Association of detectable levels of circulating tumor DNA (ctDNA) with disease burden in prostate cancer (PC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5562-5562 ◽  
Author(s):  
Gerhardt Attard ◽  
Michael Gormley ◽  
Karen Urtishak ◽  
Jason S. Simon ◽  
Deborah S. Ricci ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Disease Burden ◽  
Cox Regression ◽  
Specific Antigen ◽  
Point Mutations ◽  
Progression Free Survival ◽  
Circulating Tumor Dna ◽  
Response To Therapy ◽  
Bone Lesions ◽  
Copy Number Changes

5562 Background: PC is characterized by a relatively low prevalence of recurrent somatic point mutations. ctDNA is shed from PC and can be analyzed to profile somatic point mutations and copy number changes. We evaluated a computational approach to detect ctDNA (ie. ctDNA+) in PC based on allele frequencies of polymorphisms and mutations. We then sought to confirm the association of this biomarker with disease burden and clinical outcome. Methods: Customized, hybrid capture, high-depth next-generation sequencing was performed on pre-treatment (PT) plasma samples from a phase 2 line 3+ metastatic castration-resistant PC (mCRPC) study (NCT02854436, GALAHAD) and PT and end of treatment (EOT) samples from randomized Phase 3 study in non-metastatic (nm) CRPC (NCT01946204, SPARTAN) and from metastatic castration-sensitive PC (mCSPC) (NCT02489318, TITAN). Associations of ctDNA+ with bone lesions (number), visceral metastases (+/-), circulating tumor cells count (CTCc), and serum prostate specific antigen (PSA), alkaline phosphatase (AP) and lactate dehydrogenase (LD) were tested. Also, associations of ctDNA+ with overall survival (OS) and second progression free survival (PFS2) were evaluated in randomized studies using Cox regression. Results: ctDNA+ at PT was 7.5% in nmCRPC, 23.7% in mCSPC and 66% in heavily pre-treated mCRPC. ctDNA+ increased from PT to EOT in nmCRPC (7.5% to 27%) and mCSPC (23.7% to 63.6%). Disease burden metrics were evaluated in ctDNA+ vs ctDNA- patients. ctDNA+ was associated with higher disease burden in mCRPC (Table), nmCRPC and mCSPC. At EOT, ctDNA+ patients had shorter OS and PFS2 in nmCRPC (HR [95% CI] OS: 2.73 [1.83, 4.08], p < 0.0001; PFS2: 2.00 [1.38, 2.90], p = 0.0002) and mCSPC (HR [95% CI] OS: 7.59 [3.22, 17.91], p < 0.0001; PFS2: 4.84 [2.47, 9.47], p < 0.0001). Conclusions: ctDNA+ assessed using our novel, composite biomarker increases with advanced disease state and disease progression, is significantly associated with disease burden and poor clinical outcome in PC and could be a clinically relevant metric for monitoring response to therapy. Clinical trial information: NCT02854436 . [Table: see text]

scholarly journals Circulating tumor DNA is detectable in canine histiocytic sarcoma, oral malignant melanoma, and multicentric lymphoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anaïs Prouteau ◽  
Jérôme Alexandre Denis ◽  
Pauline De Fornel ◽  
Edouard Cadieu ◽  
Thomas Derrien ◽  
...  
Keyword(s):  
Residual Disease ◽  
Specific Antigen ◽  
Point Mutations ◽  
Antigen Receptor ◽  
Digital Pcr ◽  
Circulating Tumor Dna ◽  
Histiocytic Sarcoma ◽  
Oncology Research ◽  
Tumor Dna

AbstractCirculating tumor DNA (ctDNA) has become an attractive biomarker in human oncology, and its use may be informative in canine cancer. Thus, we used droplet digital PCR or PCR for antigen receptor rearrangement, to explore tumor-specific point mutations, copy number alterations, and chromosomal rearrangements in the plasma of cancer-affected dogs. We detected ctDNA in 21/23 (91.3%) of histiocytic sarcoma (HS), 2/8 (25%) of oral melanoma, and 12/13 (92.3%) of lymphoma cases. The utility of ctDNA in diagnosing HS was explored in 133 dogs, including 49 with HS, and the screening of recurrent PTPN11 mutations in plasma had a specificity of 98.8% and a sensitivity between 42.8 and 77% according to the clinical presentation of HS. Sensitivity was greater in visceral forms and especially related to pulmonary location. Follow-up of four dogs by targeting lymphoma-specific antigen receptor rearrangement in plasma showed that minimal residual disease detection was concordant with clinical evaluation and treatment response. Thus, our study shows that ctDNA is detectable in the plasma of cancer-affected dogs and is a promising biomarker for diagnosis and clinical follow-up. ctDNA detection appears to be useful in comparative oncology research due to growing interest in the study of natural canine tumors and exploration of new therapies.

scholarly journals Prognostic role of docetaxel-induced suppression of free testosterone serum levels in metastatic prostate cancer patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Paula Kappler ◽  
Michael A. Morgan ◽  
Philipp Ivanyi ◽  
Stefan J. Brunotte ◽  
Arnold Ganser ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
Cox Regression ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Serum Levels ◽  
Biologically Active ◽  
Free Form ◽  
Total Testosterone ◽  
The Impact

AbstractTo date, only few data concerning the biologically active, free form of testosterone (FT) are available in metastatic prostate cancer (mPC) and the impact of FT on disease, therapy and outcome is largely unknown. We retrospectively studied the effect of docetaxel on FT and total testosterone (TT) serum levels in 67 mPC patients monitored between April 2008 and November 2020. FT and TT levels were measured before and weekly during therapy. The primary endpoint was overall survival (OS). Secondary endpoints were prostate-specific antigen response and radiographic response (PSAR, RR), progression-free survival (PFS), FT/TT levels and safety. Median FT and TT serum levels were completely suppressed to below the detection limit during docetaxel treatment (FT: from 0.32 to < 0.18 pg/mL and TT: from 0.12 to < 0.05 ng/mL, respectively). Multivariate Cox regression analyses identified requirement of non-narcotics, PSAR, complete FT suppression and FT nadir values < 0.18 pg/mL as independent parameters for PFS. Prior androgen-receptor targeted therapy (ART), soft tissue metastasis and complete FT suppression were independent prognostic factors for OS. FT was not predictive for treatment outcome in mPC patients with a history of ART.

scholarly journals Downregulation and Prognostic Performance of MicroRNA 224 Expression in Prostate Cancer

2013 ◽  
Vol 59 (1) ◽  
pp. 261-269 ◽  
Author(s):  
Konstantinos Mavridis ◽  
Konstantinos Stravodimos ◽  
Andreas Scorilas
Keyword(s):  
Prostate Cancer ◽  
Cox Regression ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Prognostic Indicator ◽  
Disease Stage ◽  
Clinical Value ◽  
Prostate Tumors ◽  
Tissue Samples ◽  
Total Rna

INTRODUCTION The extensive use of prostate-specific antigen as a general prostate cancer biomarker has introduced the hazards of overdiagnosis and overtreatment. Recent studies have revealed the immense biomarker capacity of microRNAs (miRNAs) in prostate cancer. The aim of this study was to analyze the expression pattern of miR-224, a cancer-related miRNA, in prostate tumors and investigate its clinical utility. METHODS Total RNA was isolated from 139 prostate tissue samples. After the polyadenylation of total RNA by poly(A) polymerase, cDNA was synthesized with a suitable poly(T) adapter. miR-224 expression was assessed by quantitative real-time PCR and analyzed with the comparative quantification cycle method, Cq(2−ΔΔCq). We performed comprehensive biostatistical analyses to explore the clinical value of miR-224 in prostate cancer. RESULTS miR-224 expression was significantly downregulated in malignant samples compared with benign samples (P &lt; 0.001). Higher miR-224 expression levels were found in prostate tumors that were less aggressive (P = 0.017) and in an earlier disease stage (P = 0.018). Patients with prostate cancer who were positive for miR-224 had significantly enhanced progression-free survival intervals compared with miR-224–negative patients (P = 0.021). Univariate bootstrap Cox regression confirmed that miR-224 was associated with favorable prognosis (hazard ratio 0.314, P = 0.013); nonetheless, multivariate analysis, adjusted for conventional markers, did not identify miR-224 as an independent prognostic indicator. CONCLUSIONS miR-224 is aberrantly expressed in prostate cancer. Its assessment by cost-effective quantitative molecular methodologies could provide a useful biomarker for prostate cancer.

scholarly journals Days gained response discriminates treatment response in patients with recurrent glioblastoma receiving bevacizumab-based therapies

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Kyle W Singleton ◽  
Alyx B Porter ◽  
Leland S Hu ◽  
Sandra K Johnston ◽  
Kamila M Bond ◽  
...  
Keyword(s):  
Treatment Response ◽  
Proportional Hazards ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Recurrent Glioblastoma ◽  
Response To Therapy ◽  
Cytotoxic Therapy ◽  
Kaplan Meier ◽  
Recurrent Gbm

Abstract Background Accurate assessments of patient response to therapy are a critical component of personalized medicine. In glioblastoma (GBM), the most aggressive form of brain cancer, tumor growth dynamics are heterogenous across patients, complicating assessment of treatment response. This study aimed to analyze days gained (DG), a burgeoning model-based dynamic metric, for response assessment in patients with recurrent GBM who received bevacizumab-based therapies. Methods DG response scores were calculated using volumetric tumor segmentations for patients receiving bevacizumab with and without concurrent cytotoxic therapy (N = 62). Kaplan–Meier and Cox proportional hazards analyses were implemented to examine DG prognostic relationship to overall (OS) and progression-free survival (PFS) from the onset of treatment for recurrent GBM. Results In patients receiving concurrent bevacizumab and cytotoxic therapy, Kaplan–Meier analysis showed significant differences in OS and PFS at DG cutoffs consistent with previously identified values from newly diagnosed GBM using T1-weighted gadolinium-enhanced magnetic resonance imaging (T1Gd). DG scores for bevacizumab monotherapy patients only approached significance for PFS. Cox regression showed that increases of 25 DG on T1Gd imaging were significantly associated with a 12.5% reduction in OS hazard for concurrent therapy patients and a 4.4% reduction in PFS hazard for bevacizumab monotherapy patients. Conclusion DG has significant meaning in recurrent therapy as a metric of treatment response, even in the context of anti-angiogenic therapies. This provides further evidence supporting the use of DG as an adjunct response metric that quantitatively connects treatment response and clinical outcomes.

Prospective trial of nivolumab (Nivo) plus radium-223 (RA) in metastatic castration-resistant prostate cancer (mCRPC) evaluating circulating tumor DNA (ctDNA) levels as a biomarker of response.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS267-TPS267
Author(s):  
Benjamin Louis Maughan ◽  
Roberto Nussenzveig ◽  
Umang Swami ◽  
Sumati Gupta ◽  
Neeraj Agarwal
Keyword(s):  
Checkpoint Inhibitors ◽  
Immune Therapy ◽  
Prospective Trial ◽  
Progression Free Survival ◽  
Metastatic Gastric Cancer ◽  
Circulating Tumor Dna ◽  
Alpha Particles ◽  
Response To Therapy ◽  
Castration Resistant Prostate Cancer ◽  
Radium 223

TPS267 Background: RA is a calcium-mimetic radiopharmaceutical emitter of alpha particles that has been approved for treatment of mCRPC. Radiation plus checkpoint inhibitors has demonstrated promising efficacy in previous clinical trials (PMID 27466265, 23535954). Alteration to PD-1 expression has been observed with radium-223, suggesting potential synergy with Nivo (PMID 29137877). ctDNA concentration may accurately reflect overall tumor burden and response to immune therapy. ctDNA testing after 6 weeks of therapy predicts efficacy of immunotherapy in patients with metastatic NSCLC and urothelial carcinoma (PMID 30093454) and metastatic gastric cancer (PMID 30013197). Reduction of ctDNA correlated with both radiographic progression free survival (rPFS) and overall survival. We hypothesize that RA + Nivo will be safe and decrease ctDNA, which may predict response to therapy earlier than conventional scans. Methods: This is a single-arm phase I/II investigator initiated trial (NCT04109729). Primary objectives: 1) Safety, 2) Change in ctDNA after 6 weeks treatment compared to baseline. Secondary objectives: 1) PSA-PFS; 2) PSA 50% response rate; 3) Time to skeletal related event; 4) Bone metabolism marker response. Inclusion criteria: symptomatic bone metastasis, mCRPC, adequate hematopoiesis. Exclusion criteria: visceral metastasis, history of autoimmune disease and current use of immune suppression therapy. A total of 36 patients will be enrolled. Cycles are 28 days. ctDNA concentration will be measured using GuardantOMNI research platform which evaluates 500 genes. Treatment: RA (55 kBq/kg IV) monotherapy lead in for two cycles followed by RA plus Nivo (480mg IV) for an additional 4 cycles. Nivo monotherapy then continues for up to 2 years. ctDNA collected prior to combination therapy and 6 weeks after. Restaging scans done every 2 cycles while on radium-223 and every 3 cycles while on nivolumab. Clinical trial information: NCT04109729.

scholarly journals Optimizing the treatment mode for de novo metastatic nasopharyngeal carcinoma with bone-only metastasis

BMC Cancer ◽  
2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Cheng Lin ◽  
Sheng Lin ◽  
Lili Zhu ◽  
Shaojun Lin ◽  
Jianji Pan ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Bone Metastases ◽  
Protective Factor ◽  
Cox Regression ◽  
De Novo ◽  
Progression Free Survival ◽  
Rank Test ◽  
Bone Lesions ◽  
Metastatic Nasopharyngeal Carcinoma ◽  
The Difference

Abstract Background No standard radiotherapy regimens have been established for the treatment of de novo metastatic nasopharyngeal carcinoma (mNPC) with bone-only metastasis. The current study aimed to investigate the efficacy of palliative chemotherapy (PCT) plus locoregional radiotherapy (LRRT) with or without local radiotherapy (RT) for metastatic bone lesions in mNPC. Methods We retrospectively analysed 131 de novo patients with mNPC who had bone-only metastasis and received at least two cycles of PCT with LRRT. The difference in survival was evaluated by the log-rank test. Univariable and multivariable analyses were performed by Cox regression. Results The median overall survival (OS) and progression-free survival (PFS) were 33.0 months and 24.0 months, respectively. Patients with five or fewer metastatic bone lesions had significantly longer OS (72.0 months vs. 23.0 months, Hazard ratios (HR) = 0.45, p <  0.001) and PFS (48.0 months vs. 15.0 months, HR = 0.52, p = 0.004) than those who had more than five metastatic bone lesions. Patients who received four or more cycles of chemotherapy were associated with significantly longer OS (unreached vs. 19.0 months, HR = 0.27, p <  0.001) and PFS (66 months vs. 16.0 months, HR = 0.32, p <  0.001). Multivariate analysis confirmed that fewer bone metastases (≤ 5) and more chemotherapy cycles (≥ 4) were favourable prognostic factors for OS. Subgroup analysis revealed that RT to metastatic bone lesions tended to prolong OS (83.0 months vs. 45.0 months) and PFS (60 months vs. 36.5 months) in patients with five or fewer metastatic bone lesions than in those without RT to metastatic bone lesions (p > 0.05). Patients who received a RT dose > 30 Gy had neither better OS (63.5 months vs. 32.0 months, p = 0.299) nor PFS (48.0 months vs. 28.0 months, p = 0.615) than those who received a RT dose ≤30 Gy. Conclusions Local RT to bone metastases may not significantly improve survival in patients with de novo mNPC with bone-only metastasis who have already received PCT plus LRRT. Receiving four or more cycles of chemotherapy can significantly prolong survival and is a favourable independent protective factor.

ERG rearrangements and association with clinical outcome in patients (pts) receiving abiraterone acetate (AA): Results from the COU-AA-302 study in chemotherapy (chemo)-naïve metastatic castration-resistant prostate cancer (mCRPC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5004-5004 ◽  
Author(s):  
Gerhardt Attard ◽  
Johann Sebastian De Bono ◽  
Weimin Li ◽  
Arturo Molina ◽  
Thomas W. Griffin ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Abiraterone Acetate ◽  
Double Blind Study ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
Tissue Samples ◽  
Psa Response ◽  
Psa Progression

5004 Background: ERG rearrangements result in androgen receptor-modulated up-regulation of ERG and may predict for AA response in mCRPC. Concordance has been shown between ERG status in archival samples and fresh CRPC biopsies (Attard et al., Cancer Res. 2009;69:2912). In this prospectively defined biomarker sub-study, the association between ERG subtypes and clinical outcome in chemo-naïve mCRPC pts receiving AA was evaluated. Methods: COU-AA-302 is a randomized double blind study of AA (1 g) + prednisone (P) (5 mg BID) vs placebo + P in chemo-naïve mCRPC. Fluorescence in situ hybridization (FISH) assays to evaluate ERG subtypes (Attard et al., Oncogene. 2008;27:253) were conducted on 524 archival prostate tissue samples (365 biopsies, 107 RPEs, 44 TURPs, 3 bone marrows, 5 lymph nodes) from 497 pts. Clinical outcome measures included radiographic progression-free survival (rPFS) (central [CEN] and investigator [INV] reviewed), time to PSA progression (TTPP), and PSA ≥ 50% decline. Cox regression was used to evaluate association with time to event endpoints and Cochran-Mantel-Haenszel for PSA response. Results: 337 of 497 pts with tumor samples had evaluable FISH results. An ERG rearrangement was present in 117 of 337 (35%) pts. 112 pts were class Edel, 50 were 2+Edel (interstitial deletion with duplication of fusion sequences) and 18 were ESplit. A trend for an association with greater improved rPFS (CEN) and TTPP in 2+ Edel pts treated with AA + P vs ERG non-rearranged was observed (22 months [m] vs 16 m [HR: 0.59, 95% CI: 0.30-1.16], p = 0.12, and 14 m vs 8 m [HR: 0.68; 95% CI: 0.41-1.15], p = 0.15, respectively). No differences in 2+ Edel vs ERG non-rearranged were observed in the P-alone arm. No association between any ERG sub-class and either rPFS [INV] or PSA ≥ 50% decline in either treatment arm was observed. Conclusions: This represents the largest study to date to molecularly characterize CRPC pts participating in a therapeutic phase 3 trial. These data suggest that chemo-naïve mCRPC pts with a 2+ Edel rearrangement may derive a slightly greater benefit from AA and P than other pts. Clinical trial information: NCT00887198.

Association of plasma DNA repair deficient (DRD) status with clinical outcome of metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with abiraterone acetate (AA) plus prednisone/dexamethasone (+P/D).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5066-5066
Author(s):  
Dong Shen ◽  
Shibu Thomas ◽  
Florence Lefresne ◽  
Michael Gormley ◽  
Karen Urtishak ◽  
...  
Keyword(s):  
Cox Regression ◽  
Point Mutations ◽  
Progression Free Survival ◽  
Abiraterone Acetate ◽  
Castration Resistant Prostate Cancer ◽  
Plasma Dna ◽  
Target Capture ◽  
Kaplan Meier ◽  
Genomic Aberrations ◽  
Brca1 Brca2

5066 Background: Somatic DRD deficiency in 15-30% of mCRPC pts have been observed and inhibition of enzyme poly ADP ribose polymerase (PARP) could prove beneficial. We aimed to define DRD status using plasma from pts treated on AA and evaluate associations with prospectively-collected outcome measures. Methods: Plasma DNA samples (128 baseline [BL], 134 cycle 2 day 1 [C2D1], 46 progression [PROG]) from chemotherapy-naïve mCRPC pts in a phase 2 study (NCT01867710) evaluating AA+P/D were subjected to custom target-capture next-generation sequencing. DRD assay was optimized and validated to detect pathogenic point mutations, small insertions/deletions, and copy number alternations (DRD+) in 8 DRD genes: BRCA1, BRCA2, FANCA, ATM, CHEK2, HDAC2, BRIP1, and PALB2. Analysis for genomic aberrations was a secondary exploratory objective. Associations with overall survival (OS), progression-free survival (PFS), and radiographic PFS (rPFS) were assessed using Cox regression models and Kaplan Meier analyses. Results: 11.7% of BL and 17.4% of PROG were DRD+. Bi-allelic was observed in 73.3% of BL DRD+ samples. Shorter PFS was observed in BL DRD+ vs DRD- (5.3 vs 15.5 mo; HR: 2.32; 95%CI:1.39-4.28; P < 0.002). Median PFS for BL DRD biallelic + vs DRD biallelic- was 5.1 vs 15.4 mo (HR: 2.49; 95% CI: 1.23-4.38; P < 0.0095). For multivariate analysis using DRD+, ALP, and LDH as covariates, DRD+ (HR: 2.1; 95% CI: 1.18-3.75; P < 0.012) and high ALP (HR: 1.66; 95% CI: 1.08-2.56; P < 0.021) were strongly associated with worse PFS. Median OS for BL DRD+ vs DRD- was 28.8 vs 41.3 mo (HR: 1.67; 95%CI:0.88-3.18; P = 0.116). Median rPFS for BL DRD+ vs DRD- was 16.2 vs 20.9 mo (HR: 1.64; 95%CI:0.83-3.21; P = 0.152). Of 39 Pts with BL, C2D1 and PROG samples, 3 were DRD+ (7.7%) at all 3 timepoints, 3 (7.7%) only at BL, 3 (7.7%) only at PROG (bi-allelic), 2 (5.1%) had extra deletion at PROG. Conclusions: Patients with mCRPC harboring DRD+ have worse outcomes with AA and represent a population with an unmet medical need.

scholarly journals DNA Methylation Predicts Survival and Response to Therapy in Patients With Myelodysplastic Syndromes

2010 ◽  
Vol 28 (4) ◽  
pp. 605-613 ◽  
Author(s):  
Lanlan Shen ◽  
Hagop Kantarjian ◽  
Yi Guo ◽  
E Lin ◽  
Jianqin Shan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Clinical Outcome ◽  
Myelodysplastic Syndromes ◽  
Cpg Island ◽  
Progression Free Survival ◽  
Response To Therapy ◽  
Classification Systems ◽  
Epigenetic Therapy ◽  
Molecular Heterogeneity ◽  
Free Survival

Purpose The current classification systems of myelodysplastic syndromes (MDS), including the International Prognostic Scoring System (IPSS), do not fully reflect the molecular heterogeneity of the disease. Molecular characterization may predict clinical outcome and help stratify patients for targeted therapies. Epigenetic therapy using decitabine, a DNA hypomethylating agent, is clinically effective for the treatment of MDS. Therefore, we investigated the association between DNA methylation and clinical outcome in MDS. Patients and Methods We screened 24 patients with MDS for promoter CpG island methylation of 24 genes and identified aberrant hypermethylation at 10 genes. We then performed quantitative methylation analyses by bisulfite pyrosequencing of the identified genes in 317 patient samples from three independent studies and assessed relations between methylation and clinical outcome. Results In an initial training cohort of 89 patients with MDS, methylation frequencies of individual genes ranged from 7% to 70% and were highly concordant. Therefore, we defined a methylation z score based on all genes for each patient. We found that patients with higher levels of methylation, compared with patients with lower levels, had a shorter median overall survival (12.3 v 17.5 months, respectively; P = .04) and shorter median progression-free survival (6.4 v 14.9 months, respectively; P = .009). This methylation prognostic model was independent of age, sex, and IPSS group. Applied to two validation cohorts (228 patients), this model was confirmed as an independent prognostic predictor for survival. Although methylation at baseline did not correlate with clinical response to decitabine, we observed a significant correlation between reduced methylation over time and clinical responses. Conclusion DNA methylation predicts overall and progression-free survival in MDS.

scholarly journals Serum CD73 is a prognostic factor in patients with metastatic melanoma and is associated with response to anti-PD-1 therapy

2020 ◽  
Vol 8 (2) ◽  
pp. e001689
Author(s):  
Roberta Turiello ◽  
Mariaelena Capone ◽  
Diana Giannarelli ◽  
Elva Morretta ◽  
Maria Chiara Monti ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Metastatic Melanoma ◽  
Cox Regression ◽  
Therapy Response ◽  
Progression Free Survival ◽  
Serum Lactate ◽  
Response To Therapy ◽  
Serum Lactate Dehydrogenase ◽  
Cox Regression Analysis ◽  
Expression And Activity

BackgroundInhibitors of immune checkpoint programmed cell death protein 1 (PD-1) receptor on T cells have shown remarkable clinical outcomes in metastatic melanoma. However, most patients are resistant to therapy. Production of extracellular adenosine, via CD73-mediated catabolism of AMP, contributes to suppress T-cell-mediated responses against cancer. In this study, we analyzed the expression and activity of soluble CD73 in sera of patients with melanoma undergoing anti-PD-1± cytotoxic T-lymphocyte-associated antigen 4 therapy.MethodsSoluble CD73 expression and activity were retrospectively analyzed in serum of a total of 546 patients with melanoma from different centers before starting treatment (baseline) with anti-PD-1 agents, nivolumab or pembrolizumab, and compared with those of 96 healthy subjects. The CD73 activity was correlated with therapy response and survival of patients.ResultsPatients with melanoma show significantly higher CD73 activity and expression than those observed in healthy donors (p<0.0001). Elevated pretreatment levels of CD73 activity were associated with non-response to therapy with nivolumab or pembrolizumab. During treatment, levels of soluble CD73 activity remain unchanged from baseline and still stratify clinical responders from non-responders. High levels of serum CD73 enzymatic activity associate with reduced overall survival (OS; HR=1.36, 95% CI 1.03 to 1.78; p=0.03) as well as progression-free survival (PFS; HR=1.42, 95% CI 1.13 to 1.79, p=0.003). Further, the multivariate Cox regression analysis indicates that serum CD73 activity is an independent prognostic factor besides serum lactate dehydrogenase levels and the presence of brain metastases for both OS (p=0.009) and PFS (p=0.001).ConclusionOur data indicate the relevance of serum CD73 in patients with advanced melanoma receiving anti-PD-1 therapy and support further investigation on targeting CD73 in combination with anti-PD-1 antibodies.

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