) PSA (ng/ml) Hb (g/ml) ALP (U/L) 46 (0.5-2720) 122 (113-131) 151 (94-346) Detection and clinical associations of PTEN-PI3K-AKT pathway aberrations • PTEN loss was observed in 37% (85/231) of pts (Fig 1) and was independently associated with OS in AU and US cohorts (Fig 2 & Table 2). • PIK3CA gain was observed in 17% (39/231) of pts (Fig 1) and was independently associated with poor survival in the AU but not the US cohort (Table 2). US cohort n = 153 Age Median [interquartile range] 72 (66-77) Gleason score ≤ 7 ≥ 8 No biopsy / unknown 64 (42) 75 (49) 14 (9) Local treatment type, N (%) Radical prostatectomy RT +/- adjuvant ADT None or metastases at dx 62 (41) 38 (25) 53 (34) Prior treatment, N (%) Salvage local treatment Secondary hormonal treatment Docetaxel 41 (27) 110 (72) 102 (66) Baseline biochemistry, N (%) PSA (ng/ml) LDH (U/L) ALP (U/L) 20 (5.0-98) 202 (176-249) 98 (73-155) ARPI, androgen receptor pathway inhibitor; ADT, androgen deprivation therapy; ALP, alkaline phosphatase; Hb, haemoglobin; RT, radiotherapy. • In a subset of AU samples with additional plasma (n=46), low- pass WGS confirmed panel PTEN loss in 90% (28/31), and PIK3CA gain in 84% (16/19), with high correlation for absolute copy number between methods (R=0.85 and R=0.80, respectively). • Of 146 PTEN-neutral pts, 31 (21%) had alternate PTEN-PI3K-AKT aberrations (Fig 1). AU cohort AU cohort USA cohort USA cohort Corresponding author Dr Edmond Kwan [email protected] ASCO GU 2021 Abstract 159
Transcript of Plasma cell-free DNA (cfDNA) profiling of PTEN-PI3K-AKT ...
• PTEN-PI3K-AKT CNVs were readily detected using Predicine cfDNAassay, with prevalence of PTEN loss comparable to tissue studies.
• Over one-fifth of PTEN-neutral patients had other activating aberrationsin the PTEN-PI3K-AKT pathway.
• Plasma cfDNA profiling of PTEN-PI3K-AKT and AR pathway aberrationsmay identify a poor-risk cohort primed for dual AR/Akt targeted therapy.
RESULTSCONCLUSION
INTRODUCTION
Plasma cell-free DNA (cfDNA) profiling of PTEN-PI3K-AKT pathway aberrations in two multi-institutional independent metastatic castration-resistant prostate cancer (mCRPC) cohorts
AIM
• Tumor tissue from mCRPC harbors frequent copy number variations(CNVs) in the PTEN-PI3K-AKT pathway, but identifying them in plasmacfDNA has proven challenging, especially PTEN copy number loss.
• With emerging data supporting Akt inhibition in PTEN-deficient mCRPC,cfDNA assays that robustly characterize PTEN-PI3K-AKT pathwayaberrations are urgently needed.
Edmond M Kwan1,2; Chao Dai3,; Heidi Fettke1,; Christine Hauser4; Maria M Docanto1; Patricia Bukczynska4; Nicole Ng4,5,6; Siavash Foroughi5,6; Lisa-Jane K Graham7; Kate Mahon7,8,9; Winston Tan10; Xiaohong Wang,3; Zhixin Zhao3; Tiantian Zheng3; Kemin Zhou3; Jianjun Yu3; Pan Du3; Lisa G Horvath7,8,9,11; Shidong Jia3; Manish Kohli12; Arun A Azad1,13,14
1. Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, Australia. 2. Department of Medical Oncology, Monash Health, Melbourne, Australia 3. Predicine Inc., Hayward, California, USA 4. Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia 5. Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia 6. Department of Medical Biology, The University of Melbourne, Melbourne, Australia
7. Medical Oncology, Chris O’Brien Lifehouse, Sydney, Australia 8. University of Sydney, Sydney, Australia 9. Garvan Institute of Medical Research, Sydney, Australia 10. Division of Medical Oncology, Department of Medicine, Mayo Clinic, Jacksonville, FL, USA 11. Royal Prince Alfred Hospital, Sydney, Australia 12. Division of Oncology, Department of Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA 13. Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia 14. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
Using a validated cfDNA liquid biopsy assay in two independent mCRPCcohorts totalling 231 patients, our aims were to:1. Characterize the mutational landscape of PTEN-PI3K-AKT pathwayaberrations, with an emphasis on robust detection of PTEN loss.
2. Correlate genomic aberrations with longitudinal clinical outcomes.
METHODSCohort description and targeted cfDNA sequencing• Pre-treatment plasma samples were collected from mCRPC patients(pts) across two cohorts in Australia (AU; n=78) and USA (n=153).
• Plasma PTEN-PI3K-AKT pathway aberrations were characterized usingthe CLIA-certified Predicine targeted panel-based NGS cfDNA assay.1,2
• We included AR aberrations recognizing reciprocal PI3K regulation.3,4
Outcomes and analysis• Kaplan-Meier curves and multivariable Cox proportional-hazardsmodels assessed associations between PTEN-PI3K-AKT and ARpathway aberrations and overall survival.
Patient cohort• Median follow-up was 28.0 and 80.7 months in AU and US cohorts,respectively; patient characteristics for each cohort shown in Table 1.
• In the AU cohort, 49 pts (63%) commenced AR pathway inhibitors(ARPI; abiraterone or enzalutamide) and 29 pts (37%) commencedtaxane chemotherapy (docetaxel or cabazitaxel).
Figure 2: Kaplan-Meier analysis of OS according to PTEN copy number status (A,B) and cumulative CNVs in PTEN-PI3K-AKT and AR pathways (C,D).
References: 1. Fettke H et al. Eur Urol 2020;78:173-80. 2. Kohli M et al. EbioMedicine 2020;54:102728. 3. Carver BS et al.Cancer Cell 2011;19:575-86. 4. Mulholland DJ et al. Cancer Cell 2011;19:792-804.
Fig 1: Genomic landscape of PTEN-PI3K-AKT and AR pathwayaberrations in AU (top) and US (bottom) cohorts.
Table 2: MVAAU cohort (n = 78) a US cohort (n = 153) b
HR 95% CI p HR 95% CI pCNVsPTEN loss 3.0 1.5-5.7 0.001 1.9 1.3-2.9 0.002PIK3CA gain 2.9 1.5-5.5 0.001 1.7 0.92-3.0 0.09AR gain 2.2 1.2-4.1 0.02 2.3 1.5-3.4 <0.001
Cumulative PTEN-PI3K-AKT and AR pathway CNVs0 REF - - REF - -1 6.2 2.3-17 <0.001 1.8 1.2-2.8 0.006≥2 9.3 3.5-25 <0.001 3.2 2.0-5.3 <0.001
a Covariates in multivariable variable analysis (MVA): ctDNA% ≥2%, prior chemotherapy, prior ARPI, visceral metastases,baseline pain and ECOG PS ≥2. b Covariates in MVA: ctDNA% ≥2%, prior chemotherapy, alkaline phosphatase (log10).
Cumulative CNVs in PTEN-PI3K-AKT and AR pathways• Considering PTEN loss, PIK3CA gain and AR gain, cumulative CNVs(0 vs 1 vs ≥2 CNVs) in the PTEN-PI3K-AKT and AR pathways weresignificantly associated with worse clinical outcomes (Fig 2 & Table 2).
Table 1: Patient characteristics AU cohortn = 78
Age Median [interquartile range] 72 (63-78)
Gleason score≤ 7≥ 8No biopsy / unknown
19 (24)30 (50)20 (26)
Local treatment type, N (%)Radical prostatectomyRT +/- adjuvant ADTNone or metastases at dxPrimary ADT
22 (28)13 (16)40 (52)3 (4)
Prior treatment, N (%)Prior chemotherapy onlyPrior ARPI onlyPrior chemotherapy and ARPI
12 (21)26 (46)18 (32)
Baseline biochemistry, N(%)PSA (ng/ml)Hb (g/ml)ALP (U/L)
46 (0.5-2720)122 (113-131)151 (94-346)
Detection and clinical associations of PTEN-PI3K-AKT pathway aberrations• PTEN loss was observed in 37% (85/231) of pts (Fig 1) and wasindependently associated with OS in AU and US cohorts (Fig 2 & Table 2).
• PIK3CA gain was observed in 17% (39/231) of pts (Fig 1) and wasindependently associated with poor survival in the AU but not the US cohort(Table 2).
US cohortn = 153
Age Median [interquartile range] 72 (66-77)
Gleason score≤ 7≥ 8No biopsy / unknown
64 (42)75 (49)14 (9)
Local treatment type, N (%)Radical prostatectomyRT +/- adjuvant ADTNone or metastases at dx
62 (41)38 (25)53 (34)
Prior treatment, N (%)Salvage local treatmentSecondary hormonal treatmentDocetaxel
41 (27)110 (72)102 (66)
Baseline biochemistry, N (%)PSA (ng/ml)LDH (U/L)ALP (U/L)
20 (5.0-98)202 (176-249)98 (73-155)
ARPI, androgen receptor pathway inhibitor; ADT, androgen deprivation therapy; ALP, alkaline phosphatase; Hb, haemoglobin; RT, radiotherapy.
• In a subset of AUsamples with additionalplasma (n=46), low-pass WGS confirmedpanel PTEN loss in90% (28/31), andPIK3CA gain in 84%(16/19), with highcorrelation for absolutecopy number betweenmethods (R=0.85 andR=0.80, respectively).
• Of 146 PTEN-neutral pts,31 (21%) had alternatePTEN-PI3K-AKTaberrations (Fig 1).
AU cohort
AU cohort
USA cohort
USA cohort
Cor respond ing au thorDr Edmond Kwan
ASCO GU 2021 Abs t rac t
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