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Blood Jun 2018The previous edition of the consensus guidelines of the International Workshop on Chronic Lymphocytic Leukemia (iwCLL), published in 2008, has found broad acceptance by...
The previous edition of the consensus guidelines of the International Workshop on Chronic Lymphocytic Leukemia (iwCLL), published in 2008, has found broad acceptance by physicians and investigators caring for patients with CLL. Recent advances including the discovery of the genomic landscape of the disease, the development of genetic tests with prognostic relevance, and the detection of minimal residual disease (MRD), coupled with the increased availability of novel targeted agents with impressive efficacy, prompted an international panel to provide updated evidence- and expert opinion-based recommendations. These recommendations include a revised version of the iwCLL response criteria, an update on the use of MRD status for clinical evaluation, and recommendations regarding the assessment and prophylaxis of viral diseases during management of CLL.
Topics: Clinical Trials as Topic; Disease Management; Genetic Testing; Humans; Immunophenotyping; Karyotyping; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Neoplasm Staging; Neoplasm, Residual; Prognosis
PubMed: 29540348
DOI: 10.1182/blood-2017-09-806398 -
Cancer Discovery Dec 2021Growing evidence demonstrates that circulating tumor DNA (ctDNA) minimal residual disease (MRD) following treatment for solid tumors predicts relapse. These results... (Review)
Review
UNLABELLED
Growing evidence demonstrates that circulating tumor DNA (ctDNA) minimal residual disease (MRD) following treatment for solid tumors predicts relapse. These results suggest that ctDNA MRD could identify candidates for adjuvant therapy and measure response to such treatment. Importantly, factors such as assay type, amount of ctDNA release, and technical and biological background can affect ctDNA MRD results. Furthermore, the clinical utility of ctDNA MRD for treatment personalization remains to be fully established. Here, we review the evidence supporting the value of ctDNA MRD in solid cancers and highlight key considerations in the application of this potentially transformative biomarker.
SIGNIFICANCE
ctDNA analysis enables detection of MRD and predicts relapse after definitive treatment for solid cancers, thereby promising to revolutionize personalization of adjuvant and consolidation therapies.
Topics: Biomarkers, Tumor; Circulating Tumor DNA; Humans; Neoplasm Recurrence, Local; Neoplasm, Residual
PubMed: 34785539
DOI: 10.1158/2159-8290.CD-21-0634 -
Journal of Hematology & Oncology Dec 2019The biggest hurdle to targeted cancer therapy is the inevitable emergence of drug resistance. Tumor cells employ different mechanisms to resist the targeting agent. Most... (Review)
Review
The biggest hurdle to targeted cancer therapy is the inevitable emergence of drug resistance. Tumor cells employ different mechanisms to resist the targeting agent. Most commonly in EGFR-mutant non-small cell lung cancer, secondary resistance mutations on the target kinase domain emerge to diminish the binding affinity of first- and second-generation inhibitors. Other alternative resistance mechanisms include activating complementary bypass pathways and phenotypic transformation. Sequential monotherapies promise to temporarily address the problem of acquired drug resistance, but evidently are limited by the tumor cells' ability to adapt and evolve new resistance mechanisms to persist in the drug environment. Recent studies have nominated a model of drug resistance and tumor progression under targeted therapy as a result of a small subpopulation of cells being able to endure the drug (minimal residual disease cells) and eventually develop further mutations that allow them to regrow and become the dominant population in the therapy-resistant tumor. This subpopulation of cells appears to have developed through a subclonal event, resulting in driver mutations different from the driver mutation that is tumor-initiating in the most common ancestor. As such, an understanding of intratumoral heterogeneity-the driving force behind minimal residual disease-is vital for the identification of resistance drivers that results from branching evolution. Currently available methods allow for a more comprehensive and holistic analysis of tumor heterogeneity in that issues associated with spatial and temporal heterogeneity can now be properly addressed. This review provides some background regarding intratumoral heterogeneity and how it leads to incomplete molecular response to targeted therapies, and proposes the use of single-cell methods, sequential liquid biopsy, and multiregion sequencing to discover the link between intratumoral heterogeneity and early adaptive drug resistance. In summary, minimal residual disease as a result of intratumoral heterogeneity is the earliest form of acquired drug resistance. Emerging technologies such as liquid biopsy and single-cell methods allow for studying targetable drivers of minimal residual disease and contribute to preemptive combinatorial targeting of both drivers of the tumor and its minimal residual disease cells.
Topics: Biomarkers, Tumor; Drug Resistance, Neoplasm; Genetic Heterogeneity; Humans; Lung Neoplasms; Neoplasm, Residual; Prognosis; Protein Kinase Inhibitors
PubMed: 31815659
DOI: 10.1186/s13045-019-0818-2 -
Science Translational Medicine Jul 2016Detection of circulating tumor DNA (ctDNA) after resection of stage II colon cancer may identify patients at the highest risk of recurrence and help inform adjuvant...
Detection of circulating tumor DNA (ctDNA) after resection of stage II colon cancer may identify patients at the highest risk of recurrence and help inform adjuvant treatment decisions. We used massively parallel sequencing-based assays to evaluate the ability of ctDNA to detect minimal residual disease in 1046 plasma samples from a prospective cohort of 230 patients with resected stage II colon cancer. In patients not treated with adjuvant chemotherapy, ctDNA was detected postoperatively in 14 of 178 (7.9%) patients, 11 (79%) of whom had recurred at a median follow-up of 27 months; recurrence occurred in only 16 (9.8 %) of 164 patients with negative ctDNA [hazard ratio (HR), 18; 95% confidence interval (CI), 7.9 to 40; P < 0.001]. In patients treated with chemotherapy, the presence of ctDNA after completion of chemotherapy was also associated with an inferior recurrence-free survival (HR, 11; 95% CI, 1.8 to 68; P = 0.001). ctDNA detection after stage II colon cancer resection provides direct evidence of residual disease and identifies patients at very high risk of recurrence.
Topics: Circulating Tumor DNA; Colonic Neoplasms; Disease-Free Survival; Humans; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasm, Residual; Proportional Hazards Models; Prospective Studies
PubMed: 27384348
DOI: 10.1126/scitranslmed.aaf6219 -
Clinical Cancer Research : An Official... Nov 2016Over the past few years, the management of multiple myeloma has changed. We have new guidelines regarding how to set the diagnosis, when to initiate therapy, and how to... (Review)
Review
Over the past few years, the management of multiple myeloma has changed. We have new guidelines regarding how to set the diagnosis, when to initiate therapy, and how to monitor treatment response. In 2014, the updated International Myeloma Working Group (IMWG) diagnostic criteria changed the definition of multiple myeloma from being a disease defined by symptoms to a disease defined by biomarkers. Today, modern combination therapies have reported up to 60% to 80% of patients reaching a complete response. As a logical and necessary step forward, investigators have explored strategies to detect minimal residual disease (MRD) and its correlation with clinical outcomes. Recent meta-analysis data show that MRD negativity is associated with longer progression-free survival and overall survival. In 2016, the updated IMWG response criteria include MRD as the deepest level of treatment response in multiple myeloma. Simultaneously, we are still quite behind in our understanding of the heterogeneous biology of multiple myeloma and its implications for therapy. Emerging DNA sequencing data show that newly diagnosed multiple myeloma patients have a broad range of mutations, which are distributed unevenly in multiple parallel subclones already present at diagnosis. To move beyond the ill-defined category of "high-risk multiple myeloma," which confers to approximately 25% of all newly diagnosed patients, prospective studies are needed to dissect tumor biology and define multiple myeloma subtypes, and, based on biology, seek to define rational therapies for individual subtypes. This article discusses novel insights and gives perspectives on diagnosis and MRD monitoring and future directions for prognosis and clinical management of multiple myeloma. Clin Cancer Res; 22(22); 5428-33. ©2016 AACR SEE ALL ARTICLES IN THIS CCR FOCUS SECTION, "MULTIPLE MYELOMA MULTIPLYING THERAPIES".
Topics: Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Humans; Meta-Analysis as Topic; Multiple Myeloma; Mutation; Neoplasm, Residual; Prognosis; Prospective Studies; Remission Induction
PubMed: 28151710
DOI: 10.1158/1078-0432.CCR-16-0866 -
Annals of Oncology : Official Journal... Feb 2023Post-treatment detection of circulating tumour DNA (ctDNA) in early-stage triple-negative breast cancer (TNBC) patients predicts high risk of relapse. c-TRAK TN assessed... (Randomized Controlled Trial)
Randomized Controlled Trial
Results of the c-TRAK TN trial: a clinical trial utilising ctDNA mutation tracking to detect molecular residual disease and trigger intervention in patients with moderate- and high-risk early-stage triple-negative breast cancer.
BACKGROUND
Post-treatment detection of circulating tumour DNA (ctDNA) in early-stage triple-negative breast cancer (TNBC) patients predicts high risk of relapse. c-TRAK TN assessed the utility of prospective ctDNA surveillance in TNBC and the activity of pembrolizumab in patients with ctDNA detected [ctDNA positive (ctDNA+)].
PATIENTS AND METHODS
c-TRAK TN, a multicentre phase II trial, with integrated prospective ctDNA surveillance by digital PCR, enrolled patients with early-stage TNBC and residual disease following neoadjuvant chemotherapy, or stage II/III with adjuvant chemotherapy. ctDNA surveillance comprised three-monthly blood sampling to 12 months (18 months if samples were missed due to coronavirus disease), and ctDNA+ patients were randomised 2 : 1 to intervention : observation. ctDNA results were blinded unless patients were allocated to intervention, when staging scans were done and those free of recurrence were offered pembrolizumab. A protocol amendment (16 September 2020) closed the observation group; all subsequent ctDNA+ patients were allocated to intervention. Co-primary endpoints were (i) ctDNA detection rate and (ii) sustained ctDNA clearance rate on pembrolizumab (NCT03145961).
RESULTS
Two hundred and eight patients registered between 30 January 2018 and 06 December 2019, 185 had tumour sequenced, 171 (92.4%) had trackable mutations, and 161 entered ctDNA surveillance. Rate of ctDNA detection by 12 months was 27.3% (44/161, 95% confidence interval 20.6% to 34.9%). Seven patients relapsed without prior ctDNA detection. Forty-five patients entered the therapeutic component (intervention n = 31; observation n = 14; one observation patient was re-allocated to intervention following protocol amendment). Of patients allocated to intervention, 72% (23/32) had metastases on staging at the time of ctDNA+, and 4 patients declined pembrolizumab. Of the five patients who commenced pembrolizumab, none achieved sustained ctDNA clearance.
CONCLUSIONS
c-TRAK TN is the first prospective study to assess whether ctDNA assays have clinical utility in guiding therapy in TNBC. Patients had a high rate of metastatic disease on ctDNA detection. Findings have implications for future trial design, emphasising the importance of commencing ctDNA testing early, with more sensitive and/or frequent ctDNA testing regimes.
Topics: Humans; Biomarkers, Tumor; Mutation; Neoplasm Recurrence, Local; Prospective Studies; Triple Negative Breast Neoplasms; Neoplasm, Residual; Antineoplastic Agents, Immunological; Circulating Tumor DNA
PubMed: 36423745
DOI: 10.1016/j.annonc.2022.11.005 -
Nature Biotechnology Dec 2021Circulating tumor-derived DNA (ctDNA) is an emerging biomarker for many cancers, but the limited sensitivity of current detection methods reduces its utility for...
Circulating tumor-derived DNA (ctDNA) is an emerging biomarker for many cancers, but the limited sensitivity of current detection methods reduces its utility for diagnosing minimal residual disease. Here we describe phased variant enrichment and detection sequencing (PhasED-seq), a method that uses multiple somatic mutations in individual DNA fragments to improve the sensitivity of ctDNA detection. Leveraging whole-genome sequences from 2,538 tumors, we identify phased variants and their associations with mutational signatures. We show that even without molecular barcodes, the limits of detection of PhasED-seq outperform prior methods, including duplex barcoding, allowing ctDNA detection in the ppm range in participant samples. We profiled 678 specimens from 213 participants with B cell lymphomas, including serial cell-free DNA samples before and during therapy for diffuse large B cell lymphoma. In participants with undetectable ctDNA after two cycles of therapy using a next-generation sequencing-based approach termed cancer personalized profiling by deep sequencing, an additional 25% have ctDNA detectable by PhasED-seq and have worse outcomes. Finally, we demonstrate the application of PhasED-seq to solid tumors.
Topics: Biomarkers, Tumor; Circulating Tumor DNA; High-Throughput Nucleotide Sequencing; Humans; Mutation; Neoplasm, Residual
PubMed: 34294911
DOI: 10.1038/s41587-021-00981-w -
Blood Feb 2017Hairy cell leukemia is an uncommon hematologic malignancy characterized by pancytopenia and marked susceptibility to infection. Tremendous progress in the management of...
Hairy cell leukemia is an uncommon hematologic malignancy characterized by pancytopenia and marked susceptibility to infection. Tremendous progress in the management of patients with this disease has resulted in high response rates and improved survival, yet relapse and an appropriate approach to re-treatment present continuing areas for research. The disease and its effective treatment are associated with immunosuppression. Because more patients are being treated with alternative programs, comparison of results will require general agreement on definitions of response, relapse, and methods of determining minimal residual disease. The development of internationally accepted, reproducible criteria is of paramount importance in evaluating and comparing clinical trials to provide optimal care. Despite the success achieved in managing these patients, continued participation in available clinical trials in the first-line and particularly in the relapse setting is highly recommended. The Hairy Cell Leukemia Foundation convened an international conference to provide common definitions and structure to guide current management. There is substantial opportunity for continued research in this disease. In addition to the importance of optimizing the prevention and management of the serious risk of infection, organized evaluations of minimal residual disease and treatment at relapse offer ample opportunities for clinical research. Finally, a scholarly evaluation of quality of life in the increasing number of survivors of this now manageable chronic illness merits further study. The development of consensus guidelines for this disease offers a framework for continued enhancement of the outcome for patients.
Topics: Antineoplastic Agents; Cladribine; Disease Management; Humans; Leukemia, Hairy Cell; Neoplasm Recurrence, Local; Neoplasm, Residual; Pentostatin; Treatment Outcome
PubMed: 27903528
DOI: 10.1182/blood-2016-01-689422 -
Cancer Discovery Dec 2017Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies....
Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies. Here, we apply cancer personalized profiling by deep sequencing (CAPP-seq) circulating tumor DNA (ctDNA) analysis to 255 samples from 40 patients treated with curative intent for stage I-III lung cancer and 54 healthy adults. In 94% of evaluable patients experiencing recurrence, ctDNA was detectable in the first posttreatment blood sample, indicating reliable identification of MRD. Posttreatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months, and 53% of patients harbored ctDNA mutation profiles associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade. Collectively, these results indicate that ctDNA MRD in patients with lung cancer can be accurately detected using CAPP-seq and may allow personalized adjuvant treatment while disease burden is lowest. This study shows that ctDNA analysis can robustly identify posttreatment MRD in patients with localized lung cancer, identifying residual/recurrent disease earlier than standard-of-care radiologic imaging, and thus could facilitate personalized adjuvant treatment at early time points when disease burden is lowest. .
Topics: Circulating Tumor DNA; Female; Humans; Lung Neoplasms; Male; Neoplasm, Residual
PubMed: 28899864
DOI: 10.1158/2159-8290.CD-17-0716 -
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