scholarly journals Therapeutic Actionability of Circulating Cell-Free DNA Alterations in Carcinoma of Unknown Primary

2021 ◽  
pp. 1687-1698
Author(s):  
Shumei Kato ◽  
Caroline Weipert ◽  
Sophia Gumas ◽  
Ryosuke Okamura ◽  
Suzanna Lee ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Complete Response ◽  
Unknown Primary ◽  
Liquid Biopsies ◽  
Level Of Evidence ◽  
Cell Free Dna ◽  
Free Dna ◽  
Somatic Alterations ◽  
Dna Alterations ◽  
Matching Score

PURPOSE Cancer of unknown primary (CUP) is a metastatic disease with unidentifiable primary tumor. Somatic alterations can be assessed noninvasively via liquid biopsies interrogating cell-free DNA (cfDNA). METHODS We evaluated 1,931 patients with CUP with a cfDNA next-generation sequencing panel (73-74 genes). RESULTS Overall, 1,739 patients (90%) had ≥ 1 cfDNA alteration. We then explored alteration actionability (per the levels of evidence from the OncoKB database); 825 patients (47.4% of 1,739) had level 1, level 2, or resistance/R1 alterations. Among 40 clinically annotated patients with CUP who had cfDNA evaluated, higher degrees of matching treatment to alterations (Matching Score > 50% v ≤ 50%) was the only variable predicting improved outcome: longer median progression-free survival (10.4 v 2.5 months; P = .002), overall survival (13.4 v 5.7 months; P = .07, trend), and higher clinical benefit rate (stable disease ≥ 6 months/partial response/complete response; 83% v 25%; P = .003). CONCLUSION In summary, cfDNA frequently reveals strong level-of-evidence actionable alterations in CUP, and high degrees of matching to therapy correlates with better outcomes.

scholarly journals Cell-Free DNA Alterations in the AR Enhancer and Locus Predict Resistance to AR-Directed Therapy in Patients With Metastatic Prostate Cancer

2020 ◽  
pp. 680-713 ◽  
Author(s):  
Ha X. Dang ◽  
Pradeep S. Chauhan ◽  
Haley Ellis ◽  
Wenjia Feng ◽  
Peter K. Harris ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Metastatic Prostate Cancer ◽  
Progression Free Survival ◽  
Therapy Resistance ◽  
Cancer Resistance ◽  
Liquid Biopsies ◽  
Genomic Alterations ◽  
Cell Free Dna ◽  
Free Dna

PURPOSE Cell-free DNA (cfDNA) and circulating tumor cell (CTC)–based liquid biopsies have emerged as potential tools to predict responses to androgen receptor (AR)–directed therapy in metastatic prostate cancer. However, because of complex mechanisms and incomplete understanding of genomic events involved in metastatic prostate cancer resistance, current assays (eg, CTC AR-V7) demonstrate low sensitivity and remain underutilized. The recent discovery of AR enhancer amplification in > 80% of patients with metastatic disease and its association with disease resistance presents an opportunity to improve on current assays. We hypothesized that tracking AR/enhancer genomic alterations in plasma cfDNA would detect resistance with high sensitivity and specificity. PATIENTS AND METHODS We developed a targeted sequencing and analysis method as part of a new assay called Enhancer and Neighboring Loci of Androgen Receptor Sequencing (EnhanceAR-Seq). We applied EnhanceAR-Seq to plasma collected from 40 patients with metastatic prostate cancer treated with AR-directed therapy to monitor AR/enhancer genomic alterations and correlated these events with therapy resistance, progression-free survival (PFS), and overall survival (OS). RESULTS EnhanceAR-Seq identified genomic alterations in the AR/enhancer locus in 45% of cases, including a 40% rate of AR enhancer amplification. Patients with AR/enhancer alterations had significantly worse PFS and OS than those without (6-month PFS, 30% v 71%; P = .0002; 6-month OS, 59% v 100%; P = .0015). AR/enhancer alterations in plasma cfDNA detected 18 of 23 resistant cases (78%) and outperformed the CTC AR-V7 assay, which was also run on a subset of patients. CONCLUSION cfDNA-based AR locus alterations, including of the enhancer, are strongly associated with resistance to AR-directed therapy and significantly worse survival. cfDNA analysis using EnhanceAR-Seq may enable more precise risk stratification and personalized therapeutic approaches for metastatic prostate cancer.

scholarly journals Molecular profiling of advanced malignancies guides first-line N-of-1 treatments in the I-PREDICT treatment-naïve study

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Jason K. Sicklick ◽  
Shumei Kato ◽  
Ryosuke Okamura ◽  
Hitendra Patel ◽  
Mina Nikanjam ◽  
...  
Keyword(s):  
Disease Control ◽  
Progression Free Survival ◽  
Complete Response ◽  
Disease Control Rate ◽  
Unknown Primary ◽  
Combination Therapies ◽  
First Line ◽  
Free Survival ◽  
Treatment Naïve ◽  
Matching Score

Abstract Background Malignancies are molecularly complex and become more resistant with each line of therapy. We hypothesized that offering matched, individualized combination therapies to patients with treatment-naïve, advanced cancers would be feasible and efficacious. Patients with newly diagnosed unresectable/metastatic, poor-prognosis cancers were enrolled in a cross-institutional prospective study. Methods A total of 145 patients were included in the study. Genomic profiling (tissue and/or circulating tumor DNA) was performed in all patients, and PD-L1 immunohistochemistry, tumor mutational burden, and microsatellite status assessment were performed in a subset of patients. We evaluated safety and outcomes: disease-control rate (stable disease for ≥ 6 months or partial or complete response), progression-free survival (PFS), and overall survival (OS). Results Seventy-six of 145 patients (52%) were treated, most commonly for non-colorectal gastrointestinal cancers, carcinomas of unknown primary, and hepatobiliary malignancies (53% women; median age, 63 years). The median number of deleterious genomic alterations per patient was 5 (range, 0–15). Fifty-four treated patients (71%) received ≥ 1 molecularly matched therapy, demonstrating the feasibility of administering molecularly matched therapy. The Matching Score, which reflects the percentage of targeted alterations, correlated linearly with progression-free survival (R2 = 0.92; P = 0.01), and high (≥ 60%) Matching Score was an independent predictor of improved disease control rate [OR 3.31 (95% CI 1.01–10.83), P = 0.048], PFS [HR 0.55 (0.28–1.07), P = 0.08], and OS [HR 0.42 (0.21–0.85), P = 0.02]. Serious adverse event rates were similar in the unmatched and matched groups. Conclusions Personalized combination therapies targeting a majority of a patient’s molecular alterations have antitumor activity as first-line treatment. These findings underscore the feasibility and importance of using tailored N-of-1 combination therapies early in the course of lethal malignancies. Trial registration I-PREDICT (NCT02534675) was registered on August 25, 2015.

scholarly journals Circulating Cell-Free DNA in Liquid Biopsies as Potential Biomarker for Bladder Cancer: A Review

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1448
Author(s):  
Raquel Herranz ◽  
Julia Oto ◽  
Emma Plana ◽  
Álvaro Fernández-Pardo ◽  
Fernando Cana ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Progression ◽  
Specific Treatment ◽  
Predictive Biomarkers ◽  
Liquid Biopsies ◽  
Cell Free Dna ◽  
Specific Patient ◽  
Free Dna ◽  
Potential Biomarker ◽  
Cancer Types

Bladder cancer (BC) is among the most frequent cancer types in the world and is the most lethal urological malignancy. Presently, diagnostic and follow-up methods for BC are expensive and invasive. Thus, the identification of novel predictive biomarkers for diagnosis, progression, and prognosis of BC is of paramount importance. To date, several studies have evidenced that cell-free DNA (cfDNA) found in liquid biopsies such as blood and urine may play a role in the particular scenario of urologic tumors, and its analysis may improve BC diagnosis report about cancer progression or even evaluate the effectiveness of a specific treatment or anticipate whether a treatment would be useful for a specific patient depending on the tumor characteristics. In the present review, we have summarized the up-to-date studies evaluating the value of cfDNA as potential diagnostic, prognostic, or monitoring biomarker for BC in several biofluids.

scholarly journals Enhanced specificity of clinical high-sensitivity tumor mutation profiling in cell-free DNA via paired normal sequencing using MSK-ACCESS

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
A. Rose Brannon ◽  
Gowtham Jayakumaran ◽  
Monica Diosdado ◽  
Juber Patel ◽  
Anna Razumova ◽  
...  
Keyword(s):  
Cancer Patients ◽  
De Novo ◽  
Low Frequency ◽  
High Sensitivity ◽  
Clinical Analysis ◽  
De Novo Mutation ◽  
Cell Free Dna ◽  
Free Dna ◽  
Somatic Alterations ◽  
Mutation Profiling

AbstractCirculating cell-free DNA from blood plasma of cancer patients can be used to non-invasively interrogate somatic tumor alterations. Here we develop MSK-ACCESS (Memorial Sloan Kettering - Analysis of Circulating cfDNA to Examine Somatic Status), an NGS assay for detection of very low frequency somatic alterations in 129 genes. Analytical validation demonstrated 92% sensitivity in de-novo mutation calling down to 0.5% allele frequency and 99% for a priori mutation profiling. To evaluate the performance of MSK-ACCESS, we report results from 681 prospective blood samples that underwent clinical analysis to guide patient management. Somatic alterations are detected in 73% of the samples, 56% of which have clinically actionable alterations. The utilization of matched normal sequencing allows retention of somatic alterations while removing over 10,000 germline and clonal hematopoiesis variants. Our experience illustrates the importance of analyzing matched normal samples when interpreting cfDNA results and highlights the importance of cfDNA as a genomic profiling source for cancer patients.

scholarly journals Rapid response of stage IV colorectal cancer with APC/TP53/KRAS mutations to FOLFIRI and Bevacizumab combination chemotherapy: a case report of use of liquid biopsy

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Alexander Hendricks ◽  
Philip Rosenstiel ◽  
Sebastian Hinz ◽  
Greta Burmeister ◽  
Christoph Röcken ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Treatment Response ◽  
Liquid Biopsy ◽  
Metastatic Cancer ◽  
Stage Iv ◽  
Liquid Biopsies ◽  
Kras Mutations ◽  
Cell Free Dna ◽  
Stage Iv Colorectal Cancer ◽  
Free Dna

Abstract Background Liquid biopsies of blood plasma cell free DNA can be used to monitor treatment response and potentially detect mutations that are present in resistant clones in metastatic cancer patients. Case presentation In our non-interventional liquid biopsy study, a male patient in his fifties diagnosed with stage IV colorectal cancer and polytope liver metastases rapidly progressed after completing chemotherapy and deceased 8 months after diagnosis. Retrospective cell free DNA testing showed that the APC/TP53/KRAS major clone responded quickly after 3 cycles of FOLFIRI + Bevacizumab. Retrospective exome sequencing of pre-chemotherapy and post-chemotherapy tissue samples including metastases confirmed that the APC/TP53/KRAS and other major clonal mutations (GPR50, SLC5A, ZIC3, SF3A1 and others) were present in all samples. After the last chemotherapy cycle, CT imaging, CEA and CA19–9 markers validated the cfDNA findings of treatment response. However, 5 weeks later, the tumour had rapidly progressed. Conclusion As FOLFIRI+Bevacizumab has recently also been associated with sustained complete remission in a APC/TP53/KRAS triple-mutated patient, these driver genes should be tested and monitored in a more in-depth manner in future patients. Patients with metastatic disease should be monitored more closely during and after chemotherapy, ideally using cfDNA.

scholarly journals Prognostic Implications of Multiplex Detection of KRAS Mutations in Cell-Free DNA from Patients with Pancreatic Ductal Adenocarcinoma

2018 ◽  
Vol 64 (4) ◽  
pp. 726-734 ◽  
Author(s):  
Min Kyeong Kim ◽  
Sang Myung Woo ◽  
Boram Park ◽  
Kyong-Ah Yoon ◽  
Yun-Hee Kim ◽  
...  
Keyword(s):  
Kras Mutation ◽  
Progression Free Survival ◽  
Ductal Adenocarcinoma ◽  
Multiplex Detection ◽  
Kras Mutations ◽  
Cell Free Dna ◽  
Free Survival ◽  
Free Dna ◽  
Fractional Abundance ◽  
Prognostic Implications

Abstract BACKGROUND Cell-free DNA (cfDNA) is known to provide potential biomarkers for predicting clinical outcome, but its value in pancreatic ductal adenocarcinoma (PDAC) has not been fully evaluated. The aim of this study was to evaluate the clinical applicability of quantitative analysis of multiplex KRAS mutations in cell-free DNA from patients with PDAC. METHODS A total of 106 patients with PDAC were enrolled in this prospective study. The concentration and fraction of KRAS mutations were determined through multiplex detection of KRAS mutations in plasma samples by use of a droplet digital PCR kit (Bio-Rad). RESULTS KRAS mutations were detected in 96.1% of tissue samples. Eighty patients (80.5%) harbored KRAS mutations in cfDNA, with a median KRAS mutation concentration of 0.165 copies/μL and a median fractional abundance of 0.415%. Multivariable analyses demonstrated that the KRAS mutation concentration [hazard ratio (HR), 2.08; 95% CI, 1.20–3.63] and KRAS fraction (HR, 1.73; 95% CI, 1.02–2.95) were significant factors for progression-free survival. KRAS mutation concentration (HR, 1.97; 95% CI, 1.05–3.67) also had prognostic implications for overall survival. Subgroup analyses showed that KRAS mutation concentration and fractional abundance significantly affected progression-free survival in resectable PDAC (P = 0.016). Moreover, when combined with the cancer biomarker CA19-9, the KRAS mutation concentration in cfDNA showed additive benefits for the prediction of overall survival. CONCLUSIONS This study demonstrates that multiplex detection of KRAS mutations in plasma cfDNA is clinically relevant, providing a potential candidate biomarker for prognosis of PDAC.

Liquid biopsies of plasma exosomal nucleic acids, plasma cell-free DNA, and survival of patients with advanced cancers.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11551-11551
Author(s):  
Lino Moehrmann ◽  
Helen J. Huang ◽  
David S. Hong ◽  
Apostolia Maria Tsimberidou ◽  
Siqing Fu ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Prognostic Factor ◽  
Kras Mutation ◽  
Tumor Tissue ◽  
Digital Pcr ◽  
Mutation Testing ◽  
Clinical Testing ◽  
Liquid Biopsies ◽  
Cell Free Dna ◽  
Free Dna

11551 Background: Blood-based liquid biopsies offer easy accessible genomic material for molecular diagnostics in cancer. Commonly used cell-free DNA (cfDNA) originates from dying cells. In contrast exosomal nucleic acid (exoNA) originates from living cells, which can better reflect underlying cancer biology. Methods: We isolated exoNA (EXO52) and cfDNA (QIAamp Circulating Nucleic Acid kit) from plasma of patients with progressing advanced cancers and tested for BRAFV600, KRASG12/G13, and EGFRexon19del/L858R mutations using next-generation sequencing (EXO1000), droplet digital PCR (ddPCR, QX200) and BEAMing digital PCR. The results were compared to clinical testing of archival tumor tissue and correlated with survival. Results: Of the 43 patients (colorectal cancer, 20; melanoma, 8; non-small cell lung cancer, 6; ovarian cancer, 2; papillary thyroid cancer, 2; other cancers, 5) 41 had a mutation in the tumor tissue (20 [47%] BRAF mutation, 17 [40%] KRAS mutation and 4 [9%] EGFR mutation). Mutation testing of plasma exoNA from all 43 patients detected 39 (95%) of 41 mutations present in tumor tissue with 100% specificity. Mutation testing of plasma cfDNA from 39 patients using ddPCR detected 33 (89%) of 37 mutations present in tumor and testing of plasma cfDNA from 37 patients using BEAMing detected 34 (97%) of 35 mutations present in tumor tissue; however, both cfDNA methods reported an additional KRAS mutation not present in tumor tissue. Patients with high mutation allele frequency (MAF, > median) had shorter median survival compared to patients with low MAF ( < median) when using exoNA (5.9 vs. 11.8 months, P= 0.006), but not cfDNA ddPCR (6.0 vs. 7.4 months, P= 0.06) or cfDNA BEAMing (6.5 vs. 7.4 month, P= 0.07). High MAF in exoNA was an independent prognostic factor for survival in multicovariate analysis (HR 0.13, P= 0.017). Conclusions: Mutation testing of plasma exoNA for common BRAF, KRAS, and EGFR mutations has high sensitivity compared to clinical testing of archival tumor tissue and better specificity than PCR testing of plasma cfDNA. High MAF in exoNA is the independent prognostic factor for shorter survival.

Circulating cell-free DNA (ctDNA) assessments before, during, and after neoadjuvant therapy (NAC) in nonmetastatic inflammatory breast cancer (IBC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e12113-e12113
Author(s):  
Carolyn S. Hall ◽  
Salyna Meas ◽  
Vanessa Nicole Sarli ◽  
Anthony Lucci
Keyword(s):  
Breast Cancer ◽  
Pathologic Complete Response ◽  
Copy Number Variants ◽  
Residual Tumor ◽  
Complete Response ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Cell Free Dna ◽  
Free Dna ◽  
Circulating Cell Free Dna

e12113 Background: : IBC is a rare and aggressive subtype of breast cancer. A significant number of IBC patients who achieve pathologic complete response (no residual tumor in breast and axillary nodes, pCR) relapse after NAC. We hypothesized that circulating cell-free DNA (ctDNA) identified in blood before, during, and after NAC would identify novel ctDNA targets. Methods: Plasma ctDNA was extracted from 43 non-metastatic IBC patients (IRB: LAB04-0698) pre, mid, and post-NAC. The Oncomine Pan Cancer ctDNA Assay (ThermoFisher) was used for library preparation, and high throughput next generation sequencing was performed on a GeneStudio S5XL System (ThermoFisher), following manufacturer’s directions. ThermoFisher Ion Reporter 5.10 Software was used to analyze single nucleotide variants (SNVs), and copy number variants (CNVs). Results: Seventeen patients had pre-NAC ctDNA assessments; 7/17 (41%) had PIK3CA SNVs; 5/7 also had MYC or FGFR2 CNVs. Five of 17 (29%) had TP53 SNVs; 2/5 also had FGFR2 CNVs. Ten patients had mid-NAC ctDNA assessments; 9/10 (90%) had PIK3CA SNVs; 5/9 also had FGFR2 CNVs, 2/9 had FGFR2 and FGFR3 CNVs, 2/9 also had TP53 SNVs, 1/9 had FGFR2 and ERB2 CNVs. Thirty-one patients had post-NAC ctDNA assessments; 5/31 (16%) had PIK3CA SNVs; 2/5 had FGFR2 CNVs, 1/5 also had a TP53 mutation and an FGFR2 CNV, 1/5 had FGFR2 CNV, and FGFR3 CNV. Six of 31 (19%) had TP53 SNVs, 1/6 had CCND1 CNVs, no CNVs were detected in 6 patients with TP53 SNVs. Six of 31 (19%) had MAP2K1 SNVs. Three of 31 (10%) had MET SNVs; 1/3 had CCND3 CNVs, no CNVs were detected in 2 patients with MET SNVs. No SNVs or CNVs were detected in 10/31 (32%) of patients post NAC. Conclusions: ctDNA assessments before, during, and after NAC identified novel targets that could be tested in future adjuvant therapies trials in IBC patients who remain at high risk for relapse.

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