Tumor DNA Research Articles

Sensitive Detection of Gynecological Cancer Recurrence Using Circulating Tumor DNA and Digital PCR: A Comparative Study with Serum Biochemical Markers

Early detection of recurrences in gynecological cancers is crucial for women’s health. Circulating tumor DNA (ctDNA) analysis through liquid biopsy offers a promising approach for monitoring disease progression and identifying relapses. This study investigated the utility of digital Polymerase Chain Reaction (dPCR) for ctDNA detection in three gynecological cancer patients with clinically confirmed relapses during a two-year post-surgical follow-up. Patient-specific tumor mutations were identified through whole-exome sequencing (WES) and confirmed via Sanger sequencing. dPCR probes targeting these mutations were used to quantify the ctDNA levels in plasma samples collected throughout the follow-up period, and the findings were compared with standard serum biochemical markers. In two patients, persistent positive dPCR signals for the selected mutations were detected after tumor removal, with ctDNA levels progressively increasing even after post-surgical chemotherapy. Notably, dPCR identified elevated ctDNA levels before an increase in the cancer antigen 125 (CA125) biochemical marker was observed. In the third patient, no ctDNA signals from the two selected mutations were detected despite clinical evidence of recurrence, suggesting the emergence of new mutations. While this study highlights the promise of dPCR for early recurrence detection in gynecological cancers, it also underscores the critical need for comprehensive mutation panels to overcome the inherent challenges posed by tumor heterogeneity and the emergence of new mutations during disease progression.

Prognostic impact of circulating tumor DNA detection in portal and peripheral blood in resected pancreatic ductal adenocarcinoma patients

In PDAC patients, ctDNA detection’s prognostic significance needs validation especially in resected patients. This study investigated ctDNA kinetics in portal and peripheral blood before and after resection, and whether tissue mobilization during surgery influences ctDNA detection. In this single-center prospective cohort, portal and peripheral blood were drawn during pancreaticoduodenectomy before and after tissue mobilization, during 12 postoperative months and were associated with overall survival (OS), recurrence-free survival (RFS) and CA19-9 (secondary endpoints). Tumor mutations were identified using next-generation-sequencing and ctDNA detected by digital droplet PCR. From 2018 to 2022, 34 patients were included. The 2-year RFS and OS were 47.6%(95%CI[29.5; 63.6]) and 65.7%(95%CI[46.5; 79.4]) respectively. Intraoperatively, ctDNA detection in portal or peripheral blood was associated with worse RFS (HR[95%CI]3.26[1.26; 8.45],p = 0.010) and OS (HR[95%CI]5.46[1.65;18.01],p = 0.002). Portal vein sampling did not improve ctDNA detection. CtDNA levels were increased by 2.5-fold (p = 0.031) in peripheral blood after tissue mobilization but not significantly linked to RFS or OS. Detecting ctDNA intraoperatively was correlated with poorer RFS (HR [95% CI] 3.26 [1.26;8.45], p = 0.010) and 0S (HR [95% CI] 5.46 [1.65;18.01], p = 0.002). Portal vein sampling did not improve ctDNA detection. Tissue mobilization increases ctDNA levels. Intraoperative detection of ctDNA is associated with a worse prognosis.

Erratum: Circulating Tumor DNA Sequencing for Biologic Classification and Individualized Risk Stratification in Patients With Hodgkin Lymphoma

Erratum: Circulating Tumor DNA Sequencing for Biologic Classification and Individualized Risk Stratification in Patients With Hodgkin Lymphoma

Dynamics of cell-free tumor DNA correlate with early MRI response during chemoradiotherapy in rectal cancer

BackgroundIn locally advanced rectal cancer, the prediction of tumor response during and after neoadjuvant treatment remains challenging. In terms of organ preservation, adaptive radiotherapy, and intensified (total) neoadjuvant therapies, biomarkers are desirable for patient stratification.MethodsIn 16 patients, weekly blood samples (n = 86) to detect cell-free tumor DNA (ctDNA) during long-course neoadjuvant chemoradiotherapy were analyzed. Data were correlated with initial tumor volumes, MRI response in week 2 and 5 of radiotherapy as well as with pathologic tumor response after resection and outcome parameters.ResultsMost patients showed decreasing ctDNA during the course of radiochemotherapy. However, we found heterogenous dynamics of ctDNA and could identify three groups: (1) decline (2) no clear decline and/or late shedding (3) persistence of ctDNA. In seven patients we could detect significant amounts of ctDNA in week 5 or week 6 of treatment. In our pilot cohort, we did not find significant correlations of ctDNA dynamics with pathologic response or outcome parameters. However, patients with distinct decline of ctDNA had larger tumor volumes prior to treatment, and MRI imaging in week 2 and 5 revealed bigger absolute decrease of tumor volumes. If significant levels of ctDNA were found in week 5 and / or 6, patients showed less absolute tumor volume decrease in week 2 and 5.ConclusionsWeekly measurement of ctDNA during radiochemotherapy is feasible and might represent a promising biomarker. Bigger initial primary tumors showed different ctDNA shedding profiles compared with smaller primary tumors and correlations of ctDNA dynamics with early imaging response were found.

Predictive value of pre-treatment circulating tumor DNA genomic landscape in patients with relapsed/refractory multiple myeloma undergoing anti-BCMA CAR-T therapy: Insights from tumor cells and T cells.

B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T (CAR-T) therapy yield remarkable responses in patients with relapsed/refractory multiple myeloma (R/RMM). Circulating tumor DNA (ctDNA) reportedly exhibits distinct advantages in addressing the challenges posed by tumor heterogeneity in the distribution and genetic variations in R/RMM. Herein, the ctDNA of 108 peripheral blood plasma samples from patients with R/RMM was thoroughly investigated before administration of anti-BCMA CAR-T therapy to establish its predictive potential. Flow cytometry is used primarily to detect subgroups of T cells or CAR-T cells. In this study, several tumor and T cell effector-mediated factors were considered to be related to treatment failure by an integrat analysis, including higher percentages of multiple myeloma (MM) cells in the bone marrow (P=0.013), lower percentages of CAR-T cells in the peripheral blood at peak (P=0.037), and higher percentages of CD8+ T cells (P=0.034). Furthermore, there is a substantial correlation between high ctDNA level (>143ng/mL) and shorter progression-free survival (PFS) (P=0.007). Multivariate Cox regression analysis showed that high levels of ctDNA (>143ng/mL), MM-driven high-risk mutations (including IGLL5 [P=0.004], IRF4 [P=0.024], and CREBBP [P=0.041]), number of multisite mutations, and resistance-related mutation (ERBB4, P=0.040) were independent risk factors for PFS. Finally, a ctDNA-based risk model was built based on the above independent risk factors, which serves as an adjunct non-invasive measure of substantial tumor burden and a prognostic genetic feature that can assist in predicting the response to anti-BCMA CAR-T therapy. Chinese Clinical Trial Registry (ChiCTR2100046474) and National Clinical Trial (NCT04670055, NCT05430945).

Profiling Plasma Extracellular Vesicle Metabotypes and miRNAs: An Unobserved Clue for Predicting Relapse in Patients with Early-Stage NSCLC

Background and Objective: Lung cancer, the second most prevalent cancer globally, poses significant challenges in early detection and prognostic assessment. Despite advancements in targeted therapies and immunotherapy, the timely identification of relapse remains elusive. Blood-based liquid biopsy biomarkers, including circulating tumor cells (CTCs), cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), circulating-free RNAs (cfRNAs), and extracellular vesicles (EVs)/exosomes, offer promise for non-invasive monitoring. Methods: We employ a comprehensive approach integrating miRNA/lncRNA/metabolomic datasets, following a mixed-methods content analysis, to identify candidate biomarkers in NSCLC. NSCLC-associated miRNA/gene/lncRNA associations were linked to in silico-derived molecular pathways. Results: For data validation, mass spectrometry-based untargeted metabolomics of plasma EVs highlighted miRNA/lncRNA/metabotypes, linking “glycerophospholipid metabolism” to lncRNA H19 and “alanine, aspartate and glutamate metabolism” to miR-29a-3p. Prognostic significance was established for miR-29a-3p, showing lower expression in NSCLC patients with disease progression compared to stable disease (p = 0.004). Kaplan–Meier survival analysis indicated that patients with miR-29a-3p under-expression had significantly shorter overall survival (OS) (p = 0.038). Despite the expression of lncRNA H19 in plasma EVs being undetected, its expression in plasma cfRNAs correlated significantly with disease progression (p = 0.035). Conclusions: Herein, we showcase the potential of plasma EV-derived miR-29a-3p as a prognostic biomarker and underscore the intricate interplay of miRNAs, lncRNAs, and metabolites in NSCLC biology. Our findings offer new insights and avenues for further exploration, contributing to the ongoing quest for effective biomarkers in early-stage NSCLC.

Correction to: Circulating tumor DNA for monitoring classic Hodgkin lymphoma patients: Correlation with FDG‐PET/CT

Correction to: Circulating tumor DNA for monitoring classic Hodgkin lymphoma patients: Correlation with FDG‐PET/CT

First-in-human, phase 1 dose-escalation and dose-expansion study of a RET inhibitor SY-5007 in patients with advanced RET-altered solid tumors

Oncogenic RET alteration is an important, tissue-agnostic therapeutic target across diverse cancers. We conducted a first-in-human phase 1 study on SY-5007, a potent and selective RET inhibitor, in patients with RET-altered solid tumors. Primary endpoints were safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D). Secondary endpoints included pharmacokinetics and preliminary anti-tumor activity. A total of 122 patients were enrolled (17 in dose-escalation phase and 105 in dose-expansion phase), including 91 with non-small cell lung cancer, 23 with medullary thyroid cancer, 7 with papillary thyroid cancer and 1 with gastric cancer. Treatment-related adverse events (TRAEs) were reported in 96.7% of patients, with the most common grade ≥ 3 TRAEs being hypertension (22.1%), diarrhea (16.4%), hypertriglyceridemia (6.6%), and neutropenia (6.6%). The exposure to SY-5007 was dose proportional. Among the 116 efficacy-evaluable patients, the overall objective response rate (ORR) was 57.8%, with 70.0% in treatment-naïve patients and 51.3% in previously treated patients. The median progression-free survival (PFS) was 21.1 months. Efficacy was observed regardless of tumor types and previous therapies. Biomarker analysis of 61 patients with circulating tumor DNA (ctDNA)-detectable RET alterations showed an ORR of 57.4% and median PFS of 13.8 months. Rapid ctDNA clearance of RET alteration correlated with faster responses and improved outcomes. In relapsed patients, off-target induced resistance was observed in 57.1% (12/21), with no on-target RET alterations identified. In conclusion, SY-5007 was well-tolerated and showed promising efficacy in patients with RET-altered solid tumors. Serial ctDNA monitoring may unveil treatment response and potential resistance mechanisms (NCT05278364).

Comprehensive genomic profiling of circulating tumor DNA is highly concordant with solid tumor DNA and identifies additional actionable mutations among advanced ovarian and endometrial cancer patients

Comprehensive genomic profiling of circulating tumor DNA is highly concordant with solid tumor DNA and identifies additional actionable mutations among advanced ovarian and endometrial cancer patients

Discussion to: Early real-world experience monitoring circulating tumor DNA in resected early-stage non–small cell lung cancer

Discussion to: Early real-world experience monitoring circulating tumor DNA in resected early-stage non–small cell lung cancer

Surveillance of disease progression in metastatic breast cancer by molecular counting of circulating tumor DNA using Plasma-SeqSensei Breast Cancer in vitro diagnostics assay

Surveillance of disease progression in metastatic breast cancer by molecular counting of circulating tumor DNA using Plasma-SeqSensei Breast Cancer in vitro diagnostics assay

Liquid biopsy: the analysis of circulating tumour DNA

Circulating tumour DNA (ctDNA) fragments found in blood represent a critical source of information about the tumour. However, the analysis of ctDNA is challenging due to the overwhelming presence of DNA from non-malignant cells and requires the development of highly sensitive laboratory techniques. This review discusses the major categories of ctDNA biomarkers, their detection methodologies, and explores the potential of emerging technologies within the liquid biopsy field.

P214 Circulating tumor DNA (ctDNA) in surveillance and monitoring of treatment response in testis cancer- A retrospective institutional review

P214 Circulating tumor DNA (ctDNA) in surveillance and monitoring of treatment response in testis cancer- A retrospective institutional review

Personalized circulating tumor DNA analysis used for ctDNA detection and response monitoring among patients with advanced or recurrent endometrial cancer

Personalized circulating tumor DNA analysis used for ctDNA detection and response monitoring among patients with advanced or recurrent endometrial cancer

Correlation between circulating tumor DNA and imaging dynamics in gynecologic malignancies

Correlation between circulating tumor DNA and imaging dynamics in gynecologic malignancies

Monitoring of circulating tumor DNA and indication of de-escalation adjuvant targeted therapy for EGFR-mutated non-small cell lung cancer after complete resection

IntroductionEpidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the standard adjuvant treatment for patients with stage IB-IIIA EGFR-mutated non-small cell lung cancer (NSCLC). However, adapting this approach to include a molecular residual disease (MRD)-guided de-escalation strategy warrants further investigation. MethodsFrom January 2019 to December 2022, 71 patients with stage I–III NSCLC and EGFR (exon 19 del or L858R) mutations were enrolled in this observational study. A total of 375 blood samples were analyzed using the MRD_Navigator assay. Among them, 27 patients suspended EGFR-TKI treatment based on undetectable MRD and were thus included in the adaptive, de-escalation group. ResultsOverall, the sensitivity of longitudinal MRD was 86.2%. Only four patients (11.8%) recurred with longitudinal undetectable MRD, indicating a negative predictive value of 88.2%. Of the patients who had detectable MRD after surgery, nine subsequently received EGFR-TKI treatment, with only one (11.1%) achieving persistent ctDNA clearance post-EGFR-TKI. Twenty-two patients with stage IB-III disease who had previously suspended their TKI treatment based on undetectable MRD were included in the adaptive group, with an average duration of TKI 3.9 (range, 0–35.0) months. The 2-year disease-free survival rate of these 22 patients was 80.2%, and the median was not reached. Five patients (n=5/22, 22.7%) showed disease recurrence during the period of drug cessation, but were stable under EGFR-TKI treatment until the latest follow-up. Two patients remained in complete remission. ConclusionsOur initial findings underscore the potential of an adaptive, de-escalation approach to adjuvant EGFR-TKIs based on ctDNA-MRD monitoring.

Erratum: Tumor Characteristics Associated With Preoperatively Detectable Tumor-Informed Circulating Tumor DNA in Patients With Renal Masses Suspicious for Renal Cell Carcinoma.

Erratum: Tumor Characteristics Associated With Preoperatively Detectable Tumor-Informed Circulating Tumor DNA in Patients With Renal Masses Suspicious for Renal Cell Carcinoma.

Prognostic implications of minimal residual disease detection by second-look laparoscopy and circulating tumor DNA among patients with ovarian cancer after front-line therapy

Prognostic implications of minimal residual disease detection by second-look laparoscopy and circulating tumor DNA among patients with ovarian cancer after front-line therapy

Definite Treatment Delay With Neoadjuvant Chemotherapy and Longitudinal Monitoring by Circulating Tumor DNA for Advanced Cervical Cancer During Pregnancy: A Case Series and Literature Review.

Previous studies mainly concentrate on neoadjuvant chemotherapy (NACT) for delivery delay in FIGO Stage IB1-IIIB cervical cancer during pregnancy to prevent early preterm delivery while not affecting maternal outcome. Here, we described two pregnant patients with FIGO Stage IIIC cervical cancer about their diagnosis, treatment, and outcome. Both patients underwent cesarean delivery, left enlarged lymph node dissection, and longitudinal monitoring by circulating tumor DNA. Our study suggested that pregnant patient was completely response to NACT, which was confirmed by ctDNA monitoring, followed by left pelvic enlarged lymph node dissection during cesarean section and adjuvant chemoradiotherapy postpartum. The infant grew normally, without any evidence of chemotherapy-related side effects after delivery. In pregnant women with advanced cervical cancer, longitudinal ctDNA monitoring might be able to evaluate maternal response to NACT and confirm if delivery delay to optimize fetal outcome would compacting the maternal outcomes or not. Cervical cancer may not transmit across the placental barrier and so it is safe for delayed delivery until fetal maturity in utero during pregnancy.

PARPi response monitoring using personalized circulating tumor DNA testing among patients with ovarian cancer

PARPi response monitoring using personalized circulating tumor DNA testing among patients with ovarian cancer