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Clinical Cancer Research : An Official... Jun 2020Existing cell-free DNA (cfDNA) methods lack the sensitivity needed for detecting minimal residual disease (MRD) following therapy. We developed a test for tracking...
PURPOSE
Existing cell-free DNA (cfDNA) methods lack the sensitivity needed for detecting minimal residual disease (MRD) following therapy. We developed a test for tracking hundreds of patient-specific mutations to detect MRD with a 1,000-fold lower error rate than conventional sequencing.
EXPERIMENTAL DESIGN
We compared the sensitivity of our approach to digital droplet PCR (ddPCR) in a dilution series, then retrospectively identified two cohorts of patients who had undergone prospective plasma sampling and clinical data collection: 16 patients with ER+/HER2- metastatic breast cancer (MBC) sampled within 6 months following metastatic diagnosis and 142 patients with stage 0 to III breast cancer who received curative-intent treatment with most sampled at surgery and 1 year postoperative. We performed whole-exome sequencing of tumors and designed individualized MRD tests, which we applied to serial cfDNA samples.
RESULTS
Our approach was 100-fold more sensitive than ddPCR when tracking 488 mutations, but most patients had fewer identifiable tumor mutations to track in cfDNA (median = 57; range = 2-346). Clinical sensitivity was 81% ( = 13/16) in newly diagnosed MBC, 23% ( = 7/30) at postoperative and 19% ( = 6/32) at 1 year in early-stage disease, and highest in patients with the most tumor mutations available to track. MRD detection at 1 year was strongly associated with distant recurrence [HR = 20.8; 95% confidence interval, 7.3-58.9]. Median lead time from first positive sample to recurrence was 18.9 months (range = 3.4-39.2 months).
CONCLUSIONS
Tracking large numbers of individualized tumor mutations in cfDNA can improve MRD detection, but its sensitivity is driven by the number of tumor mutations available to track.
Topics: Adult; Breast Neoplasms; Circulating Tumor DNA; Combined Modality Therapy; Estrogen Receptor alpha; Female; Follow-Up Studies; Humans; Neoplasm Recurrence, Local; Neoplasm, Residual; Prognosis; Prospective Studies; Retrospective Studies; Survival Rate
PubMed: 32170028
DOI: 10.1158/1078-0432.CCR-19-3005 -
Journal For Immunotherapy of Cancer Jun 2023Liquid biopsies using cell-free circulating tumor DNA (ctDNA) are being used frequently in both research and clinical settings. ctDNA can be used to identify actionable... (Review)
Review
Liquid biopsies using cell-free circulating tumor DNA (ctDNA) are being used frequently in both research and clinical settings. ctDNA can be used to identify actionable mutations to personalize systemic therapy, detect post-treatment minimal residual disease (MRD), and predict responses to immunotherapy. ctDNA can also be isolated from a range of different biofluids, with the possibility of detecting locoregional MRD with increased sensitivity if sampling more proximally than blood plasma. However, ctDNA detection remains challenging in early-stage and post-treatment MRD settings where ctDNA levels are minuscule giving a high risk for false negative results, which is balanced with the risk of false positive results from clonal hematopoiesis. To address these challenges, researchers have developed ever-more elegant approaches to lower the limit of detection (LOD) of ctDNA assays toward the part-per-million range and boost assay sensitivity and specificity by reducing sources of low-level technical and biological noise, and by harnessing specific genomic and epigenomic features of ctDNA. In this review, we highlight a range of modern assays for ctDNA analysis, including advancements made to improve the signal-to-noise ratio. We further highlight the challenge of detecting ultra-rare tumor-associated variants, overcoming which will improve the sensitivity of post-treatment MRD detection and open a new frontier of personalized adjuvant treatment decision-making.
Topics: Humans; Circulating Tumor DNA; Neoplasm, Residual; Genomics
PubMed: 37349125
DOI: 10.1136/jitc-2022-006284 -
Cold Spring Harbor Perspectives in... Apr 2020Recurrent metastasis following extended periods of disease-free survival remains a common cause of morbidity and mortality for many cancer patients. Recurrence is... (Review)
Review
Recurrent metastasis following extended periods of disease-free survival remains a common cause of morbidity and mortality for many cancer patients. Recurrence is thought to be mediated by tumor cells that escaped the primary site early in the disease course and colonize distant organs. In these locations, cells adapt to the local environment, entering a state of long-term dormancy in which they can resist therapy. Then, through mechanisms that are poorly understood, a proportion of these cells are reactivated and become proliferative, forming lethal metastases. Here, we discuss disseminated tumor cell dormancy in recurrent metastasis. We discuss mechanisms known to control entrance of cells into dormancy, highlighting the relevant microenvironments or "niches" in which these cells reside and mechanisms known to be involved in dormant cell reactivation. Finally, we consider emerging therapeutic approaches aimed at eradicating residual disease and preventing metastatic relapse.
Topics: Animals; Disease Progression; Humans; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm, Residual; Neoplasms; Tumor Microenvironment
PubMed: 31548220
DOI: 10.1101/cshperspect.a037556 -
PLoS Medicine Oct 2021Beryne Odeny discusses PLOS Medicine's Special Issue on early cancer detection and minimal residual disease.
Beryne Odeny discusses PLOS Medicine's Special Issue on early cancer detection and minimal residual disease.
Topics: Cell-Free Nucleic Acids; Colorectal Neoplasms; DNA, Neoplasm; Early Detection of Cancer; Humans; Liquid Biopsy; Liver Neoplasms; Neoplasm Recurrence, Local; Neoplasm, Residual; Risk Factors
PubMed: 34637442
DOI: 10.1371/journal.pmed.1003794 -
Cancer Mar 2009Primary surgery followed by platinum-taxane based chemotherapy has been the standard therapy in advanced ovarian cancer. However, the prognostic role of complete and... (Randomized Controlled Trial)
Randomized Controlled Trial
Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe...
BACKGROUND
Primary surgery followed by platinum-taxane based chemotherapy has been the standard therapy in advanced ovarian cancer. However, the prognostic role of complete and so-called optimal and suboptimal debulking and its interaction with biological factors has not been not fully defined.
METHODS
Exploratory analysis was conducted of 3 prospective randomized trials (AGO-OVAR 3, 5, and 7) investigating platinum-taxane based chemotherapy regimens in advanced ovarian cancer conducted between 1995 and 2002.
RESULTS
A total of 3126 patients were analyzed. Approximately one-third each fulfilled criteria for complete resection (group A), small residual tumor burden of 1-10 mm (group B), or macroscopic residual disease exceeding 1 cm in diameter (group C). Multivariate analysis showed improved progression-free and overall survival for group A with complete resection compared with groups B or C (P<.0001). The impact of so-called optimal debulking as in group B showed a smaller prognostic impact compared with group C. Further independent prognostic factors for overall survival were age, performance status, grade, FIGO stage, and histology, namely the mucinous subtype. An interaction between residual tumor and some biologic factors was demonstrated.
CONCLUSIONS
The goal of primary surgery should be complete resection. The prognostic impact of tumor biology seemed to be partially overruled by residual tumor and further evaluation of biologic factors should stratify for residual tumor.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Humans; Middle Aged; Neoplasm, Residual; Ovarian Neoplasms; Paclitaxel; Platinum Compounds; Prognosis; Survival Analysis; Treatment Outcome
PubMed: 19189349
DOI: 10.1002/cncr.24149 -
Acta Obstetricia Et Gynecologica... Mar 2022It is debated whether women with FIGO (International Federation of Gynecology and Obstetrics) Stage IV epithelial ovarian cancer should be offered primary debulking...
INTRODUCTION
It is debated whether women with FIGO (International Federation of Gynecology and Obstetrics) Stage IV epithelial ovarian cancer should be offered primary debulking surgery (PDS) or interval debulking surgery (IDS). Furthermore, the impact of complete resection of intra-abdominal disease (R0) despite their extra-abdominal metastases is questioned. The objective of this study was to investigate the impact of intra-abdominal residual tumor, Stage IVA vs IVB, the localization and number of metastases defining Stage IV disease on overall survival (OS) comparing PDS and IDS in FIGO Stage IV epithelial ovarian cancer.
MATERIAL AND METHODS
We included 2091 women registered with Stage IIIC-IV ovarian cancer in the Danish Gynecological Cancer Database during 2009-2016. The impact of residual tumor was evaluated using univariate and multivariate analyses.
RESULTS
In total, 681 patients had stage IV disease, of whom 26% underwent PDS, 38% IDS, and 36% chemotherapy only. Overall survival for PDS and IDS were similar. Patients achieving R0 at PDS showed a tendency towards a higher OS than patients achieving R0 at IDS, though the difference was non-significant. In women with Stage IVA and IVB disease there was a survival benefit in achieving R0 both when treated with PDS and IDS. Women with Stage IVB disease treated with chemotherapy only had a significantly lower OS than patients achieving R0 at both PDS and IDS. Malignant pleural effusion and having five metastatic sites compared with having one was associated with a poorer OS.
CONCLUSIONS
Our study shows similar OS in patients with Stage IV disease treated with IDS compared with PDS. Complete intra-abdominal tumor resection improves the prognosis in both PDS and IDS in Stage IV ovarian cancer. Malignant pleural effusion seems to be a negative prognostic factor and should have more focus in future studies.
Topics: Carcinoma, Ovarian Epithelial; Cytoreduction Surgical Procedures; Female; Humans; Neoadjuvant Therapy; Neoplasm, Residual; Ovarian Neoplasms; Pleural Effusion, Malignant; Retrospective Studies
PubMed: 35187660
DOI: 10.1111/aogs.14319 -
Jornal Brasileiro de Pneumologia :... Sep 2021
Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Neoplasm Recurrence, Local; Neoplasm, Residual; Neoplasms, Second Primary
PubMed: 34495181
DOI: 10.36416/1806-3756/e20210275 -
Neurosurgery Clinics of North America Jan 2021This article discusses intraoperative imaging techniques used during high-grade glioma surgery. Gliomas can be difficult to differentiate from surrounding tissue during... (Review)
Review
This article discusses intraoperative imaging techniques used during high-grade glioma surgery. Gliomas can be difficult to differentiate from surrounding tissue during surgery. Intraoperative imaging helps to alleviate problems encountered during glioma surgery, such as brain shift and residual tumor. There are a variety of modalities available all of which aim to give the surgeon more information, address brain shift, identify residual tumor, and increase the extent of surgical resection. The article starts with a brief introduction followed by a review of with the latest advances in intraoperative ultrasound, intraoperative MRI, and intraoperative computed tomography.
Topics: Brain Neoplasms; Glioma; Humans; Monitoring, Intraoperative; Neoplasm, Residual; Neuronavigation; Neurosurgical Procedures
PubMed: 33223025
DOI: 10.1016/j.nec.2020.09.003 -
Trends in Cancer Jul 2022Genetic studies suggest that sequential dissemination from a primary metastasis, usually at the bone, is a major route of metastatic progression in early, radically... (Review)
Review
Genetic studies suggest that sequential dissemination from a primary metastasis, usually at the bone, is a major route of metastatic progression in early, radically resected cancer. Disseminated tumor cells (DTCs) can likely infiltrate but not grow, and may remain dormant once disseminated for extended intervals (from months to decades). The stationary nature of DTCs prevents them from being successfully treated as an asymptomatic residual disease in the adjuvant setting; critically, they can eventually relapse, adapt, and develop therapy resistance, causing incurable overt metastasis. Metastatic lesions usually first appear in one tissue, which invigorates metastatic cells for further dissemination to other organs, with a fatal outcome. Clinical and genetic data now indicate that metastatic lesions in one organ can seed secondary metastases in other organs: in other words, metastasis arising from metastasis. Herein we discuss recent insight into metastasis cell dormancy mechanisms, survival, communication with the local microenvironment, and eventual changes that endow DTCs with the capacity to expand and colonize to other metastatic sites.
Topics: Disease Progression; Humans; Neoplasm Recurrence, Local; Neoplasm, Residual; Tumor Microenvironment
PubMed: 35370115
DOI: 10.1016/j.trecan.2022.03.002 -
Current Oncology (Toronto, Ont.) May 2023In recent years, major advances in the understanding of acute myeloid leukemia (AML) pathogenesis, together with technological progress, have led us into a new era in... (Review)
Review
In recent years, major advances in the understanding of acute myeloid leukemia (AML) pathogenesis, together with technological progress, have led us into a new era in the diagnosis and follow-up of patients with AML. A combination of immunophenotyping, cytogenetic and molecular studies are required for AML diagnosis, including the use of next-generation sequencing (NGS) gene panels to screen all genetic alterations with diagnostic, prognostic and/or therapeutic value. Regarding AML monitoring, multiparametric flow cytometry and quantitative PCR/RT-PCR are currently the most implemented methodologies for measurable residual disease (MRD) evaluation. Given the limitations of these techniques, there is an urgent need to incorporate new tools for MRD monitoring, such as NGS and digital PCR. This review aims to provide an overview of the different technologies used for AML diagnosis and MRD monitoring and to highlight the limitations and challenges of current versus emerging tools.
Topics: Humans; Leukemia, Myeloid, Acute; Neoplasm, Residual; Prognosis; High-Throughput Nucleotide Sequencing; Mutation
PubMed: 37366878
DOI: 10.3390/curroncol30060395