Cell-free DNA (cfDNA) analysis and evaluation of BRAF amplifications and mutations in metastatic castration-resistant prostate cancer.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 255-255
Author(s):  
Peter Steinwald ◽  
Elisa Ledet ◽  
Bryce Raymon Christensen ◽  
Marcus Marie Moses ◽  
Lynne Chapman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Analysis ◽  
Castration Resistant Prostate Cancer ◽  
Braf Mutations ◽  
Cell Free Dna ◽  
Variants Of Unknown Significance ◽  
Free Dna ◽  
Increased Risk ◽  
Unknown Significance ◽  
Castrate Resistant

255 Background: Cell-free DNA (cfDNA) is an accessible method for characterizing tumoral alterations. We report cfDNA screenings of prostate cancer pts positive for BRAF amplifications/mutations in pts with metastatic CRPC. Methods: Guardant360 testing (Guardant Health, Inc.) assesses cell-free DNA analysis using sequencing to identify genomic alterations in 73 cancer-related genes in circulation. A total of 133 metastatic castrate resistant prostate cancer (mCRPC) pts in various stages of therapy had Guardant cfDNA analyses. Treatment histories prior to testing and concurrent cfDNA alterations were analyzed. Results: BRAF amplifications were detected in 32 (24%) mCRPC pts; 5 pts had concurrent BRAF mutations. Of the mutations detected, only one (K601E, n = 2) was a known activating mutation while all others were variants of unknown significance (VUS). One K601E mutation pt had no other cfDNA alterations. Additionally, 4 pts without BRAF amplification had VUS BRAF mutations. BRAF amplification pts had ≥ 2 concurrent gene amplifications/alterations with the median being 8. The most common recurrent amplifications/alterations were AR (75%), p53 (59%), CDK6 (53%), MET (50%), and MYC (50%). Abiraterone (Abi) and/or Enzalutamide (Enza) resistance was associated with BRAF amplification (p = 0.0042). Non-Abi/Enza resistance pts were less likely to have BRAF amplification. The 2 pts with BRAF K601E mutation were treated with targeted protocol therapy without success however one K601E pts was subsequently treated with cabazitaxel+carboplatin which produced a positive clinical response and a 99.79% reduction in PSA. Conclusions: Pts resistant to Abi/Enza have an increased risk of developing BRAF amplifications. BRAF amplifications arise in the context of multiple additional detectable cfDNA alterations. Identification of actionable mutations, such as BRAF K601E, illustrates the potential for cfDNA testing to direct pt treatment. As cfDNA profiling continues to expand, the ability translate alterations into clinically actionable strategies is critical.

scholarly journals Cell-free DNA as a biomarker for prostate cancer: elevated concentration and decreased fragment size

2020 ◽  
Author(s):  
Emmalyn Chen ◽  
Clinton L. Cario ◽  
Lancelote Leong ◽  
Karen Lopez ◽  
César P. Márquez ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Fragment Size ◽  
Area Under The Curve ◽  
Localized Prostate Cancer ◽  
Elevated Concentration ◽  
Castration Resistant Prostate Cancer ◽  
Cell Free Dna ◽  
Free Dna ◽  
Increased Risk ◽  
Localized Disease

AbstractPurposeProstate cancer is the most commonly diagnosed neoplasm in American men. Although existing biomarkers may detect localized prostate cancer, additional strategies are necessary for improving detection and identifying aggressive disease that may require further intervention. One promising, minimally invasive biomarker is cell-free DNA (cfDNA), which consist of short DNA fragments released into circulation by dying or lysed cells that may reflect underlying cancer. Here we investigated whether differences in cfDNA concentration and cfDNA fragment size could improve the sensitivity for detecting more advanced and aggressive prostate cancer.Materials and MethodsThis study included 268 individuals: 34 healthy controls, 112 men with localized prostate cancer who underwent radical prostatectomy (RP), and 122 men with metastatic castration-resistant prostate cancer (mCRPC). Plasma cfDNA concentration and fragment size were quantified with the Qubit 3.0 and the 2100 Bioanalyzer. The potential relationship between cfDNA concentration or fragment size and localized or mCRPC prostate cancer was evaluated with descriptive statistics, logistic regression, and area under the curve analysis with cross-validation.ResultsPlasma cfDNA concentrations were elevated in mCRPC patients in comparison to localized disease (OR5 ng/mL = 1.34, P = 0.027) or to being a control (OR5 ng/mL = 1.69, P = 0.034). Decreased average fragment size was associated with an increased risk of localized disease compared to controls (OR5bp = 0.77, P = 0.0008).ConclusionThis study suggests that cfDNA concentration and average cfDNA fragment size may provide a quick, cost-effective approach to help determine which patients will benefit most from further screening and/or disease monitoring to help improve prostate cancer outcomes.

scholarly journals Cell-free DNA concentration and fragment size as a biomarker for prostate cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Emmalyn Chen ◽  
Clinton L. Cario ◽  
Lancelote Leong ◽  
Karen Lopez ◽  
César P. Márquez ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Fragment Size ◽  
Area Under The Curve ◽  
Localized Prostate Cancer ◽  
Castration Resistant Prostate Cancer ◽  
Healthy Individuals ◽  
Cell Free Dna ◽  
Free Dna ◽  
Increased Risk ◽  
Localized Disease

AbstractProstate cancer is the most commonly diagnosed neoplasm in American men. Although existing biomarkers may detect localized prostate cancer, additional strategies are necessary for improving detection and identifying aggressive disease that may require further intervention. One promising, minimally invasive biomarker is cell-free DNA (cfDNA), which consist of short DNA fragments released into circulation by dying or lysed cells that may reflect underlying cancer. Here we investigated whether differences in cfDNA concentration and cfDNA fragment size could improve the sensitivity for detecting more advanced and aggressive prostate cancer. This study included 268 individuals: 34 healthy controls, 112 men with localized prostate cancer who underwent radical prostatectomy (RP), and 122 men with metastatic castration-resistant prostate cancer (mCRPC). Plasma cfDNA concentration and fragment size were quantified with the Qubit 3.0 and the 2100 Bioanalyzer. The potential relationship between cfDNA concentration or fragment size and localized or mCRPC prostate cancer was evaluated with descriptive statistics, logistic regression, and area under the curve analysis with cross-validation. Plasma cfDNA concentrations were elevated in mCRPC patients in comparison to localized disease (OR5ng/mL = 1.34, P = 0.027) or to being a control (OR5ng/mL = 1.69, P = 0.034). Decreased average fragment size was associated with an increased risk of localized disease compared to controls (OR5bp = 0.77, P = 0.0008). This study suggests that while cfDNA concentration can identify mCRPC patients, it is unable to distinguish between healthy individuals and patients with localized prostate cancer. In addition to PSA, average cfDNA fragment size may be an alternative that can differentiate between healthy individuals and those with localized disease, but the low sensitivity and specificity results in an imperfect diagnostic marker. While quantification of cfDNA may provide a quick, cost-effective approach to help guide treatment decisions in advanced disease, its use is limited in the setting of localized prostate cancer.

Clinical impact of detecting low-frequency variants in cell-free DNA on treatment of castration-resistant prostate cancer

2021 ◽  
pp. clincanres.2328.2021
Author(s):  
Kei Mizuno ◽  
Takayuki Sumiyoshi ◽  
Takatsugu Okegawa ◽  
Naoki Terada ◽  
Satoshi Ishitoya ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Low Frequency ◽  
Clinical Impact ◽  
Castration Resistant Prostate Cancer ◽  
Cell Free Dna ◽  
Castration Resistant ◽  
Free Dna

scholarly journals Dynamics of the cell-free DNA methylome of metastatic prostate cancer during androgen-targeting treatment

Epigenomics ◽  
2020 ◽  
Vol 12 (15) ◽  
pp. 1317-1332
Author(s):  
Madonna R Peter ◽  
Misha Bilenky ◽  
Ruth Isserlin ◽  
Gary D Bader ◽  
Shu Yi Shen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Castration Resistant Prostate Cancer ◽  
Clinical Progression ◽  
Cell Free Dna ◽  
Targeting Therapy ◽  
Castration Resistant ◽  
Free Dna ◽  
Aggressive Form ◽  
Genome Wide

Aim: We examined methylation changes in cell-free DNA (cfDNA) in metastatic castration-resistant prostate cancer (mCRPC) during treatment. Patients & methods: Genome-wide methylation analysis of sequentially collected cfDNA samples derived from mCRPC patients undergoing androgen-targeting therapy was performed. Results: Alterations in methylation states of genes previously implicated in prostate cancer progression were observed and patients that maintained methylation changes throughout therapy tended to have a longer time to clinical progression. Importantly, we also report that markers associated with a highly aggressive form of the disease, neuroendocrine-CRPC, were associated with a faster time to clinical progression. Conclusion: Our findings highlight the potential of monitoring the cfDNA methylome during therapy in mCRPC, which may serve as predictive markers of response to androgen-targeting agents.

Association of plasma cell-free DNA concentration [cfDNA] with outcome from taxane therapy (TT) for castration resistant prostate cancer (CRPC).

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 5014-5014 ◽  
Author(s):  
Niven Mehra ◽  
Rossitza Christova ◽  
Lorna Pope ◽  
Suzanne Carreira ◽  
Jane Goodall ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Plasma Cell ◽  
Castration Resistant Prostate Cancer ◽  
Cell Free Dna ◽  
Dna Concentration ◽  
Castration Resistant ◽  
Free Dna

Detection of actionable BRAF missense mutations by ctDNA-based genomic analysis in prostate cancer.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 306-306 ◽  
Author(s):  
Malshundria Prophet ◽  
Kun Xiao ◽  
Theodore Stewart Gourdin ◽  
Rebecca J Nagy ◽  
Lesli Ann Kiedrowski ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genomic Analysis ◽  
Driver Mutations ◽  
Genomic Profiling ◽  
Missense Mutations ◽  
Braf Inhibitors ◽  
Braf Mutations ◽  
Variants Of Unknown Significance ◽  
Activating Mutations ◽  
Unknown Significance

306 Background: Activating BRAF fusion proteins are rare in prostate cancer (PCa) patients. Driver missense BRAF mutations have not been reported in detail in this population. Methods: We examined ctDNA-derived genomic profiles (Guardant 360) from 2,721 unique PCa patients, to identify BRAF genomic anomalies (SNVs, amplification). The ctDNA results were compared with PCa tissue-based genomics from the TCGA database (1,851 unique patients). Results: BRAF missense mutations were found in 76 ctDNA patients (2.8%) and were from all known mutation classes (I, II, III) as well as variants of unknown significance (VUSs). Only 4 patients had the V600E mutation. Multiple examples of known, autonomously active, non-canonical mutations were found (27), including K601E (12), G469A (5), D594G (2), and G466E (2). There were 45 VUSs. Mutations were primarily clonal but subclonal mutations were also found. In addition BRAF was commonly amplified, usually in the presence of multiple other amplified genes. BRAF missense mutations were more common with ctDNA than TCGA (2.8% vs 1.4%). Neither dataset identified frequent V600E mutations (ctDNA: 4/2,721; TCGA 1/1,851). However patients with the same non-canonical BRAF mutations were found in each dataset (K601E, G469A, G466E, D594G). Each dataset contained unique mutations found in only one patient. BRAF mutations potentially treatable with BRAF or MEK inhibitors (class I, II) were about half of all mutations (ctDNA 40.8%; TCGA 50%). We treated a PCa patient with a clonal BRAF(G469A) mutation with targeted therapy. The patient was resistant to multiple lines of hormonal and cytotoxic therapy. Trametinib produced a clinical and RECIST response. Conclusions: ctDNA-based genomic analysis identified multiple BRAF amplifications and missense SNVs in PCa patients. SNVs are largely non-canonical, but include known activating mutations that could act as drivers. The analysis also identified more BRAF missense mutations than did tissue genomic profiling, but the mutational landscape, overall frequency of mutations was similar with either method. ctDNA-based genomic profiling can identify actionable BRAF driver mutations that may respond to MEK and BRAF inhibitors.

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