Activating AKT1 and PIK3CA Mutations in Metastatic Castration-Resistant Prostate Cancer

Herberts, Cameron; Murtha, Andrew J.; Fu, Simon; Wang, Gang; Schönlau, Elena; Xue, Hui; Lin, Dong; Gleave, Anna; Yip, Steven; Angeles, Arkhjamil; Hotte, Sébastien J.; North, Scott; Taavitsainen, Sinja; Beja, Kevin; Vandekerkhove, Gillian; Ritch, Elie; Warner, Evan W.; Saad, Fred; Iqbal, Nayyer; Nykter, Matti; Gleave, Martin; Wang, Yuzhuo; Annala, Matti; N., Kim; Wyatt, Alexander W.

doi:10.1016/j.eururo.2020.04.058

Cited by 62 publications

(51 citation statements)

References 32 publications

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“…Mutation clonality versus subclonality was approximated based on puritynormalized VAFs to account for variable tumor fractions between samples (Supplementary Data 7-8). Subclonal mutations were defined as those with a VAF < 25% of the tumor fraction 62,63 ; we applied this conservative threshold to account for the difficulty in accurately estimating cancer cell fractions from targeted sequencing data (where WES tools incorporating allelic copy number and ploidy estimation are not applicable).…”

Section: Methodsmentioning

confidence: 99%

Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer

Lavoie²,

et al. 2021

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Molecular stratification can improve the management of advanced cancers, but requires relevant tumor samples. Metastatic urothelial carcinoma (mUC) is poised to benefit given a recent expansion of treatment options and its high genomic heterogeneity. We profile minimally-invasive plasma circulating tumor DNA (ctDNA) samples from 104 mUC patients, and compare to same-patient tumor tissue obtained during invasive surgery. Patient ctDNA abundance is independently prognostic for overall survival in patients initiating first-line systemic therapy. Importantly, ctDNA analysis reproduces the somatic driver genome as described from tissue-based cohorts. Furthermore, mutation concordance between ctDNA and matched tumor tissue is 83.4%, enabling benchmarking of proposed clinical biomarkers. While 90% of mutations are identified across serial ctDNA samples, concordance for serial tumor tissue is significantly lower. Overall, our exploratory analysis demonstrates that genomic profiling of ctDNA in mUC is reliable and practical, and mitigates against disease undersampling inherent to studying archival primary tumor foci. We urge the incorporation of cell-free DNA profiling into molecularly-guided clinical trials for mUC.

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Section: Methodsmentioning

confidence: 99%

Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer

Lavoie²,

et al. 2021

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“…The association between NCOA2 gain and shorter OS was confirmed in the second cohort of mCRPC patients who underwent tissue whole‐exome sequencing in a previous study 4 . In this cohort, there was a higher prevalence of NCOA2 gains (20% vs. 13%), potentially due to the limitations of CNA identification in patients with low ctDNA purity 32,33 …”

Section: Discussionmentioning

confidence: 67%

Independent prognostic impact of plasma NCOA2 alterations in metastatic castration‐resistant prostate cancer

et al. 2021

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Background The androgen receptor (AR) pathway‐associated gene nuclear receptor coactivator 2 (NCOA2) has an established oncogenic role in early prostate cancer and likewise is a driver of metastatic disease and castration‐resistant prostate cancer. However, its significance as a biomarker in metastatic castration‐resistant prostate cancer (mCRPC), both alone and in conjunction with co‐occurring AR alterations using a liquid biopsy approach has not been investigated. Methods Ninety‐one patients were included in this study, (n = 68 receiving an androgen receptor pathway inhibitor and n = 23 receiving taxane chemotherapy). Up to 30 ml of peripheral blood was collected before commencing treatment from each patient. Plasma cell‐free DNA, along with a matched germline sample, underwent targeted next‐generation sequencing using a validated, highly sensitive in‐house prostate cancer panel. Variants in AR and NCOA2 were identified and correlated with clinical outcomes. Results Plasma AR and NCOA2 aberrations were identified in 35% and 13% of the cohort, respectively, whilst 8% had concurrent AR and NCOA2 alterations. NCOA2 copy number gain and any NCOA2 aberration predicted for lower prostate‐specific antigen (PSA) response rates. Likewise, median overall survival was shorter for NCOA2 gain (10.1 vs. 18.3 months; p = .004), remaining significant after adjusting for covariates including circulating tumor DNA fraction and tumor suppressor gene alterations. Importantly, dual AR and NCOA2 aberrations were also associated with inferior outcomes, including no PSA responses in patients treated with AR pathway inhibitors (0% vs. 64%; p = .02). Conclusions These data highlight the importance of identifying multiple markers of AR pathway modulation in mCRPC and represent the first instance of the assessment of plasma NCOA2 status as a prognostic biomarker for standard‐of‐care therapies. Further assessment is warranted to determine if NCOA2 aberrations are a marker of primary resistance to AR pathway inhibitors.

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“…PTEN is an important tumor suppressor, and has been found to participate in the tumorigenesis and progression via downregulation of PI3-K/Akt pathway (18)(19)(20). PTEN was a vital regulator of cell reproduction, cell cycle, apoptosis and metastasis, and its low expression might cause tumor progression including OC (21)(22)(23).…”

Section: Discussionmentioning

confidence: 99%

miR-4461 Regulates the Proliferation and Metastasis of Ovarian Cancer Cells and Cisplatin Resistance

Dou

Zhang

2021

Front. Oncol.

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microRNAs (miRNAs) are of great significance in cancer treatment, which may have a desirable result on the regulation of tumorigenesis, progression, recurrence, and chemo-resistance of ovarian cancer. However, the research on the further potential application of miR-4461 in ovarian cancer is little and limited. Therefore, the study in this paper focus on the investigation of the of miR-4461 in ovarian cancer progression and chemo-resistance. The phenomenon that the proliferation and metastasis of ovarian cancer cells can be promoted by miR4461 is revealed in functional assays. Through the bioinformatics and luciferase reporter analysis, the PTEN is validated to be the direct target of miR-4461 in ovarian. The association between the expression of miR-4461 and PTEN is negative in in human ovarian cancer tissues. The distinction of growth and metastasis capacity between miR-4461 knockdown ovarian cancer cells and control cells is partially abolished by si-PTEN. Moreover, it was found that cisplatin treatment has obvious effect on the miR-4461 knockdown ovarian cancer cells. In summary, the data given in this paper indicate that the miR-4461 can be regarded as a potential onco-miRNA in ovarian cancer by targeting PTEN.

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Activating AKT1 and PIK3CA Mutations in Metastatic Castration-Resistant Prostate Cancer

Cited by 62 publications

References 32 publications

Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer

Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer

Independent prognostic impact of plasma NCOA2 alterations in metastatic castration‐resistant prostate cancer

miR-4461 Regulates the Proliferation and Metastasis of Ovarian Cancer Cells and Cisplatin Resistance

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