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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 -
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 -
BMC Medicine May 2023The sensitivity and specificity of minimal residual disease detected by circulating tumor DNA profiling (ctDNA MRD) in lung cancer, with particular attention to the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The sensitivity and specificity of minimal residual disease detected by circulating tumor DNA profiling (ctDNA MRD) in lung cancer, with particular attention to the distinction between landmark strategy and surveillance strategy, for predicting relapse in lung cancer patients after definitive therapy has yet to be determined.
METHODS
The prognostic value of ctDNA MRD by landmark strategy and surveillance strategy was evaluated in a large cohort of patients with lung cancer who received definitive therapy using a systemic literature review and meta-analysis. Recurrence status stratified by ctDNA MRD result (positive or negative) was extracted as the clinical endpoint. We calculated the area under the summary receiver operating characteristic curves, and pooled sensitivities and specificities. Subgroup analyses were conducted based on histological type and stage of lung cancer, types of definitive therapy, and ctDNA MRD detection methods (detection technology and strategy such as tumor-informed or tumor-agnostic).
RESULTS
This systematic review and meta-analysis of 16 unique studies includes 1251 patients with lung cancer treated with definitive therapy. The specificity of ctDNA MRD in predicting recurrence is high (0.86-0.95) with moderate sensitivity (0.41-0.76), whether shortly after treatment or during the surveillance. The landmark strategy appears to be more specific but less sensitive than the surveillance strategy.
CONCLUSIONS
Our study suggests that ctDNA MRD is a relatively promising biomarker for relapse prediction among lung cancer patients after definitive therapy, with a high specificity but suboptimal sensitivity, whether in landmark strategy or surveillance strategy. Although surveillance ctDNA MRD analysis decreases specificity compared with the landmark strategy, the decrease is minimal compared to the increase in sensitivity for relapse prediction of lung cancer.
Topics: Humans; Circulating Tumor DNA; Neoplasm, Residual; Lung Neoplasms; ROC Curve; Biomarkers, Tumor; Neoplasm Recurrence, Local
PubMed: 37173789
DOI: 10.1186/s12916-023-02849-z -
Swiss Medical Weekly Jan 2019In the era of personalised medicine, genetic information is critical to directing therapeutic options, aiding risk stratification and disease monitoring of lymphomas.... (Review)
Review
In the era of personalised medicine, genetic information is critical to directing therapeutic options, aiding risk stratification and disease monitoring of lymphomas. Liquid biopsy is a novel noninvasive, real-time and tumour-specific technique, reliably reflecting the comprehensive tumour genetic profile, and thus holds great promise for the genetic assessment, response monitoring and relapse detection of lymphomas. Standard methods for disease response assessment in patients with lymphoma, including positron emission tomography, are imperfect. In other haematological malignancies, particularly leukaemias, the ability to detect minimal residual disease (MRD) is increasingly influencing treatment paradigms. However, in some subtypes of lymphoma, such as diffuse large B-cell lymphoma and classic Hodgkin’s lymphoma, the application of MRD assessment techniques such as flow cytometry or polymerase chain reaction-based methods has been challenged by the absence of circulating disease. The review summarises the applications of liquid biopsy in the assessment of tumour burden and response to therapy, noninvasive genomic profiling, and monitoring of clonal dynamics in patients with diffuse large B-cell lymphoma and classic Hodgkin’s lymphoma.
Topics: Biomarkers, Tumor; Genotyping Techniques; Hodgkin Disease; Humans; Liquid Biopsy; Lymphoma, Large B-Cell, Diffuse; Neoplasm Recurrence, Local; Neoplasm, Residual
PubMed: 30673117
DOI: 10.4414/smw.2019.14709 -
American Society of Clinical Oncology... May 2018Liquid biopsy has been used extensively in solid malignancies to detect actionable driver mutations, to monitor treatment response, to detect recurrence, to identify... (Review)
Review
Liquid biopsy has been used extensively in solid malignancies to detect actionable driver mutations, to monitor treatment response, to detect recurrence, to identify resistance mechanisms, and to prognosticate outcome. Although many liquid biopsy sequencing platforms are being used, only five test kits have received government approval. We review representative literature on these government-approved liquid biopsy kits, which are primarily used to detect EGFR mutation in lung cancer and RAS ( KRAS, NRAS, BRAF) mutations in colorectal carcinoma. Another emerging use of single-gene liquid biopsy is to detect PIK3CA mutations and to understand resistance to hormonal blockade in breast and prostate cancers. The two most commonly used next-generation sequencing (NGS) liquid biopsy tests (Guardant 360, Guardant Health; FoundationACT, Foundation Medicine Inc.) are discussed. The ability and the applicability of NGS platform to detect tumor mutation burden are also addressed. Finally, the use of circulating tumor DNA (ctDNA) to detect minimal residual disease may be the most important use of ctDNA in the setting of tumor heterogeneity. The ability to identify "shedders" and "nonshedders" of ctDNA may provide important insight into the clinicopathologic characteristics of the tumor and portend important prognostic significance regarding survival.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Drug Resistance, Neoplasm; Genetic Variation; Genomics; High-Throughput Nucleotide Sequencing; Humans; Liquid Biopsy; Mutation; Neoplasm, Residual; Neoplasms
PubMed: 30231331
DOI: 10.1200/EDBK_199765 -
Annals of Oncology : Official Journal... Oct 2023We aimed to examine circulating tumor DNA (ctDNA) and its association with residual cancer burden (RCB) using an ultrasensitive assay in patients with triple-negative...
BACKGROUND
We aimed to examine circulating tumor DNA (ctDNA) and its association with residual cancer burden (RCB) using an ultrasensitive assay in patients with triple-negative breast cancer (TNBC) receiving neoadjuvant chemotherapy.
PATIENTS AND METHODS
We identified responders (RCB 0/1) and matched non-responders (RCB 2/3) from the phase II TBCRC 030 prospective study of neoadjuvant paclitaxel versus cisplatin in TNBC. We collected plasma samples at baseline, 3 weeks and 12 weeks (end of therapy). We created personalized ctDNA assays utilizing MAESTRO mutation enrichment sequencing. We explored associations between ctDNA and RCB status and disease recurrence.
RESULTS
Of 139 patients, 68 had complete samples and no additional neoadjuvant chemotherapy. Twenty-two were responders and 19 of those had sufficient tissue for whole-genome sequencing. We identified an additional 19 non-responders for a matched case-control analysis of 38 patients using a MAESTRO ctDNA assay tracking 319-1000 variants (median 1000 variants) to 114 plasma samples from 3 timepoints. Overall, ctDNA positivity was 100% at baseline, 79% at week 3 and 55% at week 12. Median tumor fraction (TFx) was 3.7 × 10 (range 7.9 × 10-4.9 × 10). TFx decreased 285-fold from baseline to week 3 in responders and 24-fold in non-responders. Week 12 ctDNA clearance correlated with RCB: clearance was observed in 10 of 11 patients with RCB 0, 3 of 8 with RCB 1, 4 of 15 with RCB 2 and 0 of 4 with RCB 3. Among six patients with known recurrence, five had persistent ctDNA at week 12.
CONCLUSIONS
Neoadjuvant chemotherapy for TNBC reduced ctDNA TFx by 285-fold in responders and 24-fold in non-responders. In 58% (22/38) of patients, ctDNA TFx dropped below the detection level of a commercially available test, emphasizing the need for sensitive tests. Additional studies will determine whether ctDNA-guided approaches can improve outcomes.
Topics: Humans; Female; Circulating Tumor DNA; Neoadjuvant Therapy; Triple Negative Breast Neoplasms; Neoplasm, Residual; Prospective Studies; Breast Neoplasms; Neoplasm Recurrence, Local
PubMed: 37597579
DOI: 10.1016/j.annonc.2023.08.004 -
Cancer Metastasis Reviews Mar 2023Cancer is one of the three leading causes of death worldwide. Even after successful therapy and achieving remission, the risk of relapse often remains. In this context,... (Review)
Review
Cancer is one of the three leading causes of death worldwide. Even after successful therapy and achieving remission, the risk of relapse often remains. In this context, dormant residual cancer cells in secondary organs such as the bone marrow constitute the cellular reservoir from which late tumor recurrences arise. This dilemma leads the term of minimal residual disease, which reflects the presence of tumor cells disseminated from the primary lesion to distant organs in patients who lack any clinical or radiological signs of metastasis or residual tumor cells left behind after therapy that eventually lead to local recurrence. Disseminated tumor cells have the ability to survive in a dormant state following treatment and linger unrecognized for more than a decade before emerging as recurrent disease. They are able to breakup their dormant state and to readopt their proliferation under certain circumstances, which can finally lead to distant relapse and cancer-associated death. In recent years, extensive molecular and genetic characterization of disseminated tumor cells and blood-based biomarker has contributed significantly to our understanding of the frequency and prevalence of tumor dormancy. In this article, we describe the clinical relevance of disseminated tumor cells and highlight how latest advances in different liquid biopsy approaches can be used to detect, characterize, and monitor minimal residual disease in breast cancer, prostate cancer, and melanoma patients.
Topics: Male; Humans; Neoplasm, Residual; Early Detection of Cancer; Breast Neoplasms; Liquid Biopsy; Recurrence
PubMed: 36607507
DOI: 10.1007/s10555-022-10075-x -
Molecular Diagnosis & Therapy Jun 2019Circulating tumor DNA (ctDNA) is a component of cell-free DNA that is shed by malignant tumors into the bloodstream and other bodily fluids. Levels of ctDNA are... (Review)
Review
Circulating tumor DNA (ctDNA) is a component of cell-free DNA that is shed by malignant tumors into the bloodstream and other bodily fluids. Levels of ctDNA are typically low, particularly in patients with localized disease, requiring highly sophisticated methods for detection and quantification. Multiple liquid biopsy methods have been developed for ctDNA analysis in solid tumor malignancies and are now enabling detection and assessment of earlier stages of disease, post-treatment molecular residual disease (MRD), resistance to targeted systemic therapy, and tumor mutational burden. Understanding ctDNA biology, mechanisms of release, and clearance and size characteristics, in conjunction with the application of molecular barcoding and targeted error correction, have increased the sensitivity and specificity of ctDNA detection techniques. Combinatorial approaches including integration of ctDNA data with circulating protein biomarkers may further improve assay sensitivity and broaden the scope of ctDNA applications. Circulating viral DNA may be utilized to monitor disease in some virally induced malignancies. In spite of increasingly accurate methods of ctDNA detection, results need to be interpreted with caution given that somatic mosaicisms such as clonal hematopoiesis of indeterminate potential (CHIP) may give rise to genetic variants in the bloodstream unrelated to solid tumors, and the limited concordance observed between different commercial platforms. Overall, highly precise ctDNA detection and quantification methods have the potential to transform clinical practice via non-invasive monitoring of solid tumor malignancies, residual disease detection at earlier timepoints than standard clinical and/or imaging surveillance, and treatment personalization based on real-time assessment of the tumor genomic landscape.
Topics: Biomarkers, Tumor; Circulating Tumor DNA; Genomics; High-Throughput Nucleotide Sequencing; Humans; Liquid Biopsy; Molecular Diagnostic Techniques; Neoplasm, Residual; Neoplasms
PubMed: 30941670
DOI: 10.1007/s40291-019-00390-5 -
The British Journal of Radiology Jan 2023The current study aimed to investigate the value of definitive-intent (chemo)radiotherapy in treating sinonasal undifferentiated carcinoma (SNUC) in a single institution.
OBJECTIVE
The current study aimed to investigate the value of definitive-intent (chemo)radiotherapy in treating sinonasal undifferentiated carcinoma (SNUC) in a single institution.
METHODS
The medical records of 21 patients with SNUC treated with definitive-intent (chemo)radiotherapy between 2011 and 2021 in one single institution were retrospectively reviewed. We analyzed the treatment efficiency and long-term survivals.
RESULTS
A total of 21 patients were included in this cohort, 12 patients presented with T4 stage at diagnosis, and 6 in T1/T2, 3 in T3 stage. Nine patients (42.9%, 9/21) showed cervical lymph node metastases. All the patients were scheduled to receive definitive (chemo)radiotherapy and five patients had been performed surgery for residual tumor after (chemo)radiotherapy. 66.7% (14/21) of patients had a complete response after the completion of treatment, 23.8% (5/21) of partial response, one of stable disease, and one of progressed disease. The 3-year overall survival of the entire group were 86.2%, and the 3-year progress-free survival were 66.3%, respectively. 52.4% of the patients (11/21) presented orbit invasion, compared with patients without orbit invasion, the patients who had orbit invasion were not found to have significantly poor 3-year overall survival (87.5% 83.3%, = 0.38) and 3-year progression-free survival (75.0% 55.3%, = 0.59).
CONCLUSION
Definitive-intent (chemo)radiotherapy could be the preferred treatment for patients with advanced SNUC, and salvage surgery should be performed for the lesions showing stable disease, progressed disease, or residual tumor.
ADVANCES IN KNOWLEDGE
The value of definitive chemoradiotherapy in treating sinonasal undifferentiated carcinoma.
Topics: Humans; Retrospective Studies; Neoplasm, Residual; Maxillary Sinus Neoplasms; Carcinoma; Chemoradiotherapy
PubMed: 36317997
DOI: 10.1259/bjr.20220244